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Genetics: The Study of Heredity | Live Science

Friday, April 24th, 2020

Genetics is the study of how heritable traits are transmitted from parents to offspring. Humans have long observed that traits tend to be similar in families. It wasnt until the mid-nineteenth century that larger implications of genetic inheritance began to be studied scientifically.

Natural selection

In 1858, Charles Darwin and Alfred Russell Wallace jointly announced their theory of natural selection. According to Darwins observations, in nearly all populations individuals tend to produce far more offspring than are needed to replace the parents. If every individual born were to live and reproduce still more offspring, the population would collapse. Overpopulation leads to competition for resources.

Darwin observed that it is very rare for any two individuals to be exactly alike. He reasoned that these natural variations among individuals lead to natural selection. Individuals born with variations that confer an advantage in obtaining resources or mates have greater chances of reproducing offspring who would inherit the favorable variations. Individuals with different variations might be less likely to reproduce.

Darwin was convinced that natural selection explained how natural variations could lead to new traits in a population, or even new species. While he had observed the variations existent in every population, he was unable to explain how those variations came about. Darwin was unaware of the work being done by a quiet monk named Gregor Mendel.

Inheritance of traits

In 1866, Gregor Mendel published the results of years of experimentation in breeding pea plants. He showed that both parents must pass discrete physical factors which transmit information about their traits to their offspring at conception. An individual inherits one such unit for a trait from each parent. Mendel's principle of dominance explained that most traits are not a blend of the fathers traits and those of the mother as was commonly thought. Instead, when an offspring inherits a factor for opposing forms of the same trait, the dominant form of that trait will be apparent in that individual. The factor for the recessive trait, while not apparent, is still part of the individuals genetic makeup and may be passed to offspring.

Mendels experiments demonstrated that when sex cells are formed, the factors for each trait that an individual inherits from its parents are separated into different sex cells. When the sex cells unite at conception the resulting offspring will have at least two factors (alleles) for each trait. One inherited factor from the mother and one from the father. Mendel used the laws of probability to demonstrate that when the sex cells are formed, it is a matter of chance as to which factor for a given trait is incorporated into a particular sperm or egg.

We now know that simple dominance does not explain all traits. In cases of co-dominance, both forms of the trait are equally expressed. Incomplete dominance results in a blending of traits. In cases of multiple alleles, there are more than just two possible ways a given gene can be expressed. We also now know that most expressed traits, such as the many variations in human skin color, are influenced by many genes all acting on the same apparent trait. In addition, each gene that acts on the trait may have multiple alleles. Environmental factors can also interact with genetic information to supply even more variation. Thus sexual reproduction is the biggest contributor to genetic variation among individuals of a species.

Twentieth-century scientists came to understand that combining the ideas of genetics and natural selection could lead to enormous strides in understanding the variety of organisms that inhabit our earth.

Mutation

Scientists realized that the molecular makeup of genes must include a way for genetic information to be copied efficiently. Each cell of a living organism requires instructions on how and when to build the proteins that are the basic building blocks of body structures and the workhorses responsible for every chemical reaction necessary for life. In 1958, when James Watson and Francis Crick described the structure of the DNA molecule, this chemical structure explained how cells use the information from the DNA stored in the cells nucleus to build proteins. Each time cells divide to form new cells, this vast chemical library must be copied so that the daughter cells have the information required to function. Inevitably, each time the DNA is copied, there are minute changes. Most such changes are caught and repaired immediately. However, if the alteration is not repaired the change may result in an altered protein. Altered proteins may not function normally. Genetic disorders are conditions that result when malfunctioning proteins adversely affect the organism. [Gallery: Images of DNA Structures]

In very rare cases the altered protein may function better than the original or result in a trait that confers a survival advantage. Such beneficial mutations are one source of genetic variation.

Gene flow

Another source of genetic variation is gene flow, the introduction of new alleles to a population. Commonly, this is due to simple migration. New individuals of the same species enter a population. Environmental conditions in their previous home may have favored different forms of traits, for example, lighter colored fur. Alleles for these traits would be different from the alleles present in the host population. When the newcomers interbreed with the host population, they introduce new forms of the genes responsible for traits. Favorable alleles may spread through the population. [Countdown: Genetics by the Numbers 10 Tantalizing Tales]

Genetic drift

Genetic drift is a change in allele frequency that is random rather than being driven by selection pressures. Remember from Mendel that alleles are sorted randomly into sex cells. It could just happen that both parents contribute the same allele for a given trait to all of their offspring. When the offspring reproduce they can only transmit the one form of the trait that they inherited from their parents. Genetic drift can cause large changes in a population in only a few generations especially if the population is very small. Genetic drift tends to reduce genetic variation in a population. In a population without genetic diversity there is a greater chance that environmental change may decimate the population or drive it to extinction.

Mary Bagley, LiveScience Contributor

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Genetics: The Study of Heredity | Live Science

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Darwin and Genetics | Genetics

Friday, April 24th, 2020

Abstract

Darwin's theory of natural selection lacked an adequate account of inheritance, making it logically incomplete. We review the interaction between evolution and genetics, showing how, unlike Mendel, Darwin's lack of a model of the mechanism of inheritance left him unable to interpret his own data that showed Mendelian ratios, even though he shared with Mendel a more mathematical and probabilistic outlook than most biologists of his time. Darwin's own pangenesis model provided a mechanism for generating ample variability on which selection could act. It involved, however, the inheritance of characters acquired during an organism's life, which Darwin himself knew could not explain some evolutionary situations. Once the particulate basis of genetics was understood, it was seen to allow variation to be passed intact to new generations, and evolution could then be understood as a process of changes in the frequencies of stable variants. Evolutionary genetics subsequently developed as a central part of biology. Darwinian principles now play a greater role in biology than ever before, which we illustrate with some examples of studies of natural selection that use DNA sequence data and with some recent advances in answering questions first asked by Darwin.

The power of Selection, whether exercised by man or brought into play under nature through the struggle for existence and the consequent survival of the fittest, absolutely depends on the variability of organic beings. Without variability, nothing can be effected; slight individual differences, however, suffice for the work, and are probably the chief or sole means in the production of new species. Charles Darwin (1868)

CHARLES Darwin was the first person to appreciate clearly that evolution depends on the existence of heritable variability within a species to generate the differences between ancestral and descendant populations. The development of Darwin's thoughts on the nature and causes of evolution is clearly documented in his transmutation notebooks of 18361838 (Barrett et al. 1987). Once he had decided that species originated by descent with modification, Darwin quickly realized the need to find a mechanism for accomplishing the changes involved. In formulating the idea of natural selection, he was greatly influenced by the experience of breeders in artificially selecting populations of domestic animals and plants. Chapter 1 of The Origin of Species (Darwin 1859) is famously devoted to documenting the existence of variability in these populations and the effectiveness of artificial selection:

The key is man's power of cumulative selection: nature gives successive variations; man adds them up in certain directions useful to himself (Darwin 1859, p. 30).

It was only a short step to applying this observation to selection in nature:

Can it, then, be thought improbable, seeing that variations useful to man have undoubtedly occurred, that other variations useful in some way to each being in the great and complex battle of life, should sometimes occur in the course of thousands of generations? This preservation of favourable variations and the rejection of injurious variations, I call Natural Selection (Darwin 1859, pp. 8182).

Most of the books and papers that Darwin published after The Origin of Species were devoted to describing how a vast range of biological phenomenafrom the sexual systems of plants to human anatomy and behaviorcould be interpreted in terms of evolution by natural selection or by the special form of natural selection represented by sexual selection. Surprisingly (at least from today's perspective), many biologists were, for a long time, far from convinced that natural selection was the predominant guiding force in evolution. This continued into the 1920s. In the Introduction to Volume 1 of his treatise on evolutionary genetics, Sewall Wright noted:

Along with the universal acceptance by biologists of evolution as a fact, there came to be increasing dissatisfaction, during the latter part of the nineteenth century, with natural selection as the master theory of causation (Wright 1968, pp.78).

Prominent early geneticists such as William Bateson, Hugo de Vries, and Richard Goldschmidt were notorious skeptics about natural selection and the evolutionary role of the small individual differences relied on by Darwin, emphasizing instead the role of mutations with large and manifold effects (Provine 1971). Many naturalists and paleontologists held what now seem to us to be semi-mystical theories, such as internal drives to improvement or perfection; many of them espoused Lamarckian views up until the 1930s (in France and in the Soviet Union and its satellites, Lamarckism persisted well into the 1960s). In his classic history of modern science, The Edge of Objectivity, Charles Coulston Gillispie quotes the leading historian of biology in 1929, Erik Nordenskiold, as stating that the proposition that natural selection does not operate in the form imagined by Darwin must certainly be taken as proved (Gillispie 1960, p. 320). The book Evolution in the Light of Modern Knowledge, a compendium of essays by 13 leading British biologists, published by Blackie and Son in 1925 to provide (according to the publisher's note) an authoritative statement about the doctrine of evolution...after the general upheaval of fundamental theories in the past 20 years, has no index reference to natural selection. This contrasts with 3253 articles mentioning natural selection and evolution in 2008 in the Web of Science database. For a detailed discussion of anti-Darwinian evolutionary ideas, see Bowler (1983) and Gayon (1998).

Why was there such skepticism toward natural selection, and why have things changed so much? One reason was the lack during Darwin's lifetime of direct evidence for natural selection. This started to change in the late 19th and early 20th centuries through the work of Bumpus (1899) in the United States, and Weldon (1895, 1901) and his student Di Cesnola (1907) in Europe. These scientists initiated the field now known as ecological genetics, and we now have literally thousands of examples where field naturalists have demonstrated the operation of natural selection in the wild on both discrete polymorphisms and quantitative traits (Kingsolver et al. 2001; Bell 2008; Leimu and Fischer 2008).

The other major factor, of course, was the fact that Darwin failed to arrive at an understanding of the mechanism of inheritance, despite realizing its importance and devoting a vast effort to assembling evidence in his Variation of Animals and Plants Under Domestication (Darwin 1868). Unfortunately, he was unaware of Mendel's work, despite its publication 2 years earlier (Mendel 1866). Mendel's work has now, of course, permanently revolutionized our understanding of heredity, and his tragic failure to obtain recognition in his lifetime is a well-known story. It is less well known that Mendel was well aware of the importance for evolution of understanding genetics:

This seems to be the one correct way of finally reaching a solution to a question whose significance for the evolutionary history of organic forms cannot be underestimated (Mendel 1866, p. 2).

Sadly, even if Mendel had lived to see the rediscovery of his work, he probably would not have had the satisfaction of seeing it contribute to evolutionary understanding because, even after genetics had begun its rapid development in the early decades of the 20th century, evolutionary biologists initially failed to understand how to incorporate genetics into their work. We will outline these failures to achieve a synthesis later, but first consider Darwin's efforts to understand inheritance and how his approach fell short of Mendel's.

Mendel's ability to solve the most difficult problem in 19th century biology after the mechanism of evolution rests on his use of a then-unique approach: combining rigorous genetic experiments with quantitative, probabilistic predictions about their expected outcomes: in other words, using biological data to test a quantitative hypothesis. It is a triumph of productive theoretical reasoning that Mendel proposed his particulate inheritance hypothesis well before a proper understanding of the cellular basis of sexual reproduction was achieved by either animal or plant biologists (Farley 1982).

This achievement eluded Darwin, the other greatest mind in 19th century biology, although he came close to seeing the same phenomena as Mendel did and frequently looked at data in a quantitative manner (Howard 2009). Darwin repeatedly referred to the phenomenon of reversion to ancestral types in Variation of Animals and Plants Under Domestication (Darwin 1868). He also compiled examples of the transmission of traits down several generations of pedigrees and obtained help from the mathematical physicist Sir George Stokes to show that these cases are unlikely to be due to chance, one of the first examples of a test of statistical significance in biology (Darwin 1868, chap. 12).

Ironically, Darwin analyzed data from his own crossing experiments on distyly in Primula species (summarized in Darwin 1877, chap. 5), which gave what we can now see as clear evidence for Mendelian ratios (see also Bulmer 2003, p.112, and Howard 2009). In distylous species (Figure 1), the long-styled morphs (L) are now known to be homozygotes ss for the alleles at several loci in a supergene controlling style length, stamen position, pollen and stigma placement, morphology, and incompatibility, whereas the short-styled morph (S) is heterozygous Ss. The only matings that invariably succeed are L S and S L (Darwin called these legitimate pollinations), and these give a 1:1 ratio of L and S plants (Table 1). It is occasionally possible to obtain seeds by self-fertilization, in which case L plants produce only L offspring (Table 1). Darwin stated:

Distyly in primroses. (A) Long-styled (pin) and short-styled (thrum) flowers of Primula vulgaris. (B) Vertically sectioned flowers, with the compatible pollinations indicated. (Pollen from high anthers is compatible with stigmas of long-styled plants, and pollen from low anthers is compatible with stigmas of short-styled plants, while the other two types of pollinations are incompatible.)

Darwin's results for progeny of long- and short-styled Primula crossed with the same morph

From the long-styled form, always fertilised with its own-form pollen, I raised in the first generation three long-styled plants, from their seed 53 long-styled grandchildren, from their seed 4 long-styled great-grandchildren, from their seed 20 long-styled great-great-grandchildren, and lastly, from their seed 8 long-styled and 2 short-styled great-great-great-grandchildren. altogether 162 plants were raised, 156 long-styled and 6 short-styled (Darwin 1877, pp. 228229).

The few short-styled plants in the final generation were presumably contaminants (Darwin's experiments were remarkably free from them). Self-pollination of S plants should generate a 3:1 ratio, as Darwin found (see Table 1; none of the ratios deviates significantly from the expected ratio). He remarked:

I raised at first from a short-styled [P. sinensis] plant fertilised with its own-form pollen one long-styled and seven short-styled illegitimate seedlings . Dr. Hildebrand raised fourteen plants, of which eleven were short-styled and three long-styled (Darwin 1877, p. 216).

Darwin failed to understand the significance of these results because he had no model of particulate inheritance that could be applied to genetic data. Indeed, Darwin appears to have maintained a belief in the predominance of blending inheritance, as did nearly all of his contemporaries. As Fisher pointed out in chapter 1 of The Genetical Theory of Natural Selection (Fisher 1930), there are few explicit statements on this in Darwin's published works, although they appear in some of his unpublished notes and essays. In addition, chapter 15 of Variation of Animals and Plants Under Domestication (Darwin 1868) starts with a section On Crossing as a Cause of Uniformity of Character, which implicitly assumes that crossing leads to blending. It is unclear, however, to what extent he thought that an offspring was a product of the complete fusion of the genetic contributions of its parents (Bulmer 2003, chap. 4).

Blending inheritance leads to a difficulty that was forcefully pointed out by Fleeming Jenkin (Jenkin 1867), the professor of engineering at the University of Edinburgh (the building next to ours is, somewhat unfortunately perhaps, named after him). Under blending inheritance, variation decays rapidly because the genotypes of the offspring of a cross are all the same and are intermediate between those of the two parents. With random mating, the genetic variance of a quantitative trait then decays by a factor of one-half each generation (Fisher 1930, p. 4). Acceptance of blending inheritance clearly raises doubts about the ability of either natural or artificial selection to make permanent changes in a population. In the sixth edition of The Origin of Species, published in 1872, Darwin reacted to Jenkin as follows:

Nevertheless, until reading an able and valuable article in the North British Review (1867), I did not appreciate how rarely single variations, whether slight or strongly-marked, could be perpetuated (Darwin 1859, pp. 111112).

Since heritable variability is required for selection to be effective, and Darwin's survey of the results of artificial selection had convinced him that there is enough variation for it to be effective, Darwin sought a way of generating an abundance of such variation. This was provided by his theory of pangenesis, according to which variations experienced by the individual during its lifetime are transmitted to the germ cells by hypothetical gemmules (Darwin 1868, chap. 27). This is an hypothesis of the inheritance of acquired characters, which Darwin accepted as an experimentally established fact (there is an extensive discussion on the transmission of mutilations in Darwin 1868, chap. 12).

However, Darwin was clearly not quite sure about this. For example, he mentioned that the circumcision of male infants has not led to a loss of the foreskin in the Jewish community (Darwin 1868, Vol. 1, p. 558). He also noted that there are some instances of evolution that cannot be explained by this hypothesis, notably the adaptive characteristics of the sterile castes of social insects:

For no amount of exercise, or habit, or volition, in the utterly sterile members of a community could possibly have affected the structure or instincts of the fertile members, which alone leave descendants. I am surprised that no one has advanced this demonstrative case of neuter insects, against the well-known doctrine of Lamarck (Darwin 1859, p. 242).

Darwin's use of this natural case of sib selection to refute Lamarckism anticipates later uses of the same reasoning, which reached a peak of perfection in the Lederbergs' experiments on replica plating in Escherichia coli (Lederberg and Lederberg 1952).

Unlike Darwin, who regarded the inheritance of acquired characters largely as a source of variation on which selection could act, the 20th century advocates of Lamarckian inheritance viewed it as an alternative explanation of adaptive evolution. As was brilliantly laid out by Fisher in chapter 1 of The Genetical Theory of Natural Selection, and as is no doubt familiar to readers of Genetics, all the difficulties posed by blending disappear with Mendelian inheritance: variability within a population is conserved, not lost, when no evolutionary forces are acting, a genetic equivalent to Galileo's law of inertia. The inheritance of acquired characters is therefore not needed for the regeneration of genetic variability.

It is, of course, well known that our knowledge of the physical basis of genes and of their behavior now largely excludes Lamarckian inheritance. However, recent studies have uncovered some situations in which the DNA of certain genome regions is modified during the life of an individual, and these epigenetic marks with functions in developmental control and other processes can sometimes pass via meiotic divisions to descendant generations (e.g., Cubas et al. 1999; Richards 2006; Namekawa et al. 2007; Heijmans et al. 2008; Sidorenko and Chandler 2008). If variants that arise in this way are stably transmitted, then they can be treated as Mendelian variants that can be exploited in evolution. If their inheritance is unstable, as is often the case, they cannot contribute significantly to evolution.

The breakthrough in understanding the nature of variation in quantitative traits (equivalent to Darwin's slight differences, which may be called individual differences; see the epigraph to this article) came in the early years of genetics, starting with experiments with pure lines, whose individuals have virtually identical genotypes. These experiments showed that plentiful phenotypic variation exists among such individuals but is not transmissible to the offspring (Johannsen 1909; Wright 1920), leading to the rejection of Lamarckian inheritance by the genetics community. Furthermore, the variability of quantitative traits (which often show apparent blending in F1 crosses between pure lines) increases in F2 and later generations (Nilsson-Ehle 1909; East 1910), as expected with particulate Mendelian inheritance. Moreover, the factors responsible can be mapped to chromosomal regions and sometimes (with modern methods) to single genes or nucleotide variants (Flint and Mackay 2009). Even initially puzzling cases of very complex patterns of inheritance, such as beaded and truncate wing in Drosophila, were traced to factors linked to chromosomal genes, and the virtual universality of Mendelism was established by the early 1920s (Altenburg and Muller 1920). In contrast to the inheritance of acquired characters, mutations were found to be very rare, stable modifications of genes and to arise independently of whether or not they confer increased fitness in a given environment (Muller 1932).

By the 1920s, it was clear that (contrary to the beliefs of many early geneticists, who emphasized the large effects of dramatic mutations and ignored the evidence for the Mendelian basis of quantitative trait variation), Darwinian evolution by natural selection is, in fact, enabled by Mendelian inheritance: mutations in genes provide the source of new, stable variants on which selection can act. This set the stage for understanding that evolution is fundamentally a process of change in the frequencies of Mendelian variants within populations and species, leading to the development of classical population and quantitative genetics. The fascinating struggle to reach this understanding is ably described by Provine (1971).

The chief post-Darwin component of major importance in modern evolutionary thinking is the idea of genetic drift and, specifically, the possibility that a significant portion of variability and evolution of DNA sequence variants is driven by random fluctuations in the frequencies of variants with little or no effects on fitness (Kimura 1983). Darwin himself had the idea of selective neutrality:

Variations neither useful nor injurious would not be affected by natural selection, and would be left a fluctuating element, as perhaps we see in the species called polymorphic (Darwin 1859, p. 81).

In a surprising turn of events, the concept of selective neutrality has become a cornerstone of modern tests for natural selection, by providing a null hypothesis that can be tested against data on sequence variation and evolution. Evolutionary biology is now mature enough to repay its debt to genetics and indeed is now (together with genetic and molecular genetic approaches) central to work initiated with largely functional genetic motivations, including genome sequencing.

Given some genetic variation in a phenotype of interest, ecological genetic approaches can relate fitnesses to the differences between individuals within a single natural population, sometimes using data on undisturbed individuals (Bell 2008). With more disturbance to the organisms, between-population differences can also be tested for their selective importance by using methods such as reciprocal transplant experiments. Changes in genotype frequencies can be followed over time in such experiments or after perturbing alleles from their natural frequencies. These approaches have firmly documented the action of selection, sometimes on unexpected characters such as the inversion polymorphisms of Drosophila (Wright and Dobzhansky 1946). However, this approach may miss many instances of selection, because even the largest and most sensitive experiments, such as those involving competition between strains of yeast or bacteria, cannot detect selective differences <0.1% in magnitude (Dykhuizen 1990).

At the other extreme of the evolutionary timescale, the comparative approach can be used to relate differences in ecological conditions experienced by different evolving lineages to differences in the outcome of evolution by natural selection (Harvey and Pagel 1991). Darwin was the first biologist to explicitly use the comparative approach for this purpose. This approach is now highly statistical (Felsenstein 2004) and often uses sequence-based phylogenies, which have the advantage of being much less susceptible to the action of natural selection in causing variation in the rate and direction of character change than the morphological traits formerly used in phylogenetic analysis. Even without modern methods, Darwin used the comparative method to good effect in his work on plant mating system evolution, for example, in his review of the literature to show that inbreeding plants have smaller flowers and are generally less attractive to pollinators compared with outcrossing ones (Darwin 1876), a finding that has held up in more comprehensive modern studies and that tells us that attracting pollinators consumes resources (e.g., Ornduff 1969). The comparative approach is, however, incapable of providing estimates of the intensity of selection involved in causing the changes observed.

Modern DNA sequencing technology provides population geneticists with the ability to study the extent to which selection acts on variants across the genome, as opposed to mutation and random genetic drift. After several decades of using the ecological genetic and comparative approaches to detect selection in nature on visible or physiological traits, biologists can now test for the selective effects of specific genetic differences between individuals without needing to know their phenotypic effects. For these tests, neutrality provides an essential null hypothesis. With our newly acquired ability to apply statistical population genetics methods to the analysis of patterns of within-species variation and between-species divergence in large, genomewide data sets, extremely weak pressures of selection, well below the resolution of experimental methods, can be detected and measured. Many of the approaches currently being used are closely based on the classical work of Fisher, Kimura, and Wright on the behavior of variants subject to mutation, selection, and genetic drift, which are summarized in Kimura's (1983) book, The Neutral Theory of Molecular Evolution. These methods are often extremely computationally intensive, especially when complications like recent changes in population size are taken into account.

With the increasing availability of large data sets on DNA sequence variation across the genomes of humans and Drosophila melanogaster, we are getting close to answering questions such as: What is the distribution of selection coefficients for newly arising deleterious amino acid mutations? What fraction of amino acid variants distinguishing related species are fixed by natural selection, as opposed to genetic drift acting on neutral or slightly deleterious variants? To what extent are variants at synonymous coding sites and noncoding sites subject to selection, and how strong is this selection?

The results are sometimes quite startling. It has been fairly conclusively established, for example, that a typical human being is heterozygous for several hundred amino acid mutations, most of which have only very small effects on fitness (of the order of 103) (Boyko et al. 2008), that 50% of amino acid variants distinguishing related Drosophila species have been fixed by selection (Sella et al. 2009), and that more noncoding sites than coding sites in both humans and Drosophila can mutate to selectively deleterious alternatives that are rapidly removed by selection (Encode Project Consortium 2007; Haag-Liautard et al. 2007).

In addition to these direct tests of selection on variants, we can also use information on neutral or nearly neutral variants that are not themselves under selection to make inferences about selection at linked sites in the genome. One example is the detection of selective sweeps caused by the recent spread of selectively favorable mutations. The spread of an advantageous allele can quickly lead to very low variability in the gene affected, and closely linked regions may also have reduced diversity as a result of hitchhiking through the population of the segment of the chromosome that contained the original beneficial mutation (Maynard Smith and Haigh 1974). These effects on linked neutral or nearly neutral variants can be used in statistical tests for the action of natural selection. This has enabled geneticists to detect and estimate the strength of selection acting on genes such as drug resistance genes in the human malaria parasite by using the variability of microsatellite markers (e.g., Nash et al. 2005) to detect numerous examples of recent adaptations in human populations from their effects on patterns of variation at linked SNPs (e.g., Currat et al. 2002; Sabeti et al. 2002; Williamson et al. 2007; Akey 2009) and to search for genes involved in responses to artificial selection (Walsh 2008).

Conversely, high variability in a region can betray the action of natural selection acting in such a way that different alleles are maintained as polymorphisms for a long period by balancing selection; this divides the population into two or more compartments, between which neutral differences can accumulate at sites that are closely linked to the targets of selection, where recombination is ineffective at preventing differentiation between the compartments (Hudson 1990; Nordborg 1997). A well-known example is the human MHC region, in which not only are there many polymorphic amino acids in exon 2, which encodes most of the peptide-binding residues of the human mature MHC proteins, but after there are extraordinarily numerous polymorphic variants of synonymous and intron sites, compared with other loci in the same populations (Raymond et al. 2005). Similarly, frequency-dependent selection has clearly maintained sequence polymorphism for long evolutionary times at plant and fungal self-incompatibility loci, whose sequences are highly diverged (e.g., Vekemans and Slatkin 1994; Richman et al. 1996; May et al. 1999).

Not only can selection within single populations be studied by molecular evolutionary approaches, but between-population differences due to local adaptation can also be revealed by increased divergence at sites linked to the targets of selection (Beaumont and Balding 2004). Indeed, scans of human and other species' genomes for sequences that are more differentiated than most genes are a major way of discovering candidates for genes that are currently under selection (Akey 2009).

Another way in which modern evolutionary studies have contributed to genetics, as opposed to genetics contributing to evolutionary biology, is that an interest in quantifying the extent of genetic variation [initially motivated by a debate about whether variation within species is largely composed of recent mutations or includes a considerable proportion of variants maintained by balancing selection (Dobzhansky 1955; Lewontin 1974)] ultimately led to the discovery of vast numbers of DNA sequence variants that can be used as genetic markers for mapping (although these data did not in themselves settle the debate about whether selection maintains variation). The existence of abundant markers was predicted long ago:

It would accordingly be desirable, in the case of man, to make an extensive and thorough-going search for as many factors as possible that could be usedas identifiers. They should, preferably, involve character differences that are (1) of common occurrence, (2) identifiable with certainty, (3) heritable in a simple Mendelian fashion. It seems reasonable to suppose that in a species so heterozygous there must really be innumerable such factors present. It does seem clear that in the more tractable organisms, such as the domesticated and laboratory races of animals and plants, character analysis by means of linkage studies with identifying factors will come into more general use (Altenburg and Muller 1920).

In some species, naturally occurring markers can now be obtained so densely that new approaches are needed for genetic mapping because there is a very low chance of a crossover event between the closest markers (e.g., Churchill et al. 2004; Van Os et al. 2005; Flibotte et al. 2009). The possibility of obtaining large numbers of genetic markers has produced renewed progress in mapping genes affecting quantitative characters, and new approaches are being developed for such studies, including association mapping that makes use of the population genetics concept of linkage disequilibrium (associations between the allelic states of different loci or sites in a sequence; see Slatkin 2008 for an overview). The study of the population genetics of multi-locus systems once appeared to be an esoteric field, remote from empirical data, which contributed to the reputation of theoretical population genetics for dryness and irrelevance to biology. Nevertheless, very important principles were developed that are now widely used by other geneticists, including ways to measure linkage disequilibrium [also now used to estimate recombination rates in genomes by using samples of sequences from populations (Myers et al. 2005)] and the concept that selection acting on a given sequence variant or allele has effects on closely linked variants (see above).

The kinds of approaches just mentioned are no longer restricted to humans and the genetics model organisms of most interest for functional molecular genetic work. One well-established use of markers is to infer the mating systems of populations in the wild (Ritland 1990). Darwin anticipated this when he used phenotypic differences, including flower colors, that he clearly assumed to be inherited, to infer the parentage of seeds:

Altogether 233 plants were raised, of which 155 were mongrelised in the plainest manner, and of the remaining 78 not half were absolutely pure. I repeated the experiment by planting near together two varieties of cabbage with purple-green and white-green lacinated leaves; and of the 325 seedlings raised from the purple-green variety, 165 had white-green and 160 purple-green leaves. Of the 466 seedlings raised from the white-green variety, 220 had purple-green and 246 white-green leaves. These cases show how largely pollen from a neighbouring variety of the cabbage effaces the action of the plant's own pollen (Darwin 1876, p. 393).

It is now becoming possible to conduct fine-scale genetic mapping studies in nonmodel species, including those of applied interest, such as domesticated animals and plants and their pathogens, where QTL mapping is being aided by the abundant supply of new markers. Genetic mapping gives promise of testing hypotheses such as the close linkage of genes involved in heterostyly in Primula and other plant species (Li et al. 2007; Labonne et al. 2009) and mimicry in butterflies (Baxter et al. 2008), examples of problems that interested Darwin. Gene mapping is also important in modern work on the genetics of speciation, which is at last identifying genes involved in reproductive isolation between closely related species and is uncovering evidence for the DobzhankyMuller hypothesis that natural selection is important in causing genetic differences between populations that lower the survival or fertility of F1 or F2 hybrids, as a result of deleterious epistatic interactions between alleles derived from the two populations (e.g., Barbash et al. 2003; Presgraves et al. 2003). As is well known, Darwin himself found the evolution of reproductive isolation puzzling:

The importance of the fact that hybrids are very generally sterile, has, I think, been much underrated by some late writers. On the theory of natural selection the case is especially important as the sterility of hybrids could not possibly be of any advantage to them, and therefore could not have been acquired by the continued preservation of successive profitable degrees of sterility (Darwin 1859, p. 245).

However, the title The Origin of Species did not refer to this central puzzle concerning speciation, but rather to the evolution of adaptations and character differences; before the rise of genetics, it would have been virtually impossible for a correct interpretation of reproductive isolation to have been developed.

Another long-debated topic for which genetic marker availability should help our understanding is the question of the genetic basis of inbreeding depression and of heterosis. Although the deleterious effects of inbreeding were known to some earlier biologists, Darwin was the first to study the phenomenon thoroughly, because he realized that it provides an explanation for the existence of the elaborate adaptations of plants to avoid inbreeding. Darwin's book The Effects of Cross and Self Fertilization in the Vegetable Kingdom described his own experiments comparing progeny produced by self- and cross-fertilization in 57 plant species, and his summary of the main results anticipated future work that allowed us to measure inbreeding (in modern terms, inbreeding coefficients):

That certain plants, for instance, Viola tricolor, Digitalis purpurea, Sarothamnus scoparius, Cyclamen persicum, etc., which have been naturally cross-fertilised for many or all previous generations, should suffer to an extreme degree from a single act of self-fertilisation is a most surprising fact. Nothing of the kind has been observed in our domestic animals; but then we must remember that the closest possible interbreeding with such animals, that is, between brothers and sisters, cannot be considered as nearly so close a union as that between the pollen and ovules of the same flower. Whether the evil from self-fertilisation goes on increasing during successive generations is not as yet known; but we may infer from my experiments that the increase if any is far from rapid. After plants have been propagated by self-fertilisation for several generations, a single cross with a fresh stock restores their pristine vigour; and we have a strictly analogous result with our domestic animals (Darwin 1876, p. 438).

As pointed out by Fisher in his Design of Experiments (Fisher 1935, chap. 3), Darwin used paired contrasts of the performance of an inbred and an outbred plant grown in the same pot, a method that is widely used in modern biological statistics. Darwin's insight into the utility of this approach was spoiled by the reanalysis of his data conducted by his cousin, Francis Galton, a supposedly more expert statistician.

Just as with his theory of sexual selection to explain male/female dimorphism (Darwin 1871), which was largely neglected until the 1970s, the individual selective advantage to outcrossing arising from inbreeding depression postulated by Darwin was rejected by leading 20th century thinkers on plant evolution, such as C. D. Darlington and G. L. Stebbins, in favor of group selection hypotheses of advantages of increased variability to the population or species. The role of inbreeding depression in the evolution of mating systems is, however, now well established (Barrett 2002).

Although Darwin was unable to provide a satisfactory interpretation of his observations, inbreeding depression is now well known to be a genetic phenomenon, and hybrid vigor (heterosis) is widely used in agriculture. It is also well known that the genetic basis of these phenomena is difficult to ascertain and that this may impede efforts to make the best use of heterosis. There is no doubt that rare, deleterious mutations play an important role (Charlesworth and Charlesworth 1999): inbreeding, by producing homozygotes for such mutations, reduces survival and fertility because a large proportion of deleterious mutations are recessive, or partially so, and cause only slight harm when heterozygous, as was first clearly proposed by D. F. Jones (Jones 1917). Heterosis is also explicable on this basis because different inbred strains will be homozygous for different deleterious mutations, and different populations of a species in nature will differ similarly at some proportion of their genes, particularly if the populations are highly isolated (Ingvarsson et al. 2000; Escobar et al. 2008). It is still much less clear whether loci with overdominant alleles (alleles showing heterozygote advantage) also contribute any major part of inbreeding depression or heterosis, although it is intuitively easy to understand that, if such loci are common, these effects would be produced. Identification of the genetic factors involved in inbreeding depression or heterosis by the fine-scale mapping methods referred to above should help to answer these questions.

The examples that we have outlined here show the value of the ongoing interaction between genetics and the study of evolution. From being a major headache for early supporters of evolution, genetics paved the way for models of evolution based on the known properties of inheritance, so that the constraints experienced by genes and genomes in evolution were correctly incorporated into quantitative models, and new possibilities, unknown to Darwin, were discovered.

Evolutionary genetics is inherently interdisciplinary, fruitfully combining models (often mathematical and often stochastic, given the nature of genetics) with empirical data. This intellectual tradition, now 100 years old, deserves celebration along with Darwin's anniversaries. We hope that we have shown that evolution is more central to modern biological research than ever before and that this productive collaboration with genetics can be predicted to yield many further pure and applied scientific riches in the next hundred years. For this to happen, the need for a broad-enough education must be met. Biologists and doctors will need to understand genetics, and even some population genetics concepts, at least enough to collaborate with people with expertise in relevant quantitative methods. Mathematical ideas need to be demystified, as far as possible, so that biologists using phylogenetic and genetic marker or diversity analyses know what lies behind the computer programs that they use, an understanding without which the numbers that come out may lead to wrong conclusions. We need to regain a respect for the usefulness of statistics throughout biology and use it to test our ideas, as Darwin started to do. The same applies to theoretical modeling directed toward testable hypotheses, of which the idea of natural selection is still an excellent example, even though it has been extended to a far wider realm of biology than Darwin initially proposed and has given us many valuable tools at the interface between genetics and evolution. Darwin himself was interested in the functioning of organisms, not just in their morphology and relationships and the history of life, and he would surely have been delighted to see where his ideas have so far led us and how they have continued to be central within biology. In Dobzhansky's famous words:

Nothing in biology makes sense except in the light of evolution (Dobzhansky 1973).

We thank Adam Wilkins and two reviewers for their helpful suggestions for improving the manuscript.

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On National DNA Day, scientists are trying to take the colonialism out of genetics – Massive Science

Friday, April 24th, 2020

Scientists are trying to tackle the lack of diversity seen in genomics research, but even ambitious efforts, like the NIHs All of Us program, often fall short, especially when it comes to the inclusion of Indigenous communities. This is one of the reasons why the Decolonize DNA Day conference is taking place on April 24th, one day before the National DNA Day.

Traditionally, National DNA Day is an annual celebration of the discovery of DNA's double helix structure (1953) and the completion of the Human Genome Project (2003).

I was having conversations with colleagues on what would it mean to decolonize DNA, says Krystal Tsosie, an Indigenous (Din/Navajo) PhD student at Vanderbilt University. As an Indigenous academic, we always talk about what it means to Indigenize and re-Indigenize different disciplines of academia that have been historically more white-centred or white-dominated... and what it would mean to remove the colonial lens.

In collaboration with Latrice Landry and Jerome de Groot, Tsosie co-organized the Decolonize DNA Day Twitter conference to help re-frame narratives around DNA. Each speaker will have an hour to tweet out their "talk" and lead conversations on various topics, including how DNA ancestry testing fuels anti-Indigeneity and how to utilize emerging technologies to decolonize precision medicine.

There is a divide between people who are doing the science or the academic work, and the people who we want to inform, says Tsosie. Twitter is a great way to bridge that divide.

The Decolonize DNA Day conference is simply one effort to Indigenize genomics. Tsosie is also a co-founder of the Native BioData Consortium, a non-profit organization consisting of researchers and Indigenous members of tribal communities, focused on increasing the understanding of Native American genomic issues.

We dont really see a heavy amount of Indigenous engagement in genetic studies, which then means that as precision medicine advances as a whole [] those innovations are not going to be applied to Indigenous people, says Tsosie. How do we get more Indigenous people engaged?

Some of the answers can be found in a recent Nature Reviews Genetics perspective, penned by Indigenous scientists and communities, including those from the Native BioData Consortium. The piece highlights the actions that genomics researchers can take to address issues of trust, accountability, and equity. Recommended actions include the need for early consultations, developing benefit-sharing agreements, and appropriately crediting community support in any academic publications.

By switching power dynamics, were hoping to get genomic researchers to work with us, instead of against us, says Tsosie.

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On National DNA Day, scientists are trying to take the colonialism out of genetics - Massive Science

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Genetic variants linked with onset, progression of POAG – Modern Retina

Friday, April 24th, 2020

Genetic variants that are unrelated to the IOP are associated with a family history of glaucoma and play a role in the onset of primary open-angle glaucoma (POAG). Genetic variants that are related to the IOP are associated with the age at which glaucoma is diagnosed and are associated with disease progression.

What is known about POAG, the most prevalent form of glaucoma, is that increased IOP and myopia are risk factors for damage to the optic nerve in POAG.

Related: Stent offers IOP stability more than three years after surgery

A family history of glaucoma is a major risk factor for development of POAG, in light of which, therefore, genetic factors are thought to be important in the disease pathogenesis and a few genes mutations have been identified as causing POAG, according to Fumihiko Mabuchi, MD, PhD, professor, Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Kofu, Japan.

Myopia has been shown to be a risk factor for POAG in several studies. However, it can be difficult to diagnose true POAG in myopic patients and controversy exists over whether it is real risk factor.

Myopic optic discs are notoriously difficult to assess, and myopic patients may have visual field defects unrelated to any glaucomatous process.

The prevalence of POAG increases with age, even after compensating for the association between age and IOP.

Related: Preservative-free tafluprost/timolol lowers IOP well, glaucoma study shows

Part of the storyDr. Mabuchi and his and colleagues, recounted that these factors are only part of the story.

According to Dr. Mabuchi and his colleagues, cases of POAG caused by these gene mutations account for several percent of all POAG cases, and most POAG is presumed to be a polygenic disease.

Recent genetic analyses, the investigators explained, have reported genetic variants that predispose patients to development of POAG and the additive effect of these variants on POAG, which are classified as two types.

The first genetics variants are associated with IOP elevation.

Related: Sustained-release implant offers long-term IOP control, preserved visual function

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Meghan Trainor shows her work in behind the scenes video of "Genetics" performance with Nicole Scherzinger of – LaineyGossip

Friday, April 24th, 2020

Like everyone else, Im consuming everything in sight these days, because what else are we going to do, really; but also like everyone else (I suspect) Im using the time either to catch up on series I heard I should have watched, or to be pulled into whatever Netflix serves me up.

Then the other day, @ceas89 sent us a video on Twitter, and I was enthralled and also ashamed. Enthralled because it was amazing; ashamed because before now, I didnt know. The video is a behind the scenes of Trainors song Genetics, featuring Nicole Scherzinger of the Pussycat Dolls, and before I clicked, I read the tweet, which said, can you please talk about the work happening in this video? So, I played it (skip to 0:30 to really get to the goods):

The song was released in September 2019, but Meghan posted it just a couple of weeks ago. And, as @ceas89 predicted, I watched it over and over, because its incredible. And Ill confess, I didnt know this work was gonna be here. I love that theyre recording in an apartment or bungalow of some kind weve seen this kind of video before, but often in a blank, black studio. Somehow I felt more welcomed into the room in this video, which is a cool trick.

But its the dynamics of this that I love most.

Meghan starts off complimenting Nicole, in a way that might seem self-deprecating. I have the voice to record, I just dont have the dance moves to dance. Initially I was sort of frustrated with that, because I felt like the Meghan Trainor doesnt have the right body for the music industry narrative is boring, played out, and also, its patently not true. Ask Lizzo.

But as the rest of the video unfolds, its clear that what shes doing is actually trying to build Nicole up. Because its Meghans song, and she knows how it needs to go, while Nicole is anxiously trying to do her best, but is aware, maybe, that shes not *quite* nailing it. We dont see the takes where she doesnt get her vocals to where they need to be, but her affect and the way she looks at Meghan for reassurance makes it clear.

Trainor builds her up, over and over again, Oh-my-God-ing over Nicoles vocals, but also clearly directing her: what kind of tone, what kind of dynamic. Even from her slumped position on the couch shes commanding, as she tells Nicole sing with me, until its clear that Nicole has gotten it right. Wait she directs Nicole during a vocal run, and then, never missing a beat, reminds her, Its a quick but here.

Then look what happens at 2:41. Meghan lays down some vocals, and Nicole, stunned, comments, Wow, she just does it in one take and then puts her head in her hands. As @ceas89 put it, Nicole is legitimately shook, and its true. Its so easy for you, she comments to Meghan, who laughs. No self-deprecation this time

Because its clearly true. Its easy for Meghan. Its easy for her and necessary for her to tell Nicole how the song needs to be done, because she wrote it. Did you know Meghan Trainor wrote songs? I mean, I guess I assumed she wrote her own songs, but I didnt know shed also written songs for Jason Derulo, Jason Mraz, Faith Hill and Tim McGraw, Michael Bubl, and Jennifer Lopez.

I didnt know. Not really. And I should have.

I loved All About The Bass like everyone else, but as much as I appreciated the retro-bop style, I didnt love the messaging about what boys need, and the follow-ups of Dear Future Husband and Lips Are Moving seemed so retro that I lost interest. Not that Trainor cares her career has been incredibly successful whether or not I like her messaging or packaging or not.

But lets be real: I underestimated Meghan Trainor, maybe because of how she was marketed. I saw her as a gimmicky artist and look, her image does have inherent gimmick-ness to it but I let it cloud me to the phenomenal talent thats gotten her this far, and Im mad at myself for doing it. Why do talented people have to have a certain image? If she was in plaid button-downs and less lipstick in her videos, would I have seen it more? If there were more videos like this out there alongside her cutesy finger-wagging videos?

Im not saying we have to like everyone, and there are millions of talented people, and entire genres of entertainment that are just not for me, the same way some people cant abide musicals, or animation, or non-fiction. But this video was a reminder that even though I think I see through all kinds of showbiz packaging, the stuff I really value hard work, genius-level talent, industry respect is totally separate from the packaging and marketing of an artist, and I let this one slip by me before now. Thank you, @ceas89, for the education.

Whose talent do you think everyone else is sleeping on? (No, Lainey, BTS does not apply here.) Is there someone youve discovered recently, since consuming entertainment has become our collective new job? Do you have a method for exposing yourself to new stuff so you dont make snap judgments like I did? Theres nothing I love more than a celebrity surprise, so if theres someone I, or all of us, should know, hit us up. A new discovery is a delightful comfort and joy right now.

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Gods of genetic engineering: With the end of ‘Homo sapiens naturalis’ approaching, what is our place in nature? – Genetic Literacy Project

Friday, April 24th, 2020

Our society has evolved so much, can we still say that we are part of Nature? If not, should we worry and what should we do about it? Poppy, 21, Warwick.

Such is the extent of our dominion on Earth, that the answer to questions around whether we are still part of nature and whether we even need some of it rely on an understanding of what we want as Homo sapiens. And to know what we want, we need to grasp what we are.

It is a huge question but they are the best. And as a biologist, here is my humble suggestion to address it, and a personal conclusion. You may have a different one, but what matters is that we reflect on it.

Perhaps the best place to start is to consider what makes us human in the first place, which is not as obvious as it may seem.

Many years ago, a novel written by Vercors called Les Animaux dnaturs (Denatured Animals) told the story of a group of primitive hominids, the Tropis, found in an unexplored jungle in New Guinea, who seem to constitute a missing link.

However, the prospect that this fictional group may be used as slave labor by an entrepreneurial businessman named Vancruysen forces society to decide whether the Tropis are simply sophisticated animals or whether they should be given human rights. And herein lies the difficulty.

Human status had hitherto seemed so obvious that the book describes how it is soon discovered that there is no definition of what a human actually is. Certainly, the string of experts consulted anthropologists, primatologists, psychologists, lawyers and clergymen could not agree. Perhaps prophetically, it is a layperson who suggested a possible way forward.

She asked whether some of the hominids habits could be described as the early signs of a spiritual or religious mind. In short, were there signs that, like us, the Tropis were no longer at one with nature, but had separated from it, and were now looking at it from the outside with some fear.

It is a telling perspective. Our status as altered or denatured animals creatures who have arguably separated from the natural world is perhaps both the source of our humanity and the cause of many of our troubles. In the words of the books author:

All mans troubles arise from the fact that we do not know what we are and do not agree on what we want to be.

We will probably never know the timing of our gradual separation from nature although cave paintings perhaps contain some clues. But a key recent event in our relationship with the world around us is as well documented as it was abrupt. It happened on a sunny Monday morning, at 8.15am precisely.

The atomic bomb that rocked Hiroshima on August 6 1945, was a wake-up call so loud that it still resonates in our consciousness many decades later.

The day the sun rose twice was not only a forceful demonstration of the new era that we had entered, it was a reminder of how paradoxically primitive we remained: differential calculus, advanced electronics and almost godlike insights into the laws of the universe helped build, well a very big stick. Modern Homo sapiens seemingly had developed the powers of gods, while keeping the psyche of a stereotypical Stone Age killer.

We were no longer fearful of nature, but of what we would do to it, and ourselves. In short, we still did not know where we came from, but began panicking about where we were going.

We now know a lot more about our origins but we remain unsure about what we want to be in the future or, increasingly, as the climate crisis accelerates, whether we even have one.

Arguably, the greater choices granted by our technological advances make it even more difficult to decide which of the many paths to take. This is the cost of freedom.

I am not arguing against our dominion over nature nor, even as a biologist, do I feel a need to preserve the status quo. Big changes are part of our evolution. After all, oxygen was first a poison which threatened the very existence of early life, yet it is now the fuel vital to our existence.

Similarly, we may have to accept that what we do, even our unprecedented dominion, is a natural consequence of what we have evolved into, and by a process nothing less natural than natural selection itself. If artificial birth control is unnatural, so is reduced infant mortality.

I am also not convinced by the argument against genetic engineering on the basis that it is unnatural. By artificially selecting specific strains of wheat or dogs, we had been tinkering more or less blindly with genomes for centuries before the genetic revolution. Even our choice of romantic partner is a form of genetic engineering. Sex is natures way of producing new genetic combinations quickly.

Even nature, it seems, can be impatient with itself.

Advances in genomics, however, have opened the door to another key turning point. Perhaps we can avoid blowing up the world, and instead change it and ourselves slowly, perhaps beyond recognition.

The development of genetically modified crops in the 1980s quickly moved from early aspirations to improve the taste of food to a more efficient way of destroying undesirable weeds or pests.

In what some saw as the genetic equivalent of the atomic bomb, our early forays into a new technology became once again largely about killing, coupled with worries about contamination. Not that everything was rosy before that. Artificial selection, intensive farming and our exploding population growth were long destroying species quicker than we could record them.

The increasing silent springs of the 1950s and 60s caused by the destruction of farmland birds and, consequently, their song was only the tip of a deeper and more sinister iceberg. There is, in principle, nothing unnatural about extinction, which has been a recurring pattern (of sometimes massive proportions) in the evolution of our planet long before we came on the scene. But is it really what we want?

The arguments for maintaining biodiversity are usually based on survival, economics or ethics. In addition to preserving obvious key environments essential to our ecosystem and global survival, the economic argument highlights the possibility that a hitherto insignificant lichen, bacteria or reptile might hold the key to the cure of a future disease. We simply cannot afford to destroy what we do not know.

But attaching an economic value to life makes it subject to the fluctuation of markets. It is reasonable to expect that, in time, most biological solutions will be able to be synthesized, and as the market worth of many lifeforms falls, we need to scrutinize the significance of the ethical argument. Do we need nature because of its inherent value?

Perhaps the answer may come from peering over the horizon. It is somewhat of an irony that as the third millennium coincided with decrypting the human genome, perhaps the start of the fourth may be about whether it has become redundant.

Just as genetic modification may one day lead to the end of Homo sapiens naturalis (that is, humans untouched by genetic engineering), we may one day wave goodbye to the last specimen of Homo sapiens genetica. That is the last fully genetically based human living in a world increasingly less burdened by our biological form minds in a machine.

If the essence of a human, including our memories, desires and values, is somehow reflected in the pattern of the delicate neuronal connections of our brain (and why should it not?) our minds may also one day be changeable like never before.

And this brings us to the essential question that surely we must ask ourselves now: if, or rather when, we have the power to change anything, what would we not change?

After all, we may be able to transform ourselves into more rational, more efficient and stronger individuals. We may venture out further, have greater dominion over greater areas of space, and inject enough insight to bridge the gap between the issues brought about by our cultural evolution and the abilities of a brain evolved to deal with much simpler problems. We might even decide to move into a bodiless intelligence: in the end, even the pleasures of the body are located in the brain.

And then what? When the secrets of the universe are no longer hidden, what makes it worth being part of it? Where is the fun?

Gossip and sex, of course! some might say. And in effect, I would agree (although I might put it differently), as it conveys to me the fundamental need that we have to reach out and connect with others. I believe that the attributes that define our worth in this vast and changing universe are simple: empathy and love. Not power or technology, which occupy so many of our thoughts but which are merely (almost boringly) related to the age of a civilization.

Like many a traveler, Homo sapiens may need a goal. But from the strengths that come with attaining it, one realizes that ones worth (whether as an individual or a species) ultimately lies elsewhere. So I believe that the extent of our ability for empathy and love will be the yardstick by which our civilization is judged. It may well be an important benchmark by which we will judge other civilizations that we may encounter, or indeed be judged by them.

There is something of true wonder at the basis of it all. The fact that chemicals can arise from the austere confines of an ancient molecular soup, and through the cold laws of evolution, combine into organisms that care for other lifeforms (that is, other bags of chemicals) is the true miracle.

Some ancients believed that God made us in his image. Perhaps they were right in a sense, as empathy and love are truly godlike features, at least among the benevolent gods.

Cherish those traits and use them now, Poppy, as they hold the solution to our ethical dilemma. It is those very attributes that should compel us to improve the wellbeing of our fellow humans without lowering the condition of what surrounds us.

Anything less will pervert (our) nature.

Manuel Berdoy is a biologist at the University of Oxford

A version of this article originally appeared on The Conversation and has been republished here with permission. The Conversation can be found on Twitter @ConversationUS

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Gods of genetic engineering: With the end of 'Homo sapiens naturalis' approaching, what is our place in nature? - Genetic Literacy Project

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Suspect In 1981 Murder Of 17-Year-Old Sacramento Girl Identified Thanks To Genetic Genealogy – CBS Sacramento

Friday, April 24th, 2020

SACRAMENTO (CBS13) A brutal Sacramento murder case that went cold for nearly four decades has been solved thanks to genetic genealogy, detectives say.

Mary London was a 17-year-old sophomore at Sacramento High School. On the morning of Jan. 15, 1981, her body was found dumped on the side of what once was a rural stretch of San Juan Road; she had been stabbed multiple times, police said.

The case went cold and no suspect was ever identified.

That is until Thursday, when the Sacramento Police Department and Sacramento County District Attorneys Office announced that they had identified a suspect in the case.

Detectives say genetic genealogy and transitional DNA have linked a man named Vernon Parker to crime.

Investigative genetic genealogy has revolutionized law enforcements ability to solve violent crime: to identify the guilty and exonerate the innocent, said District Attorney Anne MarieSchubert in a statement about the case.

No other information, including what may have led up to the killing, was released and Parker was murdered a little over a year after Marys death, detectives say.

Genetic genealogy has helped identify a number of suspects in cases that had gone cold. The technique came to prominence in 2018 when it was credited with helping identify Joseph DeAngelo as the suspect in the Golden State Killer/East Area Rapist case.

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Could genetics explain why some COVID-19 patients fare worse than others? – Live Science

Thursday, April 23rd, 2020

Certain genetic differences might separate people who fall severely ill with COVID-19 from those who contract the infection but hardly develop a cough, a new preliminary study suggests.

The research is still in its early days, though, experts say.

The immune system can react to viruses thanks, in part, to specific genes that help cells spot unfamiliar bugs when they enter the body. The genes, known as human leukocyte antigen (HLA) genes, contain instructions to build proteins that bind to bits of a pathogen; those proteins serve as warning flags to alert immune cells. The immune cells, once trained to recognize these bits, jumpstart the process of building antibodies to target and destroy the invasive germ.

Within each individual, HLA genes code for three different classes of proteins; in other words, HLAs come in a variety of flavors, and depending on which HLAs you have, your body may be better or worse equipped to fight off certain germs including SARS-CoV-2, the virus that causes COVID-19.

In a new study, published April 17 in the Journal of Virology, researchers used computer models to predict which combination of HLAs might be best at binding SARS-CoV-2, and which might be worst.

If certain HLAs can bind well to a large proportion of the virus's proteins, "we expect there to be a more protective immune response," authors Abhinav Nellore and Dr. Reid Thompson, who lead a computational biology research group at the Oregon Health and Science University, told Live Science in an email. A better bind means that the viral proteins are more likely to be presented to immune cells and prompt the production of specific antibodies, the authors said.

"If the interaction is not stable, you will not have a proper [immune] response," said Dr. Shokrollah Elahi, an associate professor in the Department of Dentistry and adjunct associate professor in the Department of Medical Microbiology and Immunology at the University of Alberta, who was not involved in the study.

Related: 10 deadly diseases that hopped across species

But a stable bond, alone, does not guarantee the best immune response, Elahi added. If an HLA binds a viral protein that happens to be critical for the germ to replicate and survive, the subsequent antibody activity will likely target the virus more effectively than that prompted by a less important protein, Elahi said.

"This is an issue we did not address in our analysis," the authors noted. Instead, the team focused on predicting how well different HLA types could bind to bits of SARS-CoV-2. Their analysis identified six HLA types with a high capacity to bind different SARS-CoV-2 protein sequences, and three with a low capacity to do so. Specifically, a HLA type known as HLA-B*46:01 had the lowest predicted capacity to bind to bits of SARS-CoV-2.

The same HLA type cropped up in a 2003 study published in the journal BMC Medical Genetics, which assessed patients infected with SARS-CoV, a closely related coronavirus that caused an outbreak of severe acute respiratory syndrome in the early 2000s. The study found that, in a group of patients of Asian descent, the presence of HLA-B*46:01 was associated with severe cases of the infection. In their paper, the research group noted that more clinical data would be needed to confirm the connection and the same goes for the new study of SARS-CoV-2, Nellore and Thompson said.

"The most substantial limitation of our study is that this was conducted entirely on a computer and did not involve clinical data from COVID-19 patients," the authors said. "Unless and until the findings we present here are clinically validated, they should not be employed for any clinical purposes," they added.

"In the body, we have so many things interacting," Elahi said. HLAs represent just one piece of a large, intricate puzzle that comprises the human immune system, he said. To better understand the variety of immune responses to COVID-19, Elahi and his research group aim to assess markers of immune system activity in infected patients and also catalog the ratio of immune cell types present in their bodies. While taking age, sex and other demographic factors into account, these so-called immunological profiles could help pinpoint when and why the illness takes a turn in some patients.

The clinical data could be assessed in parallel with genetic data gathered from the same patients, Elahi added. Similarly, Nellore and Thompson said that "COVID-19 testing should be paired with HLA typing, wherever [and] whenever possible," to help determine how different HLA types relate to symptom severity, if at all. Partnerships with genetic testing companies, biobanks and organ transplant registries could also offer opportunities to study HLA types in larger populations of people, they said.

"We cannot in good conscience predict at this point who will be more or less susceptible to the virus because we have not analyzed any clinical outcomes data with respect to HLA type to know that any of our predictions are valid," the authors said. If future studies support the notion that some HLA genes protect people from the virus, while others place patients at greater risk, those in the latter group could be first in line for vaccination, they added.

"In addition to prioritizing vaccinating the elderly or those with preexisting conditions, one could prioritize vaccinating people with HLA genotypes that suggest the SARS-CoV-2 virus is more likely to give them worse symptoms."

The authors went on to analyze how well HLAs can bind SARS-CoV-2 as compared with other coronaviruses, such as those that cause the common cold and infect humans often. They identified several viral bits shared between SARS-CoV-2 and at least one of these common viruses, suggesting exposure to one germ could somewhat protect the body against the other.

"If someone was previously exposed to a more common coronavirus and had the right HLA types ... then it is theoretically possible that they could also generate an earlier immune response against the novel SARS-CoV-2," the authors said. On the other hand, exposure to a similar virus could leave the body ill-equipped to fight off the new one, if, for instance, "the body is using an old set of tools that aren't ideally suited to address the new problem," the authors said.

Originally published on Live Science.

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Scientists use genetics to study how the world’s three narwhal populations are affected by climate shifts – The Narwhal

Thursday, April 23rd, 2020

If you want to learn about your ancestry, you can spit into a test-tube and retrieve your DNA results a month later online.

Scientists seeking to learn about the genetics of the narwhal had to use more elaborate methods to gather DNA samples of the deep-diving whale that lives in the ice-cold waters of the Arctic.

Hoping to unravel the demographic history of the narwhal, often called the unicorn of the sea, the scientists collected narwhal tissue samples from Inuit hunters in Canadas far north and Greenland, and tested narwhal remains from archeological digs in northern Europe and Russia.

They even got permission to take samples of narwhal tusks from the King of Denmarks throne chair, made from Norwegian narwhal tusks and guarded by three life-sized silver lions with manes of real gold.

They had special access to be able to drill little tiny bits of tusk from that throne, said Steven Ferguson, an Arctic marine mammal research scientist with Fisheries and Oceans Canada.

Ferguson is one of 15 co-authors of a study, published on April 21 by the Proceedings of the Royal Society B: Biological Sciences, that helps unwind a little bit more of the mystery and mystique surrounding the narwhal, a close relative of the beluga whale.

Until recently, little was known about the light-coloured cetacean most commonly recognized for its spiralled tusk a tooth extending through its upper lip. Only in 2017 did scientists discover the narwhal uses its tusk, a sensory device, to smack fish before swallowing them.

Using a combination of genetics and habitat modelling, Ferguson and other scientists investigated how past climatic shifts affected the distribution of the narwhal, one of the Arctic species most vulnerable to climate change.

They discovered low levels of genetic diversity among the worlds three narwhal populations, the two largest of which are found in Canada.

The scientists also found that habitat availability has been critical to the success of narwhals over the past tens of thousands of years, raising concerns about the fate of the migratory whale in a rapidly warming Arctic.

There are approximately 200,000 narwhals in the world.

Populations are named for where they summer. The vast majority of narwhals are found in Canada, in two groups known as the Baffin Bay and Hudsons Bay populations. A third population, numbering about 10,000 animals, is found in Greenland, extending to Svalbard an island between Norway and the North Pole and as far as Russia.

Its pretty remarkable that Canada has this resource but its also a lot of responsibility, said Ferguson, who worked with Inuit hunters to gather tissue samples for the study.

We are the ones who are going to have to manage and conserve this species going forward into the future.

DFO scientist Steve Ferguson in the field, conducting research on the worlds narwhal populations. Photo: Steve Ferguson

Narwhals appear only to have ever been an Atlantic species, and all three populations are closely related. Researchers found narwhals have one of the lowest genetic diversities of all marine mammals.

I still dont think weve quite solved that puzzle as to why it is so low, Ferguson said in an interview. Maybe there was some kind of bottleneck way back in the past. This history thats been explained by the genomic study here hasnt really found a good explanation for that.

The study found a long-term, low overall population size that increased when suitable habitat expanded following the last Ice Age. Like other polar marine predators, narwhal populations contracted into smaller areas during the last glaciation.

Its a bit of a mystery as to how fragmented they might have been, Ferguson said.

The study also looked into the future, forecasting what impact global warming might have on populations.

Researchers estimated a 25 per cent decline in habitat suitability by 2100, with a 1.6 degrees northward shift in habitat availability, suggesting narwhal habitat is likely to contract as sea temperatures rise and sea ice continues to melt.

The genetic ghost hunters

Ferguson said there will be a slight decrease in populations, including in the east Greenland group.

Narwhal distribution will be further affected in the near future by increased human encroachment, changes in prey availability, new competitors and increased predation by killer whales, according to the study.

More open water is good for narwhals to some extent, Ferguson said. But they will have competitors and disease and problems coming from the south [and] thats going to continue to push them further north.

Much depends on narwhals having access to the habitat they need to thrive, he said.

Baffin Bay seems to be a perfect spot for them right now, at least in winter. Theyre really deep diving animals, well adapted to diving to extreme depths, up to 2 kilometres. Baffin Bay allows them to do that and has some really good food.

All other Arctic marine mammals are circumpolar, meaning they are found around the world.

But narwhal are unique, Ferguson said. They really seem to have this Atlantic Ocean habitat. So theres an open question as to what might happen as we continue to lose sea ice.

The Arctic is warming at an unprecedented rate. A new study, published in Geophysical Research Letters, predicts summer Arctic sea ice will disappear before 2050, with devastating consequences for the Arctic ecosystem.

Narwhals most vulnerable to increased shipping in Arctic

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Scientists use genetics to study how the world's three narwhal populations are affected by climate shifts - The Narwhal

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Genetic variants linked with onset, progression of POAG – Ophthalmology Times

Thursday, April 23rd, 2020

Genetic variants that are unrelated to the IOP are associated with a family history of glaucoma and play a role in the onset of primary open-angle glaucoma (POAG). Genetic variants that are related to the IOP are associated with the age at which glaucoma is diagnosed and are associated with disease progression.

What is known about POAG, the most prevalent form of glaucoma, is that increased IOP and myopia are risk factors for damage to the optic nerve in POAG.

Related: Stent offers IOP stability more than three years after surgery

A family history of glaucoma is a major risk factor for development of POAG, in light of which, therefore, genetic factors are thought to be important in the disease pathogenesis and a few genes mutations have been identified as causing POAG, according to Fumihiko Mabuchi, MD, PhD, professor, Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Kofu, Japan.

Myopia has been shown to be a risk factor for POAG in several studies. However, it can be difficult to diagnose true POAG in myopic patients and controversy exists over whether it is real risk factor.

Myopic optic discs are notoriously difficult to assess, and myopic patients may have visual field defects unrelated to any glaucomatous process.

The prevalence of POAG increases with age, even after compensating for the association between age and IOP.

Related: Preservative-free tafluprost/timolol lowers IOP well, glaucoma study shows

Part of the storyDr. Mabuchi and his and colleagues, recounted that these factors are only part of the story.

According to Dr. Mabuchi and his colleagues, cases of POAG caused by these gene mutations account for several percent of all POAG cases, and most POAG is presumed to be a polygenic disease.

Recent genetic analyses, the investigators explained, have reported genetic variants that predispose patients to development of POAG and the additive effect of these variants on POAG, which are classified as two types.

The first genetics variants are associated with IOP elevation.

Related: Sustained-release implant offers long-term IOP control, preserved visual function

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The Better Half: On the Genetic Superiority of Women review bold study of chromosomal advantage – The Guardian

Thursday, April 23rd, 2020

It was noticeable from the initial outbreak in Wuhan that Covid-19 was killing more men than women. By February, data from China, which involved 44,672 confirmed cases of the respiratory disease, revealed the death rate for men was 2.8%, compared to 1.7% among women. For past respiratory epidemics, including Sars, Mers and the 1918 Spanish flu, men were also at significantly greater risk. But why?

Much of the reason for the Covid-19 disparity was put down to mens riskier behaviours around half of Chinese men are smokers, compared with just 3% of women, for instance. But as the coronavirus has spread globally, its proved deadlier to men everywhere that data exists (the UK and US notably and questionably do not collect sex-disaggregated data). Italy, for instance, has had a case fatality rate of 10.6% for men, versus 6% for women, whereas the sex disparity for smoking (now a known risk factor) is smaller there than China 28% of men and 19% of women smoke. In Spain, twice as many men as women have died. Smoking, then, is unlikely to account for all of the sex disparity in Covid-19 deaths.

Age and co-morbidity (pre-existing health conditions, including diabetes, cardiovascular disease or cancer) are the biggest risk factors, and that describes more older men than women. There may also be a sex difference in how people fight infection, due to immunological or hormonal differences oestrogen is shown to increase the antiviral response of immune cells.

If women are mounting a more effective immune response to Covid-19, it could be because many of the genes that regulate the immune system are encoded on the X chromosome. Everybody gets one X chromosome at conception from their mother. However, sex is determined (for the vast majority) by the chromosome received from their father: females get an additional X, whereas males do not (they receive a Y). According to The Better Half by American physician Sharon Moalem, having this second X chromosome gives women an immunological advantage. Every cell in a womans body has twice the number of X chromosomes as a mans, and so twice the number of genes that can be called upon to regulate her immune response, he says. Only one of the X chromosomes in each cell will be active at any time, but having that diversity of options gives women a better immunological toolbox to fight infections.

Moalem describes the possession of XX chromosomes as female genetic superiority. In the case of Covid-19, for instance, the virus uses its spike protein as a key to unlock a receptor protein on the outside of our human cells, called ACE-2, and gain entry. As the ACE-2 protein is on the X chromosome, men will have identical versions of ACE-2 on all their cells if the virus can unlock one, it can unlock all, he wrote recently in a Twitter thread. Women, though, have two different ACE-2 genes on their two X chromosomes, which may make it harder for the Covid-19 virus to break into all their cells, as it has to unlock two different proteins. Furthermore, once the ACE-2 is unlocked, it cannot perform its function, which, in the case of lung cells, is to clear fluid buildup during infection. So males, with all of their ACE-2 proteins affected, will suffer this more than females, he says. Moalem believes this may be the crucial advantage that XX-carrying women have over XY-carrying men in Covid-19 infection mortality.

Its an intriguing theory, and in his provocative book (written before the Covid-19 outbreak) Moalem expands the XX advantage to explain a whole range of life factors, from womens increased longevity to their lesser incidence of autism. It is incontrovertible that women are far less likely to suffer from X-linked genetic disorders, which include everything from Hunter syndrome to colour-blindness, because they usually have an unaffected X chromosome to fall back on. Indeed, in the case of colour vision, Moalem posits that having a second X chromosome can give some women a visual superpower, enabling them to see 100 times the usual colour range due to the extra diversity of receptors they carry on their multiple Xs.

It is striking that Moalem barely references environmental and social factors in a book about sex differences in health outcomes

However, the evidence for other of Moalems claims for the protective role of a second X chromosome, such as in autism spectrum disorders or behavioural traits, is less convincing. A broad range of genes play complex roles in the workings of the brain, and attributing a simple chromosomal relationship is brave. (It should be noted that Moalem authored the questionable The DNA Restart: Unlock Your Personal Genetic Code to Eat for Your Genes, Lose Weight, and Reverse Ageing in 2016.)

Outside of inherited genetic disorders, such as haemophilia, most conditions are attributable to a range of factors, including cultural norms, behaviours and social and environmental aspects as well as a host of biological factors. For Covid-19, for instance, gender-based norms around smoking and hand-washing, collective or individualistic mindsets that affect compliance with social-distance requests, how polluted your city is, whether you are a caregiver, and poverty and nutrition level all play a part in determining your infection risk and disease outcome. And, as weve seen, a range of co-morbidities increase risk are they too made more likely by absence of a second X chromosome? In many cases, such as cancers and lung disease, Moalem believes so a fascinating theory that surely deserves more study.

It is striking, though, that Moalem barely references environmental and social factors in a book about sex differences in health outcomes. This is particularly problematic when discussing sex differences in the brain, given the history of prejudicial research in this area. Much as this reviewer enjoys the rare pleasure of being described as the stronger, better, and superior sex certainly it is a change from being described as the weaker sex, as women have throughout history it is nevertheless an uncomfortable valuation. Claims for significant innate cognitive or behavioural advantages between the sexes have largely been debunked in the past few years by a range of influential books and research, and while there are differences, in most cases these are at least as great between individuals of each sex as between the sexes.

This is, however, a book that openly champions women, and it is most enjoyable when giving centre stage to female scientists, who have been too often overlooked. Moalems point is that, just as womens discoveries have been ignored, so too has the importance of their second X chromosome. Even today, medical and pharmaceutical research overwhelmingly favours male subjects, blinding us to knowledge that could lead to breakthroughs, and disadvantaging women who suffer inappropriate treatments and dosing. As men continue to fill the Covid-19 morgues faster than women, Moalem is on a quest to draw the worlds attention to a chromosomal tool we might just need.

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Is anxiety genetic? It’s a combination of genes and your environment – Insider – INSIDER

Thursday, April 23rd, 2020

Anxiety disorders are the most common type of mental illness. In a given year, 19% of Americans experience an anxiety disorder, according to the National Association on Mental Illness (NAMI).

Among the most common are:

Scientists have long debated the importance of nature versus nurture in terms of human development and illness. We now know that genetics play a significant role in the development of anxiety. Particularly, researchers have found that genes on chromosome 9 are associated with anxiety.

But your experiences within your environment including family upbringing and major life events are also important factors. Here's what you need to know about how genes and life experiences contribute to anxiety.

You're more likely to develop an anxiety disorder if another member of your family also has an anxiety disorder.

Research has indicated that anxiety disorders have a heritability rate of 26% for lifetime occurrence. This heritability rate means that 26% of the variability in whether or not people develop anxiety is caused by genetics.

So, about one-quarter of your risk for developing anxiety is genetic. That means other factors, such as traumatic experiences or physical illnesses, can have a larger impact. And your family can still contribute to anxiety in ways other than genetics.

"Family provides both the genes and the environment. It might be genes or it may be because a family member modeled a very anxious way of being in the world or often a combination of both," says Elena Touroni, PsyD, a psychologist and co-CEO at My Online Therapy. "It can be difficult to disentangle genes and environment."

One 2018 study found that children with anxiety disorders were three times more likely than children without disorders to have at least one parent with an anxiety disorder. The connection was particularly strong for social anxiety.

The study authors suggest that in addition to genetic risk, parents "model" behavior that increases the risk of their child developing social anxiety. For example, a parent who avoids social events might unintentionally teach their child to do the same.

However, adults who were raised by parents with anxiety can mitigate their risk of developing an anxiety disorder by learning how to manage anxiety with effective stress-management techniques. If you're a parent with anxiety, the earlier you teach your kid about this, the better.

"The best thing you can do is be aware of the fact that there is a higher chance that you might be prone to anxiety yourself," Touroni says. "Make a conscious effort to learn techniques to calm the mind, such as mindfulness. Also, having psychological therapy will help you better understand the anxieties of the people in your family, and therefore what they have left you vulnerable to as a result."

You don't need to have a family member with an anxiety disorder in order to develop anxiety. A stressful or traumatic event, for example, can increase the risk of developing an anxiety disorder.

"The main underlying core belief of any anxiety disorder is an exaggerated sense of vulnerability in the world of yourself or the people you care about," Touroni says. "Fundamentally, it's about understanding whether your experiences led you to develop a belief that the world is a dangerous place."

In particular, child sexual abuse and family violence may lead to an increased risk for anxiety. Moreover, having three or more adverse childhood experiences these are somewhat traumatic events for children, ranging from divorced parents to abuse is associated with a higher likelihood of developing anxiety.

Different childhood experiences at home, school and elsewhere can help explain why some family members might develop anxiety while others don't.

For example, a 2018 study followed 49,524 twins for 25 years. The researchers found that as twins aged and their environments became more different, the influence of heritability on their chance of developing anxiety decreased. In short: even though the twins shared genetics, their risk factors for anxiety were affected more by their environment than their genes.

In the end, there's no concrete set of factors that can predict if you will develop anxiety, or not.

"Mental illness is very different to physical illness. We can't always find a concrete link because there are a lot of variables," Touroni says. "Our mental wellbeing is influenced by so many different factors, and because of that, it's difficult to isolate genetic loading from environmental influence."

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Is anxiety genetic? It's a combination of genes and your environment - Insider - INSIDER

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Covid-19 Arrived in Seattle. Where It Went From There Stunned the Scientists. – The New York Times

Thursday, April 23rd, 2020

SEATTLE As the coronavirus outbreak consumed the city of Wuhan in China, new cases of the virus began to spread out like sparks flung from a fire.

Some landed thousands of miles away. By the middle of January, one had popped up in Chicago, another one near Phoenix. Two others came down in the Los Angeles area. Thanks to a little luck and a lot of containment, those flashes of the virus appear to have been snuffed out before they had a chance to take hold.

But on Jan. 15, at the international airport south of Seattle, a 35-year-old man returned from a visit to his family in the Wuhan region. He grabbed his luggage and booked a ride-share to his home north of the city.

The next day, as he went back to his tech job east of Seattle, he felt the first signs of a cough not a bad one, not enough to send him home. He attended a group lunch with colleagues that week at a seafood restaurant near his office. As his symptoms got worse, he went grocery shopping near his home.

Days later, after the man became the first person in the United States to test positive for the coronavirus, teams from federal, state and local agencies descended to contain the case. Sixty-eight people the ride-share driver at the airport, the lunchmates at the seafood restaurant, the other patients at the clinic where the man was first seen were monitored for weeks. To everyones relief, none ever tested positive for the virus.

But if the story ended there, the arc of the coronaviruss sweep through the United States would look much different.

As it turned out, the genetic building block of the virus detected in the man who had been to Wuhan would become a crucial clue for scientists who were trying to understand how the pathogen gained its first, crucial foothold.

Working out of laboratories along Seattles Lake Union, researchers from the University of Washington and the Fred Hutchinson Cancer Research Center rushed to identify the RNA sequence of the cases from Washington State and around the country, comparing them with data coming in from around the world.

Using advanced technology that allows them to rapidly identify the tiny mutations that the virus makes in its virulent path through human hosts, the scientists working in Washington and several other states made two disconcerting discoveries.

The first was that the virus brought in by the man from Wuhan or perhaps, as new data has suggested, by someone else who arrived carrying a nearly identical strain had managed to settle into the population undetected.

Then they began to realize how far it had spread. A small outbreak that had established itself somewhere north of Seattle, they realized as they added new cases to their database, was now responsible for all known cases of community transmission they examined in Washington State in the month of February.

And it had jumped.

A genetically similar version of the virus directly linked to that first case in Washington was identified across 14 other states, as far away as Connecticut and Maryland. It settled in other parts of the world, in Australia, Mexico, Iceland, Canada, the United Kingdom and Uruguay. It landed in the Pacific, on the Grand Princess cruise ship.

The unique signature of the virus that reached Americas shores in Seattle now accounts for a quarter of all U.S. cases made public by genomic sequencers in the United States.

With no widespread testing available, the high-tech detective work of the researchers in Seattle and their partners elsewhere would open the first clear window into how and where the virus was spreading and how difficult it would be to contain.

Even as the path of the Washington State version of the virus was coursing eastward, new sparks from other strains were landing in New York, in the Midwest and in the South. And then they all began to intermingle.

The researchers in Seattle included some of the worlds most renowned experts on genomic sequencing, the process of analyzing the letters of a viruss genetic code to track its mutations. Before the outbreak, one of the labs had done more sequencing of human coronaviruses than anywhere else in the world 58 of them.

When a virus takes hold in a person, it can replicate billions of times, some of those with tiny mutations, each new version competing for supremacy. Over the span of a month, scientists have learned, the version of the novel coronavirus moving through a community will mutate about twice each one a one-letter change in an RNA strand of 29,903 nucleotides.

The alterations provide each new form of the virus with a small but distinctive variation to its predecessor, like a recipe passed down through a family. The mutations are so small, however, that it is unlikely that one version of the virus would affect patients differently than another one.

The virus originated with one pattern in Wuhan; by the time it reached Germany, three positions in the RNA strand had changed. Early cases in Italy had two entirely different variations.

For each case, the Seattle researchers compile millions of fragments of the genome into a complete strand that can help identify it based on whatever tiny mutations it has undergone.

What were essentially doing is reading these small fragments of viral material and trying to jigsaw puzzle the genome together, said Pavitra Roychoudhury, a researcher for the two institutions working on the sequencing in Seattle.

With some viruses, the puzzles are more challenging to assemble. The virus that causes Covid-19, she said, was relatively well behaved.

Researchers looked closely at the man who had flown in from Wuhan, who has not been publicly identified and did not respond to a request to speak to The New York Times.

They confirmed he had brought a strain of the virus that was already extending broad tentacles from the Wuhan area to Guangdong on Chinas Pacific coast to Yunnan in the mountainous west. Along the way, its signature varied significantly from the version of the virus that spread in Europe and elsewhere: Its mutations were at positions 8,782, 18,060 and 28,144 on the RNA strand.

That gave Dr. Roychoudhury and the scientists around the country she has been working with the unique ability to see what the contact tracers in Seattle had been unable to: the invisible footprints of the pathogen as it moved.

On the hunt for the viruss path through the United States, one of the first signposts came on Feb. 24, when a teenager came into a clinic with what looked like the flu. The clinic was in Snohomish County, where the man who had traveled to China lived. Doctors gave the teenager a nasal swab as part of a tracking study that was already being done on influenza in the region.

Only later did they learn that the teenager had not had the flu, but the coronavirus. After the diagnosis, researchers in Seattle ran the sample through a sequencing machine. Trevor Bedford, a scientist at the Fred Hutchinson Cancer Research Institute who studies the spread and evolution of viruses, said he and a colleague sipped on beers as they waited for the results to emerge on a laptop.

It confirmed what they had feared: The case was consistent with being a direct descendant of the first U.S. case, from Wuhan.

The teenager had not been in contact with the man who had traveled to Wuhan, so far as anyone knew. He had fallen ill long after that man was no longer contagious.

Additional sequencing in the days afterward helped confirm that other cases emerging were all part of the same group. This could only mean one thing: The virus had not been contained to the traveler from Wuhan and had been spreading for weeks. Either he had somehow spread it to others, or someone else had brought in a genetically identical version of the virus.

That latter possibility has become more likely in recent days, after new cases entered into the researchers database showed an interesting pattern. A virus with a fingerprint nearly identical to the Wuhan travelers had shown up in cases in British Columbia, just across the border from Washington State, suggesting to Dr. Bedford that it might not have been the first Wuhan traveler who had unleashed the outbreak.

Either way, the number of cases emerging around the time the teenagers illness was identified indicated that the virus had been circulating for weeks.

On its path through Washington State, one of the viruss early stops appears to have been at a square dance on Feb. 16 in the city of Lynnwood, midway between Seattle and Everett.

It was a full month since the Wuhan travelers arrival. A couple dozen square dancers had gathered for a pie and ice cream social, capping off a series of practices and events from all over the region over the course of a three-day weekend.

Three groups of square dancers swung through promenades and allemandes huffing and sweating to Free Ride and Bad Case of Loving You.

Stephen Cole, who was the dance caller that night, said he did not recall anyone showing signs of illness. But over the next few days, he and a woman who had been cuing the dance fell ill.

Another dancer, Suzanne Jones, had attended a class with Mr. Cole the day before. By the next weekend, Ms. Jones said, she started to feel symptoms she dismissed as allergies, since she had noticed the scotch broom starting to bloom.

After resting for a couple of days, Ms. Jones felt better and drove from her home in Skagit County more than 100 miles south to visit her mother in Enumclaw, helping pack some belongings for storage. On the way back, she visited the strip malls in Renton, then a store in Everett, then a laundromat in Arlington. She stopped to apply for a job with the Census Bureau.

I probably exposed a lot of people that day, she said.

Ms. Jones only realized it could be something more than allergies after getting a notification on March 2 that one of her square-dancing friends had died of the coronavirus as the outbreak began to emerge. She too tested positive.

There was minimal coronavirus testing in the United States during February, leaving researchers largely blind to the specific locations and mutations of the spread that month. The man who had traveled from Wuhan was not at the dance, nor was anyone else known to have traveled into the country with the coronavirus. But researchers learned that the virus by then was already spreading well beyond its point of origin and all the cases of community transmission that month were part of that same genetic branch.

There was another spreading event. On the Saturday after the dance, a group of friends packed the living room of a one-bedroom apartment in Seattle, sharing homemade food and tropical-themed drinks.

Over the following days, several people began coming down with coronavirus symptoms. Among people who attended, four out of every 10 got sick, said Hanna Oltean, an epidemiologist with the Washington State Department of Health.

Several people passed on the virus to others. By late March, the state health department had documented at least three generations of transmission occurring before anyone was symptomatic, Ms. Oltean said.

By then, it was becoming clear that there were probably hundreds of cases already linked to the first point of infection that had been spreading undetected. It left a lingering question: If the virus had this much of a head start, how far had it gone?

As cases of the virus spread, scientists in other states were sequencing as many as they could. In a lab at the University of California, San Francisco, Dr. Charles Chiu looked at a range of cases in the Bay Area, including nine passengers from the Grand Princess cruise ship, which had recently returned from a pair of ill-fated sailings to Mexico and Hawaii that left dozens of passengers infected with the coronavirus.

Dr. Chiu was stunned by his results: Five cases in the San Francisco area whose origins were unknown were linked back to the Washington State cluster. And all nine of the Grand Princess cases had a similar genetic link, with the same trademark mutations plus a few new ones. The massive outbreak on the ship, Dr. Chiu believed, could probably be traced to a single person who had developed an infection linked to the Washington State cluster.

But it did not stop with the Grand Princess. David Shaffer, who had been on the first leg of the cruise with members of his family, said passengers on that leg did not discover until after they disembarked that the coronavirus had been aboard when they learned that a fellow passenger had died.

He and his family felt fine when they returned to their home in Sacramento, he said, and when he started feeling sick the next day, on Feb. 22, he at first assumed it was a sinus infection.

Days later, he was tested and learned he had the coronavirus. His wife later tested positive, too, as did one of his sons and one of his grandsons, who had not been on the cruise.

Dr. Chiu remembers going over the implications in his head. If its in California and its in Washington State, its very likely in other states.

The same day Mr. Shaffer got sick, another person landed at Raleigh-Durham International Airport in North Carolina, having just visited the Life Care Center nursing home in Kirkland, which would become a center of infection. At the time, there were growing signs of a respiratory illness at the facility, but no indication of the coronavirus.

A few days later, the traveler began feeling ill, but with no sign that it might be anything serious, he went out for dinner at a restaurant in Raleigh. Just then, officials in Washington State began to report a coronavirus outbreak at Life Care Center. The person in North Carolina tested positive a few days later the first case in the state.

By the middle of March, a team at Yale gathered nine coronavirus samples from the Connecticut region and put them through a portable sequencing machine. Seven came back with connections to Washington State.

I was pretty surprised, said Joseph Fauver, one of the researchers at the lab. At the time, he said, it suggested that the virus had been spreading more than people had initially believed.

In sequencing more recent cases, the researchers have found cases emanating from a larger cluster, with its own distinct genetic signature, originating in the New York area.

A group of cases throughout the Midwest, first surfacing in early March, appears to have roots in Europe. A group of cases in the South, which emerged around the same time, on March 3, appears like a more direct descendant from China.

But of all the branches that researchers have found, the strain from Washington State remains the earliest and one of the most potent.

It has surfaced in Arizona, California, Connecticut, the District of Columbia, Florida, Illinois, Michigan, Minnesota, New York, North Carolina, Oregon, Utah, Virginia, Wisconsin and Wyoming, and in six countries.

And new cases are still surfacing.

One of the enduring mysteries has been just how the virus managed to gain its first, fatal foothold in Washington.

Did the contact tracers who followed the steps of the man who had traveled from Wuhan miss something? Did he expose someone at the grocery store, or touch a door handle when he went to the restaurant near his office?

In recent days, the sequencing of new cases has revealed a surprising new possibility. A series of cases in British Columbia carried a genetic footprint very similar to the case of the Wuhan traveler. That opened up the possibility that someone could have carried that same branch of the virus from Wuhan to British Columbia or somewhere else in the region at nearly the same time. Perhaps it was that person whose illness had sparked the fateful outbreak.

But who? And how? That would probably never be known.

Mike Baker reported from Seattle and Sheri Fink from New York.

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Covid-19 Arrived in Seattle. Where It Went From There Stunned the Scientists. - The New York Times

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Is It Too Late to Buy Shares of Seattle Genetics? – Motley Fool

Thursday, April 23rd, 2020

As the overall market declined amid the coronavirus outbreak, Seattle Genetics (NASDAQ:SGEN) shares resisted, climbing22% since the start of this year. The reason is simple: It's all about products. Seattle Genetics started the year with a newly approved drug -- Padcev, for the most common form of bladder cancer -- and investors were hopeful the U.S. Food and Drug Administration would soon approve the company's breast cancer drug, tucatinib, to be commercialized as Tukysa. Last week, that approval came -- four months earlier than expected.

Now the question is: Can Seattle Genetics move higher, or is the good news priced into the shares at this point? A look at approved treatments and market sizes can offer us some clues.

Image source: Getty Images.

Just a year ago, Seattle Genetics was a one-product company. That product -- Adcetris, for Hodgkin lymphoma -- had a particularly strong 2019 thanks to label expansions, posting a 32% increase in net salesto $627.7 million in the U.S. and Canada. Now, Seattle Genetics forecasts a slowdown in Adcetris' sales for 2020, with an increase in the range of 8% to 12%. Still, long-term growth isn't necessarily over for Adcetris as the company works to establishthe treatment as the standard of care in Hodgkin lymphoma and expand its uses.

A slowdown in growth for Adcetris is also less of a concern given the approvals of Padcev in December and Tukysa more recently, though it will take several quarters before these drugs can truly contribute to revenue. My eyes will be on Seattle Genetics' earnings reportApril 30 to see how Padcev fared during its first full quarter on the market.

Padcev is a treatmentfor locally advanced or metastatic urothelial (bladder) cancer. The approval pertains to adult patients who have previously been treated with both platinum-based chemotherapy and inhibitors of proteins that help cancer cells survive. The FDA recently granteda breakthrough therapy designation for an additional use, and after discussions with the regulatory body, Seattle Genetics is optimistic about a potential accelerated approval registration. That would be for the use of Padcev along with an immune therapy called pembrolizumab as a first-line treatment for patients with advanced forms of urothelial cancer who can't receive chemotherapy treatments that use a common treatment called cisplatin.

If sales predictions are correct, Padcev may be poised to be a blockbuster. Analysts from SVB Leerink Research predict peak sales of more than $5 billion, according to press reports. And according to Grand View Research, the global urothelial cancer drug market will reach $3.6 billion by 2023, with a compounded annual growth rate of 23%.

Tukysa might be another blockbuster opportunity. SVB Leerink expectsthat drug to generate peak sales of $1.2 billion by 2030. Tukysa is approvedin combination with trastuzumab and capecitabine for advanced or metastatic HER2-positive breast cancer. In HER2-positive breast cancer, high levels of the HER2 protein within tumors lead to the spread of cancer cells. Tukysa inhibits enzymes that activate this type of protein. A GlobalData report shows the market for HER2-positive breast cancer is set to increase 54% to $9.89 billion by 2025 from 2015.

Seattle Genetics also has about 15 programs in phase 1 or phase 2 trials among its pipeline, adding to future revenue prospects.

Seattle Genetics has steadily grown its revenuesince 2011, when Adcetris was first approved. The company's net lossnarrowed last year to $158.7 million from $222.7 million in 2018, and after fiveconsecutive quarterly losses, Seattle Genetics posted a profit in the last quarter of 2019. The company also reported an increase in cash levels, starting this year with $868.3 million in cashand investments compared with $459.9 milliona year earlier. The financial picture is brightening for Seattle Genetics, and the additions of Padcev and Tukysa should give it a further boost.

So, is it too late to buy Seattle Genetics stock? No. Though the shares only have to rise5.5% to reach Wall Street's average price estimate, for the long-term biotech investor, there is more to gain as the newly approved drugs begin adding to the company's revenue.

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Earth Day: The relevance of land genetics in the time of COVID-19 – CNBCTV18

Thursday, April 23rd, 2020

April 22 is celebrated as Earth Day across the world since 1970 after a UNESCO conference in San Francisco proposed a day in honour of the mother Earth a year earlier. On this day in 2016, a landmark Paris agreement -- The draft Climate Protection Treaty -- was signed by the US, China and 120 other countries to protect the planet.

Come 2020 and we're all fighting an unexpected war. What is ironic, is that this war is being fought by sitting at home. Yes, the worldwide lockdown due to the coronavirus pandemic has a majority of people on the planet indoors. The condition is likened to land genetics and part of it is neuroarchitecture, which is a discipline that studies how the physical environment surrounding us can modify our brains and consequently out behavior.

Despite making ourselves busy at homes by indulging in news and entertainment on screens, most of us are facing anxiety issues.

Like the human body, planet Earth too has its anatomy, which can be positive or become sick. So while were at home, lets make use of land science and come out of this lockdown to a healthier planet. This science is purely based on geology, geography and human behaviour. Moreover, the application of land genetics can have a positive effect of our health and lives overall. The theory of land genetics suggests changes in our lifestyle -- the way we use the planet -- which can bring about a long lasting positive change.

With over 80 percent of humans locked indoors, lets consider our homes as the universe and energise the land where we live.

Here are some dos and donts according to the importance of directions that you could practice.

Sleep with your head towards the south. The head is the heaviest part of the body and acts as the North Pole and theory of physics suggests that opposite poles attract each other, this would have a calming effect on you.

If sitting for long, face the east or north, it helps you concentrate better.

A family should sleep from west to east or south to north beginning with the eldest member. The wavelength of land is bigger for elders and smaller for younger members.

If a member of the family is unwell, keep him in the first quadrant of the house which is in the north-east direction. They should sleep facing the south. It will help them fight the diseases effectively. The north-east wavelength is the smallest of all.

While cooking, one should face the north or east. This is similar to the flow of blood within the body and the magnetic force of the Earth. It helps focus and the food turns out delicious.

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Genetic analysis suggests that the coronavirus was already circulating in Spain by mid-February – EL PAS in English

Thursday, April 23rd, 2020

Four pages of newsprint have the same number of letters as the genetic code of the new coronavirus: 30,000. In that brief text, there is enough information to bring the whole of humanity to its knees and force billions of people to hide away in their homes. Once the virus infects a human cell, in the throat for example, the virus is capable of reproducing up to 100,000 times in just 24 hours. Each copy can contain small errors of one letter for another and the new viruses inherit these. The history of the pandemic can be reconstructed by studying these errors.

A team of scientists from Madrids Carlos III Health Institute has analyzed the first 28 genomes of the virus in Spain. The trail of the errors does not lead to a single patient zero, but confirms that there were a multitude of entries by people who had been infected in other countries during the month of February, according to the bioinformatic specialist Francisco Dez, the first signatory of the study.

Based on the information we have today, we believe that there were at least 15 different entries in Spain

On February 23, Fernando Simn, the director of the Health Ministrys Coordination Center for Health Alerts, stated that the virus is not in Spain, nor is the disease being transmitted, nor do we currently have any cases. But it would appear that by that point the virus was already spreading unimpeded.

Dezs team has studied the nearly 1,600 complete virus genomes read by the international scientific community up until the end of March. The analysis shows that the 28 Spanish genomes belong to the three main virus families identified in the rest of the world, which are named S, G and V.

All of the viruses are very similar, in principle, with few mutations that differentiate them, which is good news, with all due care, explains Dez, who is now working at the Clnic Hospital in Barcelona. The experimental vaccines that are being investigated today are being conceived for the current genetic sequence of the virus. A high rate of mutation could ruin the efficiency of the first vaccines, which are due to arrive within a year at the earliest.

The new analysis, which has been published in an open repository and has not been externally reviewed, suggests that the common ancestor of the 1,600 viruses was in the Chinese city of Wuhan around November 24. Thirteen of the Spanish genomes belong to the S family and 11 are linked to a prior case detected on February 1 in Shanghai. The first three S viruses identified in Spain are from samples taken on February 26 and 27 in Valencia. A week before, 2,500 soccer fans from the region had traveled to Milan to see Atalanta play Valencia, an event that was described as a biological bomb by the mayor of Bergamo, Giorgio Gori.

However, genetic analysis suggests that the coronavirus from the S family was already circulating in Spain, around February 14. Another group of half a dozen cases in Madrid suggest that the G family was already circulating in the capital around February 18.

It would appear that by February 23 the coronavirus was already spreading unimpeded in Spain

The study allows for the invisible and explosive dissemination of the virus to be seen. The case of Shanghai on February 1 is apparently related to another two samples taken in France on February 25 and 26, another in Madrid on March 2, another in Chile on March 3, another in the United States on March 4, another in Georgia on March 8 and another in Brazil on March 16. The probable transmission routes become more complicated until they form a web on the world map. Dez believes that this specific branch of the virus went from Spain to another six countries.

There was no patient zero in Spain, says virologist Jos Alcam, who supervised the study along with his colleague, Inmaculada Casas. There is no patient zero when an epidemic is already so widespread. The team of geneticist Fernando Gonzlez Candelas, from the Valencian foundation Fisabio, sequenced the first three Spanish genomes of the virus on March 17. His group has now read more than a hundred. Based on the information we have today, we believe that there were at least 15 different entries in Spain. Something similar has happened in other countries, such as the US and Iceland, where multiple entries of the virus have also been identified, Gonzlez explains. Patient zero does not exist.

Gonzlez points to the limitations of these genetic studies, which are based on the complete genomes of the virus published by the scientific community in the Gisaid open repository. There are already 11,000 complete genomes from half of the world, 150 of them from Spain. But there are essential pieces missing. There are no relevant sequences from Italy in order to reach conclusions, Gonzlez complains. Without these genomes, possible routes of transmission from Italy to the rest of the world are invisible. Whats more, the image is always incomplete: there are 2.4 million confirmed cases on the planet, according to the latest data from the World Health Organization (WHO).

The Fisabio geneticist, who did not take part in the new study, is also optimistic on seeing the low diversity of the virus. SARS-CoV-2 has a mutation rate that is a thousand times slower than the flu or HIV, he says. In principle, this is good news.

Just 82 days have passed since, on February 1, the first coronavirus case was detected in Spain. The patient in question was a German tourist on the Canary Island of La Gomera. The man was linked to one of the first known outbreaks in Europe, that of a group of employees from the motor vehicle product company Webasto, who had taken part in a training course in Munich together with a Chinese colleague who had family in Wuhan.

The coronavirus, however, had already been circulating for some days, according to the genetic and epidemiological data. No border has been able to stop the virus, explains geneticist Fernando Gonzlez Candelas, from the Fisabio foundation.

The European Center for Disease Prevention and Control warned on January 18 that Wuhan airport had six weekly direct flights to Paris, three to London and another three to Rome. That was how a multitude of patient zeros traveled.

English version by Simon Hunter.

Given the exceptional circumstances, EL PAS is currently offering all of its digital content free of charge. News related to the coronavirus will continue to be available while the crisis continues.

Dozens of journalists are working non-stop to bring you the most rigorous coverage possible and meet their mission of providing a public service. If you want to support our journalism, you can do so here for 1 for the first month (10 from June). Subscribe to the facts.

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Seattle Genetics (NASDAQ:SGEN) Is In A Strong Position To Grow Its Business – Yahoo Finance

Thursday, April 23rd, 2020

We can readily understand why investors are attracted to unprofitable companies. For example, biotech and mining exploration companies often lose money for years before finding success with a new treatment or mineral discovery. But the harsh reality is that very many loss making companies burn through all their cash and go bankrupt.

So, the natural question for Seattle Genetics (NASDAQ:SGEN) shareholders is whether they should be concerned by its rate of cash burn. In this report, we will consider the company's annual negative free cash flow, henceforth referring to it as the 'cash burn'. We'll start by comparing its cash burn with its cash reserves in order to calculate its cash runway.

View our latest analysis for Seattle Genetics

A company's cash runway is calculated by dividing its cash hoard by its cash burn. When Seattle Genetics last reported its balance sheet in December 2019, it had zero debt and cash worth US$811m. In the last year, its cash burn was US$234m. That means it had a cash runway of about 3.5 years as of December 2019. Notably, however, analysts think that Seattle Genetics will break even (at a free cash flow level) before then. In that case, it may never reach the end of its cash runway. The image below shows how its cash balance has been changing over the last few years.

NasdaqGS:SGEN Historical Debt April 22nd 2020

Some investors might find it troubling that Seattle Genetics is actually increasing its cash burn, which is up 4.3% in the last year. The silver lining is that revenue was up 40%, showing the business is growing at the top line. On balance, we'd say the company is improving over time. While the past is always worth studying, it is the future that matters most of all. For that reason, it makes a lot of sense to take a look at our analyst forecasts for the company.

There's no doubt Seattle Genetics seems to be in a fairly good position, when it comes to managing its cash burn, but even if it's only hypothetical, it's always worth asking how easily it could raise more money to fund growth. Issuing new shares, or taking on debt, are the most common ways for a listed company to raise more money for its business. One of the main advantages held by publicly listed companies is that they can sell shares to investors to raise cash to fund growth. We can compare a company's cash burn to its market capitalisation to get a sense for how many new shares a company would have to issue to fund one year's operations.

Since it has a market capitalisation of US$24b, Seattle Genetics's US$234m in cash burn equates to about 1.0% of its market value. That means it could easily issue a few shares to fund more growth, and might well be in a position to borrow cheaply.

It may already be apparent to you that we're relatively comfortable with the way Seattle Genetics is burning through its cash. In particular, we think its cash runway stands out as evidence that the company is well on top of its spending. While its increasing cash burn wasn't great, the other factors mentioned in this article more than make up for weakness on that measure. Shareholders can take heart from the fact that analysts are forecasting it will reach breakeven. After considering a range of factors in this article, we're pretty relaxed about its cash burn, since the company seems to be in a good position to continue to fund its growth. Taking an in-depth view of risks, we've identified 2 warning signs for Seattle Genetics that you should be aware of before investing.

Story continues

Of course, you might find a fantastic investment by looking elsewhere. So take a peek at this free list of companies insiders are buying, and this list of stocks growth stocks (according to analyst forecasts)

If you spot an error that warrants correction, please contact the editor at editorial-team@simplywallst.com. This article by Simply Wall St is general in nature. It does not constitute a recommendation to buy or sell any stock, and does not take account of your objectives, or your financial situation. Simply Wall St has no position in the stocks mentioned.

We aim to bring you long-term focused research analysis driven by fundamental data. Note that our analysis may not factor in the latest price-sensitive company announcements or qualitative material. Thank you for reading.

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Seattle Genetics (NASDAQ:SGEN) Is In A Strong Position To Grow Its Business - Yahoo Finance

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Rapidly Revealing COVID-19s Journey and Evolution With Genetic Tracing Barcode – SciTechDaily

Thursday, April 23rd, 2020

Researchers have reported a method to quickly identify mutated versions of SARS-CoV-2, the virus that causes COVID-19. Credit: Drexel University

Drexel University researchers have reported a method to quickly identify and label mutated versions of the virus that causes COVID-19. Their preliminary analysis, using information from a global database of genetic information gleaned from coronavirus testing, suggests that there are at least six to 10 slightly different versions of the virus infecting people in America, some of which are either the same as, or have subsequently evolved from, strains directly from Asia, while others are the same as those found in Europe.

First developed as a way of parsing genetic samples to get a snapshot of the mix of bacteria, the genetic analysis tool teases out patterns from volumes of genetic information and can identify whether a virus has genetically changed. They can then use the pattern to categorize viruses with small genetic differences using tags called Informative Subtype Markers (ISM).

Major SARS-CoV-2 genetic subtypes in countries/regions with the most sequences (indicating date subtype was firstsequenced in that country/region). Subtypes with less than 5% abundance are plotted as OTHER. Credit: Drexel University

Applying the same method to process viral genetic data can quickly detect and categorize slight genetic variations in the SARS-CoV-2, the novel coronavirus that causes COVID-19, the group reported in a paper recently posted on the preliminary research archive, bioRxiv. The genetic analysis tool that generates these labels is publicly available for COVID-19 researchers on GitHub.

The types of SARS-CoV-2 viruses that we see in tests from Asia and Europe is different than the types were seeing in America, said Gail Rosen, PhD, a professor in Drexels College of Engineering, who led the development of the tool. Identifying the variations allows us to see how the virus has changed as it has traveled from population to population. It can also show us the areas where social distancing has been successful at isolating COVID-19.

Relative abundance of ISMs in DNA sequences from Canada as sampled over time. Credit: Drexel University

The ISM tool, developed by Rosen and a focused team including doctoral studentZhengqiao Zhao and Bahrad A. Sokhansani, PhD, an independent researcher and intellectual property attorney, is particularly useful because it does not require analysis of the full genetic sequence of the virus to identify its mutations. In the case of SARS-CoV-2, this means reducing the 30,000-base-long genetic code of the virus to a subtype label 17 bases long.

Its the equivalent of scanning a barcode instead of typing in the full product code number, Rosen said. And right now, were all trying to get through the grocery store a bit faster. For scientists this means being able to move to higher-level analysis much faster. For example, it can be a faster process in studying which virus versions could be affecting health outcomes. Or, public health officials can track whether new cases are the result of local transmission or coming from other regions of the United States or parts of the world.

While these genetic differences might not be enough to delineate a new strain of virus, Rosens group suggests understanding these genetically significant subtypes, where theyre being found and how prevalent they are in these areas is data granular enough to be useful.

Stacked plot of the number of sequences of the reference sequence ISM subtype (CCCCGCCCACAGGTGGG). Credit: Drexel University

This allows us to see the very specific fingerprint of COVID-19 from each region around the world, and to look closely at smaller regions to see how it is different, Rosen said. Our preliminary analysis, using publicly available data from across the world, is showing that the combination of subtypes of virus found in New York is most similar to those found in Austria, France and Central Europe, but not Italy. And the subtype from Asia, that was detected here early in the pandemic has not spread very much, instead we are seeing a new subtype that only exists in America as the one most prevalent in Washington state and on the west coast.

In addition to helping scientists understand how the virus is changing and spreading, this method can also reveal the portion of its genetic code that appears to remain resistant to mutations a discovery that could be exploited by treatments to combat the virus.

Were seeing that the two parts of the virus that seem not to be mutating are the ones responsible for its entry into healthy cells and packaging its RNA, Rosen said. Both of these are important targets for understanding the bodys immune response, identifying antiviral therapeutics and designing vaccines.

Rosens Ecological and Evolutionary Signal-Processing and Informatics Laboratory will continue to analyze COIVD-19 data as it is collected and to support public health researchers using the ISM process.

Reference: Characterizing geographical and temporal dynamics of novel coronavirus SARS-CoV-2 using informative subtype markers by Zhengqiao Zhao, Bahrad A. Sokhansanj and Gail Rosen, 10 April 2020, bioRxiv.DOI: 10.1101/2020.04.07.030759

This research is supported in part by the National Science Foundation.

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Rapidly Revealing COVID-19s Journey and Evolution With Genetic Tracing Barcode - SciTechDaily

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A coronavirus strain from Washington state was one of the earliest and most potent found and it’s in Utah – Salt Lake Tribune

Thursday, April 23rd, 2020

Seattle As the coronavirus outbreak consumed the city of Wuhan in China, new cases of the virus began to spread out like sparks flung from a fire.

Some landed thousands of miles away. By the middle of January, one had popped up in Chicago, another one near Phoenix. Two others came down in the Los Angeles area. Thanks to a little luck and a lot of containment, those flashes of the virus appear to have been snuffed out before they had a chance to take hold.

But on Jan. 15, at the international airport south of Seattle, a 35-year-old man returned from a visit to his family in the Wuhan region. He grabbed his luggage and booked a ride-share to his home north of the city.

The next day, as he went back to his tech job east of Seattle, he felt the first signs of a cough not a bad one, not enough to send him home. He attended a group lunch with colleagues that week at a seafood restaurant near his office. As his symptoms got worse, he went grocery shopping near his home.

Days later, after the man became the first person in the United States to test positive for the coronavirus, teams from federal, state and local agencies descended to contain the case. Sixty-eight people the ride-share driver at the airport, the lunchmates at the seafood restaurant, the other patients at the clinic where the man was first seen were monitored for weeks. To everyones relief, none ever tested positive for the virus.

But if the story ended there, the arc of the coronaviruss sweep through the United States would look much different.

As it turned out, the genetic building block of the virus detected in the man who had been to Wuhan would become a crucial clue for scientists who were trying to understand how the pathogen gained its first, crucial foothold.

Working out of laboratories along Seattles Lake Union, researchers from the University of Washington and the Fred Hutchinson Cancer Research Center rushed to identify the RNA sequence of the cases from Washington state and around the country, comparing them with data coming in from around the world.

Using advanced technology that allows them to rapidly identify the tiny mutations that the virus makes in its virulent path through human hosts, the scientists working in Washington and several other states made two disconcerting discoveries.

The first was that the virus brought in by the man from Wuhan or perhaps, as new data has suggested, by someone else who arrived carrying a nearly identical strain had managed to settle into the population undetected.

Then they began to realize how far it had spread. A small outbreak that had established itself somewhere north of Seattle, they realized as they added new cases to their database, was now responsible for all known cases of community transmission they examined in Washington state in the month of February.

A genetically similar version of the virus directly linked to that first case in Washington was identified across 14 other states, as far away as Connecticut and Maryland. It settled in other parts of the world, in Australia, Mexico, Iceland, Canada, Britain and Uruguay. It landed in the Pacific, on the Grand Princess cruise ship.

The unique signature of the virus that reached U.S. shores in Seattle now accounts for a quarter of all U.S. cases made public by genomic sequencers in the United States.

With no widespread testing available, the high-tech detective work of the researchers in Seattle and their partners elsewhere would open the first clear window into how and where the virus was spreading and how difficult it would be to contain.

Even as the path of the Washington state version of the virus was coursing eastward, new sparks from other strains were landing in New York, in the Midwest and in the South. And then they all began to intermingle.

The researchers in Seattle included some of the worlds most renowned experts on genomic sequencing, the process of analyzing the letters of a viruss genetic code to track its mutations. Before the outbreak, one of the labs had done more sequencing of human coronaviruses than anywhere else in the world 58 of them.

When a virus takes hold in a person, it can replicate billions of times, some of those with tiny mutations, each new version competing for supremacy. Over the span of a month, scientists have learned, the version of the novel coronavirus moving through a community will mutate about twice each one a one-letter change in an RNA strand of 29,903 nucleotides.

The alterations provide each new form of the virus with a small but distinctive variation to its predecessor, like a recipe passed down through a family. The mutations are so small, however, that it is unlikely that one version of the virus would affect patients differently than another one.

The virus originated with one pattern in Wuhan; by the time it reached Germany, three positions in the RNA strand had changed. Early cases in Italy had two entirely different variations.

For each case, the Seattle researchers compile millions of fragments of the genome into a complete strand that can help identify it based on whatever tiny mutations it has undergone.

What were essentially doing is reading these small fragments of viral material and trying to jigsaw puzzle the genome together, said Pavitra Roychoudhury, a researcher for the two institutions working on the sequencing in Seattle.

With some viruses, the puzzles are more challenging to assemble. The virus that causes COVID-19, she said, was relatively well behaved.

Researchers looked closely at the man who had flown in from Wuhan, who has not been publicly identified and did not respond to a request to speak to The New York Times.

They confirmed he had brought a strain of the virus that was already extending broad tentacles from the Wuhan area to Guangdong on Chinas Pacific coast to Yunnan in the mountainous west. Along the way, its signature varied significantly from the version of the virus that spread in Europe and elsewhere: Its mutations were at positions 8,782, 18,060 and 28,144 on the RNA strand.

That gave Roychoudhury and the scientists around the country she has been working with the unique ability to see what the contact tracers in Seattle had been unable to: the invisible footprints of the pathogen as it moved.

On the hunt for the viruss path through the United States, one of the first signposts came on Feb. 24, when a teenager came into a clinic with what looked like the flu. The clinic was in Snohomish County, Washington, where the man who had traveled to China lived. Doctors gave the teenager a nasal swab as part of a tracking study that was already being done on influenza in the region.

Only later did they learn that the teenager had not had the flu, but the coronavirus. After the diagnosis, researchers in Seattle ran the sample through a sequencing machine. Trevor Bedford, a scientist at the Fred Hutchinson Cancer Research Institute who studies the spread and evolution of viruses, said he and a colleague sipped on beers as they waited for the results to emerge on a laptop.

It confirmed what they had feared: The case was consistent with being a direct descendant of the first U.S. case, from Wuhan.

The teenager had not been in contact with the man who had traveled to Wuhan, so far as anyone knew. He had fallen ill long after that man was no longer contagious.

Additional sequencing in the days afterward helped confirm that other cases emerging were all part of the same group. This could only mean one thing: The virus had not been contained to the traveler from Wuhan and had been spreading for weeks. Either he had somehow spread it to others, or someone else had brought in a genetically identical version of the virus.

That latter possibility has become more likely in recent days, after new cases entered into the researchers database showed an interesting pattern. A virus with a fingerprint nearly identical to the Wuhan travelers had shown up in cases in British Columbia, just across the border from Washington state, suggesting to Bedford that it might not have been the first Wuhan traveler who had unleashed the outbreak.

Either way, the number of cases emerging around the time the teenagers illness was identified indicated that the virus had been circulating for weeks.

Exposing a lot of people

On its path through Washington state, one of the viruss early stops appears to have been at a square dance on Feb. 16 in the city of Lynnwood, midway between Seattle and Everett.

It was a full month since the Wuhan travelers arrival. A couple dozen square dancers had gathered for a pie and ice cream social, capping off a series of practices and events from all over the region over the course of a three-day weekend.

Three groups of square dancers swung through promenades and allemandes huffing and sweating to Free Ride and Bad Case of Loving You.

Stephen Cole, who was the dance caller that night, said he did not recall anyone showing signs of illness. But over the next few days, he and a woman who had been cuing the dance fell ill.

Another dancer, Suzanne Jones, had attended a class with Cole the day before. By the next weekend, Jones said, she started to feel symptoms she dismissed as allergies, since she had noticed the scotch broom starting to bloom.

After resting for a couple of days, Jones felt better and drove from her home in Skagit County more than 100 miles south to visit her mother in Enumclaw, helping pack some belongings for storage. On the way back, she visited the strip malls in Renton, then a store in Everett, then a laundromat in Arlington. She stopped to apply for a job with the Census Bureau.

I probably exposed a lot of people that day, she said.

Jones only realized it could be something more than allergies after getting a notification on March 2 that one of her square-dancing friends had died of the coronavirus as the outbreak began to emerge. She too tested positive.

There was minimal coronavirus testing in the United States during February, leaving researchers largely blind to the specific locations and mutations of the spread that month. The man who had traveled from Wuhan was not at the dance, nor was anyone else known to have traveled into the country with the coronavirus. But researchers learned that the virus by then was already spreading well beyond its point of origin and all the cases of community transmission that month were part of that same genetic branch.

There was another spreading event. On the Saturday after the dance, a group of friends packed the living room of a one-bedroom apartment in Seattle, sharing homemade food and tropical-themed drinks.

Over the following days, several people began coming down with coronavirus symptoms. Among people who attended, 4 out of every 10 got sick, said Hanna Oltean, an epidemiologist with the Washington State Department of Health.

Several people passed on the virus to others. By late March, the state health department had documented at least three generations of transmission occurring before anyone was symptomatic, Oltean said.

By then, it was becoming clear that there were probably hundreds of cases already linked to the first point of infection that had been spreading undetected. It left a lingering question: If the virus had this much of a head start, how far had it gone?

As cases of the virus spread, scientists in other states were sequencing as many as they could. In a lab at the University of California, San Francisco, Dr. Charles Chiu looked at a range of cases in the Bay Area, including nine passengers from the Grand Princess cruise ship, which had recently returned from a pair of ill-fated sailings to Mexico and Hawaii that left dozens of passengers infected with the coronavirus.

Chiu was stunned by his results: Five cases in the San Francisco area whose origins were unknown were linked back to the Washington state cluster. And all nine of the Grand Princess cases had a similar genetic link, with the same trademark mutations plus a few new ones. The massive outbreak on the ship, Chiu believed, could probably be traced to a single person who had developed an infection linked to the Washington state cluster.

But it did not stop with the Grand Princess. David Shaffer, who had been on the first leg of the cruise with members of his family, said passengers on that leg did not discover until after they disembarked that the coronavirus had been aboard when they learned that a fellow passenger had died.

He and his family felt fine when they returned to their home in Sacramento, California, he said, and when he started feeling sick the next day, on Feb. 22, he at first assumed it was a sinus infection.

Days later, he was tested and learned he had the coronavirus. His wife later tested positive, too, as did one of his sons and one of his grandsons, who had not been on the cruise.

Chiu remembers going over the implications in his head. If its in California and its in Washington state, its very likely in other states.

The same day Shaffer got sick, another person landed at Raleigh-Durham International Airport in North Carolina, having just visited the Life Care Center nursing home in Kirkland, which would become a center of infection. At the time, there were growing signs of a respiratory illness at the facility, but no indication of the coronavirus.

A few days later, the traveler began feeling ill, but with no sign that it might be anything serious, he went out for dinner at a restaurant in Raleigh. Just then, officials in Washington state began to report a coronavirus outbreak at Life Care Center. The person in North Carolina tested positive a few days later the first case in the state.

By the middle of March, a team at Yale gathered nine coronavirus samples from the Connecticut region and put them through a portable sequencing machine. Seven came back with connections to Washington state.

I was pretty surprised, said Joseph Fauver, one of the researchers at the lab. At the time, he said, it suggested that the virus had been spreading more than people had initially believed.

In sequencing more recent cases, the researchers have found cases emanating from a larger cluster, with its own distinct genetic signature, originating in the New York area.

A group of cases throughout the Midwest, first surfacing in early March, appears to have roots in Europe. A group of cases in the South, which emerged around the same time, on March 3, appears like a more direct descendant from China.

But of all the branches that researchers have found, the strain from Washington state remains the earliest and one of the most potent.

It has surfaced in Arizona, California, Connecticut, the District of Columbia, Florida, Illinois, Michigan, Minnesota, New York, North Carolina, Oregon, Utah, Virginia, Wisconsin and Wyoming, and in six countries.

And new cases are still surfacing.

One of the enduring mysteries has been just how the virus managed to gain its first, fatal foothold in Washington.

Did the contact tracers who followed the steps of the man who had traveled from Wuhan miss something? Did he expose someone at the grocery store, or touch a door handle when he went to the restaurant near his office?

In recent days, the sequencing of new cases has revealed a surprising new possibility. A series of cases in British Columbia carried a genetic footprint very similar to the case of the Wuhan traveler. That opened up the possibility that someone could have carried that same branch of the virus from Wuhan to British Columbia or somewhere else in the region at nearly the same time. Perhaps it was that person whose illness had sparked the fateful outbreak.

But who? And how? That would probably never be known.

Read more from the original source:
A coronavirus strain from Washington state was one of the earliest and most potent found and it's in Utah - Salt Lake Tribune

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Childhood Psychopathology Linked to Higher Levels of Genetic Vulnerability of Adult Depression – Clinical OMICs News

Thursday, April 23rd, 2020

Emotional, social, and psychiatric problems in children and adolescents have been linked to higher levels of genetic vulnerability for adult depression, according to University of Queensland scientists. They made the finding Genetic Associations Between Childhood Psychopathology and Adult Depression and Associated Traits in 42998 Individuals: A Meta-Analysis, which appears inJAMA Psychiatry, while analyzing the genetic data of more than 42,000 children and adolescents from seven cohorts across five European countries.

Christel Middeldorp, MD, PhD, a child and adolescent psychiatrist at the Child Health Research Centre at the University of Queensland, said that researchers have also found a link with a higher genetic vulnerability for insomnia, neuroticism, and body mass index.

By contrast, study participants with higher genetic scores for educational attainment and emotional wellbeing were found to have reduced childhood problems, she pointed out.

We calculated a persons level of genetic vulnerability by adding up the number of risk genes they had for a specific disorder or trait, and then made adjustments based on the level of importance of each gene. We found the relationship was mostly similar across ages.

Adult mood disorders are often preceded by behavioral and emotional problems in childhood. It is yet unclear what explains the associations between childhood psychopathology and adult traits. To investigate whether genetic risk for adult mood disorders and associated traits is associated with childhood disorders, write the investigators.

This meta-analysis examined data from 7 ongoing longitudinal birth and childhood cohorts from the U.K., the Netherlands, Sweden, Norway, and Finland. Starting points of data collection ranged from July 1985 to April 2002. Participants were repeatedly assessed for childhood psychopathology from ages 6 to 17 years. Data analysis occurred from September 2017 to May 2019.

Individual polygenic scores (PGS) were constructed in children based on genome-wide association studies of adult major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI).

Results from this study suggest the existence of a set of genetic factors influencing a range of traits across the life span with stable associations present throughout childhood. Knowledge of underlying mechanisms may affect treatment and long-term outcomes of individuals with psychopathology.

The results indicate there are shared genetic factors that affect a range of psychiatric and related traits across a persons lifespan. Around 50 percent of children and adolescents with psychiatric problems, such as attention deficit hyper-activity disorder (ADHD), continue to experience mental disorders as adults, and are at risk of disengaging with their school community among other social and emotional problems, added Middeldorp.

Our findings are important as they suggest this continuity between childhood and adult traits is partly explained by genetic risk, she continued. Individuals at risk of being affected should be the focus of attention and targeted treatment. Although genetic vulnerability is not accurate enough at this stage to make individual predictions about how a persons symptoms will develop over time, it may become so in the future, in combination with other risk factors.

Middeldorp believes that this study and others may support precision medicine by providing targeted treatments to children at the highest risk of persistent emotional and social problems.

See the original post here:
Childhood Psychopathology Linked to Higher Levels of Genetic Vulnerability of Adult Depression - Clinical OMICs News

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