StemCell Therapy

Huntsville Hospital and Kailos Genetics are teaming up to offer COVID-19 testing for businesses. Basically, all they have to do is sign up and get tested.

Troy Moore with Kailos Genetics said they're making it easy for businesses to reduce outbreaks in an office.

"The Huntsville hospital staff comes on sight and they perform the collection, and then, they bring the samples back to Kailoss lab over at HudsonAlpha," said Moore.

Businesses can sign up for weekly sentinel testing. Kailos Genetics created a viral wash as a less invasive way to get tested for COVID-19. You will get the results back within four days.

The CEO of Huntsville Hospital, David Spillers, said testing for the virus is vital.

If anything, I think testing has become more important going forward than it has been in the past, particularly with these new strains," he said.

The testing Kailos Genetics uses is able to detect both the COVID-19 we've been seeing and the new variants. Moore said consistent testing is key to reducing COVID-19 in a workplace.

What were looking for is to identify those that are carrying the virus, or have been exposed but arent showing symptoms yet, take them back out before they spread it to others, or catch those people that have been exposed very early so they dont, you know, obviously dont spread it to more," Moore said.

Moore said they will discuss with the businesses how frequently they should do sentinel testing based on individual risk factors.

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Huntsville Hospital, Kailos Genetics work to prevent coronavirus outbreaks in the workplace - WAAY

New York, Jan. 26, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Animal Genetics Market Forecast to 2027 - COVID-19 Impact and Global Analysis By Product, Genetic Material, and Services and Geography." - https://www.reportlinker.com/p06010023/?utm_source=GNW However, the market is likely to get impacted by the limited number of skilled professionals in veterinary research and stringent government regulations for animal genetics during the forecast period.

The branch of genetics that deals with the study of gene variation and inheritance in companion, domestic and wild animals is called as animal genetics.Animal genetics are used for genetic trait testing, DNA testing, and genetic disease treatment.

Animal genetics is one of the best mainstays of livestock development (alongside animal nutrition, animal health, and husbandry concerns such as housing). According to the Food and Agriculture Organization of the United Nations, it is a wide field, ranging from characterization to maintenance to genetic improvement, and involves activities at local, national, regional, and global scales.Increasing population and rapid urbanization across the world has resulted in growing preference for animal derived food products such as dairy products and meat that contain high protein.The demand for animal derived proteins and food products, which, in turn drives the growth of animal genetics market.

Growing focus on developing superior animal breeds using genetic engineering to obtain high reproduction rates for large-scale production of modified breeds is expected to drive animal genetics market during the forecast period.Based on product, the market is segmented into poultry, porcine, bovine, canine, and others.The porcine segment held the largest share of the market in 2019, whereas the same segment is anticipated to register the highest CAGR in the market during the forecast period.

Growth of this segment is attributed to rise in production of porcine and increase in pork consumption across the globe.Based on genetic material, the market is segmented into semen and embryo. The embryo segment held the largest share of the market in 2019, and the semen segment is anticipated to register the highest CAGR in the market during the forecast period.COVID-19 pandemic has become the most significant challenge across the world.This challenge would be frightening, especially in developing countries across the globe, as it may lead to reducing imports due to disruptions in global trade, which further increases the shortages of meat and dairy product supplies, resulting in a considerable price increase.

Asian countries such as China, South Korea, and India are severely affected due to COVID-19 outbreak.The World Health Organization, Food and Drug Administration, American Pet Products Association, American Veterinary Medical Cattle Health, and Welfare Group for Disease Control and Prevention are among the major primary and secondary sources referred for preparing this report.Read the full report: https://www.reportlinker.com/p06010023/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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Animal Genetics Market Forecast to 2027 - COVID-19 Impact and Global Analysis By Product, Genetic Material, and Services and Geography. -...

Fiona the hippopotamus could play a major role in her species' rebound. The world-famous hippo, who turns 4 this week at the Cincinnati Zoo, has genetics that are pretty valuable, her zookeepers said. She could play a critical role in bringing back a threatened species. Hippos are listed as a vulnerable, meaning they face a high risk of extinction in the wild. Officially, threatened species are those listed as critically endangered, endangered or vulnerable. Hippos are listed as vulnerable due to widespread poaching for meat and ivory, as well as human encroachment. It is the eventual goal to have Fiona breed in an effort to increase her species' numbers, but the timeline on when she will be able to breed remains murky.We anticipate that she will not be sexually mature until about 5 or 6 years old maybe even later than that because Fiona was a preemie, said Wendy Rice, head keeper of Africa Department at Cincinnati Zoo.Fiona was thrust into the spotlight due to her remarkable survival story. Born six weeks premature at the Cincinnati Zoo on Jan. 24, 2017, Fiona weighed only 29 pounds at birth 25 pounds less than the lowest recorded birth weight for her species. But she has rebounded from near-death, now weighing a whopping 1,600 pounds, consistent with a normal hippo her age. Fiona has a long way to go until shes considered full grown. But shes on track and making gains every day, Rice said.Already, Cincinnati's once-baby hippo has reached a certain level of maturity. And, when she's ready, Fiona will likely attempt to breed.Her fate and her love interest will likely be determined by the Hippo Species Survival Plan, a cooperation of all zoos across the United States that house hippos and breed them. The group shares information about captive populations in order to maintain genetic diversity.With Fiona being Henrys only living offspring, her genetics are fairly valuable in that theyre not well represented in the population that we have," Rice said. "Its very likely that she will get a recommendation to breed someday.So what happens then? It's highly unlikely that Fiona would move away from Cincinnati, Rice said. Instead, expect a male suitor to arrive in the Queen City.If and when she gets a recommendation for a breeding partner, theres a really good chance that the boy would have to come to Cincinnati. We do not want to have our princess leave Cincinnati, and the whole city would probably riot if she moved away.But we're still talking at least a year -- probably more -- down the road. In the meantime, Fiona will focus on growing. Right now, Rice said Fiona is probably the human equivalent of a pre-teen girl. She's growing out of her sassy phase and becoming more and more independent of her mother. In the past, wherever Bibi was, thats where Fiona was. Just this past year, shes gotten a little bit braver and bolder. Shes also starting to read boundaries a little bit better with mom. She was pushing the envelope, trying to see what she could get away with. But shes kind of settled down a bit and matured, and she can now read mama really well, Rice said. Even as the hippo matures, Rice said her personality is here to stay.Shes still full of personality and shell still come out here and put a show on for her guests," Rice said." Shell come right up to the glass and make eye contact with people. She understands that theyre here for her and that shes kind of a big deal. I think she appreciates her fandom and tries to give them the best experience possible.

Fiona the hippopotamus could play a major role in her species' rebound.

The world-famous hippo, who turns 4 this week at the Cincinnati Zoo, has genetics that are pretty valuable, her zookeepers said. She could play a critical role in bringing back a threatened species.

Hippos are listed as a vulnerable, meaning they face a high risk of extinction in the wild. Officially, threatened species are those listed as critically endangered, endangered or vulnerable. Hippos are listed as vulnerable due to widespread poaching for meat and ivory, as well as human encroachment.

It is the eventual goal to have Fiona breed in an effort to increase her species' numbers, but the timeline on when she will be able to breed remains murky.

We anticipate that she will not be sexually mature until about 5 or 6 years old maybe even later than that because Fiona was a preemie, said Wendy Rice, head keeper of Africa Department at Cincinnati Zoo.

Fiona was thrust into the spotlight due to her remarkable survival story. Born six weeks premature at the Cincinnati Zoo on Jan. 24, 2017, Fiona weighed only 29 pounds at birth 25 pounds less than the lowest recorded birth weight for her species.

But she has rebounded from near-death, now weighing a whopping 1,600 pounds, consistent with a normal hippo her age.

Fiona has a long way to go until shes considered full grown. But shes on track and making gains every day, Rice said.

Already, Cincinnati's once-baby hippo has reached a certain level of maturity. And, when she's ready, Fiona will likely attempt to breed.

Her fate and her love interest will likely be determined by the Hippo Species Survival Plan, a cooperation of all zoos across the United States that house hippos and breed them. The group shares information about captive populations in order to maintain genetic diversity.

With Fiona being Henrys only living offspring, her genetics are fairly valuable in that theyre not well represented in the population that we have," Rice said. "Its very likely that she will get a recommendation to breed someday.

So what happens then? It's highly unlikely that Fiona would move away from Cincinnati, Rice said. Instead, expect a male suitor to arrive in the Queen City.

If and when she gets a recommendation for a breeding partner, theres a really good chance that the boy would have to come to Cincinnati. We do not want to have our princess leave Cincinnati, and the whole city would probably riot if she moved away.

But we're still talking at least a year -- probably more -- down the road. In the meantime, Fiona will focus on growing.

Right now, Rice said Fiona is probably the human equivalent of a pre-teen girl. She's growing out of her sassy phase and becoming more and more independent of her mother.

In the past, wherever Bibi was, thats where Fiona was. Just this past year, shes gotten a little bit braver and bolder. Shes also starting to read boundaries a little bit better with mom. She was pushing the envelope, trying to see what she could get away with. But shes kind of settled down a bit and matured, and she can now read mama really well, Rice said.

Even as the hippo matures, Rice said her personality is here to stay.

Shes still full of personality and shell still come out here and put a show on for her guests," Rice said." Shell come right up to the glass and make eye contact with people. She understands that theyre here for her and that shes kind of a big deal. I think she appreciates her fandom and tries to give them the best experience possible.

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Fionas genetics are hugely valuable in species rebound - WLWT Cincinnati

MOUNTAIN VIEW, Calif., Jan. 26, 2021 /PRNewswire/ --Digbi Health, the first company with a clinically proven genetics and gut-microbiome based program to safely and sustainably treat and manage obesity and associated inflammatory gut, skin and cardiometabolic health issues, is now available to Blue Shield of California members, as a fully covered program, on the health plan'sWellvolution platform.

It's the first time over 60,000 physicians and clinicians practicing in California in the Blue Shield of California's network can prescribe a weight-loss program personalized on a person's genetic, gut microbiome and lifestyle. Through the Digbi Health solution, patients are supported by a team of caregivers, led by a physician and care experts trained in nutrition, cognitive behavior therapy, genetics and gut microbiome. Blue Shield of California offers access to Digbi Health through the Wellvolution platform as a fully covered program to members who qualify.

The Digbi Health Precision Care Network (PCN) is a network of physicians practicing precision medicine. As part of that network, physicians get marketing resources to educate their patients about Digbi Health on the Wellvoution platform, access to their patient's dashboard, with patient approval, and additional support from the Digbi Health care concierge team to support their patients between visits to help improve patient outcomes. Digbi Health program members without a physician can also get referred to a specialist in the PCN.

"The development of cardiovascular disease is a matter of genetic predisposition and gut microbiome composition interacting with acquired conditions, and factors such as diet, exercise, and exposure to damaging elements," said Cynthia Thaik, MD. Harvard-trained cardiologist at the Holistic Healing Heart Center and Digbi Health PCN member.

"I have already prescribed Digbi Health to a patient covered by Blue Shield of California for pre-diabetes and hypertension," she added.

Blue Shield of California is taking the lead on personalized and preventive care for their members.

Among participants participating in Wellvolution:

"We are an innovative telehealth company that supports overburdened physicians by redefining care for 100 million Americans who struggle under one-size-fits-all digital health programs, weight loss diets and stigma of "poor self-control" while fighting obesity and associated inflammatory comorbidities," said Ranjan Sinha, CEO and founder of Digbi Health.

About Digbi Health Precision Care NetworkOur network includes healthcare providers from all specialties and practice settings throughout the U.S., including bariatric surgeons, internal medicine, family medicine, chiropractitioners, nutritional experts, and others in the lifestyle and integrative medicine space using genetics, nutrigenomics, gut microbiome and lifestyle risk to treat the complexity of the multifactorial disease of obesity and its' related medical conditions. Providers can sign-up to the network at no charge here.

About Digbi HealthDigbi Health is a first-of-its-kind precision digital therapeutics company that offers a prescription-grade digitally enabled personalized obesity and obesity related gut, skin disorders, hypertension and other cardiometabolic health management programs based on an individual's gut biome, genetic risks, blood markers, and lifestyle factors. Digbi Health and members of its physician network are committed to empowering people to take control of their own health and wellness. Digbi Health is prescribed by doctors, health care providers, and insurance companies.

SOURCE Digbi Health

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Digbi Health's gut-microbiome and genetic-based obesity management program now allows 60,000 Doctors and Providers in Blue Shield of California's...

A team of researchers from the University of Maine Darling Marine Center in Walpole, Bigelow Laboratory for Ocean Sciences in East Boothbay and Maine Department of Marine Resources in West Boothbay Harbor recently published their research on the effects of ocean warming and acidification on gene expression in the earliest life stages of the American lobster.

The work was published in the scientific journal Ecology and Evolution with collaborators from the University of Prince Edward Island and Dalhousie University in Canada.

Leading the study was recent UMaine graduate student Maura Niemisto, who received her masters degree in marine science. Co-authors on the journal article were her advisers Richard Wahle, research professor in UMaines School of Marine Sciences and director of the Lobster Institute, and David Fields, senior research scientist at Bigelow Laboratory for Ocean Sciences.

Co-authors Spencer Greenwood of the University of Prince Edward Island and Fraser Clark of Dalhousie University brought the genetic expertise to the study. Jesica Waller of the Maine Department of Marine Resources conducted some of the initial studies that led to Niemistos experiments, also in the laboratories of Wahle and Fields.

The teams experiments examined the gene regulatory response of postlarval lobsters to the separate and combined effects of warming and acidification anticipated by the end of the 21st century. They found that genes regulating a range of physiological functions, from those controlling shell formation to the immune response, are either up- or down-regulated. Importantly, they observed that the two stressors combined induced a greater gene regulatory response than either stressor alone.

The results from the study indicate that changes in gene expression of postlarval lobster may act as a mechanism to accommodate rapid changes in the ocean environment. Niemisto noted that there is still need for further study to determine how rapidly populations of the species may be able to adapt to changing conditions. To better understand how gene regulation in response to environmental changes functions within the species, we should look at subpopulations and multigenerational studies to determine the extent of species capacity to respond to altered environmental conditions.

Mauras study reveals some of the hidden mechanisms species employ minute to minute and hour to hour at the cellular level to function normally in a variable environment, said Wahle. We need to gain these insights as we take on the larger challenge of understanding how species adapt on the much larger time scale of decades.

According to the National Marine Fisheries Service, the American lobster fishery is the most valuable in North America. The species holds particular socioeconomic importance in the Gulf of Maine, where sea surface temperatures are increasing at a rate faster than most of the worlds oceans and waters are more susceptible to higher rates of acidification.

The center of the American lobster range has been shifting northward in response to warming ocean temperatures. However, little is known about how the species will respond to the combined effects of increasing ocean temperatures and acidification. This study is a first step in answering that question. The species earliest life stages are thought to be especially vulnerable to these climate related challenges.

The research was supported by a grant from the NOAAs Ocean Acidification Program and the National Sea Grant Program. Additional funding for student internships came from Bigelow Laboratorys Research Experience for Undergraduates program, supported by the National Science Foundation.

Contact: Matt Norwood, matthew.norwood@maine.edu; 207.563.8220

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Research reveals genetic response of ocean warming and acidification in American lobster - UMaine News - University of Maine - University of Maine

LARGO There are roughly up to 500 boys in the world and only boys who suffer from NEMO deficiency syndrome, a rare genetic illness that affects the nervous system and leave one susceptible to infections.

Peyton Kudrnovsky and his brother Trevor are among them. Two weeks ago, 15-year-old Peyton lost his Golden Retriever Axl Rose, who had been a part of the family for 12 years. Axl always sat by Peytons side during his infusions.

Then on Saturday, his family brought home a new four-legged member of the family: Toby.

Toby is a Huskypoo a mix between a Siberian Husky and a poodle donated to the 15-year-old by the Petland Largo store.

Petland Largo manager Miranda Schimenek said they decided to donate Toby after they learned about Peytons story and the loss of Axl. The store at 10289 Ulmerton Road will also provide veterinary care and training for Toby, according to a press release.

The loss of Axl was particularly hard for Peyton, said his mother Tatiana Lee. Axl had been there every step of the way through the 15-year-olds medical treatments, she said. Axl was given to Peyton by his stepfather, Kyle Resler. But the stepfather died two years ago from cancer.

Over two years ago, we lost a loved one to terminal cancer, the mother said in a statement. Peyton had formed a very close bond with him. He was Peytons support system through the illness and we all miss Kyle very much.

They also miss Axl, who helped the family after they lost their stepfather.

He was there for us through the loss of my sons stepdad, Kyle, and would sit by Peyton as he had his infusions each week he was our rock, and we know he is looking down on us, she said. Toby will be an incredible addition to our family and I cannot thank Petland enough for their incredibly gracious gesture.

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Huskypoo puppy donated to teen with rare genetic disorder - Tampa Bay Times

Abstract

Genetic diversity and phylogenetic diversity reflect the evolutionary potential and history of species, respectively. However, the levels and spatial patterns of genetic and phylogenetic diversity of wildlife at the regional scale have largely remained unclear. Here, we performed meta-analyses of genetic diversity in Chinese terrestrial vertebrates based on three genetic markers and investigated their phylogenetic diversity based on a dated phylogenetic tree of 2461 species. We detected strong positive spatial correlations among mitochondrial DNA-based genetic diversity, phylogenetic diversity, and species richness. Moreover, the terrestrial vertebrates harbored higher genetic and phylogenetic diversity in South China and Southwest China than in other regions. Last, climatic factors (precipitation and temperature) had significant positive effects while altitude and human population density had significant negative impacts on levels of mitochondrial DNA-based genetic diversity in most cases. Our findings will help guide national-level genetic diversity conservation plans and a post-2020 biodiversity conservation framework.

Biodiversity loss and conservation are among the most concerning global issues. The Convention on Biological Diversity (CBD) was established to develop national strategies for the conservation and sustainable use of biological diversity. An endangerment status assessment of worldwide vertebrates showed that approximately 20% of vertebrates have become threatened (1). In China, the situation is even worse: 21.4% of vertebrates are threatened, including 43.1% of amphibians, 29.7% of reptiles, 26.4% of mammals, 20.4% of fishes, and 10.6% of birds (2). Thus, it is urgent to protect biodiversity regionally and globally. As the most fundamental dimension of biodiversity, genetic diversity is a key basis for species survival and ecosystem functions (3). Higher genetic diversity means higher evolutionary potential and a greater ability to respond to environmental changes (4). An increasing number of studies have shown that genetic factors play a critical role in species endangerment and extinction (57). Thus, assessment and protection of genetic diversity are becoming essential and high-priority strategies for biodiversity conservation (4). However, under the current CBD framework, the goal proposed for genetic diversity focuses mainly on the conservation of farmed and domestic animals and cultivated plants and neglects that of wild animals and plants, which would overlook genetic erosion and harm the evolutionary potential of wildlife (8). Therefore, to better conserve the genetic diversity of wildlife, it is necessary to assess genetic diversity at regional and global scales for use in the scientific designs of natural protected areas and biodiversity conservation strategies. Miraldo et al. (9) presented the first global distribution of genetic diversity for mammals and amphibians using mitochondrial cytochrome b (Cytb) and cytochrome oxidase subunit I (Co1) gene sequences. However, the grid cell size (~150,000 km2) that they used was so large that it was difficult to determine the national- or regional-level pattern of genetic diversity in detail, including in China.

Phylogenetic diversity is the sum of phylogenetic branch lengths for all of the species in an area (10). Phylogenetic diversity measures the time scale of species evolution and reflects the evolutionary history of species (11), which contributes to the selection of biodiversity conservation priority areas (1214). Higher phylogenetic diversity excluding the effect of taxonomic richness indicates a higher proportion of distantly related and anciently diverged taxa (11, 15). Previous studies have shown that regions with higher phylogenetic diversity may not necessarily have higher species diversity, which would result in neglecting the conservation of the regions (11, 16). In this case, the conservation of older evolutionary lineages might be neglected. Thus, monitoring the level and spatial distribution of phylogenetic diversity is also important for effective conservation of biodiversity.

China is one of the countries with the richest biodiversity in the world, harboring more than 3000 terrestrial vertebrates (2). In recent years, with the development of molecular genetics, genetic diversity of many species has been assessed and numerous DNA sequences have been accumulated. In this study, we focus on the patterns of genetic and phylogenetic diversity in Chinese terrestrial vertebrates, using meta-analyses of a large published dataset and a robust dated phylogenetic tree as well as species distribution. We aim to (i) reveal whether positive spatial correlation existed among species richness, genetic diversity, and phylogenetic diversity; (ii) identify hotspot regions of high genetic diversity and high phylogenetic diversity; and (iii) explore the influences of abiotic (precipitation, temperature, and altitude) and biotic (human population) factors on the levels of genetic and phylogenetic diversity. We found that, on the whole, species richness predicted phylogenetic diversity and mitochondrial DNA-based genetic diversity in a positive direction, and higher phylogenetic diversity predicted higher genetic diversity. We identified that the terrestrial vertebrates in South China and Southwest China harbored higher genetic and phylogenetic diversity than in other regions, and central South China was identified as an evolutionary museum, while the Hengduan Mountains was identified as an evolutionary cradle. We also revealed that both mean annual precipitation and temperature had significant positive effects, while altitude and human population density had significant negative impacts on levels of mitochondrial DNA-based genetic diversity in most cases. Our findings provide insights into the spatial patterns and influencing factors of genetic and phylogenetic diversity at a regional scale.

We surveyed the population-level genetic diversity data of Chinese terrestrial vertebrates (mammals, birds, reptiles, and amphibians) based on three molecular markers (mitochondrial Cytb gene sequence, mitochondrial D-loop sequence, and nuclear microsatellites). A total of 287 terrestrial vertebrate species (103 mammals, 59 birds, 31 reptiles, and 94 amphibians) were assessed for population-level genetic diversity with at least one molecular marker, accounting for 9.3% of the 3075 terrestrial vertebrates distributed in China (figs. S1 to S4 and tables S1 to S9). Two unbiased genetic diversity indices, nucleotide diversity () for the Cytb and D-loop sequences and expected heterozygosity (HE) for microsatellite, were used as measures of population-level genetic diversity. In this study, the Cytb-, D-loop, and microsatellite-based genetic diversity measures were analyzed separately (tables S1 to S9). Furthermore, the species-level genetic diversity for three genetic markers was obtained by averaging the population-level genetic diversity values (tables S10 to S12).

The species-level phylogenetic diversity of Chinese terrestrial vertebrates was surveyed on the basis of the coding sequences of five mitochondrial genes (Cytb, Co1, Nd1, 12S rRNA, and 16S rRNA). A total of 2461 terrestrial vertebrates were assessed for phylogenetic diversity with at least one available mitochondrial gene sequence, accounting for 80% of the Chinese terrestrial vertebrates (figs. S5 to S7 and table S13). On the basis of a constructed maximum likelihood phylogenetic tree and 391 available divergence times from the TimeTree database (table S14), we estimated the divergence times of these vertebrates. The results showed that the amphibians first diverged from the fishes and then the reptiles evolved from the amphibians. Both the mammals and birds evolved from the reptiles, with the mammals diverging first. These results are consistent with the general conclusion about the divergence order of the terrestrial groups (17). In this study, we used divergence time as the measure of phylogenetic diversity for further analysis.

We first divided the map of China into 0.5 0.5 (~50 km by 55 km) grid cells and then calculated the species richness, genetic diversity, and phylogenetic diversity within each grid cell. The spatial correlation tests showed that the genetic diversity measures based on mitochondrial Cytb and D-loop sequences were significantly correlated [correlation coefficient (r) = 0.385, P = 0.012]. However, no significant correlation was observed for Cytb versus microsatellites (r = 0.128, P = 0.475) and for D-loop versus microsatellites (r = 0.084, P = 0.463) (fig. S8 and table S15). The inconsistencies in spatial correlations among the three genetic markers were most likely due to different measure rationales (nucleotide diversity versus expected heterozygosity) and evolutionary rates (slowly versus rapidly evolving). The differences in correlation among the different markers were similar to that of Miraldo et al. (9).

The tests for spatial correlations between genetic diversity and species richness revealed a significant positive correlation for Cytb genetic diversity (r = 0.728, P = 0.008), and a marginally significant correlation for D-loop genetic diversity (r = 0.320, P = 0.072) (Fig. 1, A and B). These results were consistent with those of global terrestrial mammals (18) and global marine and freshwater fishes (19). However, a nonsignificant correlation for microsatellite genetic diversity (r = 0.138, P = 0.499) was detected (Fig. 1C and table S15), which was similar to AFLP marker-based genetic diversity assessment of alpine plant communities (20). The differences in correlation showed that the widely discussed correlation relationship between genetic and species diversity was genetic marker dependent.

(A to C) Correlation tests between species richness (SR) and Cytb-, D-loop, and microsatellite-based genetic diversity (GD). (D) Correlation test between SR and phylogenetic diversity (PD). (E to G) Correlation tests between PD and Cytb-, D-loop, and microsatellite-based GD.

The tests for spatial correlations between genetic diversity and phylogenetic diversity showed a significant positive correlation for Cytb (r = 0.722, P = 0.013) and a marginally significant positive correlation for D-loop (r = 0.306, P = 0.089) (Fig. 1, E and F). The results were similar to those of global terrestrial mammals (18). However, the correlation was not significant for microsatellites (r = 0.123, P = 0.566) (Fig. 1G and table S15). In addition, we selected a set of abundant terrestrial vertebrate species with a threatened status rank of LC (Least-Concern) (table S16) and tested the spatial correlations between genetic and phylogenetic diversity. The results were similar to those for all the terrestrial vertebrates (table S17).

A significant positive correlation was detected between phylogenetic diversity and species richness (r = 0.99, P < 0.001) (Fig. 1D and table S15), implying that the regions with high species richness often had high phylogenetic diversity. The significant positive correlation pattern between phylogenetic diversity and species richness may be common, as shown in different large-scale analyses focusing on birds, mammals, and angiosperms (16, 18, 21).

It is generally accepted that Chinas zoogeographical regionalization is divided into the Palaearctic and Oriental realms, including seven zoogeographical regions (22, 23). The Palaearctic realm includes the Northeast China, North China, Inner Mongolia-Xinjiang, and Qinghai-Tibet Plateau regions, while the Oriental realm consists of the Southwest China, Central China, and South China regions. We mapped the genetic diversity data onto the zoogeographical region map of China using a grid size of 0.5 0.5. Overall, the terrestrial vertebrates distributed in the Oriental realm had higher genetic diversity than those in the Palaearctic realm for all three markers (Fig. 2, A to C; fig. S9; and table S18). In the case of zoogeographical regions, the vertebrates in South China harbored the highest genetic diversity for Cytb and microsatellites, suggesting a hotspot region of genetic diversity, whereas those in North China had the lowest genetic diversity for D-loop and microsatellites (table S18). In addition, the Southwest China and west Central China harbored relatively high genetic diversity. The spatial pattern of species richness across the Palaearctic and Oriental realms was similar to that of genetic diversity (Fig. 2D). However, within the zoogeographical regions, the spatial patterns of species richness were somewhat different from those of genetic diversity. The South China region had the highest species richness, whereas the Qinghai-Tibet Plateau and Inner Mongolia-Xinjiang regions harbored the lowest species richness (Fig. 2D). These results suggest that regions with low species richness do not necessarily have low genetic diversity, such as the Qinghai-Tibet Plateau, which should be given more conservation attention. To determine the possible effects of different sample sizes of the grid cells, we examined the frequency distribution of the proportion of species with surveyed genetic diversity data in the grid cells based on the classification of seven zoogeographical regions and found similar frequency distributions on the whole across the seven regions (figs. S10 to S12).

Northeast China (NE), North China (NC), Inner Mongolia-Xinjiang (IX), Qinghai-Tibet Plateau (QT), Southwest China (SW), Central China (CC), and South China (SC). The red line indicates the boundary between the Palaearctic and Oriental realms. (A and B) Spatial patterns of Cytb- and D-loopbased GDs. measured by nucleotide diversity. (C) Spatial pattern of microsatellite-based GD measured by expected heterozygosity. (D) Spatial pattern of SR measured by number of species.

The province-level distributions of genetic diversity based on the three markers demonstrated similar patterns on the whole (figs. S13 and S14). The terrestrial vertebrates distributed in Yunnan, Guangxi, Sichuan, and Guizhou provinces harbored the highest genetic diversity. In contrast, the terrestrial vertebrates distributed in Shanxi, Shandong, Hebei, Liaoning, Jilin, Heilongjiang, and part of Xinjiang had lower genetic diversity. The terrestrial vertebrates in Qinghai and Tibet had intermediate genetic diversity. These results could help guide province-level conservation plans for genetic diversity.

The terrestrial vertebrates in the Oriental realm had significantly higher phylogenetic diversity (PD = 10,390.25 2029.43) than those in the Palaearctic realm (PD = 4942.60 1402.09) (Fig. 3, A and B). The terrestrial vertebrates in South China harbored the highest phylogenetic diversity (PD = 12,327.46 2111.27), and those in Central China and Southwest China had the second highest phylogenetic diversity. The terrestrial vertebrates on the Qinghai-Tibet Plateau had the lowest phylogenetic diversity (PD = 3936.66 1162.35) (Fig. 3B and table S18). The province-level distribution of phylogenetic diversity showed a clear pattern, in which the terrestrial vertebrates in south China had notably higher phylogenetic diversity than those in north China (fig. S15). Specifically, the vertebrates in Yunnan and Guangxi provinces had the highest phylogenetic diversity, and those in Tibet, Xinjiang, and Qinghai had the lowest phylogenetic diversity (fig. S15). These results could help guide province-level conservation plans for phylogenetic diversity.

(A) A dated phylogenetic tree of Chinese terrestrial vertebrates based on five mitochondrial genes (Cytb, Co1, Nd1, 12S rRNA, and 16S rRNA). Ma, million years. (B) Spatial pattern of PD measured by species divergence time. The red line indicates the boundary between the Palaearctic and Oriental realms. (C) Areas with significantly higher or lower PD after controlling for the confounding effect of SR. The red line indicates the boundary between the Palaearctic and Oriental realms.

As shown by the correlation analysis above, the phylogenetic diversity pattern was highly correlated with the species richness pattern (Fig. 1D). To control for the confounding effect of species richness, we detected areas with significantly higher or lower phylogenetic diversity than expected using a randomization method. The result showed that significantly higher phylogenetic diversity occurred in the central South China region, mainly including Hainan and Guangxi provinces, suggesting that these areas harbored many older terrestrial vertebrate lineages, serving as an evolutionary museum (Fig. 3C and fig. S16) (9). This result is similar to that for the phylogenetic diversity of genus-level angiosperms in China, in which the top 5% highest phylogenetic diversity and standard effective size of phylogenetic diversity were mainly located in Guangdong, Guangxi, Guizhou, and Hainan provinces (15). These results suggested that the above areas are phylogenetic diversity hotspots not only for terrestrial vertebrates but also for angiosperms in China, which deserve more conservation efforts. In contrast, significantly lower phylogenetic diversity occurred in the Southwest China region, i.e., the Hengduan Mountains, suggesting that these areas were the centers of recent speciation events and thus contained many younger lineages, serving as an evolutionary cradle (Fig. 3C and fig. S16) (15, 24). This divergence pattern is similar to that of a study on global terrestrial birds (16).

The above correlation results showed that the mitochondrial DNA-based genetic diversity was strongly correlated with species richness. Therefore, to reveal the effects of abiotic and biotic factors on genetic diversity, we performed the semi-part spatially explicit generalized linear mixed modeling (spaGLMM) analysis by regressing genetic diversity against species richness and then using the residuals of models to evaluate the effects of abiotic (mean annual precipitation, mean annual temperature, and altitude) and biotic (human population density) factors. The results showed that most of the genetic diversity measures were well predicted by these factors (Table 1). In detail, mean annual precipitation had a significant positive effect on Cytb-based genetic diversity; mean annual temperature had a significant positive effect on D-loopbased genetic diversity; and altitude and human population density had significant negative impacts on Cytb- and D-loopbased genetic diversity (Table 1). In addition, the spaGLMM analysis with the species richness included as an explanatory variable gave similar results to the semi-part spaGLMM analysis (table S19). Because the relationships between most of the factors and microsatellite-based genetic diversity were different from theoretically expected, here we did not discuss microsatellite-related results.

MAP, mean annual precipitation; MAT, mean annual temperature; ALT, mean altitude; HPD, human population density.

Because the phylogenetic diversity was very strongly correlated with species richness, we also performed the semi-part spaGLMM analysis for phylogenetic diversity. The results showed that the above abiotic and biotic factors had no significant impacts on phylogenetic diversity (Table 1), suggesting that the species richness had a much higher effect on phylogenetic diversity compared to other factors. To test this, we performed the spaGLMM analysis with species richness as an independent variable. The results showed that the importance of species richness was far more than those of other factors, indicating that phylogenetic diversity was mainly affected by species richness (table S19).

This is the first study to assess the correlation between genetic diversity and phylogenetic diversity for all the terrestrial vertebrate groups at a large spatial scale. The findings revealed a significant correlation between genetic and phylogenetic diversity for Cytb-based genetic diversity measure and a marginally significant correlation for D-loopbased measure at a grid cell scale, demonstrating the important role of phylogenetic diversity in predicting level of genetic diversity. In addition, we also found a significant positive correlation between genetic diversity and species richness for Cytb-based genetic diversity measure and a marginally significant correlation for D-loopbased measure. However, no significant correlations were detected between genetic diversity and phylogenetic diversity (or species richness) for microsatellite-based measure, suggesting that these correlations are genetic marker dependent.

Our study is also the first region-level survey and assessment of the genetic and phylogenetic diversity of Chinese terrestrial vertebrates that demonstrated the spatial distribution pattern of diversity and identified the regions of high and low genetic/phylogenetic diversity. The spatial patterns showed that the terrestrial vertebrates in South China and Southwest China harbored not only higher genetic diversity but also higher phylogenetic diversity, highlighting the high conservation priority for these hotspot regions. We also identified key areas with significantly higher or lower phylogenetic diversity after controlling for the effects of species richness and discerned the evolutionary museum and cradle for Chinese terrestrial vertebrates. In particular, we found inconsistencies among the regions in terms of genetic and species diversity. Although the terrestrial vertebrates on the Qinghai-Tibet Plateau had the lowest species richness, they had intermediate genetic diversity, possibly because of less human activity and heterogeneous abiotic effects in this region. The terrestrial vertebrates in North China and Northeast China, which are exposed to more human activity and located in north further in latitude, harbored intermediate species richness but lower genetic diversity. These results were supported by the semi-part spaGLMM analyses, which revealed that abiotic (precipitation, temperature, and altitude) and biotic factors (human population) played important roles in the spatial patterns of genetic diversity.

We investigated the effects of abiotic and biotic factors driving the spatial patterns of genetic and phylogenetic diversity at a grid cell scale. On the whole, the effects of these factors on Cytb- and D-loopbased genetic diversity were consistent with ecological and evolutionary expectations. Mean annual precipitation and temperature had significant positive effects on genetic diversity, because higher precipitation and temperature most likely provide more suitable conditions for species survival, population expansion, and speciation. In contrast, altitude had significant negative impacts on genetic diversity, because higher elevation means harsher living conditions especially for terrestrial vertebrates. For biotic factor, human population density had significant negative impacts on genetic diversity, because higher density means more human activities and more possible interference with wildlife and their habitats.

Our study summarizes the findings of genetic/phylogenetic diversity studies, revealing the basic background of genetic resources in Chinese terrestrial vertebrates, which could facilitate genetic resource protection under the CBD framework and guide future genetic/phylogenetic diversity research and conservation. In addition, compared with the total number of Chinese terrestrial vertebrates, the number of species with surveyed genetic diversity data is relatively small. To better conserve genetic diversity, scientists and managers should cooperate to perform genetic diversity surveys for more species, especially those with an unclear genetic status. Furthermore, the genetic and phylogenetic diversity of freshwater and marine vertebrates should be surveyed and assessed to protect gradually decreasing aquatic genetic resources. Last, our study is the first to use nuclear microsatellite markers to assess large-scale genetic diversity pattern and explore the relationship between genetic and phylogenetic diversity. However, it is worth noting that microsatellite-based correlation and model analyses produced different results from those based on mitochondrial DNA, which cautions us to carefully interpret results from different genetic markers.

We retrieved published literatures of population-level genetic diversity studies from public academic databases. For the English literature, we searched the Web of Science database (http://apps.webofknowledge.com/) using the search rule TS = (species Latin name OR species English name) AND TS = genetic diversity AND TS = population. For the Chinese literature, we searched the CNKI database (www.cnki.net), CQVIP database (www.cqvip.com), and Chinese Science Citation Database (http://sciencechina.cn) using the search rule species Latin name AND genetic diversity. Then, to search the literature as comprehensively as possible, we searched only the species Latin name again for species without related references or with few related references.

We screened the retrieved literature following several steps. First, we used only the literature about wild animal studies and discarded the literature studying captive populations. Second, we focused on population-level studies based on microsatellite, mitochondrial Cytb, or D-loop markers. These three markers have been widely used in population genetics and phylogeographic studies of vertebrates. For microsatellite-based studies, we extracted the expected heterozygosity (HE) values for each population of species as the measure of microsatellite genetic diversity. HE is an unbiased measure and thus insensitive to small sample sizes (25). For mitochondrial Cytb gene and D-loop sequence-based studies, we extracted Neis nucleotide diversity () values for each population of species as the measure of Cytb or D-loop genetic diversity (26). is also unbiased and thus insensitive to small sample sizes (26). If the same population had more than one HE or from different references, we used the mean value as the genetic diversity measure of this population. Last, on the basis of population-level genetic diversity data, we estimated species-level genetic diversity by averaging the population-level genetic diversity values (9). Mean genetic diversity metric has been widely applied in large-scale studies (9, 18, 19).

In total, we compiled a dataset of 287 terrestrial vertebrates, which included 103 mammals, 59 birds, 31 reptiles, and 94 amphibians, accounting for 15.6, 4.1, 6.7, and 18.6% of the respective total numbers of species (figs. S1 and S2). Overall, the assessment proportions for genetic diversity of mammals and amphibians were higher than those of birds and reptiles, with the proportion of birds being the lowest. The number of terrestrial vertebrate species with population-level genetic diversity data based on microsatellite marker (n = 151) was higher than those based on Cytb gene (n = 142) and D-loop (n = 105), accounting for 4.9, 4.6, and 3.4% of the 3075 Chinese terrestrial vertebrates, respectively (figs. S3 and S4).

Sequences of five mitochondrial genes (Cytb, Co1, 12S rRNA, 16S rRNA, and Nd1) were used to reconstruct the phylogeny of Chinese terrestrial vertebrates. The sequences of the five mitochondrial genes were searched in GenBank with the following steps. First, the available mitochondrial reference genomes were downloaded, and the corresponding coding sequences of these genes were extracted. Then, the available coding sequences for the remaining species were directly downloaded from GenBank using the species Latin name and gene name. If more than one sequence was available for the same locus of a species, the sequence with a length similar to that of the corresponding gene was selected. Last, the short genes whose coding sequence length was <300 base pairs were discarded from the dataset. After these steps, we compiled a total of 2461 species including 573 mammals, 1170 birds, 359 reptiles, and 359 amphibians, representing 87.0, 81.0, 77.2, and 71.0% of the respective total numbers of species. Our dataset covered 46 orders, 204 families, and 847 genera. For each gene, the coding sequences of 973 species were extracted from their mitochondrial genomes, while others were directly downloaded from the GenBank database. The numbers of species with Cytb and Co1 sequences were higher than those with Nd1, 12S rRNA, and 16S rRNA sequences (fig. S7).

The coding sequences of each gene were concatenated and aligned by MAFFT (27) with default parameters, and the poorly aligned sites at the beginning and the end were trimmed. Then, the aligned sequences of these five genes were imported into SequenceMatrix software (28) to construct a supermatrix with the gaps treated as missing data. A phylogenetic analysis was performed on this supermatrix using the maximum likelihood method implemented in RAxML 8.2.12 (29) with the ASC_GTRGAMMA model and 1000 bootstrap replicates. Each gene was treated as a partition, and the zebrafish was used as outgroup. On the basis of this phylogenetic tree, we used the penalized likelihood method implemented in treePL (30) to date the divergence times of these vertebrates. A total of 391 available divergence times from TimeTree (31) were selected as calibration points for the dating analysis (table S14). The prime option and through analysis were implemented with optimal parameters.

On the basis of our dated phylogenetic tree and species distribution data, we calculated Faiths phylogenetic diversity of Chinese terrestrial vertebrates using the picante package (32) in R, as widely used in phylogenetic diversity studies (33). In this study, we used divergence time as the measure of phylogenetic diversity of each species.

The distributional ranges of terrestrial vertebrate species (including mammals, amphibians, reptiles, and birds) were derived from the IUCN spatial database (www.iucnredlist.org/resources/spatial-data-download). The range of each species was originally in a vectorized shapefile format and was rasterized into a grid system with a 0.5 0.5 resolution (~50 km by 55 km). We double-checked the rasterized maps to confirm that they matched the original vectorized distributional range maps. The resultant rasterized map of each species was always conservative relative to the original vectorized map, as many margins of species fragmented distributions might not have been recorded as the presence of the species in our 0.5 0.5 grid cells. This is because the areas of these margins were too small in the corresponding grid cells. The map of China used in this study was from Resource and Environment Science and Data Center (www.resdc.cn/data.aspx?DATAID=200). The Latin name of each species was checked to avoid potential synonyms. In total, our gridded distribution database included the occurrence records for 1941 species. After matching with the genetic and phylogenetic data, the final distribution dataset used for the diversity assessment included a total of 180 species for the genetic diversity analysis and 1685 species for the phylogenetic diversity analysis.

Climate data with a 2.5 spatial resolution were collected from the WorldClim database (https://worldclim.org/). We used the two most important climatic variables, mean annual temperature and mean annual precipitation that were calculated for the climate data from 1970 to 2000, as predictors of spatial patterns of genetic and phylogenetic diversity of terrestrial vertebrates in China. Human population density in 2010 in China (in persons per square kilometer) was derived from the Gridded Population of the World collection (https://sedac.ciesin.columbia.edu/data/collection/gpw-v4). Digital elevation data with a 2.5 spatial resolution in China were originally derived from the NASA Shuttle Radar Topographic Mission and downloadable from the WorldClim database. Because we mapped the genetic and phylogenetic diversity using a grid cell size of 0.5 0.5 for each variable (including altitude), we took the average of all values within each grid cell as the variables value for the grid cell.

In many cases in which biodiversity data are collected associated with spatial information (e.g., sampling location coordinates), conventional correlation tests are not valid because the assumption of total independence of samples is violated. For spatial biodiversity data, neighboring locations can present similar biodiversity features (e.g., genetic diversity or phylogenetic diversity as investigated here), which is a phenomenon known as spatial autocorrelation, resulting in nonindependent association of biodiversity information between neighboring locations. To this end, conventional correlation tests can be misleading. To cope with this issue, we used a modified t test to account for spatial autocorrelation (34, 35) when testing the spatial associations between genetic diversity, phylogenetic diversity, and species richness. The test is based on the adjustment of the sample correlation coefficient between the two spatially correlated quantities and requires the estimation of an effective sample size (degrees of freedom).

We performed spatial correlation tests between genetic diversity based on different markers, between genetic diversity and species richness, between genetic diversity and phylogenetic diversity, and between phylogenetic diversity and species richness. In addition, we selected a set of abundant terrestrial vertebrate species with a threatened status rank of LC (2) to further explore the relationship between genetic diversity and phylogenetic diversity. The set of abundant terrestrial vertebrates included 39 species for Cytb, 25 species for D-loop, and 45 species for microsatellite (table S16). We performed the correlation analyses for Cytb-, D-loop, and microsatellite-based genetic diversity separately.

We divided the map of China into 0.5 0.5 grid cells using R software. Then, we mapped the spatial distributional patterns of species richness, genetic diversity, and phylogenetic diversity based on the diversity values calculated for each grid cell. For species richness, we summed the total number of species occurring in the grid cell. For genetic diversity, we summed the genetic diversity values of each species present within the grid cell and divided the total value by the number of species surveyed in the grid cell, as used in (9). For phylogenetic diversity, we summed the divergence times of all species surveyed within the grid cell following the definition of Faiths phylogenetic diversity (10, 15).

To detect grid cells with significantly higher or lower phylogenetic diversity than expected controlling for the confounding effect of species richness, we used a randomization protocol (36). In detail, we first computed the phylogenetic diversity for each grid cell and divided this value by the species richness found in the cell. Then, we used a random swapping algorithm to randomize the species-site binary matrix while fixing the species richness of each grid cell and the range size of each species. The randomization procedure was repeated 1000 times, and the following effective size of phylogenetic diversity-species richness was computedZPD=ObsPDMean(RandPD)SD(RandPD)where ObsPD is the observed phylogenetic diversity-species richness ratio for each grid cell. RandPD represents the random phylogenetic diversity-species richness ratio calculated for each grid cell derived from the randomized species-site matrix. Mean(RandPD) and SD(RandPD) denote the mean and standard deviation of the 1000 random phylogenetic diversity-species richness ratio values, respectively. ZPD approximately followed a standard normal distribution; as such, at the significance level of 0.05, a grid cell was identified as having statistically significantly high phylogenetic diversity given the associated species richness if ZPD > 1.96. Conversely, a grid cell was identified as having statistically significantly low phylogenetic diversity given the associated species richness if ZPD < 1.96.

Species richness might have strong associations with genetic and phylogenetic diversity (37, 38). To explore the effects of factors affecting the spatial patterns of genetic and phylogenetic diversity of Chinese terrestrial vertebrates, we performed a semi-part spaGLMM implemented in the spaMM package (39) in the R environment (40), in which the influence of species richness on genetic or phylogenetic diversity was explicitly partialled out. To do so, we firstly constructed a spaGLMM model in which species richness is the only explanatory variable of genetic or phylogenetic diversity and then we used the residuals of this model for evaluating the impacts of other abiotic and biotic factors on genetic or phylogenetic diversity. In addition, to assess the effect of species richness on genetic and phylogenetic diversity, we also performed the spaGLMM analyses with the species richness as an explanatory variable as well as other factors.

For all the above spaGLMM analyses, a correlation matrix according to the Matrn correlation function was assumed and fitted on the basis of the longitude and latitude information of the center point of each grid cell when fitting the mixed model. The Matrn correlation function, containing a scale parameter and a smoothness parameter, is widely applied to model spatial correlation by including exponential and squared exponential models as special cases (41, 42). For the modeling results of semi-part spaMM analyses, when the confidence interval of the estimated coefficient for an explanatory variable was significantly deviated from zero, the variable was considered to have a significant effect on levels of genetic or phylogenetic diversity.

R. Frankham, J. D. Ballou, D. A. Briscoe, Introduction to Conservation Genetics (Cambridge Univ. Press, 2002).

D. J. Futuyma, Evolution (Oxford Univ. Press, 2013).

R. Z. Zhang, China Animal Geography (Science Press, 1999).

M. L. Stein, Interpolation of Spatial Data: Some Theory for Kriging (Springer Press, 2012).

Acknowledgments: We thank Jiekun He for providing the map of zoogeographical regionalization. Funding: This study was supported by the National Natural Science Foundation of China (31821001); the Strategic Priority Research Program of Chinese Academy of Sciences (XDB31000000); the Biodiversity Survey, Monitoring and Assessment Project of Ministry of Ecology and Environment of China (2019HB2096001006); the National Natural Science Foundation of China (31672319); the Youth Innovation Promotion Association, CAS (2016082); and the Special Research Assistant Program of CAS. Author contributions: F.W. conceived and supervised the project. Y.H., H.F., J.C., X.Z., H.W., B.Z., L.Y., X.H., X.S., T.P., W.W., and J.L. performed the data collection. Y.H., H.F., Y.C., J.C., M.W., W.Z., L.Y., and H.H. performed the data analysis. Y.H., H.F., and Y.C. wrote the manuscript with input from F.W. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Spatial patterns and conservation of genetic and phylogenetic diversity of wildlife in China - Science Advances

TEL AVIV, Israel, Jan. 28, 2021 /PRNewswire/ --The company 'Tikun Olam Cannbit' (TASE: TKUN)is making history - The company have developed an in-house revolutionary genetic system for the identification and tracking of cannabis strains (cultivars and varieties), through the characterization of the genetic fingerprints based on the DNA sequence of each and every cannabis plant. True to its role, the system is called: Cannabis Genetic Fingerprinting, or 'CGF'.

Putting an end to the mess - the CGF system changes the rules of the game : The characterization of fingerprints by this system is being done by the genetic diagnosis of a variety of unique sequences along the cannabis plant's genome, based on a number of consecutive genetic technologies. The genetic fingerprint is actually a biological and totally natural barcode (Non-GMO), which accompanies the plant throughout its complete life cycle, and in some cases, into the final product.

The CGF system is expected to play as a substantial "game changer" in the cannabis industry, as well as set a standard in terms of strain's identification, genetic stability, uniformity (reducing the deviation ranges in the active ingredients profile), repeatability and thus resulting in improved 'Therapeutic Continuity', IP registration and protection, organization's strains bank management and tracking of cannabis strains in the future cannabis market.

This ability to identify strains accurately and independently has been considered for many decades as a "holy grail" of the cannabis world. A world comprising thousands of strains, with no ability to identify which is which in an objective manner, or to effectively track and monitor strains over time in the global space.

Till today, the identification of cannabis plants has been based on the characterization of its observable measured traits . Traits such as plant's height, color tone of the leaf, stem's diameter, the measured active ingredients profile and many more expressed and variable characteristics. However, the plant's traits are in fact varying, depending on hundreds of external varying factors, unrelated to the plant itself or its identity. Factors in the level of environmental conditions, cultivation methods, storage, as well as measurements and procedures. Factors such as lighting and radiation, fertilizers, humidity, pests, diseases, temperature, measurement tools, work methods and many other variable factors. Depending on these variables, the characteristics of the tested plant may also vary along with his identity, which is diagnosed accordingly.

Apart from the obvious use of the CGF system to identify unknown cannabis plants and hence also to identify different types of products, the company believes that based on this system, the process of registering strains as an IP rights, can also be substantially improved and streamlined.

The CGF system is currently in the commercialization phase which is expected to provide a cost effective, fast technical platform and to enable ongoing and big scale commercial use.

FOR MORE INFORMATION: Eliana Horenczyk [emailprotected]

SOURCE Tikun Olam Cannbit

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Tikun Olam-Cannbit have developed a revolutionary system for the characterization of genetic fingerprints in order to identify and track cannabis...

Sticking with what we have and selecting for superior genetics rather than importing genetics from New Zealand is seen as the way forward for Irish sheep farmers, according to Nicola Featherstone.

Nicola was speaking at the first of two virtual Teagasc Sheep Conferences which were held yesterday evening (Tuesday, January 26).

Teagasc Walsh Scholar Nicola gave an update on the INZAC trial in Teagasc Athenry, Co. Galway, which compares 1-star and 5-star Irish ewes with elite New Zealand ewes.

One question put to Nicola during yesterdays session was how relevant did she think New Zealand sheep are in an Irish context and if they are far superior to what we have here in Ireland?

She explained: During my time in New Zealand, along with visiting a number of farms, I also collaborated with a consultancy company and over there we generated a model and that model looked at all different scenarios that we could put into practice here in Ireland.

For example, whether or not we would look at importing New Zealand genetics or should we stick with what we have here in Ireland or maybe a mixture of both.

From looking at the results, it showed that the benefit, in terms of genetics and economics, would be greater for the Irish industry if we stuck with what we have rather than importing New Zealand genetics, as long as we source our genetics from more progressive breeders.

So, essentially, it means that we need commercial farmers to drive demand towards sourcing animals of superior genetics.

If we stick with the system we have which identifies the elite animals, in terms of being 5-stars, then this is the best way forward for Irish sheep farmers.

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'Sticking with what we have and selecting superior genetics seen as the way forward' - Agriland

SUZHOU, China, Jan. 18, 2021 /PRNewswire/ -- Cure Genetics announced a collaboration with Boehringer Ingelheim to develop novel Adeno-Associated Virus (AAV) vectorsleveraging Cure Genetics' proprietary VELPTM platform to develop next-generation gene therapies. This new collaboration combines Boehringer Ingelheim's experience in disease biology and gene therapy development with Cure Genetics' AAV expertise in library construction and highly efficient in vivo AAV screening. The aim is to provide potential new AAV serotypes for patients.

The clinical applications of existing AAV serotypes are limited by some of their features, such as low transduction efficiency, low tissue specificity and immunogenicity. Therefore, finding new AAV serotypes to overcome these challenges becomes critical for the majority, if not all, AAV-based gene therapies.

Comparing to other traditional vector engineering technologies, Cure Genetics' proprietary VELPTM platform encompasses key methodical innovations, including a comprehensive strategy of engineering a plasmid library with high complexity and an effective ratio. the optimized AAV production protocol ensures high genome-capsid correspondence and world-class production capacity, and the most physiologically relevant models for vector selection and validation. It enables a significantly shorter process to find the "right" AAV vectors with almost all possibility effectively covered.

Boehringer Ingelheim aspires to develop the next generation of medical breakthroughs and gene therapy is one of the focuses under exploration by the team of Research Beyond Borders. The advanced VELPTM technology platform may provide effective solutions in increasing the efficiency of novel AAV screening and help further expand our efforts in the area of gene therapy development.

"This is the very first time that a global pharmaceutical group is collaborating with a Chinese biotech in the cutting-edge field of AAV vector engineering. We appreciate the recognition of Boehringer Ingelheim's recognition of our VELPTM platform. Novel AAV vectors enlarging the therapeutic window is key to unfolding the potential of gene therapy, which is also Cure Genetics' innovative focus . We believe, together with visionary partners like Boehringer Ingelheim, the quality of life for more patients in need can be improved by next-generation gene therapy." stated Dr. Qiushi Li, Cure Genetics' Chief Operating Officer.

The collaboration with Cure Genetics was initiated by Boehringer Ingelheim China External Innovation Hub. It consists of three business units: Research Beyond Borders, Business Development and Licensing, and Venture Fund. The hub is committed to becoming the preferred partner of China's biopharmaceutical industry and bringing more Chinese innovative partnership projects to enrich Boehringer Ingelheim's global R&D pipeline, thereby ultimately benefiting more patients. So far, Boehringer Ingelheim China External Innovation Hub has established various partnerships with reputable research institutions and biotech companies in China.

About Cure Genetics

Cure Genetics is a biotech company founded in 2016, committed to expanding the frontier of gene therapy via its innovative technology of gene editing and gene delivery. With the world-leading AAV manufacturing capability, Cure Genetics' proprietary VELPTM platform enables a fast yet systematic design, selection and optimization of AAV vectors with special features and significantly better performance of in vivo gene delivery, which will empower AAV-based gene therapy to be applied in a much broader range of disease treatments.

SOURCE Boehringer Ingelheim; Cure Genetics

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BusinessA Midlothian-based agri-food biotech business that specialises in bugs has launched a new insect breeding facility and created several jobs.

Friday, 22nd January 2021, 12:30 pm

Founded by entrepreneur and PhD graduate Thomas Farrugia, Beta Bugs develops and distributes insect breeds as a source of protein for animal feed. It has expanded its team from five to ten to help drive into the wider agri-food markets.

Following the completion of his PhD and his first tasting of insects on a trip to Antwerp, Farrugia joined Deep Science Ventures where he began researching how environmentally friendly and versatile insect-based products could be and how they could provide a different source of protein which could change the feeding habits of livestock and fish farms.

He launched Beta Bugs as an insect genetics company in 2017, with the goal of creating high-performance breeds of black soldier fly to accelerate the growth of the insect farming sector.

Over the last 18 months the company based at the Easter Bush Campus has secured 133,000 of private investment alongside 1.2 million in grant funding, including 100,000 from Scottish Governments Unlocking Ambition programme and 84,000 from the Pivotal Enterprise Resilience Fund to help the company grow its operations during the coronavirus restrictions.

Support for the firm from Business Gateway Midlothian has included help with establishing the companys operations within the Science Zone in Midlothian and scaling up its breeding programme at the Easter Bush Campus, which now houses the dedicated insect breeding facility.

Farrugia said: We are delighted to be in a position to expand our team and build a dedicated insect breeding facility thanks to help from various organisations including Business Gateway Midlothian who have been instrumental in our growth since we started out.

Having our own adviser to keep us right along the way and signpost us to other available resources has been invaluable and really helped us to carve out a niche for ourselves in the UK and international genetic insect market.

Annie Watt, Business Gateway Midlothian lead, said: Beta Bugs is an innovative insect-breeding company leading the way in creating genetics for the fast growing insects-as-feed industry, which we are delighted to support.

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Midlothian bug genetics innovator launches insect breeding facility and creates jobs - The Scotsman

Researchers at the National Institutes of Health have discovered a new genetic disorder characterized by developmental delays and malformations of the brain, heart and facial features.

Named linkage-specific-deubiquitylation-deficiency-induced embryonic defects syndrome (LINKED), it is caused by a mutated version of theOTUD5gene, which interferes with key molecular steps in embryo development. The findings indicate that the newly identified pathway may be essential for human development and may also underlie other disorders that are present at birth. The information will help scientists better understand such diseases both common and rare and improve patient care. The results were reported Jan. 20, 2021 inScience Advances.

Our discovery of the dysregulated neurodevelopmental pathway that underlies LINKED syndrome was only possible through the teamwork of geneticists, developmental biologists and biochemists from NIH, said Achim Werner, Ph.D., an investigator at the National Institute of Dental and Craniofacial Research (NIDCR) and lead author. This collaboration provided the opportunity to pinpoint the likely genetic cause of disease, and then take it a step further to precisely define the sequence of cellular events that are disrupted to cause the disease.

The project began when David B. Beck, M.D., Ph.D., a clinical fellow in the laboratory of Dan Kastner M.D., Ph.D., at the National Human Genome Research Institute (NHGRI) and co-first author, was asked to consult on a male infant who had been born with severe birth defects that included abnormalities of the brain, craniofacial skeleton, heart and urinary tract. An in-depth examination of siblings and family members genomes, combined with genetic bioinformatics analyses, revealed a mutation in theOTUD5gene as the likely cause of the condition. Through outreach to other researchers working on similar problems, Beck found seven additional males ranging from 1 to 14 years of age who shared symptoms with the first patient and had varying mutations in theOTUD5gene.

The gene contains instructions for making the OTUD5 enzyme, which is involved in ubiquitylation, a process that molecularly alters a protein to change its function. Ubiquitylation plays a role in governing cell fate, where stem cells are instructed to become specific cell types in the early stages of embryo development.

Based on the genetic evidence, I was pretty sureOTUD5mutations caused the disease, but I didnt understand how this enzyme, when mutated, led to the symptoms seen in our patients, said Beck. For this reason we sought to work with Dr. Werners group, which specializes in using biochemistry to understand the functions of enzymes like OTUD5.

To start, the NIH team examined cells taken from patient samples, which were processed at the NIH Clinical Center. Normally, OTUD5 edits or removes molecular tags on certain proteins (substrates) to regulate their function. But in cells from patients withOTUD5mutations, this activity was impaired.

Using a method to return mature human cells to the stem cell-like state of embryo cells, the scientists found thatOTUD5mutations were linked to abnormalities in the development of neural crest cells, which give rise to tissues of the craniofacial skeleton, and of neural precursors, cells that eventually give rise to the brain and spinal cord.

In further experiments, the team discovered that the OTUD5 enzyme acts on a handful of protein substrates called chromatin remodelers. This class of proteins physically alters the tightly packed strands of DNA in a cells nucleus to make certain genes more accessible for being turned on, or expressed.

With help from collaborators led by Pedro Rocha Ph.D., an investigator at the National Institute of Child Health and Human Development (NICHD), the team found that chromatin remodelers targeted by OTUD5 help enhance expression of genes that control the cell fate of neural precursors during embryo development.

Taken together, the researchers concluded, OTUD5 normally keeps these chromatin remodelers from being tagged for destruction. But when OTUD5 is mutated, its protective function is lost and the chromatin remodelers are destroyed, leading to abnormal development of neural precursors and neural crest cells. Ultimately, these changes can lead to some of the birth defects seen in LINKED patients.

Several of the chromatin remodelers OTUD5 interacts with are mutated in Coffin Siris and Cornelia de Lange syndromes, which have clinically overlapping features with LINKED syndrome, said Werner. This suggests that the mechanism we discovered is part of a common developmental pathway that, when mutated at various points, will lead to a spectrum of disease.

We were surprised to find that OTUD5 elicits its effects through multiple, functionally related substrates, which reveals a new principle of cellular signaling during early embryonic development, said Mohammed A. Basar, Ph.D., a postdoctoral fellow in Werners lab and co-first author of the study. These findings lead us to believe that OTUD5 may have far-reaching effects beyond those identified in LINKED patients.

In future work, Werners team plans to more fully investigate the role that OTUD5 and similar enzymes play in development. The researchers hope the study can serve as a guiding framework for unraveling the causes of other undiagnosed diseases, ultimately helping clinicians better assess and care for patients.

Were finally able to provide families with a diagnosis, bringing an end to what is often a long and exhausting search for answers, said Beck.

Reference: Beck DB, Basar MA, Asmar AJ, et al. Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation. Sci Adv. 2021;7(4):eabe2116. doi:10.1126/sciadv.abe2116.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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New Genetic Disorder Discovered That Affects Brain and Craniofacial Skeleton - Technology Networks

Photo: ANDER GILLENEA / Contributor (Getty Images)

Remember learning about genetics for the first time in biology class? I myself dont remember much, aside from the traumatic time we had to dissect a pregnant rat (I vividly recall the smell of formaldehyde and do not wish to smell it ever again). The only other thing I vaguely remember were those squares we had to fill in. Punnett squares. Remember those? What a pain in the ass. These are two of many reasons why I never became a doctor.

Real genetics are a lot more complicated and dont fall quite so neatly into those Punnett squares, unfortunately. You might think that your genetic composition would be as simple as being an even quarter mix of each of your grandparents blended into one human being. But in reality, processes like genetic recombination shake things up considerably.

Science Alert used gummy bears to show a graphic representation of how genetics can work down the line, inspired by this tweet from NYU neuroscience prof Jay Van Bavel, who tweets as @jayvanbavel:

It is pretty adorable. And delicious. Because who doesnt love the idea of using a handful of gummy bears to depict your ancestry? Its not exactly perfect because, according to Science Alert, gummy bears dont convey dominant or recessive traits (the uppercase letters in a Punnett square are dominant, while the lowercase ones are the recessive ones, if youve forgotten). Still, its something, and in the end, youll be shoving your weirdo genetic mishmash monster gummy bears right into your face; really, there are few things better than a science experiment that you can end up eating later. Plus candy is a great way to get kids (and adults, for that matter) to pay attention. Maybe if wed used them in my biology class, I would be a doctor today.

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What better way to learn genetics than with gummy bears? - The Takeout

While smoking is linked to atherosclerotic cardiovascular disease (ASCVD), the relative contribution to each subtype is not entirely understood.

A team, led by Michael G. Levin, MD, Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, determined the link between genetic liability to smoking and the risk of coronary artery disease (CAD), peripheral artery disease (PAD), and large-artery stroke.

In the mendelian randomization study, the investigators used summary statistics from genome-wide associations of smoking from the UK Biobank (n = 462,690), Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium (n = 60,801 cases, n = 123,504 controls), VA Million Veteran Program (n = 24,009 cases, n = 150,983 controls), and MEGASTROKE (n = 4373 cases, n = 406,111 controls).

The investigators sought main outcomes of risk, defined as odds ratios (OR) of CAD, PAD, and large-artery stroke.

The researchers used 2 measures for smoking throughout the studylifetime smoking index and smoking initiation. The primary measure of smoking was lifetime smoking index, which was previously validated continuous measure that accounts for self-reported smoking status, age at initiation, age at cessation, number of cigarettes smoked per day, and a simulated half-life constant that captures the decreasing effect of smoking on health outcomes following a given exposure.

Link Between ASCV and Smoking

The investigators found genetic liability to smoking was linked to an increased risk of PAD (OR, 2.13; 95% CI, 1.78-2.56;P= 3.61016), CAD (OR, 1.48; 95% CI, 1.25-1.75;P= 4.4106), and stroke (OR, 1.40; 95% CI, 1.02-1.92;P= 0.04).

The team also found the genetic liability to smoking was associated with a greater risk of PAD than risk of large-artery stroke (ratio of OR, 1.52; 95% CI, 1.05-2.19;P= 0.02) or CAD (ratio of OR, 1.44; 95% CI, 1.12-1.84;P= 0.004).

The link between genetic liability to smoking and atherosclerotic cardiovascular diseases was independent from the effects of smoking on traditional cardiovascular risk factors.

In this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, although the estimated association was strongest between smoking and PAD, the authors wrote. The association between smoking and atherosclerotic cardiovascular disease was independent of traditional cardiovascular risk factors.

The Dangers of Smoking

Atherosclerotic cardiovascular disease impacts a number of vascular beds throughout the body, with clinical manifestations. Smoking tobacco is consistently among the leading risk factors for atherosclerotic cardiovascular disease.

Smoking also had independent effects on inflammation, endothelial function, and platelet aggregation, but it is unknown whether the effect of smoking on atherosclerotic cardiovascular disease is primarily mediated through correlated alterations of traditional cardiovascular risk factors or operates through independent mechanisms.

While the detrimental effects of smoking could persist for decades, clarifying the basis of the smoking-atherosclerosis relationship might enable more targeted risk-reduction strategies among both current and former smokers.

The study, Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases, was published online in JAMA Network Open.

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Genetic Liability to Smoking Linked to Atherosclerotic Cardiovascular Disease - MD Magazine

Genetic testing can provide crucial information about what's causing a patient's problems and what lies ahead.

But for healthy patients?It's a lottricker.

With the growing popularity of consumer genetic tests, patients are increasingly asking their doctors about whether a test could predict their vulnerability to certain conditions, such as cancer, dementia and heart disease. Acase studypublished Mondayin the Annals of Internal Medicine by researchers at Columbia University warns that doctors and patients alike should proceed carefully in understanding the context in which these tests provide useful information.

RELATED: How physicians should answer questions from patients about consumer genetic tests

Genetic testing was developed for diagnosing somebody who has a condition, or whose doctor suspects they have a condition, saidAli Gharavi, MD, professor of medicine and chief of the Division of Nephrology at Columbia University College of Physicians and Surgeons and one of the article's authors.

In that case, doctors start with a prior suspicion of a condition that can be confirmed, he told Fierce Healthcare.

But with a healthy patient, the probability of a currently undiagnosed disease is lower, which makes the probability of a false-positive result higher, he said.

As a result, physicians may need to do additional work to confirm a diagnosis. The amount of additional work required depends on the degree to which a given genetic variance has been positively correlated with a specific condition.

A relatively small number of genetic mutations are both well-studied and well-understood. Certain cancer mutations, for example, correlate strongly with the risk of developing breast cancer or ovarian cancer. However, a positive result on those tests doesnt mean an individual has one of these cancers, or even that they definitively will get them. Instead, it may simply indicate they have a higher risk of developing that cancer.

With other genetic mutations, potential variations could be falsely correlated with a disease or they could occupy a gray area classified as a variant of unknown significance. Labs tend to use this classification for variants that require more study before they can be classified either as benign or malignant.

RELATED: Ancestry rolls out more advanced DNA testing to flag risk of heart disease, breast cancer

Gharavi says its important for physicians to take the consequences of a potential false-positive into account when helping patients make a decision on whether or not to undertake a given genetic test.

Its probably better to whittle things down to what youre concerned aboutif youre concerned about Alzheimers and you conduct a test that scans the entire genome and come back with variants of unknown significance for heart disease and cancer, et cetera, then suddenly your anxiety level goes much higher.

For patients, Gharavi recommends talking to your doctor about the conditions best suited to a genetic test and ensuring you understand beforehand what the potential consequences of a positive test might be. And if the test comes up negative, remember that it doesnt mean you have no risk of contracting the disease in question.

For practitioners, Gharavi suggests bearing in mind that not all genetic tests have the same predictive capability. Understanding which tests are well-studied and correlate with specific diseases can help provide patients the education they need to decide which tests they really want, given their family history or other specific concerns.

Since research is ongoing, physicians should be aware that it can be a lot of information to stay on top of. Its all changing very quickly, so conferring with a genetic counselor or clinical geneticist also helpssomebody whos really familiar with these tests, Gharavi advises.

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More healthy patients are taking genetic test results to their docs. But there are some pitfalls - FierceHealthcare

average: (in science) A term for the arithmetic mean, which is the sum of a group of numbers that is then divided by the size of the group.

cell: The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. Depending on their size, animals are made of anywhere from thousands to trillions of cells. Mostorganisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.

develop: To emerge or to make come into being, either naturally or through human intervention, such as by manufacturing. (in biology) To grow as an organism from conception through adulthood, often undergoing changes in chemistry, size, mental maturity, size or sometimes even shape.

development: (in biology) The growth of an organism from conception through adulthood, often undergoing changes in chemistry, size and sometimes even shape.

DNA: (short for deoxyribonucleic acid) A long, double-stranded and spiral-shaped molecule inside most living cells that carries genetic instructions. It is built on a backbone of phosphorus, oxygen, and carbon atoms. In all living things, from plants and animals to microbes, these instructions tell cells which molecules to make.

egg: The unfertilized reproductive cell made by females.

embryo: The early stages of a developing organism, or animal with a backbone, consisting only one or a few cells. As an adjective, the term would be embryonic and could be used to refer to the early stages or life of a system or technology.

fraternal: Of our relating to brothers, or others with whom people develop close friendships and affection. (in genetics) The term for a type of twin birth where each baby comes from a separate fertilized egg. This is in contrast to identical twins, which result from a single fertilized egg (creating two separate but nearly identical babies).

genetic: Having to do with chromosomes, DNA and the genes contained within DNA. The field of science dealing with these biological instructions is known as genetics. People who work in this field are geneticists.

genome: The complete set of genes or genetic material in a cell or an organism. The study of this genetic inheritance housed within cells is known as genomics.

Iceland: A largely arctic nation in the North Atlantic, sitting between Greenland and the western edge of Northern Europe. Its volcanic island was settled between the late 800s and 1100 by immigrants from Norway and Celtic lands (ones governed by the Scots and Irish). It is currently home to roughly a third of a million people.

mutation: (v. mutate) Some change that occurs to a gene in an organisms DNA. Some mutations occur naturally. Others can be triggered by outside factors, such as pollution, radiation, medicines or something in the diet. A gene with this change is referred to as a mutant.

replicate: (in biology) To copy something. When viruses make new copies of themselves essentially reproducing this process is called replication.

trait: A characteristic feature of something. (in genetics) A quality or characteristic that can be inherited.

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Some identical twins dont have the exact same DNA - Science News for Students

Pharmacogenetics, or precision medicine, is still new to many pediatric providers despite its documented benefits, according to an article the Sanford Childrens Genomic Medicine Consortium published recently in The Pharmacogenomics Journal.

Pharmacogenetics uses a persons DNA to help providers choose the best medicine and dosage of medicine. And there are plenty of opportunities to use genetic traits in pediatrics, the group wrote.

Theres evidence that pharmacogenetics benefit pediatric oncology, pain management, organ transplantation, and immunosuppression, according to the journal article. Additionally, advances in technology have made it easier to study complete genomes, and providers can use that information to improve health care for children.

Ten hospitals have signed on to the consortium to rapidly integrate genetics and genomics into primary and specialty pediatric care.

Above all, the mission of the consortium is to efficiently manage resources in genetics and genomics, perform cutting-edge research and education and bring genomic medicine into pediatric practice. This will help set the standard for precision medicine in childrens health care.

The 10 member hospitals are:

A previous innovation project funded by the consortium was a study of the outcomes of rapid whole genomic sequencing in critically ill newborn infants. Another previous study evaluated the routine use of an extensive, pediatric-focused, next generation sequencing panel in the diagnosis of childhood cancers.

Posted In Children's, Company News, Genetics

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Sanford genetics group shares benefits of custom kids' care - Sanford Health News

Introduction

The Brazilian population is one of the most heterogeneous in the world, showing considerable genetic admixture among Europeans, Africans, and Native Americans.1 Among the three main groups forming the Brazilian population, Native Americans have the scarcest genetic data.

The Amazon region concentrates a greater part of the Native American populations of Brazil: there are more than 180 communities, apart from several isolated groups living in the biome, which represents approximately 200 thousand people, 86 languages, and 650 dialects.2 Specifically addressing the state of Par, the second largest state in the Brazilian Amazon region, the last census reported more than 50 thousand indigenous people and 42 different Native American groups.3

The epidemiological profile of Native American populations is very little known, which stems from the scarcity of investigations, the absence of surveys and censuses, as well as the precariousness of information systems on morbidity and mortality, which complicates any discussion about the health/disease process of indigenous peoples.4 As far as information on genetic data for that population, data availability is even more scarce.

The population paradigm of PGx is based on the frequency of numerous polymorphisms in pharmacogenes that vary widely among human populations (Suarez-Kurtz, 2010). The guidelines formulated by regulatory drug agencies for the accuracy of therapies cannot be fully applied to Native Americans or even to populations with a high degree of genetic admixture with this group, such as the Brazilian population.5 This study aims to investigate a panel of 117 polymorphisms in 35 pharmacogenes, including label recommendations or clinical evidence from international drug regulatory agencies in an Amazonian Native American population, and to compare the results obtained with global population data. Relevant pharmacogenetic biomarkers were selected from the Pharmacogenomics Knowledge Base database.7

A total of 109 Native American individuals from the Brazilian Amazon region were selected from a database of an epidemiological study investigating indigenous populations of Par. The study population was composed of 65 men and 44 women and collected from adult individuals (between 18 and 50 years old). Twenty-five samples were obtained from Asurini do Koatinemo (KOA), 41 Asurini do Trocar (ASU), and 43 Kayap-Xicrin (KAY). All the Native Americans groups are in the state of Par: the Kayap-Xikrin is located in the Catet and Trincheira Bacaj regions, both indigenous protective lands (geographic coordinates: 6.241917, 50.804833), it counts with a total population of 1800 individuals; the Asurini do Trocar settlement is located east of the Tocantins River (geographic coordinates: 3.567694, 49.711039), summing a total population of 546 individuals; and, Asurini do Koatinemo is situated on the right bank of the Xingu River (geographic coordinates: 4.230970, 52.298335), with a total population of 182 individuals. The three Native American groups are isolated from each other, located at a mean distance of 390 km between them, and do not share family relationships. For some analyses, the three Amazonian Native American populations were gathered in a group called Native Americans (NAM). The genomic data for each marker investigated in the continental populations were obtained from the Ensembl Phase 3 Project.8

Relevant pharmacogenetic biomarkers were selected from the database of the Pharmacogenomics Knowledge Base,9 a publicly available online knowledgebase website whose main objective is collecting, curating, integrating, and disseminating basic pharmacogenetic data. Here, we define biomarker as the function of a gene to code enzymes responsible for processes of pharmacokinetics or pharmacodynamics that may interfere in drug pathways, consequently affecting drug response.10

Pharmacogenetic biomarkers are labeled by levels of evidence regarding their importance to drug response. Levels of evidence rank from 1A, which denotes a variant-drug combination in a medical society-endorsed PGx guideline, or already implemented in a major health system, to level 4, which denotes annotation based on a case report, nonsignificant study or in vitro, molecular or functional assay evidence only. For the current analysis of the Native American populations, 117 biomarkers (ranked from level 1A to 2A and 3) from a total of 35 different genes, including absorption, distribution, metabolism, and excretion genes (ADME) and pharmacodynamic genes, were selected. All the biomarkers selected for this study are shown in Table 1.

Genetic material was extracted from peripheral blood using the BiopurKit Mini Spin Plus-250 commercial kit (Biopur, Brazil) according to the manufacturers recommendations. DNA concentration and purity were measured with a NanoDrop 1000 Spectrophotometer (Thermo Fisher Scientific, Wilmington, DE). The genotyping of single nucleotide polymorphisms (SNPs) was performed by allelic discrimination using TaqMan OpenArray Genotyping with a panel of 120 customized assays on the QuantStudio 12K Flex Real-Time PCR System (Applied Biosystems, Life Technologies, Carlsbad, USA) according to the protocol recommended by Applied Biosystems. Three of the 117 selected biomarkers were triallelic, specifically rs2032582 for ABCB1, rs5030865 for CYP2D6, and rs7900194 for CYP2C9, requiring two different probes per biomarker in the array, making a total of 120 assays to be analyzed (Table 1). To ensure the correct assessment of the genotypes, native samples were analyzed together with negative and positive internal quality controls. Data were analyzed with TaqMan Genotyper software v1.2.2. Copy number variation for CYP2D6 was analyzed by using TaqMan commercial probes according to the TaqMan Copy Number assay protocol recommended by Applied Biosystems and to a final volume of 10 L per reaction. Three different regions were analyzed, intron 2, intron 6, and exon 9, together with an internal 2-copy control (RNAse P). Analysis of the three regions allowed us to detect hybrids CYP2D6/2D7 and CYP2D6*36. Data were analyzed with CopyCaller software v.2 by using a two-copy as a positive control. The predicted copy number was assessed for the three probes, and the mean and standard deviation were also calculated.

Ancestry analysis was performed as described by Ramos et al 2016,11 using 61 autosomal ancestry informative markers (AIMs). Three multiplex PCR reactions were performed using the insertion/deletion markers (INDEL) and the PCR amplifications were analyzed by electrophoresis using the ABI Prism 3130 sequencer and the GeneMapper ID v.3.2 software. The individual proportions of European, African, and Native Americans genetic ancestries were estimated using the STRUCTURE v.2.3.3 software, assuming three parental populations (European, African, and Native Americans).

To compare genetic frequencies for the genes involved in the ADME processes between the three Native American populations and other reference populations, data from the 1000 Genomes Project Consortium6 were downloaded from the website, and pharmacogenetic biomarkers were carefully selected. A total of 2.613 individuals from Africa (AFR), Europe (EUR), East Asia (EAS), South Asia (SAS), and America (AMR) were used to perform discriminant analysis of principal components (DAPC) using R software with the Adegenet package.12

DAPC maximizes discrimination between the populations included in the analysis and, in this way, enables us to characterize the proximity of the NAM populations to the reference populations. Moreover, DAPC provided an informative description of the contribution of the alleles to the discriminant functions used to differentiate the populations. Two R libraries were used to obtain summary tables with descriptive information for each SNP: SNPassoc (Minor Allele Frequency, Hardy-Weinberg Equilibrium, and call rate) and GenABEL (Minor Allele Frequency, Hardy-Weinberg Equilibrium, call rate, and genotype frequencies).13,14

Haplotypes were inferred by using Pharmgkb website and the software AlleleTyper v1.0. This software interprets the real-time PCR analysis data and determines the star-allele results based on specific tables designed from haplotypes tables from Pharmgkb website. Allele Typer software allows to encompass results from SNPs and copy number variation to give a joint genotype prediction.

Furthermore, frequencies of genotypes, haplotypes, and metabolizer phenotypes were compared by Fishers exact tests. Call rates higher than 90% were obtained when analyzed with OpenArray.15

The distribution of 12 haplotypes in the three representative groups of the Native American populations of Brazil is shown in Figure 1. Of these genes, five had a significantly different distribution among the three Native Americans groups: CYP2D6 (p = 0.0047), CYP3A5 (p = 0.043), CYP4F2 (p = 0.0105), CYP2B6 (p = 0.00018), and DPYD (p = 0.0012) (Figure 1). To define the possible CYP2D6 genotypes, 22 polymorphisms were investigated, determining 11 different genotypes, of which *1/*1, *2A/*2A, *1/*4, and *1/*2A were present in all three populations investigated. The wild-type homozygous genotype (*1/*1) was the most frequently found (33%) followed by the *1/*2A genotype (32%). Wild-type homozygotes (*1/*1) were highly common in ASU (17%) and KAY (14%), while KOA presented a considerably lower frequency (4%). Some of the genotypes were detected at low frequencies and in only one of the three populations investigated, such as *2A/*9 and *1/*5 genotypes that occurred only in ASU; *1/*1xN found only in KAY; *4/*29 and *2A/*29 only in KOA. The haplotypes *9 (present in genotype *2A/* 9) and *5 (*1/*5) were exclusive in the ASU.

Figure 1 Genotype distribution of haplotype-forming genes in the three Native American populations of Brazil.

Abbreviations: A_T, Asurini do Trocar (ASU); K_X, Kayap-Xikrin (KAY); (K), Koatinemo (KOA).

Notes: *p<0.05; **p<0.01; ***p<0.001.

Another gene that also presented a distribution of genotypes with significant differences in the three indigenous communities was CYP3A5, which has five possible genotypes. Haplotype *3 was the most frequent in the Native Americans. The *1/*3 genotype was observed with high frequencies in ASU and KAY (42% and 58% individuals, respectively), in contrast with the frequency values observed in the KOA community (20% of individuals). Another genotype that confirms the prevalence of haplotype *3 in the groups is the *3/*3 genotype, which has a relatively more frequent frequency in the groups, summing 32%, 35%, and 56% of individuals in the ASU, KAY, and KOA communities, respectively. On the other hand, the*3/*6 genotype presented a rare frequency, being observed only in 4% of KOA individuals.

The CYP4F2 gene has three possible genotypes, which also presented significant differences regarding its distribution in the Brazilian Native American populations. The wild-type genotype *1/*1 was the most frequent in the groups, being found in 93%, 63%, and 84% of individuals of the ASU, KAY, and KOA communities, respectively. The genotype *1/*3 had a high frequency in the KAY population (35% individuals), whereas in the ASU, it was only found in 7% of individuals and the KOA group in 16% of individuals. Regarding the *3/*3 genotype, it was observed only in 2% of the individuals in the KAY group.

The CYP2B6 gene also presents three possibilities of genotypes, which were also different in the Native Americans evaluated. In general, the wild-type genotype (*1/*1) was observed most frequently, being observed in 68%, 28%, and 48% of individuals of the ASU, KAY, and KOA groups, respectively. The haplotype *6 presented a high frequency, mainly in the Kay population, being found in the genotypes *1/*6 (49% individuals) and *6/*6 (14% individuals).

Finally, the DPYD gene also presented three genotypes with significant differences in the studied populations. The most common genotype was the wild-type genotype (*1/*1), summing 59% of individuals in the ASU group, 49% of individuals in the KAY group, and 76% of individuals in the KOA community. The haplotype *9 was observed in both genotypes *1/*9 and *9/*9. The *1/*9 genotype was frequent in the KAY group (44% of individuals) and was also found in 12% and 20% of individuals from the ASU and KOA groups. The genotype *9/*9 exhibited low frequency, being observed only in 7% and 2% of KAY and ASU populations.

Figure 2 shows the distribution of the metabolization profile of eight genes found in the Brazilian Native American populations. For seven genes, CYP2C19, CYP2C9, CYP3A5, CYP4F2, DPYD, TPMT, and SLCOB1, we considered the assignment of phenotype-based on genotypes: poor function, decreased function, and normal function.7 For the CYP2D6 gene, the activity score (AS) classification was considered.16,17 Two genes had a significantly different profile distribution among the three communities analyzed: CYP2D6 (p = 0.0306) and CYP4F2 (p = 0.0105).

Figure 2 Metabolism profile distribution for the genes investigated in Native American populations of Brazil. For CYP2C19, CYP2C9, CYP3A5, CYP4F2, DPYD, TPMT, and SLCOB1, we considered the assignment of genotypes poor metabolizers (PM), intermediate metabolizers (IM), and extensive metabolizers (EM). For the CYP2D6 gene, the activity score (AS) classification was considered.

Abbreviations: A_T, Asurini do Trocar (ASU); K_X, Kayap-Xikrin (KAY); (K), Koatinemo (KOA).

Note: *p<0.05.

According to the combination of the CYP2D6 genotypes, we can determine the enzyme metabolic profile and classify the predictive phenotype of each individual by the activity score (AS) rate, as defined previously by Gaedigk et al, 2008,16 associating this information with the efficacy of drugs or adverse reactions during pharmacological therapies.

For the other seven genes, the normal function profiles were the most frequent in the Native Americans. The KAY population was the only one to have two individuals with AS 3, equivalent to ultrafast metabolism classification, representing approximately 5% of the total group. In the KOA, it was possible to exclusively observe one individual with poor function. The CYP4F2 gene also showed significant differences in metabolization profiles. In all the Native Americans studied, the most frequently observed profile was normal function followed by decreased function. The KAY group was the only one to present a single individual classified as poor function.

Although the distribution of the phenotypes was not statistically significant regarding the differences presented by the Native American groups, it is important to highlight the data found in two genes: CYP3A5 and SLCO1B1. Both genes showed high frequencies of poor function individuals. The poor function profile of the CYP3A5 gene was observed in 60% of individuals in the KOA community, 35% of individuals in the KAY group, and 32% of individuals in the ASU population. Regarding the SLCO1B1 gene, there were also high frequencies of poor function, approximately 20% and 19% of individuals in the ASU and the KAY communities and 16% of individuals in the KOA group.

The scatterplot shown in Figure 3 was obtained with a DAPC for the 117 PGx markers in 2613 individuals from eight global populations (EUR, AFR, EAS, SAS, AMR, KOA, ASU, and KAY). X- and Y-axis of the scatterplot describe the first and second linear discriminant (LD) function (LD1 and LD2 respectively). The AFR group formed an isolated cluster, clearly genetically differentiated from the rest of the world (x-axis). In the y-axis of the diagram, the divergence between the EUR and EAS cluster was highlighted. The SAS and AMR populations formed close clusters between themselves and the EUR cluster, demonstrating similarity between these populations for the PGx markers evaluated.

Figure 3 Discriminant analysis of principal components (DAPC) of 117 PGx. Scatterplot for the five groups of continental populations described in the 1000 Genomes Project (EUR, AFR, EAS, SAS, and AMR) and three populations of Native Americans of Brazil (KOA, ASU, and KAY).

The Native American populations formed close clusters among themselves and were closely situated between the EAS, AMR, and SAS groups, even though the ASU was the closest to the EAS group. The DAPC assigned 51% of individuals belonging to the ASU population to the EAS cluster, while the percentage of EAS-assigned individuals was lower in the other two Amerindians populations (37% for KAY and 20% for KOA). This result is in keeping with the highest percentage of Native American ancestry shown by ASU (mean value 97.4%), which was significantly higher than that shown by KOA (94.9%).

Because of the lack of clear discrimination between native American populations of Brazil in the previous analysis (Figure 3), DAPC was also performed using only the three Native American populations of Brazil (Figure 4). The ASU population forms a cluster isolated from the other two Native American populations in the x-axis (LD1) and consequently has more differences. KOA and KAY, although still forming different clusters (y-axis, LD2), have some intercession between them that shows a greater similarity of these regarding the ASU group.

Figure 4 Discriminant analysis of principal components (DAPC) of 117 PGx markers. Scatterplot for the three Native American populations of Brazil (KOA, ASU, and KAY).

Table 2 shows the list of the most contributing PGx markers to each discriminant function (LD1 and LD2) in both DAPC analysis. The first section of Table 2 shows the most important markers in the discrimination shown in Figure 3. LD1 corresponds to the x-axis demonstration of the scatterplot; this discriminant function allows differentiate the AFR population (Figure 3). Among the markers listed in LD1, we highlight CYP3A4 (rs2740574), GRIK4 (rs1954787), and OPRM1 (rs1799971), which are more relevant in differentiating AFR from other populations. The second linear discriminant (LD2) corresponds to the scatterplot demonstrative y-axis (Figure 3); along this axis, the rest of the populations are distributed. Among the markers listed in LD2, we highlight CYP1A2 (rs2069514), CYP2A6 (rs28399433), CYP2E1 (rs2070673), SLCO1B1 (rs2306283), and SOD2 (rs4880), which have been shown to have greater relevance in differentiating EUR from EAS.

Table 2 List of Most Contributing PGx Markers to Each Linear Discriminant Function (LD1 and LD2) in DAPC for Nam and 1000 Genome Populations (Top) and for the Three Native American Populations of Brazil (Bottom)

The second section of Table 2 shows the most important markers to differentiate the Brazilian Native American populations among themselves (KOA, ASU, and KAY). LD1 corresponds to scatterplots x-axis demonstration (Figure 4). Among the markers listed in LD1, we highlight ABCB1 (rs1128503), GSTP1 (rs1695), and UGT2B15 (rs1902023), which are of greater relevance in differentiating the ASU population from the other Native American populations investigated. LD2 corresponds to scatterplots y-axis demonstration (Figure 4). Among the markers listed in LD2, we highlight ABCG2 (rs2231142), CYP2E1 (rs2070673), and NAT2 (rs1041983), which are more relevant to differentiate KOA from the other Native American populations in Brazil.

The Amazonian Native American populations present low degrees of genetic admixture with non-indigenous population, a fact that is highly important for studies involving these groups, which remain genetically isolated from others and may offer advantages in genome-wide studies of hereditary diseases.18,19 The Amazonian Native Americans of this study presented mean values of Native Americans genomic ancestry of 96.2%, which confirms the low genetic admixture of these populations.

Several studies have shown large genetic variation for important PGx biomarkers between distinct populational groups.2022 The knowledge obtained to date in PGx genes in Native American populations is very limited to specific genes, failing to reach a wider genome context.23,24 The investigation of important PGx polymorphisms in the genes selected by our panel has the potential to provide powerful information regarding the predictivity of therapeutic response to the use of different drugs and xenobiotics in Amazonian Native Americans and/or admixed populations with this ethnic group. Although PGx biomarkers genotyping is useful to guarantee a more accurate prediction of the response to drugs in Amazonian Native Americans, it is also necessary to consider other factors such as ethnic origin and environmental factors of each population.

The pharmacogenomic data obtained from populations were compared to global populations from the 1000 Genomes Project Consortium.8 In our analyses, the DAPC identified a set of SNPs in PGx genes that most contributed to grouping global populations into clusters, making it possible to infer which populations have the highest level of similarity regarding PGx genes (Figure 1).

The distancing of AFR in the plot is due to the out-of-Africa hypothesis, in which modern human populations originated in Africa and migrated to other continents in the world; thus, the African populations show a greater genetic diversity that was reflected in the PGx data evaluated.25 The data demonstrate the formation of relatively close clusters among the three Amazonian Native American populations.

The SAS and AMR groups formed similar clusters regarding the PGx data evaluated. Our results showed that Amazon Native American populations are located between this cluster and the EAS grouping. The formation of the AMR population (Peru, Mexico, Puerto Rico, and Colombia) occurred through abundant mixing between European, African, and Native American groups.26,27 Therefore, the similarity between Amazonian Native American groups and AMR is possible due to the high level of admixture of these populations with indigenous peoples.19,27 Several authors have demonstrated genetic affinities between Native American and Asian populations,28,29 which corroborates the findings of our study. This similarity of PGx genes is based on the hypothesis of migration of Asian populations to the Americas through the Bering Strait.30

The DAPC analysis revealed in LD1 the most important polymorphisms capable of differentiating AFR and the rest of the world in the CYP3A4, GRIK4, and OPRM1 genes. The divergence found for these polymorphisms in AFR may influence the therapy of different drugs for the populations formed and derived from them. The CYP3A4 gene presents genetic information referenced by FDA and EMA agencies in package inserts of different drug classes, such as antineoplastics, antipsychotics, and antiretrovirals (Food and Drug Administration, n.d.; For et al, n.d.). Polymorphisms in the GRIK4 and OPRM1 genes are strongly associated with an altered response upon treatment with antidopaminergic and opioid-based drugs.3234

We observed that the PGx locus investigated could also separate EUR and EAS clusters (LD2) through the P450 family represented by three genes: CYP1A2, CYP2A6, and CYP2E1. The polymorphism in the CYP2A6 gene is particularly important because it defines the interindividual variability in the tolerability of the S1 antineoplastic therapy between European and Asian populations, which is considered a genetic-dependent scheme.35 Other genes that strongly contributed to differentiating global populations (EUR x EAS) were the SLCO1B1 and SOD2 genes. The FDA warns that higher plasma concentrations of the rosuvastatin have been seen in small groups of patients homozygous for the SLCO1B1 rs4149056 variant.31 The polymorphism in SOD2 is associated with adverse effects observed during the use of asparaginase in patients with acute lymphoid leukemia and cyclophosphamide as antineoplastic.36,37

Here, we will discuss the genotype/phenotype relationship of important PGx genes evaluated in Figures 3 and 4. Our results demonstrated significant differences at the genotype level of five genes among the Brazilian Native American groups (CYP4F2, CYP2D6, CYP2B6, DPYD, and CYP3A5) and the phenotypic profile of two genes (CYP2D6 and CYP4F2).

The CYP4F2 gene has great relevance in the evaluation of metabolism and dose adjustment of warfarin.38 A polymorphism (rs2108622) was investigated in this gene to define haplotype *3. The three Native American populations of the study demonstrated a high frequency of the wild-type homozygous genotype (*1/*1) followed by the heterozygous genotype (*1/*3). The KAY population demonstrated a differentiated metabolization profile since it was the only one to present the mutant homozygous genotype (*3/*3), which is determinant to define the PM profile. Moreover, this group also showed higher frequencies of the heterozygote genotype in comparison with the other populations investigated.

Populations from EUR, EAS, and AMR have frequencies of the CYP4F2*3 haplotype similar to the corresponding global population (24%), as described in the design from 1000 Genomes Project Consortium.8 AFR presented low frequencies of this haplotype (8%), which was similar to that found in our study for Native American populations (11%). Shendre et al showed that the warfarin dose varies according to ancestry background by the influence of the CYP4F2 gene.39 These researchers reported that the CYP4F2*3 variant was associated with higher doses of warfarin in European/American, Asian, and Hispanic populations, while Africans, Americans, and Brazilians, especially self-declared blacks, presented low frequencies of this mutation and therefore showed no need for warfarin dose adjustment.39

The CYP2D6 gene plays an important role in the metabolism of approximately 25% of clinically important drugs, including antidepressants, antipsychotics, antiarrhythmic drugs, antihistamines, -blockers, and antineoplastics.40 Polymorphisms of this gene have been extensively studied in several population groups; however, little is known about this gene in indigenous populations.41

Different studies in world populations describe a similar profile of CYP2D6 gene activity to that found in Amazonian Native Americans, with high frequencies of extensive metabolizer (EM) and low frequencies of ultra-rapid metabolizers (UM) or poor metabolizers (PM).27,40,42 In the Native American populations investigated, the alleles *1 and *2 (including *2A) were the most observed with frequencies of 58% and 32%, respectively. These alleles are associated with the normal metabolic function of the enzyme and therefore are decisive for the definition of EM, which was also the most frequent metabolic profile in the sample investigated (97%).43 These results are similar to other populations from the 1000 Genomes Project Consortium, except for AFR and EAS, which have lower frequencies of this metabolic profile.

The alleles associated with null enzyme activity (*4 and *5) were found in approximately 7% of the Native Americans, presenting in the heterozygous genotype. The PM profile was not found in any of the three Native American groups studied. This metabolic profile is considered rare in continental populations, except in Europeans.43 The frequency of PM described in the admixed population of Brazil is 4%.44 Studies have reported that other Native American populations have reduced frequencies of nonfunctional alleles in the CYP2D6 gene. In Venezuela and Mexico, mean frequencies of 3% of the *4 allele were reported,23,45 while in Costa Rica, the observed mean frequency was 7%.27 There were exceptions in Native Americans: Bribri, and Cabebar from Costa Rica, Bari from Venezuela, and Seris from Mexico presented high frequencies of the referred allele (31, 27, 42, and 21%, respectively).41,45

The intermediate metabolizer (IM) profile is defined by the presence of genotypes with reduced function alleles (*9 and *29). Data estimated by the 1000 Genomes Project demonstrate low frequencies of these alleles in world populations except for AFR, SAS, and EAS.8,43 In Native populations of the Brazilian Amazon, the IM profile was rare (1%), found exclusively in the KOA group. Our results differ from other studies with Native Americans that determined high frequencies of these alleles in Seris (41.2%) and Mayos (22.7%) from Mexico and Bari (35%) from Venezuela.41,45 Perez-Paramo et al have suggested that differentiated profiles of the null/reduced metabolic activity in the CYP2D6 gene in other indigenous populations of South America are the result of food selection and lifestyle processes that these populations have undergone.46 Patients with PM and IM profiles have a higher risk of developing adverse reactions to CYP2D6-substrate treatments.41 Therefore, the lack of PM and the low frequency of IMs in the Amazonian Native Americans of Brazil may represent a lower risk of toxicity development during these therapeutic schemes.41,45

The UM profile is determined by the presence of functional allele duplications, increasing the enzymes mechanism of action on metabolism. In the investigation of Amazonian Native Americans, the UM profile was found exclusively in the KAY population at low frequencies (2%). In the admixed population of Brazil, frequencies similar to the Amazonian Native Americans were reported (5%).16 In contrast, high percentages of UMs were described in Native Mexican populations (20%) and Guatuso from Costa Rica (18.8%).27 According to Lazalde-Ramos, the probable cause for the gain of active genes in these indigenous populations could be natural selection.41 Environmental factors, such as diet, could have exerted a selective advantage over duplicate CYP2D6 genes, increasing the survival rate of these individuals. It is believed that a similar phenomenon occurred in Ethiopia and Saudi Arabia, where the highest frequency of multiple active CYP2D6 genes has been described.41 Individuals with multiple active CYP2D6 copies metabolize drugs more rapidly; therefore, the therapeutic effect in standard doses is not achieved. For instance, reduced concentrations of drugs, such as tramadol, venlafaxine, morphine, and mirtazapine, were reported in patients with UM profiles.41

In conclusion, the Amazon Native Americans of Brazil presented high frequencies of EMs (97%), absence of PM, and low frequencies of IM (1%) and UM (2%). This population, thus, has a metabolic profile with normal CYP2D6 enzyme, mostly resulting in reduced adverse reactions and the obtention of adequate concentrations of drugs, thereby achieving the desired therapeutic effect.

The CYP2B6 gene is involved in the metabolism of several drugs, including antiretrovirals and opioids, such as efavirenz and methadone.47,48 The most frequently deficient allele of this gene is CYP2B6*6 (rs3745274), where homozygous and heterozygous carriers for this nonfunctional allele have demonstrated PM phenotypes for various drugs, such as those mentioned above.

In the Brazilian Native American populations, a relatively high frequency of the *6 alleles was observed in both the heterozygous genotype (*1/*6) and the homozygous genotype (*6/*6). The mean frequency of the *6 allele in the Amazonian indigenous populations was 27%. According to data from the 1000 Genomes Project Consortium, the mean frequency of this allele in continental populations is 32%, which is similar to the value found in the Native Americans of this study.

Due to the frequency of the *6, determinant allele for PM profile, found in the Amazonian Native American populations, it can be inferred that this population presents greater risks of developing toxicities if they are submitted to antiretroviral and opioid treatments. There are no studies investigating the CYP2B6*6 genotype in other Native American populations.

The DPYD gene is a biomarker for predicting severe toxicity in chemotherapeutic treatments, specifically fluoropyrimidine-based therapies. The guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC) describe three DPYD haplotypes as the major nonfunctional variants (*2A [rs3918290], *13 [rs55886062], and rs67376798) and strongly recommend the use of alternative drugs or the reduction (in 50%) of the standard dose of fluoropyrimidines for patients who are homozygous or heterozygous for any of these variants.49,50 These polymorphisms were investigated in the Amazonian Native American populations, but their deleterious alleles were not observed.

Another polymorphic variant of DPYD is the *9 allele (rs1801265). This mutation induces an exchange of amino acids in the gene product (dihydropyrimidine dehydrogenase [DPD]), which can affect the enzymatic activity of the protein. The allele *9 was observed in both genotypes *1/*9 and *9/*9 in our Native American populations with an average allelic frequency of 16%. This frequency is not in agreement with that found in the continental populations described in the 1000 genomes database, where the MAF is 26%. Despite the change in amino acids in the DPD protein caused by the *9 allele, there are still divergences in the literature regarding the possible alterations that this allele may cause to the metabolizing phenotypes of the DPYD gene.49,51

Thus, as the Amazonian Native Americans investigated do not have deleterious alleles of the three main polymorphic variants of the DPYD gene and as the *9 allele has not been correlated as a potential interference in therapeutic conducts, they are classified as extensive metabolizer and may, if needed, benefit from fluoropyrimidine-based treatments.

The CYP3A5 gene is highly relevant to immunosuppressive therapies (Tacrolimus, Sirolimus, s and Everolimus), and dose adjustment is recommended for these drugs based on rs776746 SNP genotyping that characterizes the *3 allele.52 Amazonian Native Americans have a high frequency of the *3 allele in the three populations evaluated and, consequently, a large number of individuals with a PM profile. Data from the 1000 Genomes Project confirm that the deleterious allele *3 in the CYP3A5 gene is strongly influenced by population groups. The frequency of this polymorphism in Amazonian Native Americans (63%) resembles SAS and EAS populations with a frequency of 69%; however, it shows divergence with the EUR (94%) and AFR (18%) populations.8

A recent study evaluated the frequency of the rs776746 polymorphism and its association with hypertension in eight indigenous populations from Mexico.53 The analysis report that the CYP3A5*3/*3 genotype frequencies ranged from 23.5% in Mexicaneros to 93.3% in Mayos, and the mean observed in the Mexican indigenous groups was 67.5% (very similar to the frequency found in the Native Americans of our study). Also, Galaviz-Hernandez et al found that the CYP3A5*3/*3 genotype was more frequent in indigenous women with higher systolic and diastolic blood pressures values.

Birdwell et al have shown an increase in the chances of having the *3 allele for individuals with greater European ancestry and a reduction for those with a greater African ancestry influence.54 A study with miscegenated transplant recipients in Brazil identified benefit when adjusting tacrolimus dose according to the genotypes *3, *6, and *7.55 The Brazilian protocol is based on the European protocol, which considers the high frequencies of the *3 allele in its population. The design of the protocol for individuals carrying the *1 allele requires an increase in the dose of tacrolimus since this allele characterizes the extensive metabolism phenotype.54,56 The Native American populations combined showed a frequency of 12% of this phenotype; consequently, these individuals may have low therapeutic efficacy with the use of tacrolimus through a standard protocol.

Although the SLCO1B1 variants did not show significant differences between the Native Americans populations, they have high frequencies of phenotypes that confer decreased or poor function of the SLCO1B1 protein-coding, which is extremely important from the pharmacogenomic point of view. The FDA and EMA have clinical recommendations based on SLCO1B1 genotyping in the use of statin therapies.57 The FDA recommends against 80 mg daily simvastatin dosage.31 In patients with the C allele at SLCO1B1 rs4149056, there are modest increases in myopathy risk, even at lower simvastatin doses (40 mg daily); if optimal efficacy is not achieved with a lower dose, alternate agents should be considered.58

Our results indicate a high frequency of the PM phenotype in samples of Amazonian Native Americans. The PM profile was characterized in our study by the high frequency of the mutant allele in the 521T> C polymorphism (defined as haplotype *5 or *15) of 43% in Amazonian Native Americans, which differs from the frequency found in other world populations from the 1000 Genomes Project (9%).6 The high frequency of this allele in Native American populations may have an important impact on the therapeutic course with the use of different statin-based drugs in these populations due to the risk of myopathies and other adverse effects resulting from therapeutic conduction.

Finally, it is well-known that important PGx loci have great variation among world populations. Therefore, investigations that analyze the pharmacogenomic profile of understudied ancestral population groups, such as Native Americans and, consequently, populations admixed with them, will facilitate the implementation of protocols of precision medicine for these populations.

Most protocols of therapeutic conduct used in Brazilian populations are based on recommendations for populations of European origin. Thus, studies that show population differences for these important loci can assist in the design of targeted protocols for Native American populations and the populations admixed with them, as these groups are commonly underrepresented in pharmacogenomic studies.

The study was approved by the National Committee for Ethics in Research (CONEP) and by the Ethics and Research Committee of the Federal University of Par, with CAAE number 20,654,313.6.0000.5172. The informed consent was obtained from each study participant, as well as the ethnic group leaders, and all research methods in this study were performed in accordance with the Declaration of Helsinki.

The authors thank the Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela (USC), Ncleo de Pesquisas em Oncologia and Laboratrio de Gentica Humana e Mdica (both from the Universidade Federal do Par) for collaborating in the development of the study; the Coordenao de Aperfeioamento de Pessoal de Nvel Superior (CAPES) for financing the first authors scholarship in Brazil and in the Doctorate Sandwich Program.

The authors acknowledge funding from the Research Support Program - Projetos temticos da Fundao Amaznia de Amparo a Estudos e Pesquisa do Par: Sade, N 006/2014 (FAPESPA/CNPq) and the Pr-Reitoria de Pesquisa e Ps-Graduao (PROPESP) of the Universidade Federal do Par (UFPA). The first authors scholarship in Brazil and the Doctorate Sandwich Program were financed by CAPES (N process: 99999.003676/2015-03). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The authors declare no conflicts of interest in this work.

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21. Jittikoon J, Mahasirimongkol S, Charoenyingwattana A, Chaikledkaew U, Tragulpiankit P, Mangmool S. Comparison of genetic variation in drug ADME-related genes in Thais with Caucasian, African and Asian HapMap populations. J Hum Genet. 2016;61(2):119127. doi:10.1038/jhg.2015.115

22. Rodrigues JCG, Fernandes MR, Guerreiro JF, Ribeiro-dos-Santos C, Santos S. Polymorphisms of ADME-related genes and their implications for drug safety and efficacy in Amazonian Amerindians. Sci Rep. 2019;9(1):7201. doi:10.1038/s41598-019-43610-y

23. Cuautle-Rodrguez P, Llerena A, Molina-Guarneros J. Present status and perspective of pharmacogenetics in Mexico. Drug Metabol Drug Interact. 2014;29(1):3745. doi:10.1515/dmdi-2013-0019

24. Chiurillo MA, Griman P, Santiago L, Torres K, Moran Y, Borjas L. Distribution of GSTM1, GSTT1, GSTP1 and TP53 disease-associated gene variants in native and urban Venezuelan populations. Gene. 2013;531(1):106111. doi:10.1016/j.gene.2013.08.055

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[Full text] Genetic Diversity of Drug-Related Genes in Native Americans of the Bra | PGPM - Dove Medical Press

Weve all heard the conspiracy theoriesabout COVID-19. Now a whole new set is emerging around COVID vaccines and spreading as virulently as the pandemic they are meant to control.

Though the public health community tends to resort to reassurances about some of the more reasonable concerns yes, the vaccines have been developedincredibly quicklyand short-term side effects can occur this post aims to do something different.

Were going right to the heart of the matter. So no, COVID-19 vaccines arent delivery vehicles for government microchips. They arent tainted by material from aborted fetuses. And they wont turn us into GMOs though some of them do use genetic engineering, and all of them use genetics more broadly.

We think this is way cool something to celebrate, not shy away from. So, were doing the deep reveal on exactly how genetics and biotechnologyhavebeen a central component of the vaccine effort. Because we know the conspiracists dont care about evidence, anyway.

First up: mRNA. It wont reprogram your brain. But it does reprogram some of your cells, in a manner of speaking. And thats not a defect its intentional.

To get your head around this you need to understand what mRNA is for. Basically, its a single-stranded nucleic acid molecule that carries a genetic sequence from the DNA in the cells nucleus into the protein factories called ribosomes that sit outside the nucleus in the cellular cytoplasm.

Thats what the m in mRNA stands for: messenger. Messenger RNA just carries instructions for the assembly of proteins from the DNA template to the ribosomes. (Proteins do almost everything that matters in the body.) Thats it.

This is useful for vaccines because scientists can easily reconstruct specific genetic sequences that encode for proteins that are unique to the invading virus. In the COVID case, this is the familiar spike protein that enables the coronavirus to enter human cells.

What mRNA vaccines do is prompt a few of your cells near the injection site to produce the spike protein. This then primes your immune system to build the antibodies and T-cells that will fight off the real coronavirus infection when it comes.

Its not hugely different from how traditional vaccines work. But instead of injecting a weakened live or killed virus, the mRNA approach trains your immune system directly with a single protein.

Contrary to assertions made by the crazies, it wont turn you or anyone else into a GMO. mRNA stays in the cytoplasm, where the ribosomes are. It does not enter the nucleus and cannot interact with your DNA or cause any changes to the genome. No Frankencure here, either.

A variant of the mRNA approach is to go one step back in the process and construct a vaccine platform out of DNA instead. This DNA template constructed by scientists to encode for the coronavirus spike protein gets into cells where it is read into mRNA and well the rest is the same.

You might ask whether this DNA can genetically engineeryourcells. Once again, the answer is no. DNA is injected in little circular pieces called plasmids not to be confused with plastics and while these do enter the nucleus, the new DNA does not integrate into your cellular genome. Got it?

This one really is genetically engineered. But what does that actually mean?

The Oxford vaccine uses what is called a viral vector approach. The scientific team took an adenovirus a type of pathogen that causes a common cold and spliced in the same spike protein genetic sequence from the coronavirus.

The adenovirus simply serves as the vehicle to get the genetic sequence into your cells. Thats why its called a viral vector after all. Viruses have been designed by billions of years of evolution precisely to figure out ways to sneak into host cells.

Note that genetic engineering is an essential part of the development process. Firstly, vector viruses are stripped of any genes that might harm you and actually cause disease. Genes that cause replication are also removed, so the virus is harmless and cannot replicate.

Then the coronavirus spike protein genes are added a classic use of recombinant DNA. So yes, the Oxford/AstraZeneca vaccine does actually mean a genetically engineered virus is injected into your body.

And thats a good thing. In the past, for example with the polio vaccine, live viruses in the vaccine can sometimes mutate and revert to being pathogenic, causingvaccine-derived polio. You can see its far better to use a GM virus that cannot cause any such harm!

As we have reported before at the Alliance for Science, the anti-GMO and anti-vaccine movementssubstantially overlap. These groups tend to share an ideology that is suspicious of modern science and fetishsize natural approaches instead. Whatever natural means.

Note that these groups are not always marginalized to the fringe where they belong. In Europe, anti-GMO regulations have stymied any substantial use of crop biotechnology for nearly two decades, hindering efforts to to make agriculture more sustainable.

And back in July, the European Parliament actually had tosuspend the EUs anti-GMO rulesin order to allow the unimpeded development of COVID vaccines. Very embarrassing for Brussels!

Will the anti-GMO and anti-vaxxer movements use their usual scaremongering tactics to drum up fear, increase vaccine hesitancy and thereby prolong the hell of the COVID-19 pandemic? That remains to be seen. If they do succeed, then tragically many more people will die and our economies will continue to suffer. Its up to all of us the grassroots pro-science movement to stop them.

Mark Lynas is an environmental/science writer. Follow Mark on Twitter @mark_lynas

A version of this article was originally posted at the Cornell Alliance for Science and has been reposted here with permission. The Cornell Alliance for Science can be found on Twitter @ScienceAlly

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Genetic engineering gave us COVID vaccines. Here's how they work, and why you shouldn't be frightened - Genetic Literacy Project

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ABOUT PREMIER MEDICAL LABORATORY

Premier Medical Laboratory Services (PMLS), based in Greenville, South Carolina, is an advanced diagnostics lab fully certified by top laboratory accrediting organizations, including Clinical Laboratory Improvement Amendments (CLIA) and COLA. PMLS has themost advanced laboratory information systems (LIS) to generate easy to read one-page test result reports with higher accuracy and a customizable report for each client. The company also is proud to offer a patient friendly billing policy. For more information, please visitwww.PreMedInc.comor call 1.877.335.2455.

ABOUT PATIA

Patia's vision is to reduce the number of cases of diabetes and improve the quality of life of diabetic people, creating solutions and supporting a healthy lifestyle.Patiahas developed a platform of solutions to prevent, manage and intervene in type 2 diabetes and gestational diabetes. This uniquely and cost-effectively platform integrates a set of high-performance genotyping tests with predictive algorithms, digital applications and lifestyle intervention. Patia's activity starts by translating the knowledge from large genetic studies on diabetes and gestational diabetes performed at prestigious academic and research institutions.

SOURCE Premier Medical Laboratory Services

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