StemCell Therapy

Kiwi agricultural research in genetics and breeding will be boosted by a new Massey University-led centre launched today.

The AL Rae Centre - named in memorial for the late Massey emeritus professor who was one of the founders of modern animal breeding - will headed by world-leading Kiwi scientist Professor Dorian Garrick, who has returned to New Zealand for the top role of chief scientist.

It aims to advance quantitative breeding, genetics and genomics to benefit the agricultural sector, along with a new wave of scientists through postgraduate courses.

Positions for four PhD scholarships, one postdoctoral fellow and two eminent visiting scientists have been created with a $250,000 gift from The Norman FB Barry Foundation.

"We cannot stress the importance of those funds to what we seek to do," co-director Professor Hugh Blair said.

"The country's top students were enticed away from discovery science in genetics because of the greater salaries in banking and other agribusinesses areas."

Low salaries for PhD students in New Zealand had resulted in more attractive opportunities for these talented people elsewhere - either completing their PhD studies overseas or going directly into employment here, Blair said.

"This had led to underachievement in discovery science for a number of years, with similar science centres around New Zealand suffering from lack of resources and a short-term focus driven by an industry keen on solving the issues at hand.

"For a number of years there has been a lack of research in quantitative genetics, in favour of molecular genetics. We want to marry these two areas to get a picture of the overall merit of the animal."

The centre will be based in AgResearch's Ruakura Research Centre, away from the university's three campuses, but closer to industries it will work with.

Blair said its big drawcard would be Garrick, who has been involved in animal evaluation programmes, performance recording databases and breeding schemes around the world.

"He is one of the world's top animal breeders and he has worked on a variety of genetic improvement programs around the world, including beef cattle, dairy cattle, dual-purpose sheep, fine-woolled sheep, pigs, elk, chickens, salmon and tree breeding."

Garrick said New Zealand had many opportunities to boost returns from its primary industries, through selection based on accurate predictions of performance using genomic data.

The work led by the centre would apply to a wide range of traits and species, and could comprise large pedigrees of millions of animals.

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New centre to boost Kiwi agricultural research - NZ Herald - New Zealand Herald

CHARLOTTESVILLE, Va. (NEWSPLEX) -- Researchers at the University of Virginia have come up with a safe way to successfully "shut off" genes, potentially leading to a cure for genetic diseases.

Gene editing, using the CRISPR system, has been around for several years, but cells would often be damaged in the editing process.

However, a team at UVA has figured out a way to silence genes without harming surrounding cells, opening the door to new methods of treating and preventing diseases that are written in an individual's genome.

The team says the discovery will eventually help doctors turn genes off that are making patients sick, while also enabling scientists to more directly research individual genes.

"For a lot of these genes in our body, we still don't know their functions," said Mazhar Adli, assistant professor in UVAs Department of Biochemistry and Molecular Genetics. "So now we are able to go and inactivate each gene and to study what the gene is doing."

Cystic fibrosis and hemophilia are among the diseases doctors could possibly treat with the gene-silencing method.

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UVA scientists successfully, safely "shut off" genes - The Charlottesville Newsplex

July 4, 2017

IVF embryos whose cells have mixed chromosomal profiles - one normal, another abnormal - still have the potential to implant in the uterus and become a healthy pregnancy, according to a study presented today at the 33rd Annual Meeting of ESHRE.

This pattern of embryonic mosaicism, which is characterised by the presence of two or more genetically distinct cell lineages, typically one with a chromosome abnormality and the other with a normal chromosome composition, has become a controversial topic in recent months, with debate over their potential viability. In the light of this latest study, which was performed by the GENOMA group and European Hospital IVF Center in Rome, Dr Francesco Fiorentino from the Molecular Genetics Laboratory of GENOMA, who will present today's study, said that its results "confirm that mosaic embryos can develop into healthy euploid [chromosomally healthy] newborns".

This possibility was first raised by Dr Fiorentino's group and the European Hospital in a letter to the New England Journal of Medicine in November 2015, which described six healthy deliveries in a small series of 18 women for whom embryo screening had found no chromosomally normal (euploid) embryos.(1) Up to this point mosaic embryos were not usually transferred in IVF because they (like all other aneuploid embryos) were considered abnormal. Even in their NEJM letter, the Rome investigators noted that "it is reasonable to assume that mosaicism reduces the likelihood of success of IVF".

The bottom line of this latest study reported at ESHRE is that success or failure following the transfer of a mosaic embryo in IVF depends on the extent of the mosaicism and chromosomal abnormality (aneuploidy) in the embryo.

The study included 73 women for whom embryo screening following IVF had found no chromosomally normal embryos for transfer. Screening had, however, identified mosaic embryos in each of these patients, which were then offered for transfer. For the purpose of the study and assessment of development potential, these mosaic embryos were classified as having low (<50%) or high (>50%) degrees of aneuploidy.

Results of the study showed that pregnancy and delivery were indeed possible following the transfer of mosaic embryos. However, the transfers of mosaic embryos with a high percentage of chromosomally abnormal cells (>50%) resulted in a live birth rate of 16.7%, with a miscarriage rate of 10%. In contrast, mosaic embryos with a lower aneuploidy percentage (<50%) resulted in a higher live birth rate of 39.5%, with miscarriage occurring in just 7.0% of the transfers. The difference between the two delivery rates was statistically significant, suggesting, said Dr Fiorentino, that "priority for transfer should be given to mosaic embryos with low levels of aneuploidy".

Dr Fiorentino said there are several reasons why an embryo with clearly detectable levels of aneuploidy might self-correct and develop into a healthy newborn. One reason, he explained, may be related to the fact that the aneuploid cells have a growth disadvantage or are simply eliminated by processes such as apoptosis. This may lead to a decline in number as the embryo develops, ultimately resulting in a normal fetus.

However, he added that mosaic embryos may now be considered a "distinct category" in terms of potential to implant and develop, lying somewhere between euploid and fully aneuploid embryos. "Euploid embryos have a higher implantation potential than mosaic embryos," said Dr Fiorentino, "and because of this we suggest that mosaic embryos should only be transferred in women with no euploid embryos available. The transfer of euploid embryos, when available, results in higher implantation rates and a lower risk of miscarriage, and represents the preferred option for IVF patients."

Dr Fiorentino added that this finding - that mosaic embryos have the potential for implantation and pregnancy and may influence the clinical outcome of IVF - now suggests that all women may benefit from aneuploidy testing before embryo transfer.

Explore further: The more eggs the better in IVF?

More information: Abstract O-182, Tuesday 4 July 2017: The extent of chromosomal mosaicism influences the clinical outcome of in vitro fertilization treatments

A higher number of eggs retrieved in an IVF treatment cycle is independently associated with more chromosomally normal embryos available for transfer, according to a new Australian study. However, the benefit of a greater ...

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The transfer of chromosomally 'abnormal' embryos can still result in pregnancy in IVF - Medical Xpress

Whole genome sequencing involves the analysis of all three billion pairs of letters in an individuals DNA and has been hailed as a technology that will usher in a new era of predicting and preventing disease.

However, the use of genome sequencing in healthy individuals is controversial because no one fully understands how many patients carry variants that put them at risk for rare genetic conditions and how theyand their doctorswill respond to learning about these risks.

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In a new paper published June 26 in the Annals of Internal Medicine by investigators at Harvard Medical School and Brigham and Womens Hospital, along with collaborators at Baylor College of Medicine, report the results of the four-year, NIH-funded MedSeq Project, the first-ever randomized trial conducted to examine the impact of whole genome sequencing in healthy primary care patients.

In the MedSeq Project, 100 healthy individuals and their primary care physicians were enrolled and randomized so that half of the patients received whole genome sequencing and half did not.

Nearly 5,000 genes associated with rare genetic conditions were expertly analyzed in each sequenced patient, and co-investigators from many different disciplines, including clinical genetics, molecular genetics, primary care, ethicsand law, were involved in analyzing the results.

Researchers found that among the 50 healthy primary care patients who were randomized to receive genome sequencing, 11 (22 percent) carried genetic variants predicted to cause previously undiagnosed rare disease.

Two of these patients were then noted to have signs or symptoms of the underlying conditions, including one patient who had variants causing an eye disease called fundus albipunctatus, which impairs night vision.

This patient knew he had difficulty seeing in low-light conditions but had not considered the possibility that his visual problems had a genetic cause.

Another patient was found to have a genetic variant associated with variegate porphyria, which finally explained the patients and family members mysterious rashes and sun sensitivity.

The other nine participants had no evidence of the genetic diseases for which they were predicted to be at risk. For example, two patients had variants that have been associated with heart rhythm abnormalities, but their cardiology workups were normal. It is possible, but not at all certain, that they could develop heart problems in the future.

Sequencing healthy individuals will inevitably reveal new findings for that individual, only some of which will have actual health implications, said lead author Jason Vassy,an HMS assistant professor of medicine at Brigham and Womens and primary care physician at the VA Boston Healthcare System.

This study provides some reassuring evidence that primary care providers can be trained to manage their patients sequencing results appropriately, and that patients who receive their results are not likely to experience anxiety connected to those results. Continued research on the outcomes of sequencing will be needed before the routine use of genome sequencing in the primary care of generally healthy adults can be medically justified, Vassy said.

Primary care physicians received six hours of training at the beginning of the study regarding how to interpret a specially designed, one-page genome testing report summarizing the laboratory analysis.

Consultation with genetic specialists was available, but not required. Primary care physicians then used their own judgment about what to do with the information, and researchers monitored the interactions for safety and tracked medical, behavioral and economic outcomes.

The researchers noted that they analyzed variants from nearly 5,000 genes associated with rare genetic diseases. These included single genes causing a significantly higher risk for rare disorders than the low-risk variants for common disorders reported by direct-to-consumer genetic testing companies. No prior study has ever examined healthy individuals for pathogenic (high-risk) variants in so many rare disease genes.

We were surprised to see how many ostensibly healthy individuals are carrying a risk variant for a rare genetic disease, said Heidi Rehm, HMS associate professor of pathology at Brigham and Women's anddirector of the Laboratory for Molecular Medicine at Brigham and Women's.

We found that about one-fifth of this sample population carried pathogenic variants, and this suggests that the potential burden of rare disease risk throughout our general population could be far higher than previously suspected,said Rehm, a co-investigator on the study who directed the genome analysis.However, the penetrance, or likelihood that persons carrying one of these variants will eventually develop the disease, is not fully known.

Additionally, investigators compared the two arms of the studyand found that patients who received genome sequencing results did not show higher levels of anxiety. They did, however, undergo a greater number of medical tests and incurred an average of $350 more in health care expenses in the six months following disclosure of their results. The economic differences were not statistically significant with the small sample size in this study.

Because participants in the MedSeq Project were randomized, we could carefully examine levels of anxiety or distress in those who received genetic risk information and compare it to those who did not, said Amy McGuire,director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine.

While many patients chose not to participate in the study out of concerns about what they might learn, or with fears of future insurance discrimination, those who did participate evinced no increase in distress, even when they learned they were carrying risk variants for untreatable conditions, saidMcGuire, who supervised the ethical and legal components of the MedSeq Project.

There has also been great concern in the medical community about whether primary care physicians can appropriately manage these complicated findings. But when a panel of expert geneticists reviewed how well the primary care physicians managed the patients with possible genetic risk variants, the experts determined that only two of the 11 cases were managed inappropriately and that no harm had come to these patients.

MedSeq Project investigators note that the studys findings should be interpreted with caution because of the small sample size and because the study was conducted at an academic medical center where neither the patients nor the primary care physicians are representative of the general population. They also stressed that carrying a genetic risk marker does not mean that patients have or will definitely get the disease in question. Critical questions remain about whether discovering such risk markers in healthy individuals will actually provide health benefits, or will generate unnecessary testing and subsequent procedures that could do more harm than good.

Integrating genome sequencing and other -omics technologies into the day-to-day practice of medicine is an extraordinarily exciting prospect with the potential to anticipate and prevent diseases throughout an individuals lifetime, said senior author Robert C. Green, HMSprofessor of medicineat Brigham and Womens Hospital,associate member of the Broad Institute of Harvard and MITandleader ofthe MedSeq Project. But we will need additionalrigorously designed and well-controlled outcomes studies like the MedSeq Project with larger sample sizes and with outcomes collected over longer periods of time to demonstrate the full potential of genomic medicine.

The MedSeq Project is one of the sites in the Clinical Sequencing Exploratory Research Consortium and was funded by the National Human Genome Research Institute, part of the National Institutes of Health.

The Genomes2People Research Program at Brigham and Womens Hospital, the Broad Institute and Harvard Medical School conducts empirical research in translational genomics and health outcomes. NIH-funded research within G2P seeks to understand the medical, behavioral and economic impact of using genetic risk information to inform future standards. The REVEAL Study has conducted several randomized clinical trials examining the impact of disclosing genetic risk for a frightening disease. The Impact of Personal Genomics (PGen) Study examined the impact of direct-to-consumer genetic testing on over 1,000 consumers of two different companies. The MedSeq Project has conducted the first randomized clinical trial to measure the impact of whole genome sequencing on the practice of medicine. The BabySeq Project is recruiting families of both healthy and sick newborns into a randomized clinical trial where half will have their babys genome sequenced. Green directs the Program.

Adapted from a Brigham and Women's news release.

Link:
Genetic Testing for the Healthy - Harvard Medical School (registration)

Three courts in Britain agreed with the hospital, as did the European Court of Human Rights, which last week rejected a last-ditch appeal by Charlies parents.

But Pope Francis and Mr. Trump have also weighed in, adding another dimension to an extraordinarily thorny bioethical and legal dispute that pits Britains medical and judicial establishment against the wishes of the childs parents.

Judges in the case have acknowledged that the case highlights differences in law and medicine and an American willingness to try anything, however unlikely the possibility of success but have held that prolonging the infants life would be inhumane and unreasonable. The case echoes the one of Terri Schiavo, a Florida woman who was left in a persistent vegetative state after a cardiac arrest and was also the subject of a court battle.

A Vatican spokesman, Greg Burke, told Vatican Radio on Sunday that the pope had been following the parents case with affection and sadness, praying that their desire to accompany and care for their own child to the end is not ignored.

Italys top pediatric hospital, which is run by the Vatican, told the Italian news agency ANSA on Monday that it would be willing to take Charlie.

We understand that the situation is desperate, said Mariella Enoc, director of the Bambino Ges hospital in Rome, noting that she had been in touch with British officials to signal a willingness to take the patient, the agency reported. We are close to the parents in prayer and, if this is their desire, we are open to receiving their child at our structure for the time it will take for him to live.

Mr. Trump, who was not known to have previously expressed a view on the matter, wrote on Twitter on Monday that if the United States could help, we would be delighted to do so.

Both the pope and the president stopped short of criticizing the court rulings or the hospital. Helen Aguirre Ferr, the director of the White House office of media affairs, said Mr. Trump had decided to speak out after he learned about this heartbreaking situation. Mr. Trump has not spoken with the family, she said, and does not want to pressure them in any way.

The president is just trying to be helpful if at all possible, she added.

Charlie was born on Aug. 4 with encephalomyopathic mitochondrial DNA depletion syndrome. He is thought to be one of only 16 children globally with the condition, the result of a genetic mutation.

Brendan Lee, the chairman of the department of molecular and human genetics at Baylor College of Medicine, who is not involved in the case, said in a phone interview that mitochondrial depletion syndrome has no cure. Treatments involve different types of vitamin supplementation, but none have been shown to definitively work through studies, he said.

Charlies parents, Connie Yates and Chris Gard, both in their 30s, have been waging a long and wrenching legal battle to keep him alive. They have raised more than 1.3 million pounds, or about $1.7 million, to help finance experimental treatment in the United States. There is also an international campaign, with an online petition, and there have been street protests in front of Buckingham Palace.

Charlie has been treated since October at Great Ormond Street Hospital, where doctors eventually decided that withdrawing life support was the only justifiable option. Although Charlies parents have parental responsibility, overriding control is by law vested in the court exercising its independent and objective judgment in the childs best interests, the hospital said in a statement laying out its position.

Siding with the hospital were the High Court, on April 11; the Court of Appeal, on May 25; and the Supreme Court of the United Kingdom, on June 8.

The High Court ruled that Charlie would face significant harm if his suffering were to be prolonged without any realistic prospect of improvement. Moreover, it said the experimental treatment, known as nucleoside therapy, would not be effective.

Money is not at issue; an academic medical center in the United States has offered to provide the experimental treatment. But a neurologist at the hospital, who has offered to oversee the treatment, told the court by telephone: I can understand the opinion that he is so severely affected by encephalopathy that any attempt at therapy would be futile. I agree that it is very unlikely that he will improve with that therapy.

Neither the hospital nor the neurologist was identified in court documents, and the White House has declined to identify either.

The Court of Human Rights ruled last week that the British courts had acted appropriately in concluding that it was most likely Charlie was being exposed to continued pain, suffering and distress, and that undergoing experimental treatment with no prospects of success would offer no benefit, and continue to cause him significant harm.

The case has drawn attention to important differences in legal systems.

Claire Fenton-Glynn, a legal scholar at the University of Cambridge who studies childrens rights, said that under British law, the courts were the final arbiter in medical disputes about the treatment of children.

She noted a 2001 case of conjoined twins, Jodie and Mary, who were born sharing an aorta. Separating the twins would lead to the death of the weaker twin; if they were not separated, both would die. A court ruled that the twins should be separated against the wishes of their parents; as expected, one died.

Courts in the United States are less inclined to get involved when there are disputes between parents and doctors, said Professor Moreno of the University of Pennsylvania, stressing that it was usually left to doctors, in consultation with parents, to decide on a childs treatment.

He noted the case of Baby Jane Doe, who was born in 1983 with spina bifida and whose parents declined to approve surgery to prolong her life. That case led to a law, signed by President Ronald Reagan, that defined instances in which withholding medical treatment from infants could be considered child abuse, but also provided that in certain cases doctors and parents might choose to withhold treatment from seriously handicapped babies when such action would merely prolong dying.

G. Kevin Donovan, the director of the Pellegrino Center for Clinical Bioethics at Georgetown University Medical Center and a professor of pediatrics, said that in the United States, if parents insisted on continuing life-prolonging treatment against a doctors advice, the child would simply be transferred to another institution willing to comply with the parents wishes.

It doesnt seem to be a supportable position morally or ethically, he said of the stance taken by the hospital in London, adding that what is legal and what is ethical are not always the same.

In the Schiavo case, her husband, who was her legal guardian, wanted to have her feeding tube removed, but her parents disagreed, setting off a seven-year fight that ended in 2005, after courts ruled in the husbands favor. Life support was removed from Ms. Schiavo, who died at 41.

In that case, too, the pope, then John Paul II, and the president, George W. Bush, weighed in. Mr. Bush signed an act of Congress allowing federal courts to intercede in the case. But their interventions did not ultimately affect the outcome.

There was no immediate response to Mr. Trumps statement from Charlies parents, who last week appeared to accept the finality of the courts rulings. Photographs of the couple sleeping with their sick child have circulated on social media recently.

We are really grateful for all the support from the public at this extremely difficult time, Ms. Yates said on Friday. Were making precious memories that we can treasure forever with very heavy hearts. Please respect our privacy while we prepare to say the final goodbye to our son Charlie.

There was also no immediate reaction from the hospital.

In Charlies case we have been discussing for many months how the withdrawal of treatment may work, the hospital said. There would be no rush for any action to be taken immediately. It added that it would consult the family and that discussions and planning in these situations usually take some days.

Follow Dan Bilefsky @DanBilefsky and Sewell Chan @sewellchan on Twitter.

Reporting was contributed by Aneri Pattani and Roni Caryn Rabin from New York, Michael D. Shear from Washington, and Elisabetta Povoledo from Rome.

A version of this article appears in print on July 4, 2017, on Page A1 of the New York edition with the headline: Dispute Over British Babys Fate Draws In President and Pope.

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Dispute Over British Baby's Fate Draws In Pope and US President - New York Times

Greenwood Genetic Center (GGC) recently recognized Kasia Ellsworth, PhD, and Catie Spellicy, PhD upon their completion of laboratory fellowships in Clinical Molecular Genetics and Genomics.

Dr. Ellsworth earned a PhD in Molecular Pharmacology and Experimental Therapeutics from Mayo Clinic College of Medicine in Rochester, Minnesota. After finishing a Clinical Biochemical Genetics fellowship at GGC in 2016, she remained at the Center to complete a second fellowship in Clinical Molecular Genetics and Genomics. Dr. Ellsworth has joined GGCs DNA Diagnostic Laboratory as a Clinical Molecular Specialist.

Dr. Spellicy earned a PhD in Human and Molecular Genetics at the University of Texas Health Science Center in Houston (UTHSCH). Prior to enrolling in GGCs program, she also completed two postdoctoral fellowships, the first studying neural tube defects, also at UTHSCH, and the second at Baylor College of Medicine where she studied the genetics of addiction. In July, she will join Mission Fullerton Genetics Laboratory in Asheville, NC as a Clinical Molecular Geneticist.

GGCs two-year fellowships include intensive training in laboratory technologies, clinical genetics and diagnostic laboratory management. GGC is one of only 44 sites in the US and the only program in SC offering this post-graduate genetics training programs in all specialty areas.

+2

Since GGCs program began in 1989, nearly 40 fellows and residents have completed the training and have gone on to practice medical genetics or lead diagnostic laboratories.

Submitted by Lori Bassett

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GGC Graduates Two from Medical Genetics Training Program - Index-Journal

Science has helped us understand how blue eyes or baldness as well as other inherited traits both harmless and harmful can run in a family. In the past few decades, largely due to the Human Genome Project and other scientific endeavors, knowledge has exploded in the field of human genetics.

Genetic services available in New Jersey include direct clinical care services as well as activities such as screening programs and laboratory services, educational activities and birth defects surveillance. The State of New Jersey partially funds a network of Genetic Centers [see the list at bottom of page] that provide testing, diagnosis, and ongoing management and comprehensive care of genetic conditions. Physicians specially trained in medical genetics, along with genetic counselors, nurses, social workers and other medical specialists provide comprehensive care to patients with genetic concerns.

Services may include some or all of the following: a review of your family and medical history; physical examination; laboratory testing; genetic counseling/education; and management or referral to other specialists experienced in treating or managing rare disorders. These services can provide information on certain disorders that you or your child may have inherited, how genetic conditions may be passed from one generation to another in a family, and what the risks are that certain conditions will affect you, your present or future pregnancies, or other members of your family.

Genetic counseling translates the science of genetics into practical information. Anyone who has unanswered questions about diseases or traits in their family should consider genetic counseling. People who might be especially interested are:

Resources:

American College of Medical Genetics (ACMG) http://www.acmg.net

Genetic Alliance http://www.geneticalliance.org/

Genetics Home Reference http://ghr.nlm.nih.gov/

Human Genetics Association of New Jersey (HGANJ) http://www.hganj.org

National Newborn Screening & Genetic Resource Center (NNSGRC) http://genes-r-us.uthscsa.edu/

National Organization for Rare Disorders, Inc. (NORD) http://www.rarediseases.org/

National Society of Genetic Counselors (NSGC) http://www.nsgc.org

Directory of Comprehensive Genetic Centers in New Jersey

*Children's Hospital of New Jersey Newark Beth Israel Medical Center 201 Lyons Avenue Newark, NJ 07112 Phone: (973) 926-4446

*Hackensack University Medical Center Genetics Service Don Imus Pediatric Center-Room 258 30 Prospect Avenue Hackensack, NJ 07601-1991 Phone (201) 996-5264 Outreach Clinics: Hoboken, Parsippany

*Saint Peter's University Hospital Institute for Genetic Medicine 254 Easton Avenue New Brunswick, NJ 08903 Phone: (732) 745-6659

*St. Joseph's Hospital and Medical Center Section of Genetics 703 Main Street Paterson, NJ 07503-2691 Phone: (973) 754-2727 Outreach Clinic: Fairfield

*UMDNJ/NJ Medical School Center for Human & Molecular Genetics 90 Bergen Street, Suite 5400 Newark, NJ 07103-2499 Phone: (973) 972-3300 Outreach Clinics: Pompton Plains, West New York

*Cooper Hospital/University Medical Center Division of Genetics 3 Cooper Plaza, Suite 309 Camden, NJ 08103 -1400 Phone: (856) 968-7255 Outreach Clinic: Childrens Regional Center at Voorhees

*Partially Funded By The New Jersey Department Of Health

Updated on 6/14/2013

Originally posted here:
NJDOH - New Born Screening & Genetic Services

Molecular genetics is the field of biology and genetics that studies the structure and function of genes at a molecular level. The study of chromosomes and gene expression of an organism can give insight into heredity, genetic variation, and mutations. This is useful in the study of developmental biology and in understanding and treating genetic diseases.

Gene amplification is a procedure in which a certain gene or DNA sequence is replicated many times in a process called DNA replication.

The recombinant DNA molecules are then put into a bacterial strain (usually E. coli) which produces several identical copies by transformation. Transformation is the DNA uptake mechanism possessed by bacteria. However, only one recombinant DNA molecule can be cloned within a single bacteria cell, so each clone is of just one DNA insert.

In separation and detection DNA and mRNA are isolated from cells and then detected simply by the isolation. Cell cultures are also grown to provide a constant supply of cells ready for isolation.

First, laboratories use a normal cellular modification of mRNA that adds up to 200 adenine nucleotides to the end of the molecule (poly(A) tail). Once this has been added, the cell is ruptured and its cell contents are exposed to synthetic beads that are coated with thymine string nucleotides. Because Adenine and Thymine pair together in DNA, the poly(A) tail and synthetic beads are attracted to one another, and once they bind in this process the cell components can be washed away without removing the mRNA. Once the mRNA has been isolated, reverse transcriptase is employed to convert it to single-stranded DNA, from which a stable double-stranded DNA is produced using DNA polymerase. Complementary DNA (cDNA) is much more stable than mRNA and so, once the double-stranded DNA has been produced it represents the expressed DNA sequence scientists look for.[4]

This technique is used to identify which genes or genetic mutations produce a certain phenotype. A mutagen is very often used to accelerate this process. Once mutants have been isolated, the mutated genes can be molecularly identified.

Forward saturation genetics is a method for treating organisms with a mutagen, then screens the organism's offspring for particular phenotypes. This type of genetic screening is used to find and identify all the genes involved in a trait.[5]

A mutation in a gene can cause encoded proteins and the cells that rely on those proteins to malfunction. Conditions related to gene mutations are called genetic disorders. However, altering a patient's genes can sometimes be used to treat or cure a disease as well. Gene therapy can be used to replace a mutated gene with the correct copy of the gene, to inactivate or knockout the expression of a malfunctioning gene, or to introduce a foreign gene to the body to help fight disease.[6] Major diseases that can be treated with gene therapy include viral infections, cancers, and inherited disorders, including immune system disorders.[7]

Gene therapy delivers a copy of the missing, mutated, or desired gene via a modified virus or vector to the patient's target cells so that a functional form of the protein can then be produced and incorporated into the body.[8] These vectors are often siRNA.[9] Treatment can be either in vivo or ex vivo. The therapy has to be repeated several times for the infected patient to continually be relieved, as repeated cell division and cell death slowly randomizes the body's ratio of functional-to-mutant genes. Gene therapy is an appealing alternative to some drug-based approaches, because gene therapy repairs the underlying genetic defect using the patients own cells with minimal side effects.[10] Gene therapies are still in development and mostly used in research settings. All experiments and products are controlled by the U.S. FDA and the NIH. [11][12]

Classical gene therapies usually require efficient transfer of cloned genes into the disease cells so that the introduced genes are expressed at sufficiently high levels to change the patient's physiology. There are several different physicochemical and biological methods that can be used to transfer genes into human cells. The size of the DNA fragments that can be transferred is very limited, and often the transferred gene is not a conventional gene. Horizontal gene transfer is the transfer of genetic material from one cell to another that is not its offspring. Artificial horizontal gene transfer is a form of genetic engineering.[13]

The Human Genome Project is a molecular genetics project that began in the 1990s and was projected to take fifteen years to complete. However, because of technological advances the progress of the project was advanced and the project finished in 2003, taking only thirteen years. The project was started by the U.S. Department of Energy and the National Institutes of Health in an effort to reach six set goals. These goals included:

The project was worked on by eighteen different countries including the United States, Japan, France, Germany, and the United Kingdom. The collaborative effort resulted in the discovery of the many benefits of molecular genetics. Discoveries such as molecular medicine, new energy sources and environmental applications, DNA forensics, and livestock breeding, are only a few of the benefits that molecular genetics can provide.[14]

NCBI: http://www.ncbi.nlm.nih.gov/About/primer/genetics_molecular.html

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Molecular genetics - Wikipedia

Molecular phylogenetics ([1][2]) is the branch of phylogeny that analyses hereditary molecular differences, mainly in DNA sequences, to gain information on an organism's evolutionary relationships. The result of a molecular phylogenetic analysis is expressed in a phylogenetic tree. Molecular phylogenetics is one aspect of molecular systematics, a broader term that also includes the use of molecular data in taxonomy and biogeography.

The theoretical frameworks for molecular systematics were laid in the 1960s in the works of Emile Zuckerkandl, Emanuel Margoliash, Linus Pauling, and Walter M. Fitch.[3] Applications of molecular systematics were pioneered by Charles G. Sibley (birds), Herbert C. Dessauer (herpetology), and Morris Goodman (primates), followed by Allan C. Wilson, Robert K. Selander, and John C. Avise (who studied various groups). Work with protein electrophoresis began around 1956. Although the results were not quantitative and did not initially improve on morphological classification, they provided tantalizing hints that long-held notions of the classifications of birds, for example, needed substantial revision. In the period of 19741986, DNA-DNA hybridization was the dominant technique.[4]

Every living organism contains DNA, RNA, and proteins. In general, closely related organisms have a high degree of agreement in the molecular structure of these substances, while the molecules of organisms distantly related usually show a pattern of dissimilarity. Conserved sequences, such as mitochondrial DNA, are expected to accumulate mutations over time, and assuming a constant rate of mutation, provides a molecular clock for dating divergence. Molecular phylogeny uses such data to build a "relationship tree" that shows the probable evolution of various organisms. With the invention of Sanger sequencing in 1977 it became possible to isolate and identify these molecular structures.[5][6]

The most common approach is the comparison of homologous sequences for genes using sequence alignment techniques to identify similarity. Another application of molecular phylogeny is in DNA barcoding, wherein the species of an individual organism is identified using small sections of mitochondrial DNA or chloroplast DNA. Another application of the techniques that make this possible can be seen in the very limited field of human genetics, such as the ever-more-popular use of genetic testing to determine a child's paternity, as well as the emergence of a new branch of criminal forensics focused on evidence known as genetic fingerprinting.

A comprehensive step-by-step protocol on constructing phylogenetic tree, including DNA/Amino Acid contiguous sequence assembly, multiple sequence alignment, model-test (testing best-fitting substitution models) and phylogeny reconstruction using Maximum Likelihood and Bayesian Inference, is available at Nature Protocol[7]

Early attempts at molecular systematics were also termed as chemotaxonomy and made use of proteins, enzymes, carbohydrates, and other molecules that were separated and characterized using techniques such as chromatography. These have been replaced in recent times largely by DNA sequencing, which produces the exact sequences of nucleotides or bases in either DNA or RNA segments extracted using different techniques. In general, these are considered superior for evolutionary studies, since the actions of evolution are ultimately reflected in the genetic sequences. At present, it is still a long and expensive process to sequence the entire DNA of an organism (its genome). However, it is quite feasible to determine the sequence of a defined area of a particular chromosome. Typical molecular systematic analyses require the sequencing of around 1000 base pairs. At any location within such a sequence, the bases found in a given position may vary between organisms. The particular sequence found in a given organism is referred to as its haplotype. In principle, since there are four base types, with 1000 base pairs, we could have 41000 distinct haplotypes. However, for organisms within a particular species or in a group of related species, it has been found empirically that only a minority of sites show any variation at all and most of the variations that are found are correlated, so that the number of distinct haplotypes that are found is relatively small.

In a molecular systematic analysis, the haplotypes are determined for a defined area of genetic material; a substantial sample of individuals of the target species or other taxon is used, however many current studies are based on single individuals. Haplotypes of individuals of closely related, but different, taxa are also determined. Finally, haplotypes from a smaller number of individuals from a definitely different taxon are determined: These are referred to as an out group. The base sequences for the haplotypes are then compared. In the simplest case, the difference between two haplotypes is assessed by counting the number of locations where they have different bases: This is referred to as the number of substitutions (other kinds of differences between haplotypes can also occur, for example the insertion of a section of nucleic acid in one haplotype that is not present in another). The difference between organisms is usually re-expressed as a percentage divergence, by dividing the number of substitutions by the number of base pairs analysed: the hope is that this measure will be independent of the location and length of the section of DNA that is sequenced.

An older and superseded approach was to determine the divergences between the genotypes of individuals by DNA-DNA hybridisation. The advantage claimed for using hybridisation rather than gene sequencing was that it was based on the entire genotype, rather than on particular sections of DNA. Modern sequence comparison techniques overcome this objection by the use of multiple sequences.

Once the divergences between all pairs of samples have been determined, the resulting triangular matrix of differences is submitted to some form of statistical cluster analysis, and the resulting dendrogram is examined in order to see whether the samples cluster in the way that would be expected from current ideas about the taxonomy of the group, or not. Any group of haplotypes that are all more similar to one another than any of them is to any other haplotype may be said to constitute a clade. Statistical techniques such as bootstrapping and jackknifing help in providing reliability estimates for the positions of haplotypes within the evolutionary trees.

Molecular systematics is an essentially cladistic approach: it assumes that classification must correspond to phylogenetic descent, and that all valid taxa must be monophyletic.

The recent discovery of extensive horizontal gene transfer among organisms provides a significant complication to molecular systematics, indicating that different genes within the same organism can have different phylogenies.

In addition, molecular phylogenies are sensitive to the assumptions and models that go into making them. They face problems like long-branch attraction, saturation, and taxon sampling problems: This means that strikingly different results can be obtained by applying different models to the same dataset.[8]

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Molecular phylogenetics - Wikipedia

Diagnostic, carrier and predictive testing is offered for a comprehensive range of single gene disorders as well as a DNA banking service whereby samples can be forwardedto external laboratories for approved requests providing funding is available.

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Molecular evolution is the process of change in the sequence composition of cellular molecules such as DNA, RNA, and proteins across generations. The field of molecular evolution uses principles of evolutionary biology and population genetics to explain patterns in these changes. Major topics in molecular evolution concern the rates and impacts of single nucleotide changes, neutral evolution vs. natural selection, origins of new genes, the genetic nature of complex traits, the genetic basis of speciation, evolution of development, and ways that evolutionary forces influence genomic and phenotypic changes.

The content and structure of a genome is the product of the molecular and population genetic forces which act upon that genome. Novel genetic variants will arise through mutation and will spread and be maintained in populations due to genetic drift or natural selection.

Mutations are permanent, transmissible changes to the genetic material (DNA or RNA) of a cell or virus. Mutations result from errors in DNA replication during cell division and by exposure to radiation, chemicals, and other environmental stressors, or viruses and transposable elements. Most mutations that occur are single nucleotide polymorphisms which modify single bases of the DNA sequence, resulting in point mutations. Other types of mutations modify larger segments of DNA and can cause duplications, insertions, deletions, inversions, and translocations.

Most organisms display a strong bias in the types of mutations that occur with strong influence in GC-content. Transitions (A G or C T) are more common than transversions (purine (adenine or guanine)) pyrimidine (cytosine or thymine, or in RNA, uracil))[1] and are less likely to alter amino acid sequences of proteins.

Mutations are stochastic and typically occur randomly across genes. Mutation rates for single nucleotide sites for most organisms are very low, roughly 109 to 108 per site per generation, though some viruses have higher mutation rates on the order of 106 per site per generation. Among these mutations, some will be neutral or beneficial and will remain in the genome unless lost via genetic drift, and others will be detrimental and will be eliminated from the genome by natural selection.

Because mutations are extremely rare, they accumulate very slowly across generations. While the number of mutations which appears in any single generation may vary, over very long time periods they will appear to accumulate at a regular pace. Using the mutation rate per generation and the number of nucleotide differences between two sequences, divergence times can be estimated effectively via the molecular clock.

Recombination is a process that results in genetic exchange between chromosomes or chromosomal regions. Recombination counteracts physical linkage between adjacent genes, thereby reducing genetic hitchhiking. The resulting independent inheritance of genes results in more efficient selection, meaning that regions with higher recombination will harbor fewer detrimental mutations, more selectively favored variants, and fewer errors in replication and repair. Recombination can also generate particular types of mutations if chromosomes are misaligned.

Gene conversion is a type of recombination that is the product of DNA repair where nucleotide damage is corrected using an homologous genomic region as a template. Damaged bases are first excised, the damaged strand is then aligned with an undamaged homolog, and DNA synthesis repairs the excised region using the undamaged strand as a guide. Gene conversion is often responsible for homogenizing sequences of duplicate genes over long time periods, reducing nucleotide divergence.

Genetic drift is the change of allele frequencies from one generation to the next due to stochastic effects of random sampling in finite populations. Some existing variants have no effect on fitness and may increase or decrease in frequency simply due to chance. "Nearly neutral" variants whose selection coefficient is close to a threshold value of 1 / the effective population size will also be affected by chance as well as by selection and mutation. Many genomic features have been ascribed to accumulation of nearly neutral detrimental mutations as a result of small effective population sizes.[2] With a smaller effective population size, a larger variety of mutations will behave as if they are neutral due to inefficiency of selection.

Selection occurs when organisms with greater fitness, i.e. greater ability to survive or reproduce, are favored in subsequent generations, thereby increasing the instance of underlying genetic variants in a population. Selection can be the product of natural selection, artificial selection, or sexual selection. Natural selection is any selective process that occurs due to the fitness of an organism to its environment. In contrast sexual selection is a product of mate choice and can favor the spread of genetic variants which act counter to natural selection but increase desirability to the opposite sex or increase mating success. Artificial selection, also known as selective breeding, is imposed by an outside entity, typically humans, in order to increase the frequency of desired traits.

The principles of population genetics apply similarly to all types of selection, though in fact each may produce distinct effects due to clustering of genes with different functions in different parts of the genome, or due to different properties of genes in particular functional classes. For instance, sexual selection could be more likely to affect molecular evolution of the sex chromosomes due to clustering of sex specific genes on the X,Y,Z or W.

Selection can operate at the gene level at the expense of organismal fitness, resulting in a selective advantage for selfish genetic elements in spite of a host cost. Examples of such selfish elements include transposable elements, meiotic drivers, killer X chromosomes, selfish mitochondria, and self-propagating introns. (See Intragenomic conflict.)

Genome size is influenced by the amount of repetitive DNA as well as number of genes in an organism. The C-value paradox refers to the lack of correlation between organism 'complexity' and genome size. Explanations for the so-called paradox are two-fold. First, repetitive genetic elements can comprise large portions of the genome for many organisms, thereby inflating DNA content of the haploid genome. Secondly, the number of genes is not necessarily indicative of the number of developmental stages or tissue types in an organism. An organism with few developmental stages or tissue types may have large numbers of genes that influence non-developmental phenotypes, inflating gene content relative to developmental gene families.

Neutral explanations for genome size suggest that when population sizes are small, many mutations become nearly neutral. Hence, in small populations repetitive content and other 'junk' DNA can accumulate without placing the organism at a competitive disadvantage. There is little evidence to suggest that genome size is under strong widespread selection in multicellular eukaryotes. Genome size, independent of gene content, correlates poorly with most physiological traits and many eukaryotes, including mammals, harbor very large amounts of repetitive DNA.

However, birds likely have experienced strong selection for reduced genome size, in response to changing energetic needs for flight. Birds, unlike humans, produce nucleated red blood cells, and larger nuclei lead to lower levels of oxygen transport. Bird metabolism is far higher than that of mammals, due largely to flight, and oxygen needs are high. Hence, most birds have small, compact genomes with few repetitive elements. Indirect evidence suggests that non-avian theropod dinosaur ancestors of modern birds [3] also had reduced genome sizes, consistent with endothermy and high energetic needs for running speed. Many bacteria have also experienced selection for small genome size, as time of replication and energy consumption are so tightly correlated with fitness.

Transposable elements are self-replicating, selfish genetic elements which are capable of proliferating within host genomes. Many transposable elements are related to viruses, and share several proteins in common.

DNA transposons are cut and paste transposable elements which excise DNA and move it to alternate sections of the genome.

non-LTR retrotransposons

LTR retrotransposons

Helitrons

Alu elements comprise over 10% of the human genome. They are short non-autonomous repeat sequences.

The number of chromosomes in an organism's genome also does not necessarily correlate with the amount of DNA in its genome. The ant Myrmecia pilosula has only a single pair of chromosomes[4] whereas the Adders-tongue fern Ophioglossum reticulatum has up to 1260 chromosomes.[5]Cilliate genomes house each gene in individual chromosomes, resulting in a genome which is not physically linked. Reduced linkage through creation of additional chromosomes should effectively increase the efficiency of selection.

Changes in chromosome number can play a key role in speciation, as differing chromosome numbers can serve as a barrier to reproduction in hybrids. Human chromosome 2 was created from a fusion of two chimpanzee chromosomes and still contains central telomeres as well as a vestigial second centromere. Polyploidy, especially allopolyploidy, which occurs often in plants, can also result in reproductive incompatibilities with parental species. Agrodiatus blue butterflies have diverse chromosome numbers ranging from n=10 to n=134 and additionally have one of the highest rates of speciation identified to date.[6]

Different organisms house different numbers of genes within their genomes as well as different patterns in the distribution of genes throughout the genome. Some organisms, such as most bacteria, Drosophila, and Arabidopsis have particularly compact genomes with little repetitive content or non-coding DNA. Other organisms, like mammals or maize, have large amounts of repetitive DNA, long introns, and substantial spacing between different genes. The content and distribution of genes within the genome can influence the rate at which certain types of mutations occur and can influence the subsequent evolution of different species. Genes with longer introns are more likely to recombine due to increased physical distance over the coding sequence. As such, long introns may facilitate ectopic recombination, and result in higher rates of new gene formation.

In addition to the nuclear genome, endosymbiont organelles contain their own genetic material typically as circular plasmids. Mitochondrial and chloroplast DNA varies across taxa, but membrane-bound proteins, especially electron transport chain constituents are most often encoded in the organelle. Chloroplasts and mitochondria are maternally inherited in most species, as the organelles must pass through the egg. In a rare departure, some species of mussels are known to inherit mitochondria from father to son.

New genes arise from several different genetic mechanisms including gene duplication, de novo origination, retrotransposition, chimeric gene formation, recruitment of non-coding sequence, and gene truncation.

Gene duplication initially leads to redundancy. However, duplicated gene sequences can mutate to develop new functions or specialize so that the new gene performs a subset of the original ancestral functions. In addition to duplicating whole genes, sometimes only a domain or part of a protein is duplicated so that the resulting gene is an elongated version of the parental gene.

Retrotransposition creates new genes by copying mRNA to DNA and inserting it into the genome. Retrogenes often insert into new genomic locations, and often develop new expression patterns and functions.

Chimeric genes form when duplication, deletion, or incomplete retrotransposition combine portions of two different coding sequences to produce a novel gene sequence. Chimeras often cause regulatory changes and can shuffle protein domains to produce novel adaptive functions.

De novo origin. Novel genes can also arise from previously non-coding DNA.[7] For instance, Levine and colleagues reported the origin of five new genes in the D. melanogaster genome from noncoding DNA.[8][9] Similar de novo origin of genes has been also shown in other organisms such as yeast,[10] rice[11] and humans.[12] De novo genes may evolve from transcripts that are already expressed at low levels.[13] Mutation of a stop codon to a regular codon or a frameshift may cause an extended protein that includes a previously non-coding sequence.

Molecular systematics is the product of the traditional fields of systematics and molecular genetics. It uses DNA, RNA, or protein sequences to resolve questions in systematics, i.e. about their correct scientific classification or taxonomy from the point of view of evolutionary biology.

Molecular systematics has been made possible by the availability of techniques for DNA sequencing, which allow the determination of the exact sequence of nucleotides or bases in either DNA or RNA. At present it is still a long and expensive process to sequence the entire genome of an organism, and this has been done for only a few species. However, it is quite feasible to determine the sequence of a defined area of a particular chromosome. Typical molecular systematic analyses require the sequencing of around 1000 base pairs.

Depending on the relative importance assigned to the various forces of evolution, three perspectives provide evolutionary explanations for molecular evolution.[14]

Selectionist hypotheses argue that selection is the driving force of molecular evolution. While acknowledging that many mutations are neutral, selectionists attribute changes in the frequencies of neutral alleles to linkage disequilibrium with other loci that are under selection, rather than to random genetic drift.[15] Biases in codon usage are usually explained with reference to the ability of even weak selection to shape molecular evolution.[16]

Neutralist hypotheses emphasize the importance of mutation, purifying selection, and random genetic drift.[17] The introduction of the neutral theory by Kimura,[18] quickly followed by King and Jukes' own findings,[19] led to a fierce debate about the relevance of neodarwinism at the molecular level. The Neutral theory of molecular evolution proposes that most mutations in DNA are at locations not important to function or fitness. These neutral changes drift towards fixation within a population. Positive changes will be very rare, and so will not greatly contribute to DNA polymorphisms.[20] Deleterious mutations will also not contribute very much to DNA diversity because they negatively affect fitness and so will not stay in the gene pool for long.[21] This theory provides a framework for the molecular clock.[20] The fate of neutral mutations are governed by genetic drift, and contribute to both nucleotide polymorphism and fixed differences between species.[22][23]

In the strictest sense, the neutral theory is not accurate.[24] Subtle changes in DNA very often have effects, but sometimes these effects are too small for natural selection to act on.[24] Even synonymous mutations are not necessarily neutral [24] because there is not a uniform amount of each codon. The nearly neutral theory expanded the neutralist perspective, suggesting that several mutations are nearly neutral, which means both random drift and natural selection is relevant to their dynamics.[24] The main difference between the neutral theory and nearly neutral theory is that the latter focuses on weak selection, not strictly neutral.[21]

Mutationists hypotheses emphasize random drift and biases in mutation patterns.[25] Sueoka was the first to propose a modern mutationist view. He proposed that the variation in GC content was not the result of positive selection, but a consequence of the GC mutational pressure.[26]

Protein evolution describes the changes over time in protein shape, function, and composition. Through quantitative analysis and experimentation, scientists have strived to understand the rate and causes of protein evolution. Using the amino acid sequences of hemoglobin and cytochrome c from multiple species, scientists were able to derive estimations of protein evolution rates. What they found was that the rates were not the same among proteins.[21] Each protein has its own rate, and that rate is constant across phylogenies (i.e., hemoglobin does not evolve at the same rate as cytochrome c, but hemoglobins from humans, mice, etc. do have comparable rates of evolution.). Not all regions within a protein mutate at the same rate; functionally important areas mutate more slowly and amino acid substitutions involving similar amino acids occurs more often than dissimilar substitutions.[21] Overall, the level of polymorphisms in proteins seems to be fairly constant. Several species (including humans, fruit flies, and mice) have similar levels of protein polymorphism.[20]

Protein evolution is inescapably tied to changes and selection of DNA polymorphisms and mutations because protein sequences change in response to alterations in the DNA sequence. Amino acid sequences and nucleic acid sequences do not mutate at the same rate. Due to the degenerate nature of DNA, bases can change without affecting the amino acid sequence. For example, there are six codons that code for leucine. Thus, despite the difference in mutation rates, it is essential to incorporate nucleic acid evolution into the discussion of protein evolution. At the end of the 1960s, two groups of scientistsKimura (1968) and King and Jukes (1969)-- independently proposed that a majority of the evolutionary changes observed in proteins were neutral.[20][21] Since then, the neutral theory has been expanded upon and debated.[21]

There are sometimes discordances between molecular and morphological evolution, which are reflected in molecular and morphological systematic studies, especially of bacteria, archaea and eukaryotic microbes. These discordances can be categorized as two types: (i) one morphology, multiple lineages (e.g. morphological convergence, cryptic species) and (ii) one lineage, multiple morphologies (e.g. phenotypic plasticity, multiple life-cycle stages). Neutral evolution possibly could explain the incongruences in some cases.[27]

The Society for Molecular Biology and Evolution publishes the journals "Molecular Biology and Evolution" and "Genome Biology and Evolution" and holds an annual international meeting. Other journals dedicated to molecular evolution include Journal of Molecular Evolution and Molecular Phylogenetics and Evolution. Research in molecular evolution is also published in journals of genetics, molecular biology, genomics, systematics, and evolutionary biology.

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Molecular evolution - Wikipedia

Tom Strachan is Scientific Director of the Institute of Human Genetics and Professor of Human Molecular Genetics at Newcastle University, UK, and is a Fellow of the Academy of Medical Sciences and a Fellow of the Royal Society of Edinburgh. Tom's early research interests were in multigene family evolution and interlocus sequence exchange, notably in the HLA and 21-hydroxylase gene clusters. While pursuing the latter, he became interested in medical genetics and disorders of development. His most recent research has focused on developmental control of the vertebrate cohesion regulators Nipbl and Mau-2.

Andrew Read is Emeritus Professor of Human Genetics at the University of Manchester, UK and a Fellow of the Academy of Medical Sciences. Andrew has been particularly concerned with making the benefits of DNA technology available to people with genetic problems. He established one of the first DNA diagnostic laboratories in the UK over 20 years ago (it is now one of two National Genetics Reference Laboratories), and was founder chairman of the British Society for Human Genetics, the main professional body in this area. His own research is on the molecular pathology of various hereditary syndromes, especially hereditary hearing loss.

Drs. Strachan and Read were recipients of the European Society of Human Genetics Education Award.

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Human Molecular Genetics - amazon.com

MOLECULAR GENETICS You Are Here* molecular basis of inheritance Genes ---> Enzymes ---> Metabolism (phenotype) Central Dogma of Molecular Biology* DNA -transcription-->RNA-translation--> Protein Concept Activity -17.1 Overview of Protein Synthesis - INFORMATION FLOW

What is a GENE = ? DNA is the genetic material... [ but what about, retroviruses, as HIV & TMV, contain RNA ] - a discrete piece of deoxyribonucleic acid - linear polymer of repeating nucleotide monomers nucleotides* --> A adenine,C cytosine T thymidine,G guanine --> polynucleotide*

Technology with a Twist - Understanding Genetics

INFORMATION PROCESSING & the CENTRAL DOGMA - the letters of the genetic alphabet... are the nucleotides A, T, G, & C of DNA - the unit of information is CODON = genetic 'word' a triplet sequence of nucleotides 'CAT' in a polynucleotide 3 nucleotides = 1 codon (word) = 1 amino acid in a polypeptide - the definition of (codon) word = amino acid - Size of Human Genome: 3,000,000,000 base pairs or 1.5b in single strand of DNA genes 500,000,000 possible codons (words or amino acids) - average page your textbook = approx 850 words thus, human genome is equal to 588,000 pages or 470 copies of bio text book reading at 3 bases/sec it would take you about 47.6 years @ 8h/d - 7d/w WOW... extreme nanotechnology Mice & humans (indeed, most or all mammals including dogs, cats, rabbits, monkeys, & apes) have roughly the same number of nucleotides in their genomes -- about 3 billion bp. It is estimated that 99.9% of the 3billion n's of human genome is same person to person.

Experimental Proof of DNA as Genetic Material...

1. Transformation Experiments of Fred Griffith... (1920's) Streptococcus pneumoniae -pathogenic S strain & benign R transforming 'principle'* (converting R to S cells) is the genetic element 2. Oswald Avery, Colin MacLeod, & Maclyn McCarty... (1940's) suggest the transforming substance* is DNAmolecules, but... 3. Alfred Hershey & Martha Chase's* 1952 bacteriophage experiments*... VIRAL REPLICATION*[ phage infection & & lytic/lysogenic* ] a genetically controlled biological activity (viral reproduction) they did novel experiment... 1st real use radioisotopes in biology* CONCLUSION - DNA is genetic material because (32P) nucleic acid not (35S) protein guides* viral replication Sumanas, Inc. animation - Lifecycle of HIV virus

Structure of DNA ..... Discovery of Double Helix... Watson's book Nobel prize* -JD Watson, Francis Crick,Maurice Wilkins, but [ Erwin Chargaff & RosyFranklin]... Race for the Double Helix "Life Story" - a BBC dramatization of the discovery of DNA. used two approaches to decipher structure: 1. model building - figure* (are the bases in/out; are the sugar-P's in/out?) 2. x-ray diffraction*pattern* favor a DNA helix of constant diameter* we know now: DNA is a double stranded, helical, polynucleotide chains, made of... 4 nucleotides - A, T, G, C (purine & pyrimidines) in 2 polynucleotide strands (polymer chains) head-tail polarity [5'-----3'] - strands run antiparallel held together via weak H-Bonds & complimentary pairing - Chargaff's rule*..... A:T G:C A + G / T + C = 1.0 Fig's:sugar-P backbone*,base*pairing, dimensions*, models of DNA structure* john kyrk's animation of DNA & Quicktime movie of DNA structure literature references & myDNAi timeline*

Replication of DNA... (Arthur Kornberg - 1959 Nobel - died 10/26/07) copying of DNA into DNA is structurally obvious??? [figure*] Patterns of Replication* = conservative, semi-conservative, & dispersive Matt Meselson & Frank Stahl1958 - experimental design* can we separate 15N-DNA from 14N-DNA - (OLD DNA from NEW DNA)? sedimentation of DNA's (sucrose gradients --> CsCl gradients* & picture*) we can predict results... figure* & overview& all possible results Sumanas, Inc. animation - Meselson-Stahl DNA Replications*

Model of Replication is bacterial with DNA polymerase III... several enzymes* form a Replication Complex (Replisome) & include: helicase - untwists DNA topoisomerase [DNA gyrase] - removes supercoils, single strand binding proteins - stabilize replication fork, Primase - makes RNA primer POL III - synthesizes new DNA strands DNA polymerase I - removes RNA primer 1 base at a time, adds DNA bases DNA ligase repairs Okazaki fragments (seals lagging strand 3' open holes) Concept Activity - DNA Replication Review Structure of DNA polymerase III* copies both strands simultaneously, as DNA is Threaded Through a Replisome* a "replication machine", which may be stationary by anchoring in nuclear matrix Continuous & Discontinuous replication occur simultaneously in both strands

EVENTS: 1. DNA pol III binds at the origin of replication site in the template strand 2. DNA is unwound by replisome complex using helicase & topoisomerase 3. all polymerases require a preexisting DNA strand (PRIMER) to start replication, thus Primase adds a single short primer to the LEADING strand and adds many primers to the LAGGING strand 4. DNA pol III is a dimer adding new nucleotides to both strands primers direction of reading is 3' ---> 5' on template direction of synthesis of new strand is 5" ---> 3' rate of synthesis is substantial 400 nucleotide/sec 5. DNA pol I removes primer at 5' end replacing with DNA bases, leaves 3' hole 6. DNA ligase seals 3' holes of Okazaki fragments on lagging strand the sequence of events in detail* and DNA Repair* Rates of DNA synthesis: myDNAi movie of replication* native polymerase: 400 bases/sec with 1 error per 109 bases artificial: phophoramidite method (Marvin Caruthers, U.Colorado); ssDNA synthesis on polystyrene bead @ 1 base/300 sec with error rate of 1/100b

GENE Expression the Central Dogma of Molecular Biology depicts flow of genetic information Transcription - copying of DNA sequence into RNA Translation- copying of RNA sequence into protein DNA sequence -------> RNA sequence -----> amino acid sequence TAC AUG MET triplet sequence in DNA --> codon in mRNA ---->amino acid in protein Information : triplet sequence in DNA is the genetic word [codon] Compare Events: Procaryotes* vs. Eucaryotes* = Separation of labor Differences DNA vs. RNA (bases & sugars) and its single stranded Flow of Gene Information (FIG*) - One Gene - One enzyme (Beadle & Tatum) 18.3-Overview: Control of Gene Expression

Transcription - RNA polymerase Concept Activity 17.2 - Transcription RNA*polymerase - in bacteria Sigma factor* binds promoter & initiates* copying* [pnpase] transcription factors* are needed to recognize specific DNA sequence [motif*], binds to promoter DNA region [ activators & transcription factors*]* makes a complimentary copy* of one of the two DNA strands[sense strand] Quicktime movie of transcription*myDNAi Roger Kornberg's movie of transcription (2006 Nobel)* Kinds of RNA [table*] tRNA - small, 80n, anticodon sequence, single strand with 2ndary structure* function = picks up aa & transports it to ribosome rRNA - 3 individual pieces of RNA - make up the organelle = RIBOSOME primary transcript is processed into the 3 pieces of rRNA pieces(picture*) & recall structure of ribosome

Other classes of RNA: small nuclear RNA (snRNP's)- plays a structural and catalytic role in spliceosome* there are 5 snRNP's making a spliceosome [U1, U2, U4, U5, & U6]; they and participate in several RNA-RNA and RNA-protein interactions

SRP (signal recognition particle) - srpRNA is a component of the protein-RNA complex that recognizes the signal sequence of polypeptides targeted to the ER - figure*

small nucleolar RNA (snoRNA) - aids in processing of pre-rRNA transcripts for ribosome subunit formation in the nucleolus

micro RNA's (micro-RNA)- also called antisense RNA & interfereing RNA; c7-fig 19.9 short (20-24 nucleotide) RNAs that bind to mRNA inhibiting it. figure* present in MODEL eukaryotic organisms as:roundworms, fruit flies, mice, humans, & plants (arabidopsis); seems to help regulate gene expression by controlling the timing of developmental events via mRNA action also inhibits translation of target mRNAs. ex: siRNA --> [BARR Body*]

TRANSLATION - Making a Protein process of making a protein in a specific amino acid sequence from a unique mRNA sequence...[ E.M. picture* ] polypeptides are built on the ribosome (pic) on a polysome [ animation*] Sequence of 4 Steps in Translation... [glossary] 1. add an amino acid to tRNA -- > aa-tRNA - ACTIVATION* 2. assemble players [ribosome*, mRNA, aa-tRNA] - INITIATION* 3. adding new aa's via peptidyl transferase - ELONGATION* 4. stopping the process - TERMINATION* Concept CD Activity - 17.4 Events in Translation Review the processes - initiation, elongation, & termination myDNAi real-time movie of translation*& Quicktime movie of translation Review figures & parts: Summary fig* [ components, locations, AA-site, & advanced animation ] [ Nobel Committee static animations of Central Dogma ]

GENETIC CODE... ...is the sequence of nucleotides in DNA, but routinely shown as a mRNA code* ...specifies sequence of amino acids to be linked into the protein coding ratio* - # of n's... how many nucleotides specify 1 aa 1n = 4 singlets, 2n= 16 doublets, 3n = 64 triplets Student CD Activity - 11.2 - Triplet Coding S. Ochoa (1959 Nobel) - polynucleotide phosphorylase can make SYNTHETIC mRNA Np-Np-Np-Np <----> Np-Np-Np + Np Marshall Nirenberg (1968 Nobel)- synthetic mRNA's used in an in vitro system 5'-UUU-3' = pheU + C --> UUU, UUC, UCC, CCC UCU, CUC, CCU, CUU the Genetic CODE* - 64 triplet codons [61 = aa & 3 stop codons] universal (but some anomalies), 1 initiator codon (AUG), redundant but non-ambiguous, and exhibits "wobble*".

GENETIC CHANGE - a change in DNA nucleotide sequence (= change in mRNA) - 2 significant waysmutation & recombination [glossary] 1. MUTATION - a permanent change in an organism's DNA*that results in a different codon = different amino acid sequence Point mutation* - a single to few nucleotides change... - deletions, insertions, frame-shift mutations* [CAT] - single nucleotide base substitutions* : non-sense = change to no amino acid (a STOP codon) UCA --> UAA ser to non mis-sense = different amino acid UCA --> UUA ser to leu Sickle Cell Anemia* - a mis-sense mutation... (SCA-pleiotropy) another point mutation blood disease - thalassemia - Effects = no effect, detrimental (lethal), +/- functionality, beneficial

2. Recombination (Recombinant DNA)newly combined DNA's that [glossary]* can change genotype via insertion of NEW (foreign) DNA molecules into recipient cell 1. fertilization*- sperm inserted into recipient egg cell* --> zygote [n + n = 2n] 2. exchange of homologous chromatids via crossing over* = new gene combo's 3. transformation* - absorption of 'foreign' DNA by recipient cells changes cell 4. BACTERIAL CONJUGATION* - involves DNA plasmidsg* (F+ & R = resistance) conjugation may be a primitive sex-like reproduction in bacteria[Hfr*] 5. VIRAL TRANSDUCTION - insertion via a viral vector(lysogeny* &TRANSDUCTION*) general transduction - pieces of bacterial DNA are packaged w viral DNA during viral replication restricted transduction - a temperate phage goes lytic carrying adjacent bacterial DNA into virus particle 6. DESIGNER GENES - man-made recombinant DNA molecules

Designer Genes - Genetic Engineering - Biotechnology

RECOMBINANT DNA TECHNOLOGY... a collection of experimental techniques, which allow for isolation, copying, & insertion of new DNA sequences into host-recipientcells by A NUMBER OF laboratory protocols & methodologies

Restriction Endonucleases-[glossary]*... diplotomic cuts (unequal) at uniqueDNA sequences Eco-R1-figure* @ mostly palindromes... [never odd or even] 5' GAATTC 3' 5' G. . . . . + AATTC 3' 3' CTTAAG 5' 3' CTTAA .. .. G 5' campbell 7/e movie* DNA's cut this way have STICKY (complimentary) ENDS & can be reannealed or spliced* w other DNA molecules to produce new genes combosand sealed via DNA ligase. myDNAi movie of restriction enzyme action*

Procedures of Biotechnology? [Genome Biology Research] A. Technology involved in Cloning a Gene...[animation* & the tools of genetic analysis] making copies of gene DNA 1. via a plasmid*[ A.E. fig& human shotgun plasmid cloning & My DNAi movie*] 2. Librariesg... [ library figure* & BAC's* &Sumanas animation - DNA fingerprint library] 3. Probesg... [ cDNAg & reverse transcriptaseg & DNA Probe Hybridizationg... cDNA figure*& cDNA library* & a probe for a gene of interest* finding a gene with a probe among a library*] 4. Polymerase Chain Reactiong & figure 20.7* & animation*+Sumanas, Inc. animation* the PCR song PCR reaction protocol & Xeroxing DNA & Taq polymerase

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Molecular Genetics - DNA, RNA, & Protein

The mission of our faculty is to conduct innovative and impactful research in Microbiology, Immunology, and Molecular Genetics and to train students and postdoctoral fellows for careers as biomedical scientists. Our faculty also instruct in the Graduate School of Biomedical Sciences and the Medical School and often collaborate with clinical scientists to facilitate the translation of bench to bedside therapies to treat human diseases. Our students acquire professional training while carrying out independent research projects in microbial pathogenesis and physiology, the immune response, and host interactions with microbial pathogens. Our administrative and research staff strive to support the research, teaching and service activities of our students and faculty.

Contact information for faculty members in the department, including email addresses and room numbers, can be found on the faculty pages.

Medical College of Wisconsin Department of Microbiology and Molecular Genetics BSB - 2nd Floor - Room 273 8701 Watertown Plank Road Milwaukee, WI 53226

(414) 955-8253 | (414) 955-6535 (fax)

The department is located on the second floor of the Basic Science Building at 8701 W. Watertown Plank Road.

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MCW: Microbiology and Molecular Genetics Department

operates within the Division of Biological Sciences. Its faculty investigate molecular aspects of biological phenomena that operate on a cellular scale. The Department currently represents research on a wide range of biological problems and systems - its internationally recognized strengths include:

- invertebrate and vertebrate development - plant development and plant pathogen interactions - molecular biology - immunology - microbiology - cellular structure and function - yeast genetics

The department administers the Cell and Molecular Biology Graduate program in the Molecular Biosciences Graduate Training Program Cluster. The cluster combines five programs: Cell and Molecular Biology (CMB), Biochemistry and Molecular Biology (BMB), Human Genetics (HG), Genetics, Genomics & Systems Biology (GGSB), and Development, Regeneration, and Stem Cell Biology (DRSB). MGCB also plays key roles in the undergraduate biology curricula at the University.

The University of Chicago's Grossman Institute of Neuroscience and the Dept. of Molecular Genetic and Cell Biology jointly invite applications for tenure-track faculty in Cellular and Molecular Neuroscience. Please see http://tinyurl.com/pu4oc46 for more information and to apply.

Lucia B. Rothman-Denes, PhD, Professor in the Department of Molecular Genetics and Cell Biology, has been elected by her peers to be a member of the National Academy of Sciences, May 2, 2014

(News archives)

Administrative Information (on-campus-only)

MGCB SEMINARS

JANUARY - MAY 2016

All seminars are at 4:00 PM in CLSC 101 (*unless indicated).

JANUARY 26, 2016 Principles of genome defense Hiten Madhani, University of California, San Francisco

FEBRUARY 23, 2016 Genome structure and integrity Doug Koshland, University of California, Berkeley

MARCH 17, 2016 Measuring the Intracellular Dew Point: Phase Transitions in Cells Cliff Brangwynne, Princeton University

APRIL 21, 2016 11th ANNUAL HASELKORN LECTURE Morality in the Microbial World the Social lives of Bacterial Cells E. Peter Greenberg, University of Washington

APRIL 26, 2016 TBA Stirling Churchman, Harvard University

MAY 26, 2016 Specificity and Evolution of Protein-Protein Interactions Michael Laub, MIT

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Molecular Genetics and Cell Biology

Genetics seems rather intimidating, but in its purest sense it is rather simple.The basis of genetics is fairly simple: DNA => RNA => A Protein.

DNA, or deoxyribonucleic acid, (DNA) is a long molecule that contains our unique genetic code. Nearly every cell in a persons body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).

The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billionof these bases, and more than 99 percent of those bases are the same in every person. The order, or sequence, of these bases determines the information available for building and maintaining an organism.

DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladders rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder.

Ribonucleic acid (RNA) is very similar to DNA, but differs in a few important structural details: RNA nucleotides contain ribose sugars while DNA contains deoxyribose and RNA uses predominantly uracil instead of thymine present in DNA. RNA is transcribed (synthesized) from DNA by enzymes called RNA polymerases and further processed by other enzymes. RNA serves as the template for translation of genes into proteins, transferring amino acids to the ribosome to form proteins, and also translating the transcript into proteins.

RNAs serve as the working set of blue prints for a gene. Each gene is read, and then the messenger RNAs are sent to the molecular factories (ribosomes) that build proteins. These factories read the blueprints and use the information to make the appropriate protein. When the cell no longer needs to make any more of that protein, the RNA blueprints are destroyed. but because the master copy in the DNA remains intact, the cell can always go back to the DNA and make more RNA copies when it needs more of the encoded protein.

An example would be the suns UV light activating the genes in your skin cells to tan you. The gene is read and the RNA takes the message or blueprint to the ribosomes where melanin, the protein that tans your skin, is made.

As we discussed, each gene is made up of a series of bases and those bases provide instructions for making a single protein. Any change in the sequence of bases may be considered a mutation. Most of the mutations are naturally-occurring. For example, when a cell divides, it makes a copy of its DNA and sometimes the copy is not quite perfect. That small difference from the original DNA sequence is a mutation.

Mutations can also be caused by exposure to specific chemicals, metals, viruses, and radiation. These have the potential to modify the DNA. This is not necessarily unnatural even in the most isolated and pristine environments, DNA breaks down. Nevertheless, when the cell repairs the DNA, it might not do a perfect job of the repair. So the cell would end up with DNA slightly different than the original DNA and hence, a mutation.

Some mutations have little or no effect on the protein, while others cause the protein not to function at all. Other mutations may create a new effect that did not exist before. Many diseases are a result of mutations in certain genes. One example is the gene for sickle cell anemia. The mutation causing the blood disorder sickle cell anemia is a single nucleotide substitution (A to T) in the base number 17 out of 438 As, Ts, Cs and Gs . By changing the amino acid at that point, the impact is that the red blood cells are no longer round, but sickle in shape and carry less oxygen.

Some of these changes occur in cells of the body such as in skin cells as a result of sun exposure. Fortunately these types of changes are not passed on to our children. However, other types of errors can occur in the DNA of cells that produce the eggs and sperm. These errors are called germ line mutations and can be passed from parent to child. If a child inherits a germ line mutation from their parents, every cell in their body will have this error in their DNA. Germ line mutations are what cause diseases to run in families, and are responsible for hereditary diseases.

Sudden cardiac death (SCD) is a widespread health problem with several known inherited causes. Inherited SCD generally occurs in healthy individuals who do not have other conventional cardiac risk factors. Mutations in the genes in charge of creating the electrical activity of the heart have been found to be responsible for most arrhythmias, among them Short QT Syndrome, Long QT Syndrome, Brugada Syndrome, Familial Bundle Branch Block, Sudden Infant Death Syndrome and Sudden Unexpected Death Syndrome.

As researchers discover the role genes play in disease, there will be more genetic tests available to help doctors make diagnoses and pinpoint the cause of the disease. For example, heart disease can be caused either by a mutation in certain genes, or by environmental factors such as diet or exercise to name a few.

Physicians can easily diagnose a person with heart disease once they present symptoms. However, physicians can not easily identify the cause of the heart disease is in each person. Thus, most patients receive the same treatment regardless of underlying cause of the disease.

In the future, a panel of genetic tests for heart disease might reveal the specific genetic factors that are involved in a given person. People with a specific mutation may be able to receive treatment that is directed to that mutation, thereby treating the cause of the disease, rather than just the symptoms.

The ultimate goal of the MMRLs Molecular Genetics Program is to identify the factors that are responsible for these diseases. This knowledge will facilitate the development ofgene-specific therapies and cures for arrhythmias and identify individuals at risk for sudden cardiac deaths.

With the addition of the Molecular Biology and Molecular Genetics programs, MMRL is now integrally involved in both basic and clinical research, and is among the relatively few institutions worldwide with a consistent and concerted focus on bridging basic and clinical science. With an eye toward designing specific treatments and cures for disease, the Laboratorys research has the potential to affect us all.

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Molecular Genetics - mmrl.edu

Contact: (0191) 241 8600 - Dr David Bourn, Head of Laboratory, Molecular Genetics

The molecular laboratory service provides genetic diagnosis for those families suffering from inherited conditions caused by mutation of specific single genes.Testing is performed using a variety of DNA analysis techniques to identify causative mutations or to track defective genes through families.

The Molecular Genetics Laboratory operates within the Professional Guidelines of the Clinical Molecular Genetics Society (CMGS).

The laboratory is accredited by Clinical Pathology Accreditation

Clinical scientists and MLSO staff are State Registered with the Health Professions Council after the required period of training.

The Molecular Genetics Laboratory participates in the following external quality assurance schemes:

Northern Genetics Service Institute of Genetic Medicine Central Parkway Newcastle upon Tyne NE1 3BZ

Tel: 0191 241 8600

The laboratory operates Monday to Friday between the hours of 08.30 and 17.00.For the receipt and analysis of very urgent samples outside these hours, please make special arrangements with the laboratory.

Head of Laboratory

Dr David Bourn

telephone: 0191 241 8600

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Newcastle Hospitals - Molecular Genetics

Jeffrey M. Friedman Professor; Investigator, HHMI

The application of modern methods in genetics has led to the identification of a new hormone, leptin, that regulates body weight. Leptin is an adipose tissue hormone that interacts with receptors in the brain to regulate food intake, energy expenditure and other neuroendocrine systems. The molecular mechanisms of leptin in the brain are under investigation. These studies are being conducted in parallel with efforts to identify obesity genes in the human.

1995 Amgen Inc.

Although the physiological regulation of body weight and appetite has been strongly suggested by experimental evidence, the elucidation of the relevant molecular mechanisms has proven difficult. The possible role of a brain-gut peptide, cholecystokinin (CCK), in these processes was the initial subject of investigation in this laboratory. CCK has been extensively evaluated as a possible satiety factor. CCK is secreted as a 33 amino acid peptide from endocrine cells in the jejeunum where it is released in response to nutrient in the intestinal lumen. The same CCK precursor is posttranslationally processed to an 8 amino acid peptide in brain. The single copy CCK gene is differentially regulated in brain and intestine during development and expressed ectopically in a class of primitive neuronal tumors3-6. The physiological role of CCK in controlling appetite is unclear. In 1973 Smith and Gibbs showed that injections of CCK reduce food intake in food deprived rodents. In addition, the levels of brain CCK were reported by Straus et al to be low in genetically obese (ob) mice8. However, nonpeptide CCK antagonists developed by Squibb and other pharmaceutical companies do not affect food intake and body weight in the long term9. Moreover, overexpression of CCK in transgenic mice did not affect food intake or body weight (unpublished data). Genetic mapping of the CCK gene to mouse chromosome 9 excluded it as being etiologic in any of the inherited rodent obesity syndromes10. These data raised the question as to the molecular basis of the phenotype in genetically obese (ob) and diabetic (db) mice.

Mutations in the mouse ob and db genes result in obesity and diabetes in a syndrome resembling morbid human obesity11, 12. Coleman, using the method of parabiosis, predicted that the ob gene encoded a novel hormone and that the db gene encoded its receptor11. Recent data from this laboratory are consistent with this hypothesis. The ob gene was identified by positional cloning and found to encode a 4.5 kB RNA expressed exclusively in adipocytes13-16. The ob gene product, known as LEPTIN, circulates as a 16 kilodalton protein in mouse and human plasma but is undetectable in plasma from C57BL/6J ob/ob mice17. Plasma levels of this protein are increased in diabetic (db ) mice, a mutant thought to be resistant to the effects of ob17. The levels of protein are also increased in several other genetic and environmentally induced forms of rodent obesity including mice with lesions in the hypothalamus16. Daily intraperitoneal injections of recombinant mouse leptin reduced body weight of ob/ob mice by 30% at 2 weeks and by 40 % after four weeks but had no effect on db/db mice17. The protein reduced food intake and increased energy expenditure in ob/ob mice. Injections of wild type mice twice daily with the mouse protein resulted in a sustained 12% weight loss, decreased food intake and a reduction of body fat from 12.2 to 0.7%. Recombinant human leptin reduced body weight with equivalent potency to mouse leptin when injected into ob mice17. In human, the plasma level of leptin correlated with body mass index (BMI) and % body fat18. However at a given BMI, there was significant variability in the leptin level. In all cases analyzed weight loss in human was associated with a decrease in plasma leptin concentration18. These data suggest that leptin serves an endocrine function to regulate body fat stores. In most instances, obesity is associated with an apparent decrease in sensitivity to endogenous leptin resulting in a compensatory increase in adipocyte mass. However, in a subset of cases human obesity appears to result from subnormal leptin secretion18-20.

The complete insensitivity of db mice to leptin and the identical phenotype of ob and db mice suggested that the db locus encodes the leptin receptor 11, 17. The db gene was localized to a 300 kB interval on mouse chromosome 419-21. Exon trapping and cDNA selection identified a candidate gene in this region. This candidate was found to be identical to a receptor (ob-R) which was functionally cloned from choroid plexus21, 22. However, because this receptor was normal in db mice, the possibility was raised that the db mutation affected an alternatively spliced form. The Ob-R gene was found to encode at least five alternatively spliced forms 21. One of the splice variants is expressed at a high level in the hypothalamus and at a lower level in other tissues. This transcript is mutant in C57BL/Ks db/db mice21. The mutation is the result of abnormal splicing leading to a 106 bp insertion into the 3' end of its RNA. The mutant protein is missing the cytoplasmic region and is likely to be defective in signal transduction. A nonsense mutation in facp rats, a rat equivalent of db, leads to premature termination NH2-terminal of the transmembrane domain (unpublished data). These data suggest that the weight reducing effects of leptin are mediated by signal transduction through a receptor in the hypothalamus and elsewhere.

Further studies have revealed that the Stat3 transcription factor is activated specifically in hypothalamus within 15 minutes of a single injection of leptin in ob and wild type but not in db mice23. In situ hybridization indicates that Ob-Rb is expressed in three different hypothalamic regions: the arcuate, ventromedial and lateral hypothalamic nuclei (in preparation). Lesions of each of these nuclei are known to affect body weight regulation. Further characterization of the neurons in these brain regions and their connections will have important implications for our understanding of leptin's actions and the molecular mechanisms regulating body weight.

Advances in genetics make it possible to identify human disease genes. The implementation of a genetic approach to the study of obesity will help establish whether the human ob or db genes account for genetic forms of obesity and also lead to the identification or validation of other candidate genes. Such studies require that large numbers of families be collected in which the trait of interest is inherited.

In order to implement this approach for the study of obesity, this laboratory has developed a collaboration with the Department of Health on the island of Kosrae in Micronesia. The citizens of this island have a high incidence of obesity, the basis of which is not understood. The Kosraen population is highly admixed between Micronesian and Caucasian ancestors, a fact that facilitates genetic analysis. A study has now been completed in which the entire adult population of Kosrae over twenty years of age, ~2500 individuals, has had a complete medical workup including measurements of height, weight, blood pressure, and glucose levels. In addition, measurements of serum insulin, and eventually leptin, will be made. Measurements of serum cholesterol, and triglycerides have already been completed by Dr. Jan Breslows laboratory at Rockefeller University. In collaboration with the Stoffel laboratory, DNA has been isolated from each individual as well as information about the identity and medical status of other family members. To date, all 2500 DNA samples have been processed ad genetic analyses have begun. The availability of a complete clinical profile on an entire population, combined with modern methods in genetics should make it possible to establish the possible relationship of genetic variation at the human ob and db genes to human obesity. In addition, a highly admixed population provides an opportunity to identify additional loci that affect the control of body weight, as well as the medical problems that are often associated with obesity such as hypertension, diabetes, heart disease.

Future studies will also focus on the physiologic effects of leptin. These include studies of leptin's effects on lipid metabolism, glucose metabolism and insulin action. Available data suggest that neurons in the hypothalamus are a principle target of leptin actin. Studies to establish the neurotransmitter profile and projection of Ob-Rb positive neurons have begun. Analysis of the electrophysiologic effects of leptin on these cells will proceed simultaneously. Efforts to produce a higher activity version of leptin are also underway in studies of the structure function relationship of leptin and its receptors (collaborative with the Burley laboratory).

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The Rockefeller University Laboratory of Molecular Genetics

We use DNA analysis techniques on blood samples to carry out testing for a wide range of genetic disorders. Full details of all the tests available and the turnaround times are in ourdirectory of tests for bothinherited and acquired disorders. Pleasecontact us if the test you require is not listed in our directory.

The types of investigation include:

The laboratory offers testing for a range of core disorders plus a set of more specialist services for which samples are received on a supra-regional or national basis.

The laboratory is also a member of theUKGenetic Testing Network (UKGTN) and we can forward DNA samples to other UK genetics laboratories for testing of a large range of single gene disorders, where appropriate. ContactUKGTN or our laboratory for full details. Details of services for rare disorders not currently available in the UK are available fromOrphanet andGeneTests as well as our laboratory.

DNA can be extracted from 2ml saliva (collected using the OrageneTM DNA collection system), or using buccal swabs (collected using the IsoHelixTM system). Please note that buccal swabs may not necessarily provide sufficient DNA for all available tests. Please contact us using these sampling methods to ensure that the test required can be carried out. DNA can be extracted from fresh or frozen tissue samples, and it also possible to obtain limited results for some assays from blood spots or paraffin embedded fixed tissue samples. Please contact us before using these sampling methods to ensure that sufficient DNA of appropriate quality for the test required can be extracted. Prenatal diagnosis for single gene disorders is usually carried out on chorionic villus samples, but amniotic fluid or fetal blood samples can be used where necessary. Rapid aneuploidy (QF-PCR) testing can be carried out on DNA extracted from amniotic fluid or chorionic villus samples, as appropriate.

Please note that clotted blood samples or samples that are inadequately labelled or packaged will not be accepted by the laboratory. If samples are known to present a high risk to laboratory staff, then this should be clearly indicated on the referral card and sample tube.

We can provide advice on scientific and technical issues. Please call us on 0151 702 4228. The Trust voice mail system operates on all external lines. When diverted to voice mail, please leave a message and someone from the laboratory will get back to you as soon as possible. In addition the laboratory has the nhs.net email account dna.liverpool@nhs.net that is monitored daily. This account is suitable for receipt of patient-identifiable information sent to the laboratory providing the sender also uses an nhs.net account. Patient-identifiable information should NOT be sent to other laboratory email addresses.

Please note for advice on clinical and counselling issues, telephone theClinical Genetics Service on 0151 802 5001.

Mailing address for correspondence and samples

Merseyside and Cheshire Regional Molecular Genetics Laboratory Liverpool Womens NHS Foundation Trust Crown Street Liverpool L8 7SS

Other ways of contacting the laboratory

Tel: 0151 702 4228 Fax: 0151 702 4226 E-mail: dna.liverpool@nhs.net

Laboratory Staff

Head of Laboratory - Roger Mountford (Consultant Clinical Scientist) Tel: 0151 702 4219 E-mail: roger.mountford@lwh.nhs.uk

Duty Head Victoria Stinton (State Registered Clinical Scientist) Tel: 0151 702 4231 Email: Victoria.Stinton@lwh.nhs.uk

Other Scientific staff

Emma McCarthy - State Registered Clinical Scientist - 0151 702 4011 Diane Cairns - State Registered Clinical Scientist - 0151 702 4225 Kym Jones - State Registered Clinical Scientist - 0151 702 4225 Abi Rousseau - State Registered Clinical Scientist - 0151 702 4011 Trudie Cottrell - STP Trainee Healthcare Scientist (Genetics) 0151 702 4011 John Hall - Trainee Clinical Molecular Geneticist 0151 702 4011 Emma Brownsell - Trainee Clinical Molecular Geneticist 0151 702 4225

Laboratory working hours

Laboratory working hours are: 9am -5:30pm Monday - Friday (An out-of-hours service is not currently provided)

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Molecular Genetics - Liverpool Women's NHS Foundation Trust

Mona Batish, Ph.D. Research Focus: Exploring the gene expression regulation by single molecule RNA imaging

Vivian Bellofatto, Ph.D. Research Focus: Regulation of Gene Expression in Parasitic Protozoa

Purnima Bhanot, Ph.D. Research Focus: Biology of the Malaria Parasite, Plasmodium

Raymond Birge, Ph.D. Research Focus: Cellular actions of oncogenes and proto-oncogenes; Recognition and phagocytosis of apoptotic cells

Sylvia Christakos, Ph.D. Research Focus: Mechanisms involved in the pleitropic actions of 1,25 dihydroxyvitamin D3

Emanuel Goldman, Ph.D. Research Focus: Accuracy and Efficiency of Protein Synthesis Elongation in Escherichia coli

Laura Goldsmith, Ph.D. Research Focus: Signal transduction mechanisms involved in ovarian hormone production and function

Utz Herbig, Ph.D. Research Focus: Telomere induced Senescence in Cancer and Aging

Richard Howells, Ph.D. Research Focus: Investigation of opioids, opioids receptors, opioid tolerance and physical dependence and the therapeutic potential of these drugs as anti-cancer agents

M. Zafri Humayun, Ph.D. Research Focus: Fidelity of DNA Replication

Hieronim Jakubowski, Ph.D. Research Focus: Homocysteine in Protein Structure/Function andHuman Disease

David B. Kaback, Ph.D. Research Focus: Meiotic Pairing and Chromosome Segregation

Sergei Kotenko, Ph.D. Research Focus: Study of cytokines, their receptors and biological activities

Suriender Kumar, Ph.D. Research Focus: Proteolytic enzymes in tumor growth, inflammation and bone resorption

Deborah Lazzarino, Ph.D. Research Focus: Cellular and molecular events that regulate the growth and differentiation of mammary epithelial cells, particularly to identify, isolate and characterize mammary stem and progenitor cells in hopes of understanding the role they play in normal and disease states of the breast.

Michael Lea, Ph.D. Research Focus: Regulation of growth and differentiation of cancer cells

Hong Li, Ph.D. Research Focus: Proteomics and bioinformatics research

David Lukac, Ph.D. Research Focus: Molecular host-virus interactions that regulate lytic reactivation of Kaposi's Sarcoma-associated Herpesvirus from latency

Carol Lutz, Ph.D. Research Focus: Regulation of gene expression by post-transcriptional mechanisms

Wlodek Mandecki, Ph.D. Research Focus: Ribosome as Molecular Machine for Acquiring Sequence Information

Mukund Modak, Ph.D. Research Focus: Molecular effectors of enzymatic synthesis of DNA

Matthew B. Neiditch, Ph.D. Research Focus: Structural Biology of Bacterial Quorum Sensing Signal Transduction

Patrick O'Connor, Ph.D. Research Focus: Molecular mechanisms that regulate bone regeneration

Virendranath Pandey, Ph.D. Research Focus: HIV-1 and HCV replication; Development of antiviral/virucidal drugs

Nikhat Parveen, Ph.D. Research Focus: Virulence factors of Pseudomonas aeruginosa and Lyme disease spirochete, Borrelia burgdorferi

Melissa Rogers, Ph.D. Research Focus: Cellular and molecular biology of BMP2

Katsunori Sugimoto, Ph.D. Research Focus: Cell Cycle, DNA damage signaling, Checkpoint, Cellular signal transduction, telomere regulation, Cancer

Carolyn Suzuki, Ph.D. Research Focus: Regulation of mitochondrial genome stability and expression; Mitochondrial apoptosis

Bin Tian, Ph.D. Research Focus: Study of RNA genomics and post-transcriptional gene regulation by bioinformatics approaches

Ian P. Whitehead, Ph.D. Research Focus: Signal Transduction and Oncogenesis

Hua Zhu, Ph.D. Research Focus: Herpesviruses and Host Cell Interaction

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Laboratories - Rutgers New Jersey Medical School