Category Archives: Human Genetics

NEW YORK A suite of new studies has examined how one cell develops into all the tissues of the human body by tracing and investigating the mutations they acquire over time.

As cells divide, they acquire mutations that are then passed on to their daughter cells. The resulting patterns of mutations can be used to trace back a cell's family tree, possibly all the way to the first cell. In four new studies appearing Wednesday in Nature, teams of researchers from across the world used this approach to study the earliest stages of human development as well as the later accumulation of somatic mutations, including ones linked to cancer.

"Exploring the human body via the mutations cells acquire as we age is as close as we can get to studying human biology in vivo," Luiza Moore, a researcher at the Wellcome Sanger Institute and first author of one of the studies, said in a statement. "Our life history can be found in the history of our cells, but these studies show that this history is more complex than we might have assumed."

Tracing these mutations back in time revealed differences in mutation rates very early in embryonic development. Researchers led by the Sanger Institute's Michael Stratton uncovered a pattern of mutations that indicated a high initial mutation rate that then fell in a study that combined laser capture microdissections with whole-genome sequencing of samples from three individuals. A team led by the Korea Advanced Institute of Science and Technology's Young Seok Ju similarly found a high mutational rate during the early stages of development that then declined, using a capture-recapture approach.

The Stratton-led team estimated that the first two cell divisions had mutation rates of 2.4 per cell per generation, which then fell to 0.7 per cell per generation. This dip, they said, is likely due to the activation of the zygotic genome that increases the ability to repair DNA.

These early cells also contributed unequally to the development of subsequent lineages, though the degree of asymmetry varied from person to person. Ju and his colleagues reported, for instance, that for one individual in their analysis, 112 early lineages split at a ratio of 6.5:1, rather than the expected 1:1.

Stratton and his colleagues, meanwhile, reported that one individual in their study had a 69:31 contribution of the initial daughter cells to subsequent lineages, while another had a 93:7 ratio based on bulk brain samples, but an 81:19 ratio based on colon samples.

This, they said, indicates that the lineage commitment of cells is not fixed. Ju and his colleagues likewise said their finding suggested a stochasticity of clonal segregation in humans, unlike the deterministic embryogenesis observed in C. elegans.

These analyses also shed light on the development of somatic mutations later in life. KAIST's Ju and his colleagues, for instance, found most mutations are specific to certain clones, while in a separate study, the Sanger's Moore and her colleagues, who examined the mutational landscape of 29 cell types from three individuals through sequencing, found mutationrates varied by cell type and were very low in spermatogonia.

Ju and his colleagues also reported that normal tissues harbored known mutational signatures, including UV-mediated DNA damage and endogenous clock-like mutagenesis. Similarly, Moore and her colleagues noted known mutational signatures within normal tissues. They found, for instance, the aging-related SBS1 and SBS5 mutational signatures to be the most common signatures across all cell types, while other signatures were more prominent in certain cell types but not others. The SBS88 signature, which is due to a strain of E. coli, for example, was present among colorectal and appendiceal crypts.

Chen Wu, an investigator at the Chinese Academy of Medical Sciences, and her colleagues also found the aging-related SBS1 and SBS5 mutational signatures to be common among normal tissues, based on their sequencing analysis of microbiopsies from five individuals. Other tissues, like the liver and lung, also harbored other mutational signature like SBS4, which is associated with tobacco smoking.

Some of the mutations present in normal somatic tissues are typically associated with cancer, Wu and her colleagues added. They found mutations in 32 cancer driver genes were widespread among their normal tissue samples, though varied by organ. For instance, driver mutations were present in 6.5 percent of pancreas parenchyma samples and in 73.8 percent of esophageal samples.

Additionally, many normal tissue samples harbored as many as three cancer driver mutations. This, Harvard Medical School's Kamila Naxerova noted in a related commentary in Nature, begins to blur the line between what is normal and what is cancer. "Indeed, if cells with three driver mutations can easily be found in a small tissue sample, cells with four or five drivers probably exist in that tissue as well without necessarily giving rise to cancer," she wrote. "These new insights invite us to reconsider how we genetically define cancer."

Overall, she added that "the four studies provide an impressive demonstration of the power of modern genetics to decode the cellular dynamics that unfold in our bodies over time."

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Genetic Analyses Trace How Mutations Accumulate in Cells of the Human Body Over Time - GenomeWeb

Credit: Pixabay.

On the face of it, homosexual behavior and Darwins theory of evolution dont match. Genes have to be passed to offspring otherwise they die out, hence any genes that will make an animal more likely to engage in same-sex mating ought to quickly be eliminated from the population. Yet same-sex behavior is quite prevalent among human populations across the globe.

In a new study published in Nature Human Behavior, researchers led by Brendan Zietsch, Associate Professor at the School of Psychology at the University of Queensland, have found compelling clues in our genomes that may resolve this paradox. According to the findings, the same genes that may drive homosexuality in some individuals may enhance the reproductive success of heterosexual individuals.

In other words, genes that offer evolutionary advantageous effects to some people may result in homosexual offspring in subsequent generations as an unintended effect.

For their study, the researchers analyzed the genetic effects associated with same-sex sexual behavior in a dataset of 477,522 people from the UK and the US that contains a wealth of genetic and health information. They performed the same analysis for opposite-sex sexual behavior in a sample of 358,426 people from the same countries.

Participants in the opposite-sex dataset reported how many sexual partners they had in their lifetime. The number of opposite-sex sexual partners is an indicator of mating success, which during evolution would have led to more children

The researchers scoured millions of individual genetic variants that were associated with two variables: whether people ever had a same-sex partner and how many partners they had in their lifetime.

Each variable had many associated genetic variants spread through the genome. And although each of these variants had a tiny effect, in aggregate their effects were substantial.

Ultimately, this analysis showed that the genetic effects associated with ever having had a same-sex partner were also associated with having had more opposite-sex partners among people who never engaged in same-sex behavior.

In order to verify the confidence of their results, the researchers replicated their findings by narrowing the study conditions. Specifically, they performed the same analysis on a sample of individuals with predominantly or exclusively same-sex partners. The results remained largely consistent.

Lastly, the researchers tested whether physical attractiveness, risk-taking propensity, and openness to experience may also influence the results.

In other words, could genes associated with these variables be associated with both same-sex sexual behavior and with opposite-sex partners in heterosexuals? In each case, we found evidence supporting a significant role for these variables, but most of the main results remained unexplained. So we still dont have a solid theory on exactly how these genes confer an evolutionary advantage. But it might be a complex mix of factors that generally make someone more attractive in broad terms, explained Zietsch in an article.

These findings were also validated by an evolutionary computer simulation that crunched the numbers and found that in the lack of any countervailing benefits to genes associated with same-sex sexual behavior, these genes disappear from the gene pool.

Of course, this isnt the last word on the matter. Important limitations include samples involving Western white participants which may not be representative of the general population. Secondly, the number of opposite-sex sexual partners reported in individuals today may not necessarily reflect the same reproductive advantage in our evolutionary past.

Even so, this hypothesis seems like the most solid explanation for same-sex behavior in humans proposed thus far.

I am aware some people believe it is inappropriate to study sensitive topics such as the genetics and evolution of same-sex sexual behavior. My perspective is that the science of human behavior aims to shine a light on the mysteries of human nature and that this involves understanding the factors that shape our commonalities and our differences, Zietsch wrote. Were we to avoid studying sexual preference or other such topics due to political sensitivities, we would be leaving these important aspects of normal human diversity in the dark.

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Whats the evolutionary explanation for homosexuality? Ironically, genes that help people make more babies may be involved - ZME Science

The Roman Catholics of Goa-- Kumta and Mangalore regions, are the remnants of very early lineages of Brahmin community of India, majorly with Indo-European-specific genetic composition, according to a study conducted by the Centre for Cellular and Molecular Biology (CCMB)

The study throws vital light on the genetic history of the Roman Catholic populations of West Coast India.

This multi-disciplinary study, using history, anthropology and genetics information, has helped us in understanding the population history of Roman Catholics from one of the most diverse and multicultural region of our country, said Dr. Vinay K Nandikoori, Director, CCMB, Hyderabad.

The west coast of India harbours a rich diversity of various ethno-linguistic human population groups. The Roman Catholic is one such distinct group, whose origin is much debated. Some historians and anthropologists relate them to ancient group of Gaud Saraswat. Others believe they are members of the Jews Lost Tribes in the first century migration to India.

Till date, no genetic study was done on this group to infer their origin and genetic history.

The first high throughput study was conducted by Dr Kumarasamy Thangaraj, Chief Scientist, CSIR-Centre for Cellular and Molecular Biology (CCMB) & Director, Centre for DNA Fingerprinting and Diagnostics, Hyderabad and Dr. Niraj Rai, Senior Scientist, DST-Birbal Sahni Institute of Palaeosciences (BSIP), Lucknow.

Researchers analysed DNA of 110 individuals from Roman Catholic community of Goa-- Kumta and Mangalore. They compared the genetic information of the Roman Catholic group with previously published DNA data from India and West Eurasia. They put this information alongside archaeological, linguistic, and historical records. All of these helped the researchers fill in many of the key details about the demographic changes and history of the Roman Catholic population of South West of India since the Iron Age (until around 2,500 years ago), and how they relate to the contemporary Indian population.

It found that consequences of Portuguese inquisition in Goa on the population history of Roman Catholics. They also found some indication of Jewish component. This finding has been published in Human Genetics on August 23.

Our genetic study revealed that majority of the Roman Catholics are genetically close to an early lineage of Gaur Saraswat community, Dr. Kumarasamy Thangaraj, senior author of the study, said in a statement.

He further added, More than 40 percent of their paternally inherited Y chromosomes can be grouped under R1a haplogroup. Such a genetic signal is prevalent among populations of north India, middle East and Europe, and unique to this population in Konkan region.

This study strongly suggests profound cultural transformations in ancient South West of India. This has mostly happened due to continuous migration and mixing events since last 2500 years, according to Dr. Niraj Rai, co- corresponding author of the paper.

The origins of many population groups in India like the Jews and Parsis are not well-understood. These are gradually unfolding with advances in modern and ancient population genetics. Roman Catholics is one of them with much debated history of origin based on inferences of anthropologists and historians,said Lomous Kumar, first author of the paper.

The other institutes involved in this study are Mangalore University, Canadian Institute for Jewish Research, and Institute of Advanced Materials, Sweden.

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Roman Catholics of west coast of India have Brahmin lineages: CCMB Study - BusinessLine

Brain development that occurs after birth is also important. Rebecca Saxe at MIT is working to understand the brain structures and activities responsible for social cognition, which allows us to consider the mental states of other people.

Saxe has discovered a particular brain region that is key; by studying how activity in this region and others changes over the course of childhood, she may be able to understand how social abilities develop. She has also found that these brain activity patterns are altered in people with autism spectrum disorders.

Even though researchers are starting to understand some of the processes that govern development and have identified things that can derail it, were far from being able to intervene when such problems occur. But as we gain insights, we could someday test therapies or other ways to address these developmental issues.

Computational neuroscientists use mathematical models to better understand how networks of brain cells help us interpret what we see and hear, integrate new information, create and store memories, and make decisions.

Understanding how the activity of neurons governs cognition and behavior could lead to ways to improve memory or understand disease processes.

Terry Sejnowski, a computational neurobiologist at the Salk Institute, has built a computer model of the prefrontal cortex and analyzed its performance on a task in which a person (or machine) has to sort cards according to a rule thats always changing. While humans are great at adapting, machines generally struggle. But Sejnowskis computer, which imitates information flow patterns observed in the brain, performed well on this task. This research could help machines think more like humans and adapt more quickly to new conditions.

Aude Oliva, the MIT director of the MIT-IBM Watson AI Lab, uses computational tools to model and predict how brains perceive and remember visual information. Her research shows that different images result in certain patterns of activity both in the monkey cortex and in neural network models, and that these patterns predict how memorable a certain image will be.

Research like Sejnowskis may inspire smarter machines, but it could also help us understand disorders in which the function of the prefrontal cortex is altered, including schizophrenia, dementia, and the effects of head trauma.

Researchers are trying to determine the genetic and environmental risk factors for neurodegenerative diseases, as well as the diseases underlying mechanisms.

NHUNG LE

Improving prevention, early detection, and treatment for diseases like Alzheimers, Parkinsons, Huntingtons, chronic traumatic encephalopathy, and ALS would benefit millions of people around the world.

Yakeel Quiroz, at Massachusetts General Hospital, studies changes in brain structure and function that occur before the onset of Alzheimers symptoms. Shes looking for biomarkers that could be used for early detection of the disease and trying to pinpoint potential targets for therapeutics. One potential biomarker of early-onset Alzheimers that shes founda protein called NfLis elevated in the blood more than two decades before symptoms appear. Quiroz has also identified a woman with a protective genetic mutation that kept her from developing cognitive impairments and brain degeneration even though her brain showed high levels of amyloid, a protein implicated in Alzheimers development. Studying the effects of this beneficial mutation could lead to new therapies.

Researchers at the Early Detection of Neurodegenerative Diseases initiative in the United Kingdom are analyzing whether digital data collected by smartphones or wearables could give early warnings of disease before symptoms develop. One of the initiatives projectsa partnership with Boston Universitywill collect data using apps, activity tracking, and sleep tracking in people with and without dementia to identify possible digital signatures of disease.

As we learn more about the underlying causes of neurodegenerative diseases, researchers are trying to translate this knowledge into effective treatments. Advanced clinical trials targeting newly understood mechanisms of disease are currently under way for many neurodegenerative disorders, including Alzheimers, Parkinsons, and ALS.

Connectomics researchers map and analyze neuronal connections, creating a wiring diagram for the brain.

Understanding these connections will shed light on how the brain functions; many projects are exploring how macro-scale connections are altered during development, aging, or disease.

Mapping these connections isnt easythere may be as many as 100 trillion connections in the human brain, and theyre all tiny. Researchers need to find the best ways to label specific neurons and track the connections they make to other neurons in remote parts of the brain, refine the technology to collect these images, and figure out how to analyze the mountains of data that this process produces.

Link:
Eight ways scientists are unwrapping the mysteries of the human brain - MIT Technology Review

As anyone who has ever lived with a dog will know, it often feels like we dont get enough time with our furry friends. Most dogs only live around ten to 14 years on average though some may naturally live longer, while others may be predisposed to certain diseases that can limit their lifespan.

But what many people dont know is that humans and dogs share many genetic similarities including a predisposition to age-related cancer. This means that many of the things humans can do to be healthier and longer lived may also work for dogs.

Here are just a few ways that you might help your dog live a longer, healthier life.

One factor thats repeatedly linked with longevity across a range of species is maintaining a healthy bodyweight. That means ensuring dogs arent carrying excess weight, and managing their calorie intake carefully. Not only will a lean, healthy bodyweight be better for your dog in the long term, it can also help to limit the impact of certain health conditions, such as osteoarthritis.

Carefully monitor and manage your dogs bodyweight through regular weighing or body condition scoring where you look at your dogs physical shape and score them on a scale to check whether theyre overweight, or at a healthy weight. Using both of these methods together will allow you to identify weight changes and alter their diet as needed.

Use feeding guidelines as a starting point for how much to feed your dog, but you might need to change food type or the amount you feed to maintain a healthy weight as your dog gets older, or depending on how much activity they get. Knowing exactly how much you are feeding your dog is also a crucial weight-management tool so weigh their food rather than scooping it in by eye.

More generally, good nutrition can be linked to a healthy ageing process, suggesting that what you feed can be as important as how much you feed. Good nutrition will vary for each dog, but be sure to look for foods that are safe, tasty and provide all the nutrients your dog needs.

Exercise has many physiological and psychological benefits, both for our dogs (and us). Physical activity can help to manage a dogs bodyweight, and is also associated with anti-ageing effects in other genetically similar species.

While exercise alone wont increase your dogs lifespan, it might help protect you both from carrying excess bodyweight. And indeed, research suggests that happy dog walks lead to both happy dogs and people.

Ageing isnt just physical. Keeping your dogs mind active is also helpful. Contrary to the popular adage, you can teach old dogs new tricks and you might just keep their brain and body younger as a result.

Even when physical activity might be limited, explore alternative low-impact games and pursuits, such as scentwork that you and your dog can do together. Using their nose is an inherently rewarding and fun thing for dogs to do, so training dogs to find items by scent will exercise them both mentally and physically.

Other exercise such as hydrotherapy a type of swimming exercise might be a good option especially for dogs who have conditions which affect their ability to exercise as normal.

Like many companion animals, dogs develop a clear attachment to their caregivers. The human-dog bond likely provides companionship and often, dog lovers describe them as a family member.

A stable caregiver-dog bond can help maintain a happy and mutually beneficial partnership between you and your dog. It can also help you recognise subtle changes in your dogs behaviour or movement that might signal potential concerns.

Where there is compatability between caregiver and dog, this leads to a better relationship and even benefits for owners, too, including stress relief and exercise. Sharing positive, fun experiences with your dog, including playing with them, are great for cementing your bond.

Modern veterinary medicine has seen substantial improvements in preventing and managing health concerns in dogs. Successful vaccination and parasite management programmes have effectively reduced the incidence of disease in both dogs and humans including toxocariasis, which can be transmitted from dog faeces to humans, and rabies, which can be transmitted dog-to-dog or dog-to-human.

Having a good relationship with your vet will allow you to tailor treatments and discuss your dogs needs. Regular health checks can also be useful in identifying any potential problems at a treatable stage such as dental issues or osteoarthritis which can cause pain and negatively impact the dogs wellbeing.

At the end of the day, its a combination of our dogs genetics and the environment they live in that impacts their longevity. So while we cant change their genetics, there are many things we can do to improve their health that may just help them live a longer, healthier life.

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Five ways to help your dog live a longer, healthier life - The Conversation UK

Changing your diet to improve your health is nothing newpeople with diabetes, obesity, Crohns disease, celiac disease, food allergies, and a host of other conditions have long done so as part of their treatment. But new and sophisticated knowledge about biochemistry, nutrition, and artificial intelligence has given people more tools to figure out what to eat for good health, leading to a boom in the field of personalized nutrition.

Personalized nutrition, often used interchangeably with the terms precision nutrition or individualized nutrition is an emerging branch of science that uses machine learning and omics technologies (genomics, proteomics, and metabolomics) to analyze what people eat and predict how they respond to it. Scientists, nutritionists, and health care professionals take the data, analyze it, and use it for a variety of purposes, including identifying diet and lifestyle interventions to treat disease, promote health, and enhance performance in elite athletes.

Increasingly, its being adopted by businesses to sell products and services such as nutritional supplements, apps that use machine learning to provide a nutritional analysis of a meal based on a photograph, and stool-sample tests whose results are used to create customized dietary advice that promises to fight bloat, brain fog, and a myriad of other maladies.

Nutrition is the single most powerful lever for our health, says Mike Stroka, CEO of the American Nutrition Association, the professional organization whose mandate includes certifying nutritionists and educating the public about science-based nutrition for health care practice. Personalized nutrition will be even bigger.

In 2019, according to ResearchandMarkets.Com, personalized nutrition was a $3.7 billion industry. By 2027, it is expected to be worth $16.6 billion. Among the factors driving that growth are consumer demand, the falling cost of new technologies, a greater ability to provide information, and the increasing body of evidence that there is no such thing as a one-size-fits-all diet.

The sequencing of the human genome, which started in 1990 and concluded 13 years later, paved the way for scientists to more easily and accurately find connections between diet and genetics.

When the term personalized nutrition first appeared in the scientific literature, in 1999, the focus was on using computers to help educate people about their dietary needs. It wasnt until 2004 that scientists began to think about the way genes affect how and what we eat, and how our bodies respond. Take coffee, for instance: Some people metabolize caffeine and the other nutrients in coffee in a productive, healthy way. Others dont. Which camp you fall into depends on a host of factors including your genetics, age, environment, gender, and lifestyle.

More recently, researchers have been studying connections between the health of the gut microbiome and conditions including Alzheimers, Parkinsons, and depression. The gut microbiome, the bodys least well-known organ, consists of more than 1000 species of bacteria and other microbes. Weighing in at almost a pound, it produces hormones, digests food that the stomach cant, and sends thousands of different diet-derived chemicals coursing through our bodies every day. In many respects the microbiome is key to understanding nutrition and is the basis of the growth in personalized nutrition.

Blood, urine, DNA, and stool tests are part of the personalized nutrition toolkit that researchers, nutritionists, and health care professionals use to measure the gut microbiome and the chemicals (known as metabolites) it produces. They use that data, sometimes in conjunction with self-reported data collected via surveys or interviews, as the basis for nutrition advice.

Link:
The Poop About Your Gut Health and Personalized Nutrition - WIRED

The genetics and genomics revolution has at its core information and techniques that can be used to change humanness itself as well as the concepts of what it means to be human. The age-old human fantasies of the mythical chimeras of the ancients, supernatural intelligence, wiping disease from human inheritance, designing a better human being, the fountain of youth, and even immortality now have biotechnical credence in the theoretical promises of genetics and genetic engineering. Not only can humanity's collective genetic inheritance be shaped by selecting which embryos are allowed to develop via pre-implantation genetic diagnosis, but genetic engineering, the availability of the human embryo for experimentation, and combining genes from many species require only sufficient imagination to catalyze the designing of a new humanity.

To talk about some of the implications of these technologies, Wake Forest University School of Medicine held a conference entitled Genetics, Biotechnology and the Future: Medical, Scientific and Religious Perspectives on January 24, 2004 in Winston-Salem, North Carolina in partnership with The Center for Bioethics and Human Dignity. The conference was co-sponsored by the Bioethics Task Force of Wake Forest University, Christian Medical and Dental Associations, Piedmont Bioethics Network, and Trinity International University.

The conference brought together leaders from medicine, science, law, ethics, religion, and patient advocacy to examine how genetics and biotechnology should be used to shape our future. The overall goal of the conference was to spur in-depth deliberation across spheres of influence during the formative stages of genetic and biotechnological disciplines. The conference, promoted through Bioethics.com and other international venues, was a stimulating and rewarding experience featuring insightful exchange among the various fields.

In addition to discussing the genetic revolutions, competing conceptions of the human embryo's moral status were also debated at the conference. Greater support was voiced for a view in which "respect" entails more than just insisting that the benefits of killing be great enough. An embryo is a human being--genetically human and a being who will develop through a lifelong cycle, like other human beings, as long as suitable nurture and environment are provided. To diminish that being's status, because of the stage of development at the moment, appeared arbitrary to many--though some supported doing so.

While science is billed as morally neutral, there are many fallacies with this oversimplification. Science lacks moral neutrality not only in the priorities set but also in the hypotheses proposed and the questions asked, because the prevailing philosophical values of our culture influence all of these. The swaying of scientific aims by philosophical values is more fundamental to science's impact on our future than the actual gains of explorations themselves.

The conference noted that the medical profession--countering the narrowly focused, specific question-answering capabilities of science--humanizes scientific activity. The patient advocacy role of a physician takes the empirical-pragmatic scientific "logical way" of medicine into account, but guides patients to act consistently with their whole persons, not just their physical bodies. Medicine at its best never advocates a cure at the expense of denigrating a patient's soul. Medicine begins the ethical reflection on the "should we" questions. Recently, though, medicine has increasingly been preoccupied with patient autonomy and utility, and the need for the valuable counterbalance that can be provided by religious influences has become more apparent. Autonomy and utility should not trump all other ethical concerns.

To read current justifications of human cloning, embryonic stem cell research, and genetic intervention, though, one would think that constraining any scientific freedom is the ultimate evil. On the contrary, the greater evil arguably lies in allowing scientific development to proceed without ethical moorings. One would also think from current discussions that great medical benefits constitute their own justification; whereas common sense tells us otherwise. We don't remove all of the vital organs from a single healthy person just because a larger number of people can be enabled to live as a result.

Religious perspectives have a significant role to play in the ethical use of genetics and biotechnology--to connect autonomous choices with larger communal concerns. Religious views help ensure that scientific advances not only expand choices and produce benefits but do so without undermining our humanity and dignity in the process. This conference shattered the oft-quoted misconception that those who hold strong religious opinions are antagonistic to scientific investigation. Rather, all spheres of influence agreed on the high value of scientific and medical investigation with an aim to restore human health and alleviate disease and suffering. The consensus was that society should no longer allow these spheres of influence to remain separate and isolated in theoretical blindness. Rather society must prioritize cross-disciplinary examination to ensure that the future of human genetics and biotechnology is not only scientifically sophisticated and medically productive but also truly humane.

It is a cultural necessity today to have bioethics dialogs among informed citizens representing all spheres of influence. More opportunities like this are needed that bring together people of differing views to discuss and assess some of the most crucial issues of our time.

Editor's Note: The above text has been adapted from an article appearing in the Journal of International Biotechnology Law 1:2 (March, 2004): 53-55. The journal invited the authors to write the article, which discusses the most important ideas that emerged at the Center's latest regional conference, for its March 2004 issue.

To inquire about holding a CBHD conference in your area, please email the Center at info@cbhd.org.

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Genetics, Biotechnology, and the Future | The Center for ...

June 9, 2020

The genome is the complete set of your DNA, including all of your genes. The human genome was first decoded nearly two decades ago. The genetic sequencing of thousands of genomes has allowed researchers to begin to understand how the human body is built and maintained.

But each persons genome is unique. Not enough genomes have been sequenced to understand all the ways that genetic variation can contribute to disease. To better understand the genetic diversity of the human genome, the Genome Aggregation Database (gnomAD) Consortium was formed over eight years ago to collect and study the genomes of people around the world.

The international gnomAD team of over 100 scientists released its first set of discoveries in a collection of seven papers published on May 27, 2020 in Nature, Nature Communications, and Nature Medicine. The work was funded in part by several NIH institutes (see Funding section below for full list).

The flagship paper cataloged the genetic variation in both the protein coding and non-coding regions of human DNA. Included were more than 125,000 exomes (which include only the parts that code for proteins) and 15,000 whole genomes, from populations in Europe, East and South Asia, Africa, and more. The researchers identified a total of 241 million variants that were either small single point mutations (changes in a single DNA building block, called a nucleotide) or insertions or deletions of short pieces of DNA.

The team explored how likely certain variants are to cause a loss of function in the proteins produced from the gene. Protein-coding genes were categorized based on their ability to tolerate genetic variations without being disrupted or inactivated by them. This analysis found more than 443,000 genetic variants that were likely to cause a loss of protein function.

The second paper explored why mutations identified as likely to cause a loss of function dont always cause the problems that might be expected. The team found that such variants are within segments of DNA that are often spliced out of the final mRNA copies of the gene used to produce proteins.

A third paper detailed the analysis of more than 433,000 structural variants in the human genome. Structural variants are changes that span long stretches of DNA, of at least 50 nucleotides. Structural variants were less likely to appear in protein coding regions than in non-protein coding regions. The team estimated that only about 0.13% of people carry a structural variant with any clinical significance.

The fourth paper explored how loss of function variations could be used to identify new drug targets. The fifth paper provided an example of how gnomAD could be used to validate drug targets. It analyzed the effects of loss of function variants in a gene called LRRK2, which has been associated with Parkinsons disease. The results suggestthat therapies to inhibit the LRRK2 protein would be unlikely to cause severe side effects.

The sixth paper described the impacts of variants in the region that sits immediately before the protein coding region of genes, called the 5 untranslated region. The researchers identified specific genes where variants in this region could lead to disease. One novel variant they uncovered was tied to neurofibromatosis. Finally, the last paper showed how gnomAD could be used to analyze multi-nucleotide variantsclusters of two or more variants that are often inherited together.

The wide-ranging impact this resource has already had on medical research and clinical practice is a testament to the incredible value of genomic data sharing and aggregation, says Dr. Daniel MacArthur at the Broad Institute of MIT and Harvard, who is a lead author on the papers. More than 350 independent studies have already made use of gnomAD for research on cancer predisposition, cardiovascular disease, rare genetic disorders, and more since we made the data available.

The consortiums next steps are to expand gnomAD to increase the number of genomes and diversity of populations included. We are very far from saturating discoveries or solving variant interpretation, MacArthur says. The next steps for the consortium will be focused on increasing the size and population diversity of these resources, and linking the resulting massive-scale genetic data sets with clinical information.

by Tianna Hicklin, Ph.D.

References:

The mutational constraint spectrum quantified from variation in 141,456 humans. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, O'Donnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME; Genome Aggregation Database Consortium, Neale BM, Daly MJ,MacArthur DG. Nature. 2020 May;581(7809):434-443. doi: 10.1038/s41586-020-2308-7. Epub 2020 May 27. PMID:32461654.

Transcript expression-aware annotation improves rare variant interpretation. Cummings BB, Karczewski KJ, Kosmicki JA, Seaby EG, Watts NA, Singer-Berk M, Mudge JM, Karjalainen J, Satterstrom FK, O'Donnell-Luria AH, Poterba T, Seed C, Solomonson M, Alfldi J; Genome Aggregation Database Production Team; Genome Aggregation Database Consortium, Daly MJ,MacArthur DG. Nature. 2020 May;581(7809):452-458. doi: 10.1038/s41586-020-2329-2. Epub 2020 May 27. PMID:32461655.

A Structural Variation Reference for Medical and Population Genetics Collins RL, Brand H, Karczewski KJ, Zhao X, Alfldi J, Francioli LC, Khera AV, Lowther C, Gauthier LD, Wang H, Watts NA, Solomonson M, O'Donnell-Luria A, Baumann A, Munshi R, Walker M, Whelan CW, Huang Y, Brookings T, Sharpe T, Stone MR, Valkanas E, Fu J, Tiao G, Laricchia KM, Ruano-Rubio V, Stevens C, Gupta N, Cusick C, Margolin L; Genome Aggregation Database Production Team; Genome Aggregation Database Consortium, Taylor KD, Lin HJ, Rich SS, Post WS, Chen YI, Rotter JI, Nusbaum C, Philippakis A, Lander E, Gabriel S, Neale BM, Kathiresan S, Daly MJ, Banks E, MacArthur DG, Talkowski ME. Nature. 2020 May;581(7809):444-451. doi: 10.1038/s41586-020-2287-8. Epub 2020 May 27. PMID:32461652.

Evaluatingdrugtargetsthroughhumanloss-of-functiongeneticvariation. Minikel EV, Karczewski KJ, Martin HC, Cummings BB, Whiffin N, Rhodes D, Alfldi J, Trembath RC, van Heel DA, Daly MJ; Genome Aggregation Database Production Team; Genome Aggregation Database Consortium, Schreiber SL, MacArthur DG. Nature. 2020 May;581(7809):459-464. doi: 10.1038/s41586-020-2267-z. Epub 2020 May 27. PMID:32461653.

The effect of LRRK2 loss-of-function variants in humans. Whiffin N, Armean IM, Kleinman A, Marshall JL, Minikel EV, Goodrich JK, Quaife NM, Cole JB, Wang Q, Karczewski KJ, Cummings BB, Francioli L, Laricchia K, Guan A, Alipanahi B, Morrison P, Baptista MAS, Merchant KM; Genome Aggregation Database Production Team; Genome Aggregation Database Consortium, Ware JS, Havulinna AS, Iliadou B, Lee JJ, Nadkarni GN, Whiteman C; 23andMe Research Team, Daly M, Esko T, Hultman C, Loos RJF, Milani L, Palotie A, Pato C, Pato M, Saleheen D, Sullivan PF, Alfldi J, Cannon P,MacArthur DG. Nat Med. 2020 May 27. doi: 10.1038/s41591-020-0893-5. Online ahead of print. PMID:32461697.

Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals. Whiffin N, Karczewski KJ, Zhang X, Chothani S, Smith MJ, Evans DG, Roberts AM, Quaife NM, Schafer S, Rackham O, Alfldi J, O'Donnell-Luria AH, Francioli LC; Genome Aggregation Database Production Team; Genome Aggregation Database Consortium, Cook SA, Barton PJR,MacArthur DG, Ware JS. Nat Commun. 2020 May 27;11(1):2523. doi: 10.1038/s41467-019-10717-9.PMID:32461616.

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Funding:NIHs National Institute of General Medical Sciences (NIGMS), National Human Genome Research Institute (NHGRI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Mental Health (NIMH), and National Heart, Lung, and Blood Institute (NHLBI), National Institute of Allergy and Infectious Diseases (NIAID), National Center for Advancing Translational Sciences (NCATS), National Institute of Dental and Craniofacial Research (NIDCR), and National Center for Research Resources (NCRR); Swiss National Science Foundation; BioMarin Pharmaceutical Inc.; Sanofi Genzyme Inc.; Broad Institute; Wellcome Trust; Medical Research Council (UK); University of Sheffield; Barts Charity; Health Data Research UK; NHS National Institute for Health Research; Rosetrees/Stoneygate Imperial College; Simons Foundation; National Science Foundation; Desmond and Ann Heathwood; Southern California Diabetes Endocrinology Research Center; Michael J. Fox Foundation; Estonian Research Council; Royal Brompton and Harefield NHS Foundation; Imperial College London; Fondation Leducq; Department of Health, UK; Swiss National Science Foundation; Imperial College Academic Health Science Centre; Nakajima Foundation Scholarship.

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Clemson Universitys Center for Human Genetics opened July 1, 2018, and is dedicated to advancing knowledge of the fundamental principles by which genetic and environmental factors determine and predict both healthy traits and susceptibility to disease.The Center for Human Genetics, which is part of theCollege of Science, is housed inSelf Regional Hall, a 17,000-square-foot building that opened in February 2017. The sparkling facility is nestled within the sprawling campus of theGreenwood (S.C.) Genetic Center, which has a long history of clinical and research excellence in the field of medical genetics and caring for families impacted by genetic disease and birth defects.

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Clemson University has further enhanced its standing as a pioneer in the field of human genomics by hiring a renowned scientist to lead the way.Groundbreaking geneticist Trudy Mackay has been named director of Clemsons Center for Human Genetics and has been tasked with building a team of researchers whose goal will be to significantly advance our understanding of genetic disorders.

Read more about the Center for Human Genetics

Oct. 25, 2018:Mackay to be honored at Trinity College Dublin

Oct. 8, 2018:CHG receives $1.87 million from NIH to advance research

Aug. 8, 2018:CHG opens its doors to the world

Feb. 15, 2017:CHG unveils new facility on Greenwood Genetic Center campus

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Almost a quarter of people who suffer severe forms of Covid-19 have a genetic or immune anomaly, a major Paris hospital group has said, citing two new French studies.

In a statement, the Assistance publique Hpitaux de Paris (AP-HP) highlighted two new studies on the subject. Both were published in scientific journal Science Immunology.

They are the result of international collaboration, including researchers from national medical institute lInstitut national de la sant et de la recherche mdicale (Inserm), the University of Paris, and the human genetics lab of infectious diseases at the AP-HP.

In the first study, researchers focused on men, as they are more likely to suffer from severe forms of Covid. Researchers sequenced the X chromosome of 1,202 male patients who had had a severe form of the virus.

Of these, 16 patients were found to have a genetic variation on the TLR7 gene, dubbed a loss of function, which led to the development of severe forms of the virus.

This is because this gene plays a major role in the production and mechanism of IFN 1, which is a protein that is produced in response to a viral threat, and which inhibits the replication of the virus in infected cells, the AP-HP said.

It summarised: The 16 patients who presented a deficit in IFN 1 stopped their cells from being able to fight against the SARS-CoV-2 infection, which explains the severe forms.

The study recruited patients from all over the world, involving 400 research centres in 38 different countries the hospital group said, which enabled researchers to gather a representative sample of people and avoid excess ethnicity bias.

This means that the results can be used to make predictions and conclusions about the general population.

Overall, the study concluded: It appears that 1.3% of several forms of Covid-19 can be explained by a genetic abnormality of the TLR7 gene in men. This deficit is more frequent (1.8%) in patients under 60.

The second study showed that 15-20% of severe forms of Covid are due to the patients blood having antibodies that specifically target the IFN 1.

The study looked at 3,595 patients who had had a severe form of Covid, 1,639 who had an asymptomatic form, and 34,159 people in good health. The participants were from 38 different countries.

In its statement, AP-HP said: They showed that these antibodies block the protecting effects of IFN 1 on the virus replication. The SARS-CoV-2 virus penetrates into the cells without meeting any resistance and replicates uncontrollably.

The study also showed that these antibodies against IFN 1 increase with age. They are very rare before the age of 65 (0.2-0.5%), and increase exponentially as you age, reaching 4% between the ages of 70-79, and 7% between the ages of 80-85.

Researchers do not yet know why this is, but the study does partly help to explain why age is a risk factor in the development of severe forms of Covid.

France is still recording relatively high numbers of cases of the virus, and of hospital admissions.

The most recent figures to August 21 from Sant publique France show that there were 22,636 confirmed cases in the previous 24 hours, and 81 deaths. There were 6,008 new hospitalisations in the past seven days, and 1,316 critical care admissions in the same time, including 969 into intensive care units.

Record 6million Covid tests taken in France after health pass extended200 anti-health pass protests to take place in France this SaturdayFrance hits 40 million goal for full vaccinations against Covid-19

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French study: 20% severe Covid patients have genetic or immune issue - The Connexion