Category Archives: Human Genetics

For more than a decade, archaeologists thought they were looking at a bear. Known to experts as PP-00128, the fragment of bone found in a southeastern Alaskan cave seemed to be from some large mammal that lived in the area thousands of years ago. But ancient DNA evidence has given this unassuming shard of bone a new identity. The sliver did not belong to a bear, but at 10,150 years old, the most ancient dog yet found in the Americas.

The surprising realization was published today in a study in the Proceedings of the Royal Society B. While looking for Ice Age bear bones to examine, University of Buffalo geneticist Charlotte Lindqvist set about analyzing PP-00128. Perhaps the DNA would reveal what sort of bear the bone came from and how it was related to other ursids. But when Lindqvist and colleagues analyzed the DNA extracted from the bone, they found something very different. This bear was a dog.

Ten or twenty years ago, we would have looked through a pile of bone fragments and not seen this, says Durham University archaeologist Angela Perri, who was not involved in the new study. This is a nice example of what can be done with some of these advanced methods, she adds, noting that mass screening of archaeological material can turn up new clues that might otherwise be missed. Advances in how ancient DNA is extracted, corrected for any modern contaminants and sequenced have allowed researchers to quickly assess the genetics of organisms much faster than ever before, building a growing database that can be used to detect broader patterns. The more ancient DNA thats recovered, analyzed and placed in the database, the bigger the sample researchers have to work from when trying to understand how organismsbe it dogs or humans relate to each other.

Dogs have been with humans for a very long time. Around 23,000 years ago, in whats now Siberia, humans and gray wolves were hemmed in by the encroaching glaciers of the last Ice Age. No one knows for sure exactly how the two species started their relationship, with the leading hypothesis being that the friendlier wolves got used to people who gave them scraps or let them raid garbage piles, but that was the crucible in which the first domesticated dogs were born.

From there, the history of people and dogs was intertwined. Genetic evidence of both humans and dogs, published earlier this year by Perri and colleagues, suggest that they left Eurasia together as people and their pooches crossed the Bering Land Bridge to the ancient Americas together. Now, hot on the heels of that discovery, Lindqvist and colleagues have identified PP-00128 as a genetic cousin of those first Siberian dogs.

In this particular case, the happenstance discovery helps bring some resolution to a disjunction in the archaeological record. The archaeological evidence for humans and dogs in the New World is sparse and there is a gap in time between archaeological evidence and genetic estimates when it comes to both the entrance of humans and dogs to the Americas south of the ice sheets, Lindqvist says. The genetics seemed to suggest earlier arrivals for both dogs and people, but the archaeological evidence was often much younger than what the genetics suggested. But by looking at both where PP-00128 existed in time, as well as its genetic connections to both Eurasian and American dogs, a new perspective is starting to come together.

The bone comes from a critical time. Its age is a shade older than other early dog bones found in current-day Illinois, indicating that dogs domesticated in Eurasia spread with people through the Americas. The dogs from the Midwest form a genetic group together with others from places like Alabama and Missouri, part of the dispersal of people through the continent. What makes PP-00128 distinct is that its from an earlier group of dogs with ties to Siberia, and its location is especially important. The bone fragment was uncovered in a cave that is close to another archaeological site containing human remains of similar age along the Alaskan coast.

Archaeologists and anthropologists have long debated when and how people traveled from Eurasia across the Bering Land Bridge to the Americas. For decades, the prevailing thought was that migrating groups took advantage of receding ice sheets to take a central corridor between the continents, going through the middle of whats now Alaska before venturing further south. But the discovery of a domesticated dog along Alaskas Blake Channel points to a growing body of evidence that people traveled between the continents by moving along the coast, perhaps using early watercraft to move across the wetter stretches. Ice retreated from the coast before the interior, with estimates suggesting that people could have traveled through the area as early as 17,000 years ago and certainly by 15,000 years ago. I think that their paper most importantly makes a strong case for coastal migration into the Americas, Perri says, with the peopling of the continent starting with the coasts and later expanding more inland as the ice continued to withdraw.

Additional finds and analysis will test the ideaPerri notes that even earlier dogs are likely to be found along the route between Siberia and Alaska. But the close association between people and dogs so far back in time underscores an important point. The movement and locations of ancient dogs are proxies to the movement of people, and vice versa, because our histories are closely linked, Lindqvist says. Not far from where the 10,150-year-old dog bone was found, archaeologists have found 10,300-year-old human remains in a cave called Shuk Ka on nearby Prince of Wales Island, underscoring that people and dogs were here together. As Perri notes, Where people go, dogs go.

The emerging picture doesnt rest on any single discovery, but many different threads. The location, time and genetics of PP-00128 lined up with new hypotheses about when and where both dogs and people arrived in the Americas. Encroaching ice may have brought people and the ancestors of dogs together in Siberia, but when the ice thawed they could begin to travel together. Sometimes in science it is very exciting when multiple different pieces of evidence come together, Lindqvist says.

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Ancient DNA Reveals the Oldest Domesticated Dog in the Americas - Smithsonian Magazine

Most of us living on planet Earth have to make it through some amount of cold weather for at least part of the year, and new research has identified a specific genetic mutation that makes a fifth of us more resilient to cold conditions.

The genetic mutation in question stops the production of the protein -actinin-3, which is important for skeletal muscle fibre: The protein is only found in fast-twitch (or white) fibres and not in slow-twitch (or red) fibres.

Based on the new study's results, people without -actinin-3 have a higher proportion of slow-twitch fibres, and one of the consequences is that the body tends to conserve energy by building up muscle tone through contractions rather than shivering.

"This suggests that people lacking -actinin-3 are better at keeping warm and, energy-wise, at enduring a tougher climate, but there hasn't been any direct experimental evidence for this before," says physiologist Hkan Westerblad, from the Karolinska Institutet in Sweden.

"We can now show that the loss of this protein gives a greater resilience to cold and we've also found a possible mechanism for this."

The researchers recruited 42 men to sit in 14-degree Celsius (57.2-degree Fahrenheit) water while their temperatures and muscles were measured. The chilly immersion lasted 20 minutes at a time with 10-minute breaks, for up to two hours in total.

The proportion of participants who could keep their body temperature above 35.5 degrees Celsius (95.9 degrees Fahrenheit) was higher in those with the -actinin-3 mutation versus those without 69 percent of volunteers versus 30 percent.

In other words, the genetic mutation appeared to help these participants to conserve energy more efficiently and build up a greater resilience to the cold.

The team also conducted follow-up experiments in mice with the same mutation in order to check whether having this mutation could have something to do with increasing brown fat stores a well-known heat-generating tissue in mammals but that didn't turn out to be the case.

People lacking -actinin-3 might be better braced for a cold water swim or a bout of wintry weather, but it could also leave them more vulnerable to obesity and type-2 diabetes if they're inactive, the researchers say. It might also increase the risk of falling as they get older, as fast-twitch fibres handle speedy muscle movements.

"The mutation probably gave an evolutionary advantage during the migration to a colder climate, but in today's modern society this energy-saving ability might instead increase the risk of [these] diseases, which is something we now want to turn our attention to," says Westerblad.

As previous research has shown, -actinin-3 deficiency has increased across the population as humans have moved from warmer to colder climes, although questions remain about whether this mutation is present at birth and affects infant mortality.

It's also interesting to note that athletes who excel at sports involving explosiveness and strength (such as sprinting) are more likely to not have this lack of -actinin-3, while for endurance sports the stats are reversed.

As for future research, the team is keen to look at how this might all work at the molecular level, as well as how it could affect muscle disease. For now, it's an important new discovery about this genetic mutation and the allele or gene form associated with it.

"These findings provide a mechanism for the increase in [these gene variants'] frequency as modern humans migrated from Africa to the colder climates of central and northern Europe over 50,000 years ago," conclude the researchers in their published paper.

The research has been published in the American Journal of Human Genetics.

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Don't Suffer in The Cold? Turns Out There's a Genetic Mutation For That - ScienceAlert

20 years ago, humans first discovered the richness and complexity of their genetic heritage. A long-term venture that has monopolized hundreds of researchers for 15 years, but it has changed biology and medicine.

February 15, 2001, first snatch Genome Humans have revealed Famous newspaper Nature. This publication will forever change the history of biology and medicine. For the first time, humanity has its marrow, its ADN And his Genoa. Although incomplete, this is the first Sequencing The human genome requires the work of hundreds of researchers from around the world, all working together in the same consortium: Human Genome Project.

Twentieth anniversary of the publication of the article in Nature It is an opportunity to return to this incredible scientific adventure that began in the late 1970s. Before daring to attack 23 pairs, several researchers tested their sequencing technique to test simple organisms. Chromosomes Of the human genome.

It all started in the mid-1980s, when all three scientists had the same awareness. For the discovery of the 1975 Nobel Laureate Renato Dalbeco without consulting each other Oncogenes, Robert Sinsheimer and Charles Delisi of the University of California, Santa Cruz, argue to fill an important gap: the human genome continues to grow deeper and deeper. At that point, sequencing Genetic It is still in its infancy. Scientists rubbed his shoulder with his genome phage X174 and its 5.375 Nucleotides In 1977, to the 1978 SV40 with 5,224 nucleotides. In the early 1980s, scientists achieved further growth by aligning elongated genomes, including phase 2 of 1982 and its 48,502 nucleotides. On the human side, theADN Mitochondrial, Its 16,569 nucleotides pass through the sequencing mill for the first time. The latter 16 genes are identified.

These first works are the fertile ground for a more ambitious project to be formed in 1985. To create a comprehensive genetic map of the human genome. The Human Genome Project Born in 1988, with him Human Genome Organization (Hugo), responsible for coordinating the efforts of scientists around the world. The project takes 15 years to learn about the human genome, as well as others Model creatures Important in biology and medicine. thats all National Institute of Health, Its first director Francis Crick, Co-discovery of the dual helix structure of the project-leading DNA.

Scientists in 1995 Human Genome Project Together in Bermuda make a decision to change everything. When the sequencing is complete, it should be available to everyone. Each decrypted sequence must be shared in an Internet database, thus forming an invisible treasure that is the genetic heritage of mankind. Thus, three years before the deadline, the first raw sequences appear in the review Nature What do they say about the abyss that was the human genome at the time?

The first rough map of the human genome actually contains the genetic heritage of several unknown donors. Each donor gave their consent before taking five to ten DNA samples.

To form this genetic map, we first had to cut the DNA into a thousand pieces. Bacterial synthetic chromosomes (BACs) contained fragments of DNA with a base of 100 to 200 kPa formed a large library. Its like separating and storing each sheet of a book. To reconstruct the book, the BACs were arranged individually, as we read each page of the book, before putting the whole story together before putting them back together. The resulting genetic map includes 4.26 gigabases or 4.26.109 The letters A, T, C or G that follow each other, we have never understood such a long genome!

Although this is only a draft of the human genome, it has identified important points in our genetic heritage:

It required two years of work Human genome tweaking, Final sequences Finally published Nature In October 2004. Since then, knowledge about our genes, their effects on diseases, and how they work has been growing. Currently, this is the mapping done Genome Reference Consortium Based on the performance of in 2019 Human Genome Project, Is considered Reference.

Today, artificial intelligence is pushing human genetics backwards as computers can create from scratch. Human genomes that do not match the genetic makeup of any living human being.

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20 years ago, humans first adjusted their genome - SwordsToday.ie

Although Dr Kendler is internationally renowned and highly respected for his work in psychiatric genetics, he has been further catapulted into fame over the past 2 decades through his widely read commentaries on the philosophical foundations of psychiatry. I recently had the pleasure of reading the book Toward a Philosophical Approach to Psychiatry: The Writings of Kenneth Kendler. The book is a selection of 21 of his most important philosophical and historical papers published throughout his career, addressing topics such as the classification and nature of mental disorders, mind-body relationship, causality and explanation in psychiatry, and historical studies in psychiatric nosology. My admiration of Kendler is no secret at this point.

AFTAB: I really like your description of how psychiatric nosology sits in a historically contingent developmental arc. How is this history relevant to ongoing nosological debates in psychiatry, and how has ignorance of this history impeded our efforts at making progress?

KENDLER: With respect to psychiatric nosology, there is quite a bit of truth to 2 worn maxims: (1) If you dont know where you have been it is hard to see where you are going, and (2) if you dont know your history, youre are at high risk to repeat your prior mistakes. So, I think history can provide a context and a background for what nosology can do and where it has taken wrong roads in the past.

AFTAB: I read that you collaborated with a translator to obtain English translations of Kraepelins previously untranslated works. Will these translations be published or see the day of light in some manner?

KENDLER: They are all sitting on my hard drive, and that of the translator Ms Astrid Klee, but there is a lot more there than just Kraepelin. A very small percentage of the relevant German psychiatric literature of the late 19th and early 20th centuries have been translated. I have thought about trying to set up a website to make these widely available. That will take time, energy, and a bit of resources. If any of these readers want to help, be in touch.

AFTAB: You have argued for a scientific pluralism where there are multiple explanatory perspectives available to us to understand psychiatric disorders, and one perspective cannot be reduced to another perspective. You describe your pluralism as empirical and hard-nosed, by which you mean that risk factors must earn their place at the table. It is a little unfortunate that many discussions of pluralism in psychiatry tend to get stuck in debating the merits and demerits of the biopsychosocial model. For the most part, you have managed to stay away from those controversies and have successfully charted a course for pluralism independent of any baggage that the biopsychosocial model brings. Is it time for our field to abandon the biopsychosocial model?

KENDLER: Its core idea was on target, but its implementation was so non-specific as to blunt any rigor it might have once had and its ultimate utility. I would not mourn its passing, but it did some important historical work.

AFTAB: DSM-5 defines mental disorder as a syndrome that, among other things, reflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning. What is the intended meaning of the term dysfunction? Did the members of the DSM committee have any clarity or consensus regarding what it means?

KENDLER: The hope that we could have a crisp set of inclusion and exclusion criteria for what constitutes a psychiatric dysfunction is a wonderful idea but (in my view, not for lack of trying) impossible. There are too many social and conceptual nuances. So, although there is a general idea of what dysfunction means, operationalizing in the way that would give substantial sharp precision to the definition has not proved possible.

AFTAB: Could you articulate what that general idea of dysfunction is? I am also interested in whether dysfunction necessarily implies that the locus of the problem is primarily inside the individual and not in interpersonal relations and social context? And, if there is such an implication, does this relegate interpersonal and social causal risk factors to a more secondary status?

KENDLER: The general idea of dysfunction is commonsensicalthat the relevant psychobiological system is not doing what it is supposed to do. Examples might include providing your higher centers with an approximately veridical sense of the world around you, keeping levels of anxiety roughly appropriate to the real dangers being confronted, producing mood states approximately congruent to the environmental situation, etc. The DSMs have traditionally seen disorders as existing within individuals and, for example, avoided providing diagnoses for dysfunctional marriages or families. So, in that sense, the underlying disturbance is seen to exist within individuals. I do not see that definition having much of anything to do with the causes. Environmental experiences like severe childhood sexual abuse can clearly cause dysfunctional mood-modulation systems as well as a high genetic vulnerability.

AFTAB: To what extent is the dappled distribution of causal risk factors of psychiatric disorders a result of the heterogeneity of constructs? For example, a discussion of the distribution of causal risk factors of chronic fever disorder is not likely to be very meaningful. Furthermore, it is true for major depressive disorderas a category that no single causal risk factor has dominant explanatory power, but it may be the case for specific individuals with depression that there are causal risk factors of large explanatory power. What are your thoughts?

KENDLER: I dont buy it. Most psychiatric disorders are, I think, multifactorial all the way down. I also think that for a few affected individuals they do suffer from disorders largely as a result of one major cause. I sometimes call your model the mental handicap model. Imagine you were a physician in the mid-19th century caring for what would then have been called idiots or imbeciles. If you could apply modern diagnostic methods to that group, a fair proportion would have a range of specific causes: Down syndrome, fragile X, a host of autosomal recessive disorders impacting on all kinds of brain-relevant genes that, when mutated, produce widespread central nervous system dysfunction, a range of small deletions, and a whole bunch would be nonspecific multifactorial. That is, a lot of your cases (but far from all) would have largely monocausal conditions. This has been long postulated for psychiatric illness. It has, in my judgment, been largely a pipe dream. I think that lesson applies more broadly.

AFTAB: Your philosophical writings are published and featured prominently in leading American psychiatric journals, which do not usually publish articles related to philosophy of psychiatry. I have wondered if one of the reasons mainstream journals are so receptive to your philosophical workaside from the undisputed academic quality and rigoris that your conclusions do not threaten or destabilize the status quo in a way that conclusions of some of the other philosophical commentators do. It was interesting to me that one of your more controversial articleson the dopamine hypothesis of schizophreniawas also the one that had a difficult time getting accepted. Why are leading American psychiatry journals publishing so few philosophical articles and so afraid of controversy?

KENDLER: I have made a deliberate attempt over the past 15-plus years to try to crack open the leading psychiatric journals for articles with a primary philosophical and/or historical content.

I agree with you that my ability to do that has been, in part, a result of the fact that I have achieved some standing in empirical areas of psychiatric research. To be vernacular, I have accumulated some street cred. I also think the papers were written in a way the audience could understand and that spoke to their concerns. I did not consciously edit the papers to make them less controversial. I still think that nonscholarly issues impacted on the problems we had with the dopamine hypothesis paperthat was perhaps a special case. I do not want to blow up psychiatry. I believe quite deeply in our clinical and research mission, but we surely can think more clearly about a number of issues in our clinical work, nosology and research.

AFTAB: Some critics hold the view that if a classification can be misused, it will be misused. To what extent should the concern for misuse constrain classification decisions? Do the creators of DSM have a responsibility to make academic as well as public educational efforts to reduce the ways in which the diagnostic manual is misunderstood and misused?

KENDLER: Our primary responsibility on DSM is to our patients and the research community that we assist. But possible misuse does, appropriately, arise in nosologic debates. For example, it played a key role in the opposition to the late-luteal-phase dysphoric debate in DSM-IVthat the diagnoses would be used in ways prejudicial to women. So, it would be unrealistic for DSM to ignore completely the possible misuse of the document. But, if the chips are down, I think serving our patients and research is the more important mission. It is impossible to control all the possible misuses of DSM and, if you took that concern too far, it would be paralyzing.

AFTAB: You have argued persuasively that the conditions we call psychiatric disorders are not merely constructed by individuals and cultures, and that these conditions have some basis in the objective reality, but what do you say about the construct of mental disorder itself? To what extent are concepts of health and disease, and characterizations of disorder grounded in objective reality?

KENDLER: As an aggregate concept, I think psychiatric illness (or mental illness) is a real thing out in the world. Going from that to specific disorders, be it schizophrenia or narcissistic personality disorder, that is harder, and the role of social construction or historical accident becomes greater. A metaphor (not my own) is to imagine rewinding the tape of history, say, to 20 centuries BCE and re-running it 100 times until society and medicine developed enough to establish something like what we call psychiatry. I would bet that some construct like insanity/schizophrenia would be there almost all the time. I would not say that for a number of more specific disorders in our manual.

AFTAB: You have stated that psychiatric disorders are multicausal, similar to how coronary artery disease, hypertension, and type 2 diabetes are multicausal in medicine. Multifactorial disorders can still have final common pathways onto which those risk factors converge, and those final common pathways provide a lot of explanatory power.

For example, multiple causal risk factors for diabetes converge onto insulin production or insulin resistance. Do you imagine that various causal risk factors for psychiatric disorders also converge onto final common pathways? If it turns out that psychiatric disorders are more like homeostatic property clusters, then it may very well be the case that there may be no final common pathway. In that situation would it still be fair to say that psychiatric disorders are multicausal in the same way as diabetes mellitus is?

KENDLER: Great question and topical. I have been involved with a research team trying to determine the biological coherence of the signals emerging from genome-wide association studies. This is a question rather closely related to the one you pose. I guess my main answer is I hope so. As you note, that is the case for lots of other complex disorders. To be a bit more precise, I think it is realistic that our big syndromes (eg, schizophrenia, alcohol use disorder, depression, anxiety disorders) reflect broad syndromes with some meaningful subtypes within them for which different therapies might have different success. It is awfully optimistic to think that all of them go through one tight final common pathway at which an intervention, properly designed, could be nearly curative for all cases. But similarly, the idea that there are hundreds of kinds of each disorder, each with its own needed therapy, is both very pessimistic and likely unrealistic.

AFTAB: You may not remember during the 2016 American Psychiatric Association Annual Meeting, I approached you nervously after a session to express my admiration of your philosophical work. I was a second-year resident at that time. You gave me advice that was something along the lines of It is very important that you read a lot and that you read very widely. That often comes to my mind because every day I discover that there is so much more to learn. I am impressed by how you have managed to apply ideas from other areas of philosophy of science to psychiatry. Given that you have limited time, how do you prioritize and decide what you will read?

KENDLER: There is never enough time to read everything of interest; I often think of the metaphor of trying to drink a waterfall. I am rather disciplined in what I read. I am good at skimming, and if the first 20 pages dont look good, then I bail. The older I have gotten, the less patient I am with philosophical books written for other professional philosophers, filled with philosophy-speak. If they are not interested in communicating with me, I have to be very, very interested in what they are saying to soldier on.

I read 5 or 6 books at once. I am now reading about the history of genetics and cannot get enough of it. I read very little fiction. But I do keep up other lines of reading, usually late at night, that help keep me rounded, or listen to Audible when I bike or commute. Recently, I have been reading more history of psychiatry than philosophy. I have lots of bookshelves at my home and work office, but I am running out of space.

AFTAB: This may be an unfair question: If posterity could remember you predominantly for either your research work in psychiatric genetics or your philosophical work in psychiatry, what would you prefer it to be?

KENDLER: I have to laughyes unfairSophies choice that I cannot answer. I hope I am remembered, if at all, as someone who has tried to weave together empirical and conceptual work. It has been a wonderful career, and the older I get, the harder it is to pull these 2 parts of what I do apart. My identity is with the whole of it.

Conversations in Critical Psychiatry is an interview series that explores critical and philosophical perspectives in psychiatry and engages with prominent commentators within and outside the profession who have made meaningful criticisms of the status quo. The opinions expressed in the interviews are those of the participants and do not necessarily reflect the opinions of Psychiatric TimesTM.

Interviews published in this series can be accessed at http://www.psychiatrictimes.com/series/critical-conversations-in-psychiatry.

Dr Aftab is a psychiatrist in Cleveland, Ohio, and clinical assistant professor of psychiatry at Case Western Reserve University. He has been actively involved in initiatives to educate psychiatrists and trainees on the intersection of philosophy and psychiatry. He is also a member of the Psychiatric TimesTM Advisory Board.

An earlier version of this article, Weaving Conceptual and Empirical Work in Psychiatry: Kenneth S. Kendler, MD, was published online ahead of print on May 26, 2020. -Ed

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A Psychiatrist Weaving Conceptual and Empirical Work - Psychiatric Times

There are some clues already. Researchers have identified an association between type O and rhesus negative blood groups, and a lower risk of severe disease. But while scientists have hypothesised that people with certain blood types may naturally have antibodies capable of recognising some aspect of the virus, the precise nature of the link remains unclear.

But Bobe is far from the only scientist attempting to tease apart what makes Covid-19 outliers unique. Mayana Zatz, director of the Human Genome Research Centre at the University of So Paulo has identified 100 couples, where one person got Covid-19 but their partner was not infected. Her team is now studying them in the hope of identifying genetic markers of resilience. "The idea is to try and find why some people who are heavily exposed to the virus do not develop Covid-19 and remain serum negative with no antibodies," she says. "We found out that this is apparently relatively common. We received about 1,000 emails of people saying that they were in this situation."

Zatz is also analysing the genomes of 12 centenarians who have only been mildly affected by the coronavirus, including one 114-year-old woman in Recife who she believes to be the oldest person in the world to have recovered from Covid-19. While Covid-19 has been particularly deadly to the older generations, elderly people who are remarkably resistant could offer clues for new ways to help the vulnerable survive future pandemics.

But while cases of remarkable resilience are particularly eye-catching for some geneticists, others are much more interested in outliers at the other end of the spectrum. Over the past couple of months, studies of these patients have already yielded key insights into exactly why the Sars-CoV-2 virus can be so deadly.

Disrupting the body's alarm system

Last summer, Qian Zhang had arrived for a dental appointment when her dentist turned to her and asked, "How come some people end up in intensive care with Covid-19, while my sister got it and didn't even know she was positive?"

As a geneticist working at The Rockefeller University, New York, it was a question that Zhang was particularly well equipped to answer. Over the past 20 years, Rockefeller scientists have probed the human genome for clues as to why some people become unexpectedly and severely ill when infected by common viruses ranging from herpes to influenza. "In every infectious disease we've looked at, you can always find outliers who become severely ill, because they have genetic mutations which make them susceptible," says Zhang.

The rest is here:
The disease-resistant patients exposing Covid-19's weak spots - BBC News

Have you ever wondered why some people can walk out in a t-shirt when its -15 C while others start shivering as soon as the temperature drops into the single digits? A new study published in the American Journal of Human Geneticsmay finally have your answer. Researchers have found that people lacking a certain protein in their muscles are more resilient to the cold, and interestingly enough, this genetic mutation may also give you a higher capacity for endurance athletics.

RELATED: The science behind cold weather and running performance

In the study, 42 men between the age of 18 and 40 sat in cold water (14 C) until their body temperature had dropped to 35.5 C. While the participants were submerged in the water, researchers used electromyography to measure their muscle electrical activity, and took biopsies of their muscles to observe their protein content and fibre-type composition.

The results found that people who lacked the protein -aktinin-3 were better at keeping warm and, from an energy perspective, were better at enduring a toucher climate. This protein is found only in fast-twitch muscle fibres, and is lacking in about 20 per cent of the population. Its absence is due to a genetic mutation, and scientists believe that the presence of this mutated gene increased when humans migrated from Africa to colder climates in central and Northern Europe. According to the authors of the study, this is the first direct experimental evidence that this gene provides resilience to the cold.

We here show an improved body temperature defence during cold-water immersion in humans deficient of the sarcomeric protein -actinin-3 expressed in fast-twitch skeletal muscle, they said in their report.

The participants who lacked -aktinin-3 had a greater proportion of slow-twitch muscle fibres, and their genetic mutation allowed them to maintain their body temperature in a more energy-efficient way while their body was cooling. They also shivered less, which is a reaction activated by fast-twitch fibres, and instead increased the activation of slow-twitch fibres that produce heat by increasing baseline contraction.

The authors also noted that people who lack -aktinin-3 rarely excel at sports that require explosive power or strength, likely because they have fewer fast-twitch muscle fibres. These people tend to have a greater capacity for endurance sports, which is not surprising since endurance athletes tend to have more slow-twitch muscle fibres. Of course, there are other factors that can affect your bodys ability to handle cold, so not every runner is going to thrive in cold conditions, and being a runner doesnt automatically mean you have this genetic mutation (nor does having it mean youll be a better distance runner). Even if you are a dedicated runner, you still only have a one in five chance of lacking -aktinin-3.

So if youre one of the lucky ones who doesnt mind the cold, maybe you have this genetic mutation. The rest of us will just continue to bundle up and wait for summer.

RELATED: The key to winter running? Modify your expectations

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Study finds 20% of people are genetically resilient to the cold - Canadian Running Magazine

When President Bill Clinton took to a White House lectern 20 years ago to announce that the human genome sequence had been completed, he hailed the breakthrough as the most important, most wondrous map ever produced by humankind. The scientific achievement was placed on par with the moon landings.

It was hoped that having access to the sequence would transform our understanding of human disease within 20 years, leading to better treatment, detection and prevention. The famous journal article that shared our genetic ingredients with the world, published in February 2001, was welcomed as a Book of Life that could revolutionise medicine by showing which of our genes led to which illnesses.

But in the two decades since, the sequence has underwhelmed. The potential of our newfound genetic self-knowledge has not been fulfilled. Instead, what has emerged is a new frontier in genetic research: new questions for a new batch of researchers to answer.

Today, the gaps between our genes, and the switches that direct genetic activity, are emerging as powerful determinants behind how we look and how we get ill perhaps deciding up to 90% of what makes us different from one another. Understanding this genetic dark matter, using the knowledge provided by the human genome sequence, will help us to push further into our species genetic secrets.

Cracking the human genetic code took 13 years, US$2.7 billion (1.9 billion) and hundreds of scientists peering through over 3 billion base pairs in our DNA. Once mapped, our genetic data helped projects like the Cancer Dependency Map and the Genome Wide Association Studies better understand the diseases that afflict humans.

But some results were disappointing. Back in 2000, as it was becoming clear the genome sequence was imminent, the genomics community began excitedly placing bets predicting how many genes the human genome would contain. Some bets were as high as 300,000, others as low as 40,000. For context, the onion genome contains 60,000 genes.

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Read more: Explainer: what is a gene?

Dispiritingly, it turned out that our genome contains roughly the same number of genes as a mouse or a fruit fly (around 21,000), and three times less than an onion. Few would argue that humans are three times less complex than an onion. Instead, this discovery suggested that the number of genes in our genome had little to do with our complexity or our difference from other species, as had been previously assumed.

Access to the human genome sequence also presented the scientific community with a huge number of important ethical questions, underscored in 2000 by Prime Minister Tony Blair when he cautioned: With the power of this discovery comes the responsibility to use it wisely.

Ethicists were particularly concerned about questions of genetic discrimination, like whether our genes could be used against us as evidence in a court of law, or as a basis for exclusion: a new kind of twisted hierarchy determined by our biology.

Some of these concerns were addressed by legislation against genetic discrimination, like the US Genetic Information Nondiscrimination Act of 2008. Other concerns, like those around so-called designer babies, are still being put to the test today.

Read more: Should we edit the genomes of human embryos? A geneticist and social scientist discuss

In 2018, human embryos were gene edited by a Chinese scientist, using a method called CRISPR which allows targeted sections of DNA to be snipped off and replaced with others. The scientist involved was subsequently jailed, suggesting that there remains little appetite for human genetic experimentation.

On the other hand, to deny available genetic treatments to willing patients may one day be considered unethical just as some countries have chosen to legalise euthanasia on ethical grounds. Questions remain about how humanity should handle its genetic data.

With human gene editing still highly contentious, researchers have instead looked to find out which genes may be responsible for humanitys illnesses. Yet when scientists investigated which genes are linked to human diseases, they were met with a surprise. After comparing huge samples of human DNA to find whether certain genes led to certain illnesses, they found that many unexpected sections of the genome were involved in the development of human disease.

The genome contains two sections: the coding genome, and the non-coding genome. The coding genome represents just 1.7% of our DNA, but is responsible for coding the proteins that are the essential building blocks of life. Genes are defined by their ability to code proteins: so 1.7% of our genome consists of genes.

The non-coding genome, which makes up the remaining 98.3% of our DNA, doesnt code proteins. This largely unknown section of the genome was once dismissed as junk DNA, previously thought to be useless. It contained no protein-creating genes, so it was assumed the non-coding genome had little to do with the stuff of life.

Bewilderingly, scientists found that the non-coding genome was actually responsible for the majority of information that impacted disease development in humans. Such findings have made it clear that the non-coding genome is actually far more important than previously thought.

Within this non-coding part of the genome, researchers have subsequently found short regions of DNA called enhancers: gene switches that turn genes on and off in different tissues at different times. They found that enhancers needed to shape the embryo have changed very little during evolution, suggesting that they represent a major and important source of genetic information.

These studies inspired one of us, Alasdair, to explore the possible role of enhancers in behaviours such as alcohol intake, anxiety and fat intake. By comparing the genomes of mice, birds and humans we identified an enhancer that has changed relatively little over 350 million years suggesting its importance in species survival.

When we used CRISPR genome editing to delete this enhancer from the mouse genome, those mice ate less fat, drank less alcohol, and displayed reduced anxiety. While these may all sound like positive changes, its likely that these enhancers evolved in calorifically poor environments full of predators and threats. At the time, eating high-calorie food sources such as fat and fermented fruit, and being hyper-vigilant of predators, would have been key for survival. However, in modern society these same behaviours may now contribute to obesity, alcohol abuse and chronic anxiety.

Intriguingly, subsequent genetic analysis of a major human population cohort has shown that changes in the same human enhancer were also associated with differences in alcohol intake and mood. These studies demonstrate that enhancers are not only important for normal physiology and health, but that changing them could result in changes in behaviour that have major implications for human health.

Given these new avenues of research, we appear to be at a crossroads in genetic biology. The importance of gene enhancers in health and disease sits uncomfortably with our relative inability to identify and understand them.

And so in order to make the most of the sequencing of the human genome two decades ago, its clear that research must now look beyond the 1.7% of the genome that encodes proteins. In exploring uncharted genetic territory, like that represented by enhancers, biology may well locate the next swathe of healthcare breakthroughs.

This article was updated on February 21, 2021 to clarify that DNA base pairs are not made from proteins.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

The Conversation

Alasdair Mackenzie receives funding from the BBSRC, Tenovus (Scotland) and Medical Research Scotland

Andreas Kolb does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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The human genome at 20: how biology's most-hyped breakthrough led to anticlimax and arrests - Yahoo Eurosport UK

Dictyostelium fruiting body. Image: Bruno in Columbus/Wikimedia Commons.

In 1989, in my newly set up laboratory at the Centre for Cellular and Molecular Biology (CCMB), Hyderabad, I began to explore how free-living soil amoebae called cellular slime moulds respond to anti-fungal compounds called phytoalexins.

Plants make phytoalexins in response to fungal attack and injury. It is likely that amoebae encounter these compounds in the soil around plant roots. This research led us, in ten years, to discover the human gene encoding an enzyme, C-14 reductase, for making cholesterol, which is an important constituent of our cell membranes although having too much of it is bad for the heart.

Other scientists subsequently showed that mutations in this gene cause a severe genetic condition called Greenberg dysplasia, which kills foetuses before birth because their bones fail to develop properly. This story illustrates how research not intended to investigate human health and disease can sometimes end up being medically relevant.

Cellular slime mould amoebae feed and multiply on bacteria growing on decaying organic matter. When the bacteria run out, the amoebae starve, and this prompts them to gather in their hundreds of thousands and form multi-cellular aggregates. Each aggregate then transforms itself into a small fruiting body composed of a slender stalk that holds aloft a droplet of cells. These cells develop into long-lived vegetative spores.

Ants, snails, and other small animals brushing past the droplet disperse the spores to new food sources, where each spore germinates to release a single amoeba that forages for bacteria, multiplies and repeats this life cycle.

We examined the response of the cellular slime mould Dictyostelium discoideum to pisatin, the major phytoalexin of the garden pea (Pisum sativum). Pisatin, extracted from pea seedlings, at a dose of 150 g /ml in salt solution quickly killed the amoebae suspended therein but a lower dose (50 g/ml) did not.

Interestingly, amoebae exposed for 30 minutes to the low dose acquired resistance to a subsequent challenge at the high dose. Since in their natural setting amoebae likely encounter a low concentration first, pisatin might not trouble the amoebae too much.

Intriguingly, still lower concentrations (5 g/ml) prevented starving amoebae from aggregating. Amoebae are great foragers of bacteria, and pisatin might be the plants way to recruit them to continue foraging around root lesions and help disinfect the lesion of potentially pathogenic bacteria.

Alternatively, the presence of pisatin might signal to the amoebae that a nearby plant is in trouble, with promise of an imminent windfall of decaying organic matter and bacteria, and hence to defer fruiting body formation.

Exposure to the low dose, however, did not induce pisatin-resistance in a D. discoideum mutant whose mutation had to do with the synthesis of a compound called sterol. Why did we examine this mutant? Because we had previously used the sterol mutants for genetic analysis, so they were readily available at hand, and it is always a good practice to test any new phenomenon in a variety of different strains.

In 1990, the famous geneticist Robin Holliday visited the CCMB and advised us to explore these phenomena in fungi. I wrote to the Fungal Genetics Stock Center, USA, requesting them to send us standard and sterol mutant strains of the bread mould Neurospora crassa.

The very first experiment with Neurospora revealed the mutants were much more sensitive to pisatin concentrations that had no effect on the wild type (i.e. non-mutant).

Also read: With an Eye on the Future, India Needs More Cryo-Electron Microscopes

Around then, I received a Rockefeller Foundation Fellowship to visit the University of Arizona, to use reagents available there to examine whether the inducible pisatin resistance of the Dictyostelium amoebae depended on their turning on an enzyme to degrade pisatin. It did not.

Contemporaneously, Marc Orbach had joined the university as a new faculty member. In his earlier research, Orbach had constructed a library of the Neurospora genome. Under his tutelage, I used the library to select for a DNA sequence that when introduced into the Neurospora mutant reversed its pisatin-sensitive character because it carried a functional copy of the missing gene.

Back at CCMB, K.G. Papavinasasundaram, a postdoctoral scientist, sequenced the selected DNA and found that it shared extensive similarity with the gene for C-14 reductase in yeast. This was not very surprising because yeast and Neurospora are evolutionarily closer to each other than, say, to chickens. But very unexpectedly, the Neurospora gene also shared an equal similarity with a chicken protein called LBR.

LBR has an important role in the vertebrate cell nucleus but no one suspected it also had a role in cholesterol biosynthesis. We were lucky that the Neurospora genes sequence followed the yeast and chicken gene sequences into the DNA sequence database, because it fell to us to spot the similarity between the three sequences.

We dont know why the scientists who uploaded the second sequence failed to find its similarity with the first. Subsequently, we showed that expression of a segment of human LBR in the Neurospora mutant could reverse its pisatin-sensitive phenotype. This established that LBR is a sterol biosynthetic enzyme.

LBR is one of two human genes coding for C-14 reductase. Mutations in it disrupt normal cholesterol synthesis and possibly allow build up of toxic byproducts, but we still do not know how this results in foetal bone growth and development defects.

The other human gene coding for C-14 reductase is TM7SF2. Mice whose TM7SF2 gene was knocked-out were healthy, suggesting that in them the LBR version fully compensates the loss.

It is possible that LBR is the housekeeping enzyme whereas TM7SF2 is a tunable version that can adjust to the local cholesterol demand. Human TM7SF2 did not rescue either the Neurospora or yeast sterol mutants. The TM7SF2 protein might need to be modified before its enzyme activity can be turned on, and yeast and Neurospora cells might not be capable of making the modification.

If this hypothesis is correct, then by testing different LBR/TM7SF2 chimeric proteins for function in Neurospora or yeast, one might be able to identify the modification target.

The twists and turns of our research as it meandered from the high-altitude isolation of phytoalexin-responses of soil amoebae to the busy delta of studies on human genes and disease exemplifies the contingent nature of research.

D.P. Kasbekar is a retired scientist.

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How Research Not Intended To Be About Disease Can End up Being Medically Relevant - The Wire Science

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Gaucher Disease Treatment Market is projected to grow at a healthy CAGR over the next years by regions | Keyplayers :Acetelion Pharmaceutical (J&J...

Pacific Biosciences of California, Inc (NASDAQ: PACB ) is a biotechnology company that produces DNA sequencing technology for use in a variety of scientific research purposes. Using Pacific Bioscience of California machines, scientists in laboratories around the world are able to rapidly and accurately observe DNA in real-time, allowing for access to a full spectrum of genetic information that was never before been available. As a relatively young company, their hardware and software developments have already led to several significant scientific advancements and as a result, Pacific Biosciences of California has become one of the most well-known names in the biotechnology space.

Based in Silicon Valley, Pacific Biosciences of California, Inc. (PacBio) is a biotechnology company that focuses on creating products and technologies that are used to advance genetic research. The company was founded by Dr. Stephen Turner in 2004 under the name Nanofluidics, Inc. before being renamed a few years later. After only a few short decades, the company has expanded to over 400 employees and boasts a wide range of products including sequencing machines, analytical software, and consumables, which are chemicals used in the process of converting DNA into a format that is ready to be read by sequencing machines.

The company operates in three main niches: plant and animal science, human biomedical research, and microbiology and infectious diseases. Using PacBio machines, plant and animal science research can be conducted on organisms as small as mosquitos that contain as little as 5 nanograms of DNA. Through the study of plant and animal genetics, PacBios technology fuels research that has been used to explore innovative ways of improving food and energy supply. Within the human biomedical science sector, research using PacBio products and services allows for the exploration of genetic variations to determine potential hidden hereditary causes of diseases. By being able to pinpoint epigenetic changes, the specific genetic variation that is behind diseases will be easier to understand. As this technology becomes more widely available due to lower costs, doctors will be able to improve the solve rate involved with diagnosing patients. Finally, PacBio machines are relied upon heavily for microbial and infectious diseases research, which has led to breakthroughs in finding cures and vaccines for a variety of viruses, bacteria, and other microbiotic organisms.

The company is well known for developing innovative technology to study DNA, RNA, and protein synthesis and regulation. In 2011, Pacific of California released its first product, PacBio RS, a DNA sequencing machine, into the market. The PacBio RS was the first machine that used Single-Molecule Real-Time (SMRT) sequencing technology. SMRT is a sequencing technology developed by PacBio that allows scientists to understand the inner workings of biological systems through real-time observation. The SMRT technology has the ability to sequence whole genomes or target specific sections of DNA/RNA. The technology also allows complex populations of bacteria, viruses, and other diseases to be tracked and responses to drug treatments to be observed. The two main advantages of PacBios SMRT sequencing machines over competitors are their low per-genome costs and high volume output. Upon the launch of their first product the PacBio RS, SMRT sequencing had the ability to read 1,110 bases, which are the smallest units of DNA. This technology underwent further innovation throughout the years, and the latest iteration, named the Sequel II system, now has the ability to read upwards of 500 million bases. For these advancements, PacBio and their Sequel II machine received an award from The Scientist for Top 10 Innovations in 2019.

These developments have made present-day DNA reading much faster and more cost-effective than any of its predecessors. The newest systems developed by PacBio also have reading accurate rates of over 99.9% accuracy, which is important to ensure trust and validity within the scientific community. Due to these benefits, this machine has become the first choice of scientists who seek highly accurate readings of large portions of DNA and other genetic material.

As genetic sequencing becomes more and more affordable, new uses for the technology are being discovered every day. PacBio estimates that 10 million human genetic sequences will be conducted annually by 2025 and that one day, the technology will become a routine part of healthcare. With trusted and reliable hardware and software, PacBio is well-positioned to continue its domination in terms of market share and remains a well-regarded partner for companies around the world.

The SMRT sequencing technology developed by PacBio is one of the best in the industry and has garnered interest from competitors. Illumina, another leader in the biotechnology sector, made a move to buy the company for $1.2 billion in 2018. The deal ultimately fell through, with both companies citing the lengthy regulatory approval process as the main reason for mutually agreeing to terminate the contract. Despite this, the interest from other companies shows the attractiveness of SMRT sequencing technology and the complementary role it could play for other emerging biotechnology innovations.

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As a company that has only been in existence for under two decades, the innovations made possible by the SMRT sequencing technology developed by PacBio have already had a lasting impact on the scientific community. As costs continue to drop, DNA sequencing has the potential to become a mainstream part of everyday healthcare. The potential market reach of this technology is nearly limitless. As a leader in the space, Pacific Biosciences of California is very well positioned to take advantage of the very promising future growth in the industry.

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Investing in Pacific Biosciences of California, Inc (NASDAQ:PACB) - Securities.io