Category Archives: Human Genetics

The combination of genomics, transcriptomics and proteomics sheds light on autoimmune thyroid disease, other autoimmune diseases and AML

REYKJAVIK, Iceland, June 24, 2020 /PRNewswire/ -- Scientists at deCODE genetics, a subsidiary of Amgen, and their collaborators from the Icelandic healthcare system, University of Iceland and the Karolinska Institute in Sweden, today publish a studyin Nature, comparing over 30 thousand patients with autoimmune thyroid disease from Iceland and UK with 725 thousand controls. Autoimmune thyroid disease (AITD) is the most common autoimmune disease and is highly heritable. The scientists found 99 sequence variants that associate with autoimmune thyroid disease and 84 of those had not been associated with the disease before.

One of the newly discovered sequence variants is in a gene that codes for the FLT3 receptor (fms-related tyrosine kinase 3) on blood cells and immune cells, and is of large interest for several reasons.

First, it strongly increases the risk of autoimmune thyroid disease and other autoimmune diseases, both systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and celiac disease. Thesediseases are all characterized by autoantibodies and are more common in women than men. Furthermore, patients with thesediseases are quite often affected by autoimmune thyroid disease as well.

Second, it is known that activating somatic mutations in the FLT3 gene associate with acute myeloid leukemia (AML). Therefore, the scientists tested whether this FLT3 germline variant, affects the risk of AML like it increases the risk of autoimmune diseases. It turned out that it almost doubles the risk of AML, but not the risk of cancer overall.

Third, it is quite remarkable that this variant in FLT3, which is in anintron of the gene and does not directly affect coding sequence, can have so strong effect on disease risk. It turns out that the variant introduces a stop codon in one-third of the transcripts, which results in a shorter protein that lacks the kinase part, which is essential for its function.

Finally, this variant in FLT3 affects the plasma levelsof several other proteins in the body, especially the ligand of FLT3, resulting in almost double the level in carriers. This molecular couple, the FLT3 receptor and its ligand, has a key role in the development of blood cells that are important in both acute myeloid leukemia and immune responses. Hence, this variant is a loss of function mutation that through compensatory increase in the level of the ligand, acts as a gain of function.

"This report describes a novel major risk gene for several autoimmune diseases, discovered through a genome-wide study on autoimmune thyroid disease, and how the risk variant affects the gene product, FLT3, and consequently the level of the ligand to the FLT3 receptor in blood, thereby demonstrating its functional importance," says Prof. Saedis Saevarsdottir, scientist atdeCODEgenetics and first author on the paper

"The discoveries presented in this paper are based on the sequential application of genomics, transcriptomics and proteomics; the combination of these three omics in a hypothesis independent manner yields a remarkably powerful approach to the study of human disease," says Kari Stefansson, CEO of deCODE genetics and senior author on the paper.

Based in Reykjavik, Iceland, deCODE is a global leader in analyzing and understanding the human genome. Using its unique expertise in human genetics combined with growing expertise in transcriptomics and population proteomics and vast amount of phenotypic data, deCODE has discovered risk factors for dozens of common diseases and provided key insights into their pathogenesis. The purpose of understanding the genetics of disease is to use that information to create new means of diagnosing, treating and preventing disease. deCODE is a wholly-owned subsidiary of Amgen (NASDAQ: AMGN).

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Contact: Thora Kristin AsgeirsdottirPR and CommunicationsdeCODE geneticsthoraa@decode.is+354 894 1909

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deCODE Genetics: Loss of Function Variant in FLT3 Strongly Increases the Risk of Autoimmune Thyroid Disease and Other Autoimmune Diseases - Yahoo...

Scientists, biotech companies, and medical societies are reacting with outrage and dismay to President Trumps executive order (EO), signed on June 21, 2020, that restricts the issuance of new work visas for skilled workers and managers (and au pairs) through the end of 2020.

The visas affected include the H-1B, H-4, H-2B, L-1, and J categories. The EO means that foreign graduate students and postdocs would be banned from entering the United States. Almost every major research lab includes a diverse mix of research talent from around the world. Many of these scientists eventually lead their own groups, move to industry, and/or become naturalized U.S. citizens.

In the science community, many are reacting and expressing their concerns about the future of labs, and how the EO will affect research and innovation. Akiko Iwasaki, PhD, who is a professor in the department of immunobiology and department of molecular, cellular, and developmental biology at Yale University (and an investigator of the Howard Hughes Medical Institute) expressed her dismay.

Iwasaki tweeted: This is the worst thing thats happened to U.S. science and innovation. Banning immigrant scientists will lead to a devastating loss in creativity and productivity. Pretty much every lab in the U.S. will suffer.

The EO also extends Trumps April 22 order denying green cards to applicants in several immigrant visa categories. The Trump Administration says its goal is to protect 520,000 jobs and get Americans back to work. We have a moral duty to create an immigration system that protects the lives and jobs of our citizens, stated President Trump.

But many scientists in academia and industry not only disagree with the executive order but also highlight how their labs would look without their immigrant postdocs. Samantha Morris, PhD, an assistant professor of genetics, and developmental biology at Washington University School of Medicine, expressed her frustrations on Twitter.

I invest a lot of energy trying to recruit postdocs to my lab. I haven't received a SINGLE non-immigrant postdoc application in the past five years

Samantha Morris (@morris_lab) June 23, 2020

Florian Krammer, PhD, professor of microbiology at the Icahn School of Medicine at Mount Sinai in New York, expressed concern about colleagues working on SARS-CoV-2. I am about to hire a postdoc from Spain who is specialized in vaccine production and a postdoc from Japan who is specialized in mucosal immunity to virus infections. I might not be able to hire them if this is signed. Both would have worked on SARS-CoV-2 and influenza virus. Krammer also posted a picture of his lab with and without immigrants, and the image paints a picture of what research labs may look like.

My lab with and without immigrants. pic.twitter.com/aLJmUQFXEM

Florian Krammer (@florian_krammer) June 15, 2020

Lars Dietrich, PhD, associate professor, Department of Biological Sciences at Columbia University, who came to the U.S. through a work visa expressed his thoughts on the EO. The visa situation is disturbing. I came to the U.S. on a J1 visa, then transferred to H-1B before becoming faculty at Columbia University. Ive always been inspired by the way that, in U.S. academia, people of diverse backgrounds can come together to do transformative science. It reflects values that the U.S. can be proud of, and it sets an example. It really saddens me to see the erosion of this commitment to diversity.

Rebecca Bernhard, a partner at the law firm Dorsey & Whitney in immigration, labor and employment practices, highlighted some exemptions in the EO. One key exemption is for workers involved in the U.S. food supply system. This exemption should cover people involved in meatpacking and processing plants, as well as all aspects of the food supply chain from production to transportation and logistics, Bernhard said.

Another key exemption is for medical personnel working on COVID-19 research or treatment. Most physicians, nurses, and other medical personnel should still be able to obtain visas, Bernhard stated.

But what will this mean for companies working on vaccines and treatments for COVID-19? Major companies such as Moderna Therapeutics, GlaxoSmithKline, Inovio, and others who are currently working on a vaccine or treatment for COVID-19, had received approvals from the Department of Labor to hire foreign workers with either green cards or H-1B work visas more than 11,000 times from 2010 to 2019.

The American Society of Human Genetics (ASHG), the worlds largest genetics organization, is urging the White House to rescind their executive order as it will hinder the progress of science and better human health. They also point out the importance of connecting globally especially with the coronavirus crisis.

ASHG is deeply committed to a diverse and inclusive research workforce and honors those who come to U.S. labs from across the world to contribute to genetics and genomics advances in this country, said ASHG president Anthony Wynshaw-Boris, MD, PhD. Their experiences enrich American science and global science, and it is precisely Americas commitment to international collaboration that has made the U.S. a recognized global scientific leader. As the SARS-CoV-2 pandemic illustrates, we should be expanding global research connections that harness all minds to solve a problem, not closing our doors.

In a strongly worded statement, Kevin Wilson, director of public policy and media relations at the American Society for Cell Biology (ASCB), said the EO will hurt science in the United States. The decision by the Trump Administration to freeze through 2020 important U.S. visa programs that allow future scientists from around the world to come to the United States to learn is reprehensible. It goes against everything the United States stands for and violates the principle that scientific excellence requires collaboration, regardless of nationality.

The ASCB statement continued: It is American science and scientists who are the real victims of these policies. Without these talented individuals from around the globe, American biomedical research will not remain the world leader it is. If these policies are allowed to remain in place, the United States will no longer lead but will have to settle for the role of runner up.

H-1B visas are used for skilled workers and are common in the technology industry; H-4 visas are given to spouses of H-1B visa holders. H-2B visas apply to seasonal workers; L-1 visas are used for managers or executives transferring to the United States from positions abroad; and J-1 visas are given to scholars, researchers, and au pairs. The EO stops the issuance of all J-1s except for those going to physicians, medical researchers, or secondary school students. The order does not apply to immigrants already living and working in the United States nor to permanent residents seeking to become citizens.

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Scientists and Societies Decry Trump Executive Order on Immigration Visas - Genetic Engineering & Biotechnology News

Tobacco smoke, UV radiation, and certain chemicals are some of the factors that can damage the genetic material of cells, triggering cancer. These factors modify individual letters in the DNA code, called nucleotides. When a cell divides, some of these errors or lesions are resolved by a mechanism called DNA repair, but others remain unrepaired and become permanent changes in the DNA, known as mutations. This can result in health problems, such as cancer. Such mutational processes are extremely complex and there are still many unanswered questions about how they work.

A new study led by the University of Cambridge and the University of Edinburgh, and supported by EMBL-EBI, has examined the evolution of tumours in mice following chemical damage. The research, published in the journal Nature, shows that DNA lesions caused by chemical damage are not eliminated immediately, but are passed on unrepaired through several rounds of cell division.

Lesion segregation

The researchers also found that, during cell division, the two DNA strands each with its own set of lesions and mutations, are separated into two daughter cells with different patterns of DNA changes. During further rounds of replication, the lesions repeatedly generate new combinations of mutations. This phenomenon, called lesion segregation, can result in extremely complex patterns of mutations in a tumours genome.

The researchers used the DNA-damaging chemical diethylnitrosamine to induce liver tumours in mice, and then analysed the tumour genomes.

Persistent DNA lesions induced by chemotherapeutic agents segregate and produce several generations of further mutations. We need to be aware of this therapeutically, and in future drug development," says Martin Taylor from the University of Edinburghs MRC Human Genetics Unit.

A model for mutational processes

These new insights into how mutational processes work are interesting and unexpected, says Paul Flicek, Associate Director of EMBL-EBI Services. The idea that DNA lesions are not resolved within a cell cycle and stay around for a long time is an important one. It shows that cells can evolve faster than the machinery can fix them and this has implications for how we think about cancer.

Image: Artist's impression of DNA lesions. Credit: Petra Korlevic

Find out more about the study:

Source articlesAITKEN, S.J., et al. (2020). Pervasive legion segregation shapes cancer genome evolution. Nature. Published online 24 06; DOI: 10.1038/s41586-020-2435-1

FundingThis project was supported by a strategic sequencing award and Institutional core funding from Cancer Research UK, as well as grants from the European Research Council, UKRI/Medical Research Council, and Wellcome.

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Unpicking the complexity of DNA mutations - Cambridge Network

Published 30 June 2020

A radical new way of thinking about soil has finally solved the mystery of why adding organic material like manure improves flood and drought resilience, climate control and crop yields - universal ecosystem services that are widely recognised as worth billions to the global economy.

Founded on more than 50 years worth of data from a unique field experiment, researchers have demonstrated that common farming practices drain the soil of carbon, altering the structure of soils microscopic habitat and, remarkably, the genetics of microbes living within it.

The team of microbiologists and physicists, led by Rothamsted Research, considered almost 9,000 genes, and used X-ray imaging to look at soil pores smaller than the width of a human hair, and in concert with previous work, have started forming what they envisage will be a universal Theory of Soil (see Notes).

In healthy soils, relatively low nitrogen levels limit microbes ability to utilise carbon compounds, so they excrete them as polymers which act as a kind of glue - creating a porous, interconnected structure in the soil which allows water, air, and nutrients to circulate.

Writing in the journal Scientific Reports, the researchers reveal that the Victorian-era switch from manure to ammonia and phosphorous based fertilizers has caused microbes to metabolise more carbon, excrete less polymers and fundamentally alter the properties of farmland soils when compared to their original grassland state.

Lead researcher Professor Andrew Neal said: We noticed that as carbon is lost from soil, the pores within it become smaller and less connected.This results in fundamental changes in the flow of water, nutrients and oxygen through soil and forces several significant changes to microbial behaviour and metabolism. Low carbon, poorly connected soils are much less efficient at supporting growth and recycling nutrients.

A lack of oxygen in soil results in microbes having to turn to nitrogen and sulphur compounds for their energy-inefficient processes, he says, which result in increased emissions of the greenhouse gas nitrous oxide among other issues.

The closed soil structure also means microbes need to expend more energy on activities such as searching out and degrading less easily accessible organic matter for nutrients.

Conversely, in carbon-rich soil there is an extensive network of pores which allow for greater circulation of air, nutrients and retention of water.

Professor Neal added: Manure is high in carbon and nitrogen, whereas ammonia-based fertilisers are devoid of carbon. Decades of such inputs - and soil processes typically act over decades - have changed the way soil microbes get their energy and nutrients, and how they respire.

Whilst soil carbon was already known to drive climate and water cycles the world over, it took a chance discussion between experts working at very different scales to discover the reason why.

The idea to look at this link between the living and non-living components of soil came about through a discussion between an expert in microbial genetics Professor Andrew Neal, and Professor John Crawford now at the University of Glasgow - who studies the way complex systems behave.

Despite carbons critical role, the mechanisms underlying carbon dynamics and the link to soil water were poorly understood, said Professor Neal.Society struggles with the concept of what soil is and how it can be managed effectively because it is such a complex combination of biological, chemical and physical processes.

We took inspiration from a theory proposed by Richard Dawkins in the 1980s that many structures we encounter are in fact products of organisms genes Dawkins used the examples of bird nests and beaver dams.This view helped us understand soil as a product of microbial genes, incorporating organic materials from plants and other inputs to create all-important structure.

We have shown for the first time a dynamic interaction between soil structure and microbial activity - fuelled by carbon - which regulates water storage and gaseous flow rates in soil with real consequences for how microbes respire.

The group, which also involved scientists from the University of Nottingham, are the first to seriously study the details of this intimate two-way relationship between the microscopic life in soil and its structure at scales relevant to microbial processes.

The results also demonstrated why soils can sometimes show great resilience to human interventions.

Although years of intensive management practices have altered what compounds microbes predominantly live on and increased the frequency of genes that allow this lifestyle, very few genes are ever completely lost from the system. That crucially allows soils to respond to changes and these results can really help with any future remediation efforts, said Professor Neal.

Microbes are very good at acquiring genes from each other, which is why rather than look at different species we looked at the abundance of different genes and what functions they ultimately coded for.

The results also have implications for farmers, where the addition of nitrogen and phosphorous fertilizers - and not carbon - may in fact be leading to a degradation of the natural fertility and the efficiency with which nutrients are processed in their soils that will be detrimental to the long term productivity of their farm.

The negative impacts of increased leakiness of the soil system include nutrient loss to the atmosphere and rivers.

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And finally... Where there's muck, there's brass - Scottish Construction Now

Researchers have discovered that Mediterranean populations may be more susceptible to an autoinflammatory disease because of evolutionary pressure to survive the bubonic plague. The study, carried out by scientists at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, determined that specific genomic variants that cause a disease called familial Mediterranean fever (FMF) may also confer increased resilience to the plague.

The researchers suggest that because of this potential advantage, FMF-causing genomic variants have been positively selected for in Mediterranean populations over centuries. The findings were published in the journal Nature Immunology.

Over centuries, a biological arms race has been fought between humans and microbial pathogens. This evolutionary battle is between the human immune system and microorganisms trying to invade our bodies. Microbes affect the human genome in many ways. For example, they can influence some of the genomic variation that accumulates in human populations over time.

"In this era of a new pandemic, understanding the interplay between microbes and humans is ever critical," said Dr. Dan Kastner, NHGRI scientific director and a co-author on the paper. We can witness evolution playing out before our very eyes.

One such microbe is Yersinia pestis, the bacterial agent responsible for a series of well-documented bubonic plague(link is external) epidemics that led to over 50 million deaths.

FMF, like the plague, is an ancient disease. It is the most common periodic fever syndrome, and symptoms of FMF include recurrent fevers, arthritis, rashes and inflammation of the tissues that line the heart, lungs, and abdominal organs. FMF may also lead to renal failure and death without treatment. The disease appears across the Mediterranean region and mostly affects Turkish, Jewish, Armenian and Arab populations.

Genomic variants in the MEFV gene cause FMF. MEFV encodes a protein called pyrin. In healthy people, pyrin plays a role in the inflammatory response of the body. Pyrin is activated when there is an immune response (for example, in the event of an infection). Pyrin increases inflammation and the production of inflammation-related molecules.

In contrast, FMF patients produce abnormal pyrin because of genomic variants (mutations) in the MEFV gene. Mutated pyrin does not need an infection or other immune trigger to be activated; rather, it is able to directly predispose people to seemingly unprovoked episodes of fever and inflammation.

The MEFV mutations also have other usual properties. Researchers have discovered that people with only one copy of a MEFV genomic variant that causes FMF do not get the disease. Also, prior to effective treatment, those with two copies have high mortality rate by the age of 40, but usually live long enough to have children.

Despite the lower survival rate, almost 10% of Turks, Jews, Arabs and Armenians carry at least one copy of an FMF-causing genomic variant. If chance were the only factor, that percentage would be much lower.

The researchers proposed that this higher percentage was a consequence of positive natural selection, which is an evolutionary process that drives an increase in specific genomic variants and traits that are advantageous in some way.

"Just like sickle cell trait is positively selected for because it protects against malaria, we speculated that the mutant pyrin in FMF might be helping the Mediterranean population in some way," said Jae Jin Chae, Ph.D., senior author of the paper and a staff scientist in NHGRI's Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch. "The mutant pyrin may be protecting them from some fatal infection."

The team turned to Yersinia pestis, the infamous bubonic plague-causing bacterium, as a possible candidate for driving the evolutionary selection for FMF mutations in the Mediterranean population.

It turns out Yersinia pestis contains a particular molecule that represses the function of pyrin in healthy individuals. In doing so, the pathogen suppresses the body's inflammatory response to the infection. This way, the body cannot fight back.

"Inflammation is a process in which white blood cells protect the body from infection. From the host's point of view, inflammation helps us survive. From the bacteria's point of view, inflammation is something to be evaded by any means available," said Daniel Shriner, Ph.D., staff scientist in the Center for Research on Genomics and Global Health at NHGRI.

Researchers were struck by the fact that Yersinia pestis affects the very protein that is mutated in FMF. They considered the possibility that FMF-causing genomic variants may protect individuals from the bubonic plague caused by Yersinia pestis.

The idea that evolution would push for one disease in a group to fight another may seem counterintuitive. But it comes down to what is the least bad option.

The average mortality rate of people with bubonic plague over centuries has been as high as 66%, while, even with a carrier frequency of 10%, less than 1% of the population has FMF. Theoretically, the evolutionary odds are in the latter's favor.

But first, the team had to verify if two of the genomic variants that cause FMF had indeed undergone positive selection in Mediterranean populations.

For this, they performed genetic analysis on a large cohort of 2,313 Turkish individuals. They also examined genomes from 352 ancient archaeological samples, including 261 from before the Christian era. The researchers tested for the presence of two FMF-causing genomic variants in both groups of samples. They also used population genetics principles and mathematical modeling to predict how the frequency of FMF-causing genomic variants changed over generations.

"We found that both FMF-causing genomic variants arose more than 2,000 years ago, before the Justinian Plague and the Black Death. Both variants were associated with evidence of positive selection," said Elaine Remmers, Ph.D., associate investigator in NHGRI's Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch.

Researchers then studied how Yersinia pestis interacts with FMF-causing genomic variants. They took samples of particular white blood cells from FMF patients. In addition, they took samples from people who carry just one copy of the genomic variants (hence, do not get the disease).

The team found that Yersinia pestis does not reduce inflammation in white blood cells acquired from FMF patients and people with one copy of FMF-causing genomic variants. This finding is in stark contrast to the fact that Yersinia pestis reduces inflammation in cells without FMF-associated mutations.

The researchers thought that if Yersinia pestis does not reduce inflammation in people with FMF, then perhaps this could potentially increase patients' survival rate when infected by the pathogen.

To test this hypothesis, the researchers genetically engineered mice with FMF-causing genomic variants. They infected both healthy and genetically engineered mice with Yersinia pestis. Their results showed that infected mice with the FMF-causing genomic variant had significantly increased survival as compared to infected healthy mice.

These findings, in combination, indicate that over centuries, FMF-causing genomic variants positively selected in Turkish populations play a role in providing resistance to Yersinia pestis infection. Whether the same is true for other Mediterranean populations remains to be seen. The study offers a glimpse into the unexpected and long-lasting influence of microbes on human biology.

ReferencePark, Y.H., Remmers, E.F., Lee, W. et al. Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis. Nat Immunol (2020). https://doi.org/10.1038/s41590-020-0705-6.

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

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Cause of Common Autoinflammatory Disease May Have Protected Ancestors From Plague - Technology Networks

On March 16, a single tweet mobilized an army of over 700 geneticists from 36 countries to battle a tiny virus by trying to understand the role human genetics plays in why some people have no reaction to COVID-19, and others get very sick and die. Goal: aggregate genetic and clinical information on individuals affected by COVID-19, tweeted Andrea Gemma, a geneticist at the Institute for Molecular Medicine in Helsinki, Finland. Just a few weeks later the COVID-19 Host Genetics Initiative was up and running and is now identifying human genes associated with COVID and its symptomsnothing definitive yet, although the possibility of breakthroughs has been substantially improved by the combined DNA-discovery firepower of over 150 labs and biobanks that store and analyze millions of human genomes.

Nor is this pandemic display of raw scientific muscle and intensity of focus unique right now. Pandemic-bound researchers around the world are combining forces for possibly the largest scientific hive-mind effort in history thats converging on a single conundrum. It also arrives as a slew of technologies developed over the past generation are coming online and being applied to the COVID puzzleeverything from CRISPR gene editing and faster and cheaper genetic sequencing to social media and the integration of artificial intelligence and machine learning in bioresearch and health IT.

COVID-19 has ravaged bioscience just like it has cut a destructive and sometimes deadly swath through much of what we used to call normal. Yet even as labs have shuttered, experiments have halted, and droves of scientists and technicians have been laid offand research and clinical attention has been diverted from any disease thats non-COVIDis it possible that some scientific silver linings may emerge out of this tragic Year of the Pandemic?

Could we see a near-future surge of scientific advancement, what Stanford bio-informaticist Carlos Bustamante likened to what happened when we went to the moon? You had all this spillover technology that gave us, say, the Internet, he said. Or is it possible that somewhere, somehow, a new respect for science and evidence will emerge out of COVID-19? Theres kind of a reward system now for people to pay attention to facts, said George Church, Professor of Genetics at Harvard Medical School, rather than just making stuff up. And that reward is in terms of fewer relatives and friends and colleagues dying.

As the world is teetering and we struggle to absorb a daily barrage of less than sanguine newsnot only about COVID but also in politics, racial relations, and the economy NEO.LIFE asked prominent bioscientists and big thinkers if there might be glimmers of hope that will emerge when the all clear is finally declared.

Im seeing an intensity of purpose like Ive never seen before, said Eric Topol, director and founder of the Scripps Research Translational Institute. Putting this great big brain trust in science on such a seemingly insurmountable problem will change how we do things going forward.

We are seeing biologists working with statisticians, public health experts collaborating with logistics experts, added Katharina Voltz, founder and CEO of OccamzRazor. With the coronavirus, you need the experts on SARS, on spike proteins, on pulmonary diseases, to all come together and collaborate on a shared canvas.

Were asking questions we never asked about, say, the flu, added Carlos Bustamante, attributing this to the rise of the hive mind. For instance, were learning about COVID at a molecular phenotyping detail like weve not done for any other infectious disease. (Molecular refers mostly to genetics, and phenotype to observable traits in a human or other organism.) Its been amazing for this disease how weve accepted that different people respond differently to this infection. That is not true of almost any other large-scale infection we talk about.

We can take heart that for the first time in history we have the computing power to actually make sense of all of this complexity as artificial intelligence and machine learning in biology is moving from hype to reality. One of the trends that were seeing now is the application of machine learning to dissect and extract patterns from a deluge of genomic, proteomic, metabolic data, said Katharina Voltz. We can perform many experiments in silicoon the computerand only run the most important crucial parts of the experimental method in the lab, as a confirmation of our theoretical models.

Machine learning is going to transform how we think in biology, agreed Wayne Koff, CEO, Human Vaccines Project. Its going to generate hypotheses. We will be able to better focus on smaller groups of peoplethe vulnerable groups, the diseased, the elderly, the poor, the newborns, those living in the developing world.

Computers and the Internet are also lifelines for all of us personally needing to stay connected, and as biomedicine tries to navigate a world of shelter-in-place and social distancing. Weve just dragged the country through half a decade of telemedicine in three months, said Carlos Bustamante. Are we going to now give that all up and go back to having to wait in the doctors office with everybody else coughing to see a doctor?

I think this pandemic will be a big moment for biology, said synthetic biologist Pamela Silver, professor of Biochemistry and Systems Biology at Harvard Medical School. Biologys going to fix the COVID problem, but it can also fix a ton of other problems, tooproblems like the environment, food, and other diseases. And the only way were going to get there is with engineering biologymanipulating and improving the biological mechanisms.

One way to accomplish this is what Silver and other synthetic biologists call plug and playthe creation of basic biological components for research and for developing treatments and preventatives like vaccines that have been synthesized in a lab, ready to be deployed, say, when the next virus arrives. Im thinking that as we learn how to manipulate viruses and create methods for booting up responses faster it becomes a kind of plug-and-play system that is nimble, said Silver, and this goes not just for vaccines. It goes for everything, anything. You have a new disease, or any kind of therapeutic, and youre better prepared.

Eric Topol, however, frets about the neglect or lack of emphasis on non COVID-19 diseases. This is a concern and will continue to be for the near future. Katharina Volz added that once this crisis is over, we need to hyper-focus on other diseases, too. You really have to put this same urgency that we have for COVID now and apply it to other diseases that may have a potentially bigger economic and personal impact than COVID, she said, Alzheimers and Parkinsons and many others.

Weve just dragged the country through half a decade of telemedicine in three months.

Scientists also worry about the leadership vacuum they see in the world. I hope, as we go forward, we will get better leadership, said Eric Topol. Weve seen how science can contribute where it was given true authority, so I think thats going to be another path forwardI hopealthough in the U.S. we have horrible tensions between politics and science that shouldnt exist.

No one really knows what biomedicine will look like when this is over. But it is comforting to know that something positive may come out of COVID. As Carlos Bustamante said: I want everything I do to be drafted behind COVID. Im thinking of the mother of all cycling teams. [Cycling teams assign one cyclist to ride first in line so the others can draft behind them, which makes it easier for them to pedal]. And youre drafting behind COVID, and then once youve reached the finish line, you can take that energy and hopefully channel it into other disease areas that can be cured.

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After the MadnessPandemic Silver Linings in Bioscience - NEO.LIFE

The Genome Aggregation Database (gnomAD) Consortium has released seven papers leveraging its database to study genetic variants and their potential for guiding discovery of safer drugs.

The Genome Aggregation Database (gnomAD) Consortium has announced the release of the first seven papers based on discoveries from their database of more than 125,000 exomes and 15,000 whole genomes from populations around the world.

Since 2012 the consortium, originally the Exome Aggregation Consortium (ExAC), has expanded upon the work of the 1000 Genomes Project and other similar efforts to catalogue human genetic variation. From the initial release of whole exome data in October 2014, the database has grown to include genomes and exomes from more than 25,000 people of East and South Asian descent, nearly 18,000 of Latino descent and 12,000 of African or African-American descent, known as the gnomAD v2.1.1 dataset.

According to the consortium, more than 100 scientists and groups internationally have provided data and/or analytical effort to the consortium.

The studies cover several areas, including:

These studies represent the first significant wave of discovery to come out of the gnomAD Consortium, said Daniel MacArthur, scientific lead of the gnomAD project, a senior author on six of the studies, an institute member in the Program in Medical and Population Genetics at the Broad Institute of MIT and Harvard, and director of Centre for Population Genomics at the Garvan Institute of Medical Research and Murdoch Childrens Research Institute in Australia. The power of this database comes from its sheer size and population diversity, which we were able to reach thanks to the generosity of the investigators who contributed data to it, and of the research participants in those contributing studies.

Two of the seven papers demonstrate the utility of the large genomic datasets for learning about rare or understudied types of genetic variants.

One such study, the flagship paper published in Nature, led by MacArthur and Konrad Karczewski, first author of the paper and a computational biologist at the Broad Institute and Massachusetts General Hospitals (MGHs) Analytic and Translational Genetics Unit, maps loss-of-function (LoF) variants.

LoFs are genetic changes that are thought to completely disrupt the function of protein-coding genes.

By comparing the number of variants in each gene across the more than 443,000 LoF variants the team identified in the gnomAD dataset, the authors were also able to classify all protein-coding genes according to how tolerant they are to disruptive mutations. The classification system pinpoints genes that are more likely to be involved in severe diseases such as intellectual disability.

The gnomAD catalog gives us our best look so far at the spectrum of genes sensitivity to variation and provides a resource to support gene discovery in common and rare disease, Karczewski explained.

In their paper, also published in Nature, graduate student Ryan Collins, Broad associated scientist Harrison Brand, institute member Michael Talkowski and colleagues used gnomAD to explore structural variants.

Structural variants include duplications, deletions, inversions and other changes involving larger DNA segments (generally >50-100 bases long). Their study presents gnomAD-SV, a catalogue of more than 433,000 structural variants identified within nearly 15,000 of the gnomAD genomes, that represents most of the major known classes of structural variation.

Structural variants are notoriously challenging to identify within whole genome data, and have not previously been surveyed at this scale, noted Talkowski, who is also a faculty member in the Center for Genomic Medicine at MGH. But they alter more individual bases in the genome than any other form of variation, and are well established drivers of human evolution and disease.

The authors were surprised to find that >25 percent of all rare LoF variants in the average individual genome are actually structural variants and that many people carry what should be deleterious or harmful structural alterations, without the expected phenotypes or clinical outcomes. They also highlighted that genes were just as sensitive to duplications as they were deletions.

We learned a great deal by building this catalogue in gnomAD, but weve clearly only scratched the surface of understanding the influence of genome structure on biology and disease, Talkowski said.

Two of the studies describe how the diverse, population-scale data could be used by researchers to pick drug targets.

One of these studies was based on musings by Broad associated scientist Eric Minikel, about whether genes with naturally-occurring predicted LoF variants could be used to assess the safety of targeting those genes with drugs. He suggested that if a gene is naturally deactivated without harmful effects, then it could possibly be safe to inhibit with a drug.

Minikel, MacArthur and golleagues leveraged the gnomAD dataset to explore this question, the results and their suggestions for how insights about LoF variants can be incorporated into the drug development process were published in Nature Medicine.

The collaborators on the study used the data on LoF variants to study the potential safety liabilities of reducing the expression of a gene called LRRK2. This gene is associated with risk of developing Parkinsons disease and so is a desirable target for intervention strategies.

The team predicted from the data that drugs able to reduce LRRK2 protein levels or partially block the genes activity are unlikely to have severe side effects.

Weve cataloged large amounts of gene-disrupting variation in gnomAD, MacArthur said. And with these two studies weve shown how you can then leverage those variants to illuminate and assess potential drug targets.

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First studies of human genetic variation released by gnomAD Consortium - Drug Target Review

Love it or hate it, rocket is popular all over the world. Also known as arugula, roquette and rucola, its known for its pungent and peppery flavours. It might look like an unassuming leafy vegetable, but the reasons for its taste, health benefits and whether we like it all comes down to genetics.

Rocket actually encompasses several species, all of them part of the same family as broccoli, cabbage, kale, mustard and watercress the Brassicales. Its distinctive aroma and flavours are created by chemical compounds produced by its leaves, called isothiocyanates. Some of these compounds can be eye-wateringly hot, whereas others can have a radishy flavour or none at all.

In the wild, isothiocyanates are thought to help defend plants from herbivores and disease, and also help it tolerate environmental stress. But for humans, eating isothiocyanates confers health benefits. Studies have shown them to have anti-cancer properties, and anti-neurodegenerative effects against diseases such as Alzheimers.

For this reason, plants containing isothiocyanates interest scientists particularly those with little taste and flavour. One such compound is sulforaphane, which is found in rocket and broccoli. Several years ago, researchers produced a super broccoli with high amounts of sulforaphane. Consumers couldnt taste the difference, and it was later shown to be effective in preventing and slowing prostate cancer and in lowering cholesterol.

But one advantage with rocket is that it doesnt need cooked to be eaten. Heating other Brassicales, like broccoli, to over 65 inactivates myrosinase, which is an enzyme in their tissues that converts compounds called glucosinolates into sulforaphane and other isothiocyanates when people chew these plants. If the myrosinae is inactivated, consumers will receive little or none of the associated health benefits, no matter how much are bred into the plants.

Chewing aside, theres some evidence to suggest that our gut microflora possess their own myrosinase and can convert glucosinolates to isothiocyanates for us. The amounts this produces are likely to be quite small, but release may be sustained, exposing our cells to compounds like sulforaphane for longer periods.

But the biggest barrier to people getting these beneficial molecules from rocket is the taste. This depends on when and where rocket crops are grown. In the summer, leaves can be extremely spicy and pungent, whereas in the winter they can be bland and tasteless.

Growth temperature likely plays a big role in determining the amounts of isothiocyanates released from leaves. Probably a stress response by the plants, it means hotter countries like Italy may produce more pungent leaves.

You can test this effect at home. Get two small pots and some rocket seeds from a local garden centre or supermarket. Plant two or three seeds in each. Keep one well watered and relatively shaded, and the other in direct sunlight, watering infrequently. After a few weeks, taste the leaves from each pot one should taste much hotter.

The taste and flavour of rocket also varies because of the genetics of different varieties. Not only do leaves contain hot, pungent isothiocyanates, but also sugars (which create sweetness); pyrazines (which can smell earthy and pea-like); aldehydes (which smell like grass); alcohols (one in particular smells just like mushrooms); and many other types yet to be identified.

Recently, the worlds first rocket genome and transcriptome sequence was produced from the Eruca sativa species, allowing researchers to understand which genes may be responsible for making the compounds related to taste and flavour. Its genome contains up to 45,000 genes, which is more than the 42,611 genes humans are thought to have.

The research also found that different varieties produce more isothiocyanates and sugars than others. This explains why leaves can taste so different in the supermarket, even when bought from the same shop at the same time of the year. By knowing which genes are expressed in tissues and when, we can select rocket plants with improved taste and flavour profiles and breed new and improved cultivars.

To further complicate matters, our own genetics mean we dont all taste chemical compounds the same. We have many thousands of different odour receptors in our brains, and many different combinations of taste receptors on our tongues. These genetic differences are one of the reasons why coriander tastes different to different people. Those with a variant of the OR6A2 gene perceive the leaves as having a soapy flavour, which is thanks to the aldehyde compounds in coriander that activate this receptor variant.

Depending on whether you have a functioning or non-functioning copy of certain taste receptor genes, you may not be able to taste certain compounds at all. In the other extreme, if you have two working copies of a particular gene, some foods may taste unbearably bitter and unpleasant.

Another classic example is Brussels sprouts. Some people love them, while others loathe them. This is because of the gene TAS2R38 which gives us the ability to taste the bitter glucosinolate compounds in these vegetables as well as rocket.

Those people with two working copies of the gene are bitter supertasters. People with only one are medium tasters, while those with no working copies are blind to these compounds. So what is intense and inedible to one person might be pleasant and mild to another.

This partly explains peoples general food preferences and rocket leaves are an excellent example of these processes in action. A consumer study of rocket leaves showed that some people like them hot and pungent, others like them sweet and mild, and others just dont like them at all.

However, peoples culture and life experience probably also determine whether they like rocket and other foods. A previous study of rocket showed that peoples genetic differences are not necessarily an indicator of whether they will like something. Its perfectly possible to be a bitter supertaster and like rocket and Brussels sprouts depending on your upbringing and exposure to them.

Another study showed that preference for flavour and pungency of white radish is linked to differences in geography and culture. Japanese and Korean people liked pungency created by an isothiocyanate much more than Australians. Pickled radish is a common condiment in Asian countries: being regularly exposed to a food may predispose people to like it, irrespective of their taste sensitivity.

Very little is currently known about the interactions between plant and human genotypes. But ongoing research aims to find out which compounds people with different TAS2R38 genotypes are sensitive to. This will make it possible in the future to selectively breed in (or out) certain genes, and produce rocket types tailored to a persons preferences.

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Rocket, arugula, rucola: how genetics determines the health benefits and whether you like this leafy green - The Conversation UK

Intravacc, a translational research and development vaccine institutes, with a track record in developing viral and bacterial vaccines, has announced more details on its development of an intranasal vaccine against COVID-19. The vaccine will be developed through a newly established public private partnership that combines the vaccine development technology from Intravacc, the viral vector technology and animal technologies from Wageningen Bioveterinary Research (WBVR) based in the Netherlands, and the coronavirus expertise from Dutch Utrecht University.The aim of this partnership is to develop an intranasal vaccine to protect humans against COVID-19. The vaccine will consist of a Newcastle disease virus (NDV) vector that expresses the immunogenic spike (S) protein of SARS-CoV-2, which is an important target for neutralizing antibodies. NDV has been shown to be safe for intranasal/intratracheal delivery in mammals, including non-human primates.The advantage of a nasal vaccination is that it induces both mucosal and systemic immunity, whereas an intramuscular vaccination primarily induces an antibody response. In addition, intranasal vaccination may also confer protection against infections at other mucosal sites, such as the lungs, intestines and genital tract. On top of this, the nasal cavity is also easily accessible.Intravacc will develop a scalable vaccine production process using its FDA-approved Vero cell platform, in preparation of GMP productions. WBVR has developed a technique called reverse genetics, which allows the genetic modification of Newcastle disease virus (NDV). NDV can cause disease in birds but is harmless for mammalian species including humans. WBVR has used the reverse genetics technique to develop NDV as a vaccine vector against human and animal infectious diseases. This vector technology will now be used to generate a vaccine against COVID-19.Intravaccs strength is its ability of bridging the gap between academia and research centers towards pharma. Together with our partners WBVR and Utrecht University, we combine our expertise in developing an intranasal corona virus vaccine, commented Dr. Jan Groen, CEO of Intravacc. Our safe Vero cell platform, widely used for the production of Polio vaccines, put us in the position to fast track the production of pilot lot of this NCD vector-based vaccine concept and to subsequently transfer this to large vaccine manufactures.

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Intravacc Partners with Wageningen Bioveterinary Research and Utrecht University - Contract Pharma

West Asia, which includes Anatolia (present-day Turkey), the Northern Levant and the Southern Caucasus is seen in a partial map obtained by Reuters June 1, 2020. An international team of researchers showed populations from Anatolia and the Caucasus started genetically mixing around 6,500 BC and that small migration events from Mesopotamia 4,000 years ago brought further genetic mixture to the region. The orange marker shows the route from Central Asia. DNA from a lone ancient woman revealed proof of long distance migration during the late Bronze age about 4,000 years ago from Central Asia to the Mediterranean Coast. Courtesy of Max Planck-Harvard Research center for the Archaeoscience of the Ancient Mediterranean/Handout via REUTERS

WASHINGTON (Reuters) - The bones of a woman of Central Asian descent found at the bottom of a deep well after a violent death in an ancient city in Turkey are helping scientists understand population movements during a crucial juncture in human history.

Researchers have dubbed her the lady in the well and her bones were among 110 skeletal remains of people who lived in a region of blossoming civilization running from Turkey through Iran between 7,500 and 3,000 years ago.

The study provided the most comprehensive look to date of genetics revealing the movement and interactions of human populations in this area after the advent of agriculture and into the rise of city-states, two landmarks in human history.

The remains of the lady in the well, found in the ruins of the ancient city of Alalakh in southern Turkey, illustrated how people and ideas circulated through the region.

Her DNA showed she hailed from somewhere in Central Asia - perhaps 2,000 miles (3,200 km) or more away. She died at about 40 to 45 years old, the researchers said, probably between 1625 BC and 1511 BC. Her body bore signs of multiple injuries.

How and why a woman from Central Asia - or both of her parents - came to Alalakh is unclear, said Ludwig Maximilian University Munich archaeologist Philipp Stockhammer, co-director of the Max Planck-Harvard Research Center for the Archaeoscience of the Ancient Mediterranean and co-author of the study published in the journal Cell.

Trader? Slaves? Marriage? What we can say is that genetically this woman is absolutely foreign, so that she is not the result of an intercultural marriage, Stockhammer added. Therefore, a single woman or a small family came this long distance. The woman is killed. Why? Rape? Hate against foreigners? Robbery? And then her body was disposed in the well.

Reporting by Will Dunham; Editing by Sandra Maler

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'Lady in the well' sheds light on ancient human population movements - Reuters