Daily Archives: July 5, 2020

The Victorian health minister, Jenny Mikakos, announced on Friday that early genomic sequencing had pointed to a super spreader of Covid-19 as a source for many new infections across Melbournes north and west.

The revelation comes after the states premier, Daniel Andrews, also credited genomic testing for exposing an infection-control failure in the hotel quarantine program through late May and early June.

While contact tracing detectives were praised for their work during the early months of outbreak, genomic sequencing experts are now playing an increasingly significant part in containing community transmission in what has become Australias largest cluster.

Heres what you need to know about genomic sequencing.

Genomic sequencing analyses the virus sample taken from a diagnosed patient and compares it with other cases.

Prior to Covid-19, genomic sequencing has been used in Australia to trace the source of outbreaks of food-borne bacteria and hospital infections.

After a Covid-19 test (which gathers saliva from the back of the throat and nose) returns a positive result, the swab used goes through several steps to separate the RNA molecules from mucus proteins so they can be captured, then converted into DNA that can be read.

As a virus passes from human to human, the virus changes slightly. While the genome of one Covid-19 patient compared with the person they caught it from will appear almost identical, after the virus has been transmitted onto further people, differences between the strands of the virus they carry become more apparent.

Rory Bowden, the head of the Centre for Genomics at the Walter and Eliza Hall Institute of Medical Research in Melbourne, told the Guardian the information allowed scientists to do detective work to understand patterns of spread of pathogens in populations.

The SARS-CoV-2 genome, at more than 30,000 nucleotides, is long for an RNA virus, so while there were few changes initially, there is room for quite a lot of information about each strains history to accumulate.

He said that by the time the virus arrived in Australia, the different changes, or mutations, of Covid-19 define branches on a tree. Each branch of Covid-19 that exists in Australia could be linked back to China in the original instance, as well as via an outbreak in a foreign country.

Bowden said that when Wuhan experienced the first outbreak, the genomes in the city were mostly identical.

He said genomic testing was particularly informative for tracing the current outbreaks in Victoria, whereas earlier on in the pandemic in Australia, and in overseas countries recording higher daily totals, the methods would not be as useful.

With SARS-CoV-2, there are still not that many variant positions to tell different branches of the tree apart. The thing that helps us is that in Australia, most cases are linked back, through one or a few generations of transmission, to the virus imported from all around the world by returning travellers, Bowden said.

If all we had was community spread from a single source introduction to Victoria, it is unlikely we would be able to tell the different clusters apart.

Benjamin Howden, who leads the public health epidemiology team at Melbourne Universitys Doherty Institute, is currently working with state authorities to use genomic sequencing to track Covid-19 cases.

Howden said that as of Friday, about 80% of Victorias cases had been genomically sequenced.

He said bioinformaticians, who apply information technology to biological and medical research, gathered each patients genome data and compared it against other patients in the state.

A genomic epidemiologist then matched the historical data of each strand recorded to the patient that provided the sample.

Matching the genomic findings to epidemiological information means authorities can tell if a new patient caught a virus from a known source of the virus, and can work to identify the point or person of transmission.

It also means authorities can divert resources more urgently into understanding and containing a case if genomic testing shows someone has caught a strain previously only recorded in a different geographic area.

In the case of the super spreader suggested on Friday, the genomic data of all of the patients infected by them would have very few variations. This is because the transmissions originated from just one person, as opposed to several people passing it along and giving a strain further chances to mutate.

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Genomic sequencing: what it is and how it's being used against Covid-19 in Victoria - The Guardian

The National Institutes of Health has announced the provision of $75 million in funding over five years for the Electronic Medical Records and Genomics (eMERGE) Genomic Risk Assessment and Management Network, which establish protocols and methodologies for improved genomic risk assessments for diverse populations and to integrate their use in clinical care. The eMERGE Network is supported by the National Human Genome Research Institute (NHGRI), part of NIH.

The funding will build upon the existingeMERGE Networkto support both a coordinating center and clinical sites specifically focused on better understanding disease risk and susceptibility by combining genomic and environmental factors and investigating how future findings can be used to help clinicians and patients manage disease risk.

About $61 million in total will be awarded over a period of five years to four clinical and six enhanced diversity clinical sites from around the United States (see below for full list). The enhanced diversity clinical sites will recruit a higher percentage of patients from diverse ancestries. $13.4 million will be awarded for an eMERGE Network coordinating center at Vanderbilt University. Funding will go into effect in June 2020.

The goal of the clinical sites is to recruit participants from diverse groups, such as racial or ethnic minority populations, underserved populations, or populations who experience poorer medical outcomes. The sites will then conduct and validate genomic risk-assessment and management methods for a number of common diseases.

Approximately half of the clinical sites will recruit about 10,000 patients, with the aim that 35% or more come from such diverse groups. The other clinical sites, called enhanced diversity clinical sites, will recruit about 15,000 patients, with 75% or more coming from diverse ancestries.

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NHGRI first initiated the eMERGE Network in 2007. Since then, the network has successfully conducted groundbreaking research on how to effectively use electronic health records and large biorepositories for genomics research in order to eventually integrate genomic information into clinical care.

More recent research has highlighted the need to generate datasets from more diverse populations to better understand estimates of disease risk in the general population.

To date, polygenic risk scores, a new approach for assessing disease risk based on DNA variants, have been developed and validated in studies that almost exclusively involved people of European ancestry. It is not clear how well the findings from these initial studies can be used for risk assessment in non-European ancestry populations. In addition, calculating polygenic risk scores usually do not include variables such as age, body-mass index, alcohol use and other clinical data, all of which can affect an individuals risk for certain diseases.

The new sites within the eMERGE Network aim to investigate ways to incorporate additional clinical data into the risk score calculations. Researchers have termed this combined score as genomic risk assessment or integrated risk score.

The new eMERGE Genomic Risk Assessment and Management Network will also develop ways to better incorporate computer-based programs, which analyze electronic health records and provide reminders and prompts to healthcare providers, into clinical practice. This process, called electronic clinical decision support, is meant to help physicians and other healthcare professionals make clinical decisions for their patients.

The sites will use the newly developed protocols to estimate risk for common, complex diseases of public health importance (e.g., coronary heart disease, Alzheimers disease, and diabetes). They will also look to understand how health management recommendations can be introduced to clinicians using electronic health records. In addition, the sites will provide guidance on how to share genomic-based and integrated risk score information electronically using the Fast Healthcare Interoperability Resources (FHIR ) standard, which provides specifications for how to exchange health information electronically.

The eMERGE Network will also leverage the NHGRI Genomic Data Science Analysis, Visualization, Informatics Lab-space (AnVIL) cloud-based resource to develop tools and workflows for generating integrated risk scores, which will be shared with the biomedical research and clinical genomics communities.

The new clinical sites will be led by:

The new enhanced diversity clinical sites will be led by:

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NIH funds centers to improve the role of genomics in assessing and managing disease risk - National Human Genome Research Institute

A research programme pioneering the use of whole genome sequencing in the NHS has diagnosed hundreds of patients and discovered new genetic causes of disease.

The project, the results of which were published in the journal Nature, offered whole-genome sequencing as a diagnostic test to patients with rare diseases across an integrated health system, a world first in clinical genomics.

Whole genome sequencing is the technology used by the 100,000 Genomes Project, a service set up by the government which aims to introduce routine genetic diagnostic testing in the NHS. The integration of genetic research with NHS diagnostic systems increases the likelihood that a patient will receive a diagnosis and the chance this will be provided within weeks rather than months.

The multi-centre study, led by researchers at the National Institute for Health Research (NIHR) BioResource together with Genomics England, demonstrates how sequencing the whole genomes of large numbers of individuals in a standardised way can improve the diagnosis and treatment of patients with rare diseases.

The researchers, including experts from the University of Bristol, studied the genomes of groups of patients with similar symptoms, affecting different tissues, such as the brain, eyes, kidney, blood, or the immune system. They identified a genetic diagnosis for 60 per cent of individuals in one group of patients with early loss of vision.

Principal investigators Andrew Mumford, Professor of Haematology, and Moin Saleem, Professor of Paediatric Renal Medicine, led the set-up of the programme and oversaw regional enrolment in the South West. Professor Mumford provided national oversight for blood related disorders, while Professor Saleem managed inherited kidney diseases.

Professor Mumford and researchers in the School of Cellular and Molecular Medicine collaborated with the Bristol NIHR Biomedical Research Centre and the University of Cambridge to develop ways to improve the genetic identification of blood disorders, contributing significantly to the breakthrough diagnostic potential.

Professor Mumford said: This pioneering study illustrates the power of whole genome sequencing for diagnosis of rare human diseases. The approach developed in this research has paved the way for the flagship 100,000 Genomes Project and the introduction of whole genome sequencing into standard NHS care.

Professor Saleem established the UK National Renal Rare Disease Registry, and the national and international NephroS (Nephrotic Syndrome) groups, based within the UK Renal Registry in Bristol. These provided recruitment, essential genetic data, and DNA collection for the study. Researchers in Bristol provided functional and clinical insights leading to the discovery of causative genes relating to kidney disorders.

Professor Saleem said: Rare diseases in their entirety are common, in that there are more than 7,000 different rare diseases in total affecting about 7 per cent of the population. Most have a genetic cause, so this research for the first time brings the most powerful genetic sequencing capabilities to apply across the whole health service, meaning all patients will now have the best possible chance of finding their individual genetic defect.

In the study, funded mainly by the National Institute for Health Research, the entire genomes of almost 10,000 NHS patients with rare diseases were sequenced and searched for genetic causes of their conditions. Previously unobserved genetic differences causing known rare diseases were identified, in addition to genetic differences causing completely new genetic diseases.

The team identified more than 172 million genetic differences in the genomes of the patients, many of which were previously unknown. Most of these genetic differences have no effect on human health, so the researchers used new statistical methods and powerful supercomputers to search for the differences which cause disease a few hundred needles in the haystack.

Using a new analysis method developed specifically for the project, the team identified 95 genes in which rare genetic differences are statistically very likely to be the cause of rare diseases. Genetic differences in at least 79 of these genes have been shown definitively to cause disease.

The team searched for rare genetic differences in almost all of the 3.2 billion DNA letters that make up the genome of each patient. This contrasts with current clinical genomics tests, which usually examine a small fraction of the letters, where genetic differences are thought most likely to cause disease. By searching the entire genome researchers were able to explore the switches and dimmers of the genome the regulatory elements in DNA that control the activity of the thousands of genes.

The team showed that rare differences in these switches and dimmers, rather than disrupting the gene itself, affect whether or not the gene can be switched on at the correct intensity. Identifying genetic changes in regulatory elements that cause rare disease is not possible with the clinical genomics tests currently used by health services worldwide. It is only possible if the whole of the genetic code is analysed for each patient.

Dr Ernest Turro, from the University of Cambridge and the NIHR BioResource, said: We have shown that sequencing the whole genomes of patients with rare diseases routinely within a health system provides a more rapid and sensitive diagnostic service to patients than the previous fragmentary approach, and, simultaneously, it enhances genetics research for the future benefit of patients still waiting for a diagnosis.

"Thanks to the contributions of hundreds of physicians and researchers across the UK and abroad, we were able to study patients in sufficient numbers to identify the causes of even very rare diseases."

Paper:

Whole-genome sequencing of patients with rare diseases in a national health system, by Ernest Turro et alin Nature.

There are thousands of rare diseases and, together, they affect more than three million people in the UK. To tackle this challenge, the NIHR BioResource created a network of 57 NHS hospitals which focus on the care of patients with rare diseases.

Based on the emerging data from the present NIHR BioResource study and other studies by Genomics England, the UK government previously announced that the NHS will offer whole-genome sequencing analysis for all seriously ill children with a suspected genetic disorder, including those with cancer. The sequencing of whole genomes will expand to one million genomes per year by 2024.

Whole-genome sequencing will be phased in nationally for the diagnosis of rare diseases as the standard of care, ensuring equivalent care across the country.

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July: Genome sequencing rare diseases | News and features - University of Bristol

For the nascent brain of a human embryo to develop into the complex organ that controls human consciousness, a finely tuned sequence of genetic events has to take place; hundreds of genes are activated and deactivated in a precise symphony. Mutations in these genes disrupt the molecular instruments of the symphony and, if they occur in genes that are important for brain development, can result in neurological diseases such as autism and epilepsy. Researchers have long struggled to understand how mutations in regulatory regions of the genome--the conductors, rather than the instruments--can also make this process go awry.

Now, researchers at Gladstone Institutes and UC San Francisco (UCSF) Weill Institute for Neurosciences have created a comprehensive region-specific atlas of the regulatory regions of the genome linked to human embryonic brain development.

"This gives us a searchable, data-rich atlas of part of the developing human brain," said Katie Pollard, PhD, director of the Gladstone Institute of Data Science and Biotechnology. "This is a valuable tool for probing the underlying biology of neurodevelopmental disorders."

Pollard and UCSF professor of psychiatry John Rubenstein are the senior authors of the new study, published online in the journalCell.

Only about two percent of the human genome encodes actual genes. Much of the rest of the genome contains regulatory elements, the conductors that control when and where those genes are activated. Genes important for specific aspects of liver function, for example, don't need to be turned on in brain cells, so different regulatory elements are needed to control gene expression in those tissues.

When researchers analyze the DNA of people with neurodevelopmental disorders, they often uncover dozens, if not hundreds, of natural variations in DNA sequences. However, only a minority of those variants may be related to the disorder itself, and pinning down which are important is difficult.

"Much of the genome is still this vast and mysterious place because we don't know which parts of the genome play roles in which tissues," said Eirene Markenscoff-Papadimitriou, PhD, a postdoctoral researcher at the UCSF Weill Institute for Neurosciences and co-first author of the paper.

In the new study, the researchers studied cells from a section of the developing human brain called the telencephalon. This region contains structures responsible for sensory processing, voluntary movement, language, and communication.

The team took advantage of the fact that inside cells, the genome is tightly wound into a dense structure known as chromatin. This three-dimensional structure reveals the important parts of the genome in any given cell by exposing the stretches of regulatory DNA needed for the cell to function. Using a technology called ATAC-seq, the team cut up exposed DNA in embryonic brain cells. By analyzing where these cuts are made, they were able to surmise what parts of the genome are exposed and might contain important regulatory regions.

Their initial experiments revealed more than 103,000 regions of open chromatin in the developing brain cells. To narrow down that list, the researchers turned to a machine-learning approach. They wrote a computer program that uses information already known about regulatory DNA to help pick out patterns specific to brain cells.

"We wanted to whittle this initial list down to a smaller set that was the most likely to be important to regulating brain development," said Gladstone Research Scientist Sean Whalen, PhD, co-first author of the new paper.

If a regulatory region was similar to one known to only be active in limbs or lungs, for instance, the machine-learning program concluded that it wasn't a brain-specific enhancer. In the end, the group came up with a set of about 19,000 regulatory regions of the genome expected to play a role in brain development.

To show the utility of the new dataset, the researchers looked more closely at two sections of the genome that appeared in the new atlas that had also been previously implicated in autism and epilepsy. The DNA sequences, they showed, did indeed act as enhancers in brain cells--they had the ability to turn on genes.

"We can now use this approach to ask how all sorts of other mutations affect the non-coding genome," said Markenscoff-Papadimitriou. "This atlas points us in the direction of specific brain regions that are affected by genetic mutations."

If a research team finds hundreds of genetic variants associated with a neurodevelopmental disease, for instance, they can now use the atlas to cross-check which variants are part of the 19,000 regions identified as critical to brain development. That can help them home in on which variants are worth follow-up studies, rather than spending months testing genetic variants that end up to be unrelated to disease.

"We think our data will help a lot of other research groups further their work," agreed Whalen. Beyond studying diseases, he says the resource will be useful for basic science on how the brain develops.

Reference: Markenscoff-Papadimitriou, E., Whalen, S., Przytycki, P., Thomas, R., Binyameen, F., Nowakowski, T. J., Kriegstein, A. R., Sanders, S. J., State, M. W., Pollard, K. S., & Rubenstein, J. L. (2020). A Chromatin Accessibility Atlas of the Developing Human Telencephalon. Cell, 0(0). https://doi.org/10.1016/j.cell.2020.06.002

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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Chromatin Atlas Is a Genomic Map of the Brain's Development - Technology Networks

PepsiCo partnered with the government, academics and other companies to sequence the oat genome in four months, a development the food and beverage giant said may lead to heartier varieties with improved sustainability, taste and nutrition.

The food and beverage company, which uses the grain in its Quaker-branded oatmeal, bars and other products, is releasing the data free for public use because it "serves a broader purpose" to help improve sustainability and the livelihood of farmers who grow the crop, RenLammers, PepsiCo's chief science officer, told Food Dive.

Until now, he said the oat has not been heavily invested in by the food industry because it is not one of the more widely used commodities like corn or wheat. But with more information known about its genetic components, the hope is that it could spur additional use of oats, as well as more research.

"We want to sort of re-energize the conversation and the innovation intensity in this, for what we believe is a very important crop,"Lammerssaid.

The oat has seen its popularity remain largely steady in recent years, with the average person consuming about 4.8 pounds of oat products each year,according to Statista.

But the grain has received more attention recently because it contains a number of attributes popular with consumers. It is rich in anti-oxidants, high in fiber and associated with combating chronic illnesses, such as heart disease.

Oatmeal also is easy to prepare and can be eaten on the go, making it popular with busy consumers looking to fill up with essential nutrients.The global market size for oatmeal, for example,is expected to reach $3.32 billion by 2026, a compound annual growth rate of 4.76%,according to data from Fortune Business Insights.

"We live in a consumer goods world, you want to continue to improve. ... We felt more could be done in the world of oats. We felt there wasn't enough investment and attention going into it."

RenLammers

Chief science officer, PepsiCo

The oat genome is much larger and more complex than other major crops like corn and soy, which historically have had extensive private funding for research, he said.The limited genetic knowledge publicly available about the grain has in turn slowed discovery and breeding of better oat varieties for farmers, the environment and consumers.

"There is a do-good element here in terms of sharing some of your technology,"Lammers noted. "But if you combine it with other layers of advances that we've built over the years, flavoring being one of them, then I think we are still in a very competitive" position.

The genome sequence will help PepsiCo breed oats for a host of sustainability attributes, including increased yields;improved disease resistance;healthier soils that sequester carbon and reduce water run-off; and lower the amount of land and other resources needed to grow oats. Understanding the full genome will also improve the New York company's ability to identify oats rich in fiber and essential nutrients, while creating more flavorful varieties that could widen its appeal with consumers.

"Understanding the complete genome also helps you in targeting these individual qualities, and ultimately benefiting consumers,"Lammers said. "We live in a consumer goods world, you want to continue to improve. ... We felt more could be done in the world of oats. We felt there wasn't enough investment and attention going into it."

To expedite the sequencing of the oat genome, PepsiCo worked with Corteva Agriscience, the University of North Carolina at Charlotte and the University of Saskatchewan, which supplied the oat variety. This is the first time the 122-year-old beverage and snack giant has ever sequenced a specific ingredient. Lammers said while the company is focused on oats for now and doesn't have any immediate plans to work on other commodities, it could consider other ingredients in the future.

"We felt we've always had a good, strong pipeline in our innovation from an oats perspective, but you need to continue to innovate,"Lammers said. "What we hope is we will continue to drive innovation in an important category for us, and an important brand in Quaker Oats."

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PepsiCo partners to sequence the oat genome for the 1st time - Food Dive

News Release

Monday, June 29, 2020

Genomic variants that cause common periodic fever have spread in Mediterranean populations over centuries, potentially protecting people from the plague.

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 journalNature Immunology.Additional support for the research was provided by the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Center for Research on Genomics and Global Health.

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 isYersinia pestis, the bacterial agent responsible for a series of well-documented bubonic plague epidemics that led to over 50 million deaths.

FMF, like the plague, is anancientdisease. 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 theMEFVgene cause FMF. MEFVencodes 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 theMEFVgene. 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.

TheMEFV mutations also have other usual properties. Researchers have discovered that people with only one copy of aMEFVgenomic 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 toYersinia 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 outYersinia pestiscontains 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 thatYersinia pestisaffects 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 byYersinia 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 howYersinia pestisinteracts 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 thatYersinia pestisdoes 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 thatYersinia pestisreduces inflammation in cells without FMF-associated mutations.

The researchers thought that ifYersinia pestisdoes 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 withYersinia 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.

About the National Human Genome Research Institute (NHGRI) is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at: https://www.genome.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

On June 30, the release was amended to include additional funding information.

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NIH study shows genomic variation causing common autoinflammatory disease may increase resilience to bubonic plague - National Institutes of Health

A stretch of DNA linked to Covid-19 was passed down from Neanderthals 60,000 years ago, according to a new study.

Scientists dont yet know why this particular segment increases the risk of severe illness from the coronavirus. But the new findings, which were posted online on Friday and have not yet been published in a scientific journal, show how some clues to modern health stem from ancient history.

This interbreeding effect that happened 60,000 years ago is still having an impact today, said Joshua Akey, a geneticist at Princeton University who was not involved in the new study.

This piece of the genome, which spans six genes on Chromosome 3, has had a puzzling journey through human history, the study found. The variant is now common in Bangladesh, where 63 percent of people carry at least one copy. Across all of South Asia, almost one-third of people have inherited the segment.

Elsewhere, however, the segment is far less common. Only 8 percent of Europeans carry it, and just 4 percent have it in East Asia. It is almost completely absent in Africa.

Its not clear what evolutionary pattern produced this distribution over the past 60,000 years. Thats the $10,000 question, said Hugo Zeberg, a geneticist at the Karolinska Institute in Sweden who was one of the authors of the new study.

One possibility is that the Neanderthal version is harmful and has been getting rarer over all. Its also possible that the segment improved peoples health in South Asia, perhaps providing a strong immune response to viruses in the region.

One should stress that at this point this is pure speculation, said Dr. Zebergs co-author, Svante Paabo, the director of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

Researchers are only beginning to understand why Covid-19 is more dangerous for some people than others. Older people are more likely to become severely ill than younger ones. Men are at more risk than women.

Social inequality matters, too. In the United States, Black people are far more likely than white people to become severely ill from the coronavirus, for example, most likely due in part to the countrys history of systemic racism. It has left Black people with a high rate of chronic diseases such as diabetes, as well as living conditions and jobs that may increase exposure to the virus.

Genes play a role as well. Last month, researchers compared people in Italy and Spain who became very sick with Covid-19 to those who had only mild infections. They found two places in the genome associated with a greater risk. One is on Chromosome 9 and includes ABO, a gene that determines blood type. The other is the Neanderthal segment on Chromosome 3.

But these genetic findings are being rapidly updated as more people infected with the coronavirus are studied. Just last week, an international group of scientists called the Covid-19 Host Genetics Initiative released a new set of data downplaying the risk of blood type. The jury is still out on ABO, said Mark Daly, a geneticist at Harvard Medical School who is a member of the initiative.

The new data showed an even stronger link between the disease and the Chromosome 3 segment. People who carry two copies of the variant are three times more likely to suffer from severe illness than people who do not.

After the new batch of data came out on Monday, Dr. Zeberg decided to find out if the Chromosome 3 segment was passed down from Neanderthals.

About 60,000 years ago, some ancestors of modern humans expanded out of Africa and swept across Europe, Asia and Australia. These people encountered Neanderthals and interbred. Once Neanderthal DNA entered our gene pool, it spread down through the generations, long after Neanderthals became extinct.

Most Neanderthal genes turned out to be harmful to modern humans. They may have been a burden on peoples health or made it harder to have children. As a result, Neanderthal genes became rarer, and many disappeared from our gene pool.

But some genes appear to have provided an evolutionary edge and have become quite common. In May, Dr. Zeberg, Dr. Paabo and Dr. Janet Kelso, also of the Max Planck Institute, discovered that one-third of European women have a Neanderthal hormone receptor. It is associated with increased fertility and fewer miscarriages.

Dr. Zeberg knew that other Neanderthal genes that are common today even help us fight viruses. When modern humans expanded into Asia and Europe, they may have encountered new viruses against which Neanderthals had already evolved defenses. We have held onto those genes ever since.

Dr. Zeberg looked at Chromosome 3 in an online database of Neanderthal genomes. He found that the version that raises peoples risk of severe Covid-19 is the same version found in a Neanderthal who lived in Croatia 50,000 years ago. I texted Svante immediately, Dr. Zeberg said in an interview, referring to Dr. Paabo.

Dr. Paabo was on vacation in a cottage in the remote Swedish countryside. Dr. Zeberg showed up the next day, and they worked day and night until they posted the study online on Friday.

Its the most crazy vacation Ive ever had in this cottage, Dr. Paabo said.

Tony Capra, a geneticist at Vanderbilt University who was not involved in the study, thought it was plausible that the Neanderthal chunk of DNA originally provided a benefit perhaps even against other viruses. But that was 40,000 years ago, and here we are now, he said.

Its possible that an immune response that worked against ancient viruses has ended up overreacting against the new coronavirus. People who develop severe cases of Covid-19 typically do so because their immune systems launch uncontrolled attacks that end up scarring their lungs and causing inflammation.

Dr. Paabo said the DNA segment may account in part for why people of Bangladeshi descent are dying at a high rate of Covid-19 in the United Kingdom.

Its an open question whether this Neanderthal segment continues to keep a strong link to Covid-19 as Dr. Zeberg and other researchers study more patients. And it may take discoveries of the segment in ancient fossils of modern humans to understand why it became so common in some places but not others.

But Dr. Zeberg said that the 60,000-year journey of this chunk of DNA in our species might help explain why its so dangerous today.

Its evolutionary history may give us some clues, Dr. Zeberg said.

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DNA Linked to Covid-19 Was Inherited From Neanderthals, Study Finds - The New York Times

Jul 4th 2020

A CENTURY AND a half ago an alien insect alighted in Europe. It displaced millions, ruined local economies and forced scientists, politicians and ordinary folk into a frenzy of defensive activity. Phylloxera, a member of the group known to entomologists as Hemiptera, or true bugs (as opposed to all the other critters known colloquially as bugs), appeared in France in the 1860s and proceeded to eat its way through many of the Old Worlds vines.

It then spread to pastures new. It was first recorded in Australia in 1875 and in South Africa in 1886, threatening similar devastation to the vineyards of those European colonies. Eventually, French and American scientists found a solution by grafting European vines onto the imported roots of American ones. Now, a more recent group of French and American researchers report in bmc Biology that they have sequenced phylloxeras genome, and that hidden within this lie clues to the insects origins and spread.

Nineteenth-century agronomists rapidly divined that phylloxera had come from North America. That fact provided the rationale behind their graft-based answer to the problemwhich is still all that stands between cultivated vines and the bug. This is that having co-evolved with the insect, American vines had developed resistance to it. But where exactly it came from on that continent, nobody knew. One theory held British gardeners responsible because they had brought wild American vines to Europe for decorative purposes. From Britain, this theory went, phylloxera reached the European mainland via the south of France, the first place where it devastated vineyards. That, though, turns out to be a calumny against les Anglais.

By comparing the genetic sequence of European phylloxera with those of populations from wild vines in the United States, Claude Rispe and Fabrice Legeai of the French National Research Institute for Agriculture, Food and the Environment (INRAE) and their colleagues have narrowed the search to the once-French territory of the Mississippi Valley (the upper Mississippi, to be precisethough one of the papers authors, Paul Nabity of the University of California, Riverside, plans to keep following the river south, sampling phylloxera as he goes, so the matter is not closed). The evidence is that there is a striking similarity between the European sequence and that of two phylloxera populations on a wild vine called Vitis riparia in Wisconsin and Illinois. This is enough, Dr Nabity says, to indicate that V. riparia was the bugs original host and the upper Midwest its source.

If correct, says Franois Delmotte, who works at INRAEs campus in Bordeaux and is one of the projects leaders, the finding fits with certain historical facts. Though the Mississippi valley was annexed from France by Britain and Spain in the mid-18th century, and passed eventually to the United States, many French settlers remained in the area and France retained trading links, particularly with New Orleans, for a long time. Dr Delmotte says it would not be surprising if, in the 19th-century age of steamships and naturalists, phylloxera survived on cuttings of V. riparia stored in a cool, dry hold to be brought to a botanical garden in France. Or, even more ironically, that it was imported with vines destined to cure their French cousins of an earlier imported blightpowdery mildew.

The genetic diversity of European phylloxera is limited compared with that of its North American counterpart, says Dr Rispe. That points to there having been only one or two introductions, with subsequent diffusion of the pest by people and their agricultural machines. However, another of the papers authors, Astrid Forneck of the University of Natural Resources and Life Sciences in Vienna, says it remains a possibility that a separate introduction infested eastern Europe, perhaps via the Austro-Hungarian empires experimental vineyards at Klosterneuburg.

In America phylloxera attacks wild vines leaves. It stimulates them to create galls in which it can live and feed, but which, from the plants point of view, serve to isolate the problem. When it attacks cultivated vines, though, it goes for the roots. These root galls open a plant to infection by bacteria and fungi, leading to its death. For a long time, researchers hunted for a single molecule, produced by the insect, that stimulated the growth of galls. Blocking the action of this, they hoped, would phylloxera-proof all vines. But here the sequencing project produced a disappointment. There is no such molecule. The researchers identified many genes2,300 of them, more than a tenth of the insects genomethat encode proteins which it secretes while feeding on the vine. These enable it to evade the plants immune system while diverting resources from its host.

The work now begins of teasing out what each of those genes does, and, ultimately, how phylloxera manipulates a plant and adapts to a new host. This information may in turn generate new weapons against the creature. That could be valuable in parts of viticultures New World, such as Australia, where vines remain ungrafted and phylloxera is still a problem. It might also help if the insect ever evolves the ability to evade the natural resistance of American vine roots that currently stands between European growers and disaster. For Dr Forneck, this prospect is not outlandish. The insect is already adapting to a warmer world, and shifting its range. Further shifts in its physiology are perfectly possible.

This article appeared in the Science & technology section of the print edition under the headline "The root of the problem"

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A pests genome reveals its past - The Economist

ETF Trends CEO Tom Lydon discussed the ARK Genomic Revolution Multi-Sector Fund (ARKG)on this weeks ETF of the Week podcast with Chuck Jaffe on the MoneyLife Show.

The ARK Genomic Revolution ETF (ARKG) is an actively-managed fund from the team at ARK Invest that tries to pick the companies best positioned to profit from advancements in energy, automation, manufacturing, materials, and transportation.

ARKG is an outperforming biotech ETF. Its had an 11.2% 1-week return and isone of the best performing non-leveraged ETFs of the second quarter +67.7% Q2.ARKG is up 41% year-to-date. In comparison, the Nasdaq Biotechnology Index is up 14.6% year-to-date. TheS&P 500 is -3.5% year-to-date.

As it stands, theres short-term support from the hope of a viable coronavirus, COVID-19 drugforexample, Inovio Pharmaceuticals. The Department of Defense provided funding to Inovio Pharmaceuticals (NasdaqGS: INO) to scale up the manufacturing of a DNA vaccine for the novel coronavirus.Inovio was among the first groups to tackle the COVID-19 problem back in January.

The company has advanced to human testing and scored a $71 million contract from the U.S. government for a delivery device of the potential vaccine.According to Inovio Pharma, the new device runs on A.A. batteries and can function reliably in challenging environments, which can be beneficial during pandemics when vaccine demand is extremely high and can be utilized more efficiently in some areas of the world suffering from inadequate health systems and supply chains.

This is not just a short-term Coronavirus story. Itcapitalizes on greater merger and acquisition activity as more large companies try to expand into specialized offerings.

ARKGcapitalizes on innovative, specialized drugs that are being developed by many overlooked names.Invitae Corp. (NYSE: NVTA) announced a $1.4 billion deal for ArcherDX, potentially bolstering the genetic information companys offering lineup and growth outlook. Theagreement to acquire genomics analysis company ArcherDX is expected to create a hub for precision oncology, diagnostics, therapy optimization, and monitoring.

ARKGincludes companies that merge healthcare with technology and capitalize on the revolution in genomic sequencing.These companies try to understand better how biological information is collected, processed, and applied by reducing guesswork and enhancing precision; restructuring health care, agriculture, pharmaceuticals, and enhancing our quality of life.

The convergence of Artificial Intelligence (A.I.), Next Generation DNA Sequencing (NGS) and CRISPR gene-editing has the potential to boost the efficiency of drug development radically.Breakthroughs in genomic science can present new treatments to help patients recover from what were once believed to be incurable afflictions.

The global genomics market was worth $851.96 million in 2019.It is expected to grow at a compound annual growth rate (CAGR) of 14.71% and reach $1.5 billion by 2023.

Rising government funds for research on genomics drives the growth of the single-cell genomics market.The government funding focuses on efforts to resolve the complexity of the human genome, the genomic basis of human health and disease, and ensure that genomics is used safely to enhance patient care and benefit society through government, public and private institutions.

Related:ETF of the Week: Roundhill Sports Betting & iGaming ETF (BETZ)

Scientists have identified more than 50,000 genetic diseases caused by single-gene mutations, many of which are likely to be treated through genomic approaches, including several methods that have already begun to receive FDA approval.

Looking ahead, CRISPR-based innovations are expected to accelerate, given the technologys ease of use, cost-efficacy, a growing body of research surrounding its safety and AI-powered CRISPR nuclease selection tools. CRISPR could also be utilized to address some of the most prominent healthcare problems, which opens up a significant investment opportunity in monogenic diseases.

Bolstering the case forARKGover the long-term is the importance of genomics in an array of clinical trials. Drug development companies are making clinical trials more efficient by using NGS to find and enroll patients likely to respond. Half of the clinical trials and 80% of oncology trials now collect genetic information.ARK believes that clinical trials using genetic diagnostics will result in fewer failed drugs and will increase capital efficiency.

Originally posted here:
ETF of the Week: ARK Genomic Revolution Multi-Sector Fund (ARKG) - ETF Trends

An important milestone in the fight against Covid-19 came in early January, when the entire viral genome of the novel coronavirus that causes the disease was sequenced for the first time. Since then, the full coronavirus genome, taken from thousands of infected patients around the globe, has been sequenced.

This vast bank of genome sequences is an important resource. Particularly as viruses such as coronavirus have a high mutation rate, with the genome sequence varying up to 0.02%. This may sound low, but considering the human genome varies by only 0.001% between individuals, its clear the virus mutates much faster than we do and can quickly evolve.

Sequencing the coronavirus at different points in time can tell us how it is adapting and can indicate the direction it is likely to take.

In a recent study, the London School of Hygiene and Tropical Medicine analysed the viral genome sequences isolated from over 5,000 Covid-19 patients around the world. So what does this analysis of genome variations tell us? What implications does it have for vaccines, treatments and testing? And what does it tell us about the future direction of this destructive pathogen?

All viral vaccines contain material that resembles the virus they are trying to protect against. This fools the immune system into mounting a response and producing antibodies ready to be used should it ever encounter the real thing. In the case of the coronavirus, the immune system produces antibodies that target the spike protein the part of the virus that is used to invade our cells.

One concern is that the virus will mutate to form escape mutants. These are mutated versions of the virus that the vaccine-induced antibodies wont recognise. We see this with other viruses, such as influenza. The flu vaccine has to be altered each year to counter changes to circulating strains.

Luckily, the novel coronavirus has a lower mutation rate than influenza. And while the London School of Hygiene and Tropical Medicine study identified changes in the S gene the gene that makes the spike of the various virus strains, mutations in this gene were comparatively rare. Mutations in the epitope regions the sites in the spike protein the antibodies attach to were also infrequent.

Initial searches for an effective treatment have focussed on existing drugs, as seen in recent reports of the success of dexamethasone. While this drug prevents a hyperactive immune reaction to the virus, other promising drugs, such as remdesivir, directly target the virus itself. Remdesivir specifically targets the enzyme the virus needs to replicate.

Previous studies found two mutations in the enzyme gene that confer resistance to remdesivir, but the London School of Hygiene and Tropical Medicine study didnt find many instances of these mutations. Wide use of the drug, however, will put selective pressure on the virus environmental factors that contribute to evolutionary change so monitoring these mutations will be important.

To diagnose a current infection, diagnostic tests look for certain genes from the virus. The accuracy of these tests depends on the target areas of the genome being as expected.

The first published diagnostic method, released shortly after the first viral genome was sequenced, screened for more than one viral gene considered to be well conserved across viral strains. Well-conserved genes are important for the virus to function and so tend not to change as the organism evolves. Most diagnostic tests since have continued to screen for two or more coronavirus genes, although the genes they test for often vary.

The authors of the LSHTM study looked for variations in regions of the genome screened for in common diagnostic tests and found several mutations that could result in false negatives, where a person has the disease but the test says they dont. These mutations had a strong geographical distribution, so clinical scientists need to be aware of locally circulating strains when considering which tests to use.

Similarly, once restrictions on international travel are relaxed, scientists will need to be wary of possible false negatives among imported cases of the disease.

Some viruses that cross the species barrier into humans are ill-equipped to replicate in their human host and fail to sustain a presence in the human population. However, the coronavirus has already achieved sustained human-to-human transmission, but will this presence be maintained? And if so, will the virus evolve to become more or less lethal?

Like mutations in any organism, for a viral mutation to prevail, it must provide an evolutionary advantage. There is no evolutionary advantage to a virus if it kills its host, particularly if it kills the host before transmitting to a new one. But evoking symptoms in the infected person, such as coughing and sneezing, can help the virus transmit to a new host and this does offer an evolutionary advantage.

To identify which mutations may help the virus survive, the authors of the study set out to identify convergent mutations mutations that occurred in different parts of the world and at a higher than random rate, suggesting that these mutations benefit the survival of the virus.

Although scientists have analysed many genomes, the study of the genome-disease relationship is still a work in progress. Unfortunately, there is a bias in the database of genome sequences because samples from patients with more severe symptoms are more likely to be sequenced, making it difficult to associate particular mutations to how severe the disease is.

Of course, disease outcomes are affected by other factors, too, such as how old or sick the host is. The effect of interventions also has to be considered. Until a large dataset of genome data from mild or non-symptomatic patients from a diverse population is available, it will be difficult to deduce how the convergent mutations identified translate to severity of disease.

Claire Crossan, Research Fellow, Virology, Glasgow Caledonian University.

This article first appeared on The Conversation.

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What coronavirus mutations mean for its vaccine, treatment and testing - Scroll.in