Daily Archives: February 2, 2021

LONDONEvery week across the U.K., a fleet of courier trucks ferries chilled waste material from half a million Covid-19 tests to agenome-sequencing facility in Cambridgeshire, eastern England.

The daily operation is part of a Covid-19 surveillance system that has made the U.K. the worlds leading sequencer of the coronavirusgenomeand helped it to spot a more contagious, and possibly more deadly, variant of the virus that in most countries would have long gone unnoticed.

Viral sequencingproducing a kind of bar code for the virushas in recent months emerged as crucial in the global hunt for versions of the pathogen that are better adapted to infect humans, evade vaccines and possibly to kill. Virus variants first identified in the U.K., South Africa and Brazil have provoked concern among experts.

The variant the sequencers uncovered in the U.K., which is now the dominant variety in the country, has a mutation that appears better able to bind onto human cells. Studies suggest it is 50% more transmissible than the previous prevalent variant while other research suggests it could be at least 30% more deadly.

New viral variants are more likely to be spotted in the U.K. than anywhere else. As of Jan. 29, the U.K. had submitted 44%, or around 190,000, of the genomes held in a global library run by the nonprofit Global Initiative on Sharing All Influenza Data, or Gisaid. That is around 5.1% of the nearly four million cases detected in the U.K.

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How the U.K. Became World Leader in Sequencing the Coronavirus Genome - The Wall Street Journal

What is a genome

A genome is a collective term for all the genetic material within an organism. In essence,the genome decides exactly what that organism will look and act like at birth one huge, expansive instruction manual that tellscells their duties. Every living thing has a genome, from bacteria to plants to humans, and they are all different in size with various combinations of genes inside.

The human genome packs in 30,000 genes, but this is just 1% of the total genetic material contained within. Quite frankly, its a mess in there much of the genetic material is duplicated DNA that (supposedly) does very little, and the vast majority of DNA simply doesnt code for anything(these sections are calledintrons). That isnt to say it does nothing. In fact,recent studieshave shown us that non-coding DNA is essential to controlling whether our genes get switched on or not. However, most of the time its the actual genes that are the important bit.

Studying the genome of humans and other organisms is vitalfor a number of reasons.Firstly, it helps us characterize each one before genomics, scientists simply grouped animals and plants by what they looked like, but research into their genes now allows for accuratecharacterization oforganismsinto specificgeneraand species.

In humans, genomic research has allowed researchers to understand the underlying causes of many complex diseases and find possible targets for treatment.Currently, the best tool to do thisisgenome-wide association studies (GWAS).

The idea behind GWAS is relatively intuitive simply take a group of people with the disease you wish to study, and compare their genomesfor common genetic variants that could predict the presence of that disease.These studies have illuminated a huge number of variants linked with higher disease prevalence while also helping researchers to understand the role each gene playsin the human body.Although powerful, GWAS studies are purely a starting point. Following a large-scale GWAS, researchers must thenanalyzeany variants that are highlighted in great depth, and many times such research will provide nothing of clinical relevance. However, itsstill our best way of identifying risk variants in genetic disease.

So,we know the genome is packed to the brim with genes that code for proteins, separated by large strings ofnon-coding DNA. However, when cells replicateearly in development they usually go throughchromosomal recombination, in which chromosomes trade regions of their genetic code between each other. This spreads genes to many different positions (called loci)throughout the genome. If we can make a map of these genes, we candiscover their function, how they are inherited, or target them with therapies.

Therefore, we want to create a genome map.There are two types of maps used in genomics: genetic maps and physical maps.

Physical mapsare relatively straightforward, in which genomic loci are mapped based on the physical distance between them, measured in base pairs.The most common way to create a physical map of a human genome is byfirst breaking the DNA sequence into many fragments, before using a variety of different techniques to identify how those pieces fit back together. By understanding which pieces overlapand reconstructing the shattered genome, scientists can gain a decently accurate map of where each gene lies.

Genetic mapsare slightly different,using specific marker regions within the DNA that are used as trackers. These mapsrequiresamples (usually saliva) from family members,which are then compared toidentifyhow much recombination has occurred that includes markers of interest. The principle is thatif two genes are close together on thechromosome, thenthey are more likely to travel together through the genome as it recombines. By using this data,scientists can get a rough idea of where specific genes lie on chromosomes. However, it is not as accurate as physical mapping andrelies heavilyon a decentpopulation size andthe number of genetic markers used.

A genome browser is any available database that allows a user to access and compare genomes in an intuitive way. When you map or sequence a genome, the data is prettymessy.Genomes are usually stored in huge files, calledFASTAfiles, that contain extensive strings of letters that would look foreign to most users. Genome browsers take this data and make it accessibleto scientists around the globe.

Many genome browsers are available online, containing bacterial, model organism, and human reference genomes.

Genomelinkis one of the latest examples of public access and analysis of genomes. The industry took off in recentyears, with the rapid rise of sites that provide ancestry and medical information based on genomic sequencing, includingAncestryand23andMe.These sites work by comparing genetic markers associated with different populations should you share specific regions of DNA that correspond with African populations, for example, you may have some relation to African ancestors. Each site uses its own markers, so information may vary between tests, and some have disputed the true accuracy of these tests, although advances in genomics have significantly improved them in recent years.

Genomelinkgoes further than most sites, claiming to provide information on a huge variety of genetic traits that a user may have. These include metabolism, sports performance, and even personality traits such as loneliness. Each trait isdrawn from genome correlation studies, with each taking a specific trait and comparing the genomes of each carrier of that trait.

However, although bothGenomelinkand other sites use up-to-date reference genomes and are usually relatively accurate, they should never be substituted for medical information. If you believe you carry a pathogenic genevariant, you should seek advice from a genomic counselor.

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Genomes, Maps, And How They Affect You - IFLScience

A team led by Prof. SU Bing from the Kunming Institute of Zoology(KIZ) of theChinese Academy of Sciences (CAS), Prof. LI Cheng from Peking University, and Prof. ZHANG Shihua from the Academy of Mathematics and Systems Science of CAS has reported the highest resolution by far of the 3D genome of the primate brain, and demonstrated the molecular regulatory mechanisms of human brain evolution through cross-species multi-omics analysis and experimental validation. The studywas published inCell.

The unique pattern of human brain development stems from accumulated genetic changes during human evolution. Among the huge number of diverging genetic changes, only a small portion of the between-species changes have been functionally important.The challenge isto identify the causal changes responsible for the unique pattern of human brain development and their regulatory mechanisms. Macaque monkeys, genetically similarto humans,arethe ideal modelfor studyingthe origin and developmental mechanisms of the human brain.

The genome of mammalian species including humans is abouttwo meters long and is compiled in the nucleus with a diameter of only 10 micrometers. This nonrandom compilation is characterized by organized three-dimensional (3D) distribution, which is important for cell proliferation and differentiation during development. Recently, the invention of whole-genome chromosomal structure capture technology (referred to as Hi-C) providesagreat opportunity for dissecting the fine-tuned organization of the genome during brain development.

In this study, the researchers conducted cross-species analyses of brain 3D genomes through cross-disciplinary collaboration.

They first constructed a high-resolution 3D chromatin structure map of the macaque fetal brain usingthe Hi-C technique. Reaching a 1.5kb resolution, this Hi-C map represents the highest resolution of primate brains so far achieved, and ithas become a useful omics dataset for revealing the 3D genome organization in detail. Meanwhile, the researchers generated a transcriptome map, a chromatin open region map and a map of the anchor protein CCCTC-binding factor (CTCF).

Based onthese multi-omics data, the researchersconstructed for the first timea fine map of the chromatin structure of the macaque fetal brain and identified the chromatin structure in different scales, including compartments, topologically associating domains (TADs) and chromatin loops. They also identified regulatory elements in the genome such as enhancers.

Using published human and mouse brain Hi-C data, they then performed a cross-species comparisons, and discovered many human-specific chromatin structural changes, including 499 human-specific TADs and 1266 human-specific loops. Notably, the human-specific loops were shown to beenriched with enhancer-enhancer interactions, representing the origin of a mechanism for fine-tuning brain development during human evolution.

Based on the analysis of single-cell transcriptome data on human brain development, the researchersobserved that these human-specific loop-related genes are highly expressed in the subplate lamina, a transient zone of the developing brain critical for neural circuit formation and plasticity. The subplate lamina hadbeen found to showan extradentary expansion compared to that of the macaque and mouse, and is about four times the thickness of the cortical plate. The subplate starts to decrease after birth and eventually disappears, andlittle is knownabout this transient zone. Thisfinding provides the first evidence for the key role of the subplate in forming human-specific brain structures during development.

In addition, the researchers discovered that many human-specific mutations (e.g.,point mutations and structural changes) are located in the TAD boundary and loop anchor regions, which may lead to the origin of novel binding sites of transcriptional factors and human-specific chromatin structures.

The researchers studied an example involving theEPHA7gene, which is highly expressed in the subplate and is critical for neuronal dendrite development. The human-specific point mutations of EPHA7 lead to the formation of human-specific enhancers and loops. Through an experiment involving enhancer knockout in cell lines, they proved that human-specific EPHA7 enhancers can cause regulatory changes in EPHA7 expression and affect dendrite development.

This study sheds new light on the genetic mechanisms of human brain origin and serves as a valuable resource for 3D brain genomes.

Reference: Luo X, Liu Y, Dang D, et al. 3D Genome of macaque fetal brain reveals evolutionary innovations during primate corticogenesis. Cell. doi:10.1016/j.cell.2021.01.001.

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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3D Genome of the Primate Brain in High Resolution - Technology Networks

Throughout the COVID-19 pandemic, scientists have tried to understand and track SARS-CoV-2 without a proper parts list.

Much of the research emphasis has been on proteins such as the spike proteins that cover the COVID-19 virus and attach themselves to human cells. Scientists continue to study how these proteins function and interact.

But Yale biochemist Anna Marie Pyle says there is also much to be gained by understanding the RNA of the virus and the structures within it. The shapes formed by the RNA in a viral genome influence its efficiency at copying itself, making proteins, and packing into the viral particle, which is a key factor in pathogenicity.

Pyle and her team have spent 10 months cataloguing and exploring the intricate biological makeup of the viral RNA genome after it infects a human cell. The result is a detailed map of the SARS-CoV-2 genome with an unprecedented level of detail that contains more than 100 identifiable structures within the genomic RNAs of the virus.

The genome RNA folds up like origami... certain aspects of the virus, such as how fast it copies itself, will be controlled by these shapes.

Anna Marie Pyle

It has a well-organized genomic architecture, said Pyle, a Sterling Professor of Molecular, Cellular and Developmental Biology and professor of chemistry at Yale. The genome RNA folds up like origami, into distinct shapes that impact how well the virus functions. This is important because certain aspects of the virus, such as how fast it copies itself, will be controlled by these shapes.

The researchers developed a technique to probe the role of individual RNA structures by designing modified, synthetic nucleic acids that interact with specific regions in the virus, and watching the nucleic acids effects on viral growth.

Pyles lab had been conducting genome mapping for other RNA molecules before shifting its focus to SARS-CoV-2. What the researchers found, they said, was surprising: an RNA genome in which more than half of its 30,000 nucleotides are packed into loops, knots, stems, and other stable structures. This is in stark contrast to the majority of viruses, that have large, unorganized areas.

In a series of new studies published in the journals Molecular Cell and Journal of Virology, and posted on the pre-print website bioRxiv, Pyle and her colleagues present their findings.

In addition to mapping the virus genome and identifying structures within it, part of the team led by Dr. Craig Wilen, assistant professor in laboratory medicine and immunobiology, shows how SARS-CoV-2 RNAs change within a human cell over time.

Pyle said the teams work will aid in identifying better ways to detect the virus using diagnostic kits and new therapeutic strategies for fighting SARS-CoV-2, as well as providing the scientific community with crucial information to fight new coronaviruses that may emerge in the years ahead.

This research gives us a look under the hood of coronaviruses for the first time.

When a new virus comes along and is wreaking havoc, its often something we havent seen before, Pyle said. Its helpful to have an established parts list for understanding how it is likely to behave and what it is likely to do. This research gives us a look under the hood of coronaviruses for the first time.

Pyle called special attention to a quartet of Yale graduate students whose work helped propel the research: Han Wan in molecular, cellular & development biology, Nicholas Huston in molecular biophysics & biochemistry, Rafael Tavares in chemistry, and Madison Strine in immunobiology and laboratory medicine.

This is the first time weve looked at the full, structural genome of the virus in living cells, Wan noted. Im proud to have contributed to something that will be so useful.

Huston, who lost a grandfather to COVID-19 during the pandemic, echoed the personal commitment and sentiment that infused the research. Weve been able to reveal how much information you can get, just by looking at the structures in this virus, he said. This virus killed someone I loved. Now Im helping to kill the virus.

Additional Yale co-authors of one or more of the new studies include Gandhar Mahadeshwar, Neal Ravindra, Mia Alfajaro, Victor Gasque, Victoria Habet, Jin Wei, Renata Filler, Klara Szigeti-Buck, Bao Wang, Guilin Wang, Ruth R. Montgomery, Stephanie Eisenbarth, Adam Williams, Akiko Iwasaki, Tamas Horvath, Ellen Foxman, Richard W. Pierce, and David van Dijk.

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Yale scientists map the shape of the SARS-CoV-2 genome - Yale News

The speakers will discuss what is currently known about genomic drivers of heart failure and opportunities for novel therapeutics being explored in their own research programs.

TORONTO (PRWEB) February 02, 2021

Heart failure is a significant global health issue. More than half of the people who develop heart failure die within five years. Current treatments do not help the largest group of these patients those with heart failure with preserved ejection fraction (HFpEF) and have limited effectiveness for those with reduced injection fraction (HFrEF).

HFpEF has been called the greatest unmet need in cardiovascular disease given the number of heart failure deaths per year and the proportion of patients with HFpEF. Despite significant research into the drivers of heart failure, many patients remain undiagnosed or poorly managed and new therapies are needed.

This webinar will cover recent advances in heart failure genomics with a focus on translating findings into improved therapeutics and diagnosis. Genuity Science and their colleagues are building large-scale real-world datasets combining whole-genome sequencing and detailed longitudinal clinical data from thousands of participants. For heart failure, these datasets help scientists discover and validate new drug targets for heart failure and are enriched with participants with HFpEF. Additionally, the speakers will discuss what is currently known about genomic drivers of heart failure and opportunities for novel therapeutics being explored in their own research programs.

Join guest speakers Benoit Tyl, MD, FESC, Medical and Scientific Director, Cardiology, Servier; Marc Semigran, MD, Senior Vice President, Medical Sciences, Myokardia; Irene Blat, PhD, Senior Director of Data Products and Analytics, Genuity Science; and webinar host Ellen Gordon, PhD, Vice President, Business Development, Genuity Science for the live webinar on Tuesday, February 23, 2021 at 10am EST (3pm GMT/UK).

For more information, or to register for this event, visit Genomic Advances in Heart Failure.

ABOUT XTALKS

Xtalks, powered by Honeycomb Worldwide Inc., is a leading provider of educational webinars to the global life science, food and medical device community. Every year, thousands of industry practitioners (from life science, food and medical device companies, private & academic research institutions, healthcare centers, etc.) turn to Xtalks for access to quality content. Xtalks helps Life Science professionals stay current with industry developments, trends and regulations. Xtalks webinars also provide perspectives on key issues from top industry thought leaders and service providers.

To learn more about Xtalks visit http://xtalks.comFor information about hosting a webinar visit http://xtalks.com/why-host-a-webinar/

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Genomic Advances in Heart Failure, Upcoming Webinar Hosted by Xtalks - PR Web

Genome sequencing can teach us a huge amount about a species, and now scientists have completed the sequence for one of the weirdest and most intriguing animals in the world. The Australian lungfish is a living fossil from the time our ancestors first crawled out of the oceans, and its genome reveals that its our closest living fish relative and it has the largest genome of any animal sequenced so far.

The Australian lungfish is one of six lungfish species in the world, and its a bizarre creature. As the name suggests, it has a lung in its back that lets it breathe air, and it can walk along the riverbed like a salamander thanks to its fleshy, well-formed pectoral and pelvic fins.

With those two features working together, the Australian lungfish likes to crawl out of its home in rivers and freshwater pools and venture onto dry land. Its not truly amphibious, but it has been known to live out of water for several days at a time provided its skin doesnt dry out too much.

Thats a throwback to one of the most important steps in evolutionary history, when the first animals crawled out of the oceans onto dry land during the Devonian period, some 420 million years ago. The Australian lungfish is one of the closest living relatives to those pioneering sea creatures, and because its remained largely unchanged by evolution for well over 100 million years, its genome potentially preserves insights into that key period.

So scientists in Europe set out to sequence that complete genome. This has already been done for many animals, plants and microbes of interest, including humans, mice, worms, mosquitoes, Tasmanian tigers, sharks, apples, tomatoes, wheat, barley, and the Black Death bacteria.

It turns out that the Australian lungfish has the largest genome of any animal ever sequenced, containing around 43 billion DNA nucleotides. Thats 14 times bigger than the human genome, and quite a leap above the previous record holder, the axolotl, on 32 billion.

The team found that the staggering size mostly came down to repetition. About 90 percent of the lungfish genome was made up of repeating sequences, which can have variable positions in the genome. In this respect, the team says the lungfish actually more closely resembles land vertebrates than other fish.

With the genome fully sequenced, the researchers were able to confirm that the lungfish is the closest living fish relative of all tetrapods, the absolutely gigantic group of land animals containing everything with the familiar body structure of four limbs coming off a central trunk. That means reptiles, birds, and mammals, including humans.

In fact, were more similar than you might think. The genes that control embryonic development of the lungfishs lungs are the same ones as in humans, which show that the evolution in both species can be traced to the same origin. The development of the bones in their fins is also controlled by the same genes as those of our hands.

The team also discovered some genomic pre-adaptions to life on the land. The lungfish genome had expanded in areas linked to air breathing, limb development, reproduction, and the ability to smell the air.

All up, sequencing the genome of the Australian lungfish will help improve our understanding of one of the most important transitions in evolutionary history.

The research was published in the journal Nature.

Source: University of Konstanz

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"Living fossil" genome sequence reveals clues to evolution of life on land - New Atlas

Precision surveillance combining genomic sequencing and conventional surveillance was able to delineate a large nosocomial influenza A virus (IAV) outbreak and map the source to a single patient. The findings from this investigation, published in Clinical Infectious Diseases, revealed the source of the outbreak was not health care workers (HCWs) as was initially believed.

Over 12 days in early 2019, 89 HCWs and 18 inpatients within a single hospital were identified as cases of influenza-like illness, triggering the investigation. During this investigation, 91 inpatients and 290 HCWs were screened via temperature checks, symptom surveys, and molecular testing for IAV, influenza B, and respiratory syncytial virus. Of these, 18 patients (19.8%) and 89 HCWs (29.7%) tested positive for IAV.

The HCWs testing positive were distributed across 29 different work assignments and 87 of the 89 (>90%) were vaccinated with the quadrivalent seasonal influenza virus vaccine 2 to 5 months before diagnosis (average: 108 days). Investigators highlight that most of these HCWs had minor symptoms not normally classified as influenza-like illness due to the absence of fever. This prompted the removal of fever as a requirement from the investigations case definitions.

Complete genomic sequences were obtained for 214 IAV isolates, 126 from the original hospital where investigation and surveillance were performed and 88 from a second hospital undergoing surveillance only. Comparison revealed a cluster of 66 isolates differing by 3 or fewer single-nucleotide variants (SNVs), suggesting a single viral clone was behind the outbreak.

The outbreak cluster was identified as influenza A H1N1pdm09 and was found in 43 HCWs and 17 inpatients. All HCWs included in this cluster had been vaccinated. Outbreak virus strains with representative variants, 5 in total, were cultured for functional characterization and did not show antigenic drift. A further analysis of genomes from cases identified by the conventional investigation during days 0 to 3 of the outbreak and the mining of electronic records provided a timeline of the earliest 9 cases. An interaction network based on available contact records found that almost all cases trace back to these 9 cases and identified the origin as a single patient and a few interactions in the emergency department.

Biospecimens from 22 HCWs whose tests were performed at labs outside of the health system in question were unavailable, limiting the investigation results. Also, only partial genomes were recovered from 2 specimens linked to the epidemiological outbreak investigation.

According to investigators, enhanced screening and isolation of emergency department patients with respiratory symptoms, even when not their primary complaint, are important steps to mitigating outbreaks. Also, better recognition by leadership that HCW transmission can occur with mild symptoms along with improved education of staff to avoid working while ill and extended sick leave were recommended by investigators. Finally, the investigators believe these findings are applicable to a range of respiratory pathogens, including SARS-CoV-2, and that implementation of precision surveillance will be critical for identification and mitigation of nosocomial outbreaks.

Disclosure: One study author declared an affiliation with Sema4.

Reference

Javaid W, Ehni J, Gonzalez-Reiche AS, et al. Real-time investigation of a large nosocomial influenza A outbreak informed by genomic epidemiology. Clin Infect Dis. Published online November 30, 2020. doi:10.1093/cid/ciaa1781

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Nosocomial Influenza Outbreak Investigation Informed by Genomic Analyses - Infectious Disease Advisor