Daily Archives: March 28, 2020

Thirty thousand base pairs make up the (relatively tiny) SARS-CoV-2 genome. A singular genome holds limited information. But, by comparing multiple genomes from different patients, animals, places, or time periods, the DNAs information can be unlocked. From where the virus originated to how it spilled over from animals into humans, how quickly it mutates, and how those changes affect infectionsgenome comparisons may provide the answers.

The SARS-CoV-2 genome, initially reported on January 12, has been studied extensively in the last month, with the hope of uncovering useful information about COVID-19. Indeed, the U.K. has established a massive collaboration to sequence as many COVID-19 cases as possible. Some researchers, such as Trevor Bedford, PhD, associate member at the Fred Hutchinson Cancer Research Center in the Vaccine and Infectious Disease Division and an affiliate associate professor in the department of genome sciences and the department of epidemiology at the University of Washington, analyze viral genomes from the pandemic in real time, as the data materialize. These data and analyses are available on the open-source platform Nextstrain, co-developed by Bedford.

In the last month, Bedford has been able to form early hypotheses regarding the virus. One, according to his tweets on March 24, offered information regarding how SARS-CoV-2 mutates and what that might mean for COVID-19 vaccination and immunity. In the thread, Bedford predicts that it will take the virus a few years to mutate enough to significantly hinder a vaccine. He goes on to suggest that we should see occasional mutations to the spike protein of SARS-CoV-2 that allow the virus to partially escape from vaccines or existing herd immunity, but that this process will most likely take years rather than months.

A looming question of the COVID-19 pandemic remains unsolved. That is, how did the virus spillover into humans?

A paper published recently in Nature (originally published in the preprint server bioRxiv on February 18) sought to answer this question. The focus of the paper, Identifying SARS-CoV-2 related coronaviruses in Malayan pangolins, was to analyze the genomes of coronaviruses found in pangolins, and draw conclusions from the data.

Their results: more work needs to be done.

The COVID-19 outbreak has been tentatively associated with a seafood market in Wuhan, China, where, the authors write, the sale of wild animals may be the source of zoonotic infection. Based on genomic data, bats have been suggested as the likely reservoir hosts for SARS-CoV-2. But, it remains unknown if the virus went from bats to humans, or if an intermediate host facilitated the spillover.

The researchers found that, indeed, Malayan pangolinsintercepted from a smuggling operation in southern Chinadid have SARS-CoV-2-related coronaviruses. The authors noted that, Metagenomic sequencing identified pangolin-associated coronaviruses that belong to two sub-lineages of SARS-CoV-2-related coronaviruses, including one that exhibits strong similarity to SARS-CoV-2 in the receptor-binding domain.

The authors concluded that this multiple lineage finding of pangolin coronavirus and their similarity to SARS-CoV-2 suggests that pangolins should be considered as possible hosts in the emergence of novel coronaviruses and should be removed from wet markets to prevent zoonotic transmission.

The role that pangolins play in the emergence of SARS-CoV-2 is still unclear, noted Edward Holmes, PhD, professor at the University of Sydney, Australia and an adjunct professor, Fudan University, Shanghai, China. However, he added, It is striking is that the pangolin viruses contain some genomic regions that are very closely related to the human virus. The most important of these is the receptor-binding domain that dictates how the virus is able to attach and infect human cells.

It is clear that wildlife contains many coronaviruses that could potentially emerge in humans in the future, noted Holmes. A crucial lesson from this pandemic, he continued, to help prevent the next one is that humans must reduce their exposure to wildlife, for example by banning wet markets and the trade in wildlife.

Last week, Nature Medicine published a Correspondence, The proximal origin of SARS-CoV-2, which Holmes co-authored, working with scientists from the department of immunology and microbiology at The Scripps Research Institute, the University of Edinburgh, Columbia University, and Tulane University.

The research, using comparative analysis of genomic data, both proved that SARS-CoV-2 evolved naturally, and disproved the idea that it is a manufactured biological agent.

There is simply no evidence that SARS-CoV-2 came out of a lab, Holmes said.

In doing this work, the group looked closely at the receptor-binding domain (RBD) of the viral spike protein that SARS-CoV-2 uses to bind to cell surface receptors and gain entry into human host cells to help shape their spillover hypotheses. The authors noted that, although the RaTG13 bat virus remains the closest to SARS-CoV-2 across the genome, some pangolin coronaviruses exhibit strong similarity to SARS-CoV-2 in the RBD of the spike protein, including all six key RBD residues. This finding, they concluded, shows that the SARS-CoV-2 spike protein optimized for binding to human-like ACE2 is the result of natural selection.

The genomes of SARS-CoV-2 holds many answers to the questions scientists are searching for at a feverish pace. It is clear that understanding the evolutionary pathway by which this novel coronavirus has transferred to humans will help us not only combat the current pandemic but assist in identifying future threats from other coronaviruses and other species.

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Mining the SARS-CoV-2 Genome for Answers - Genetic Engineering & Biotechnology News

Genomics has come a long way since the central dogma (the notion that DNA is the master controller that calls all the shots) and junk DNA (the expectation that much of the genome is non-functional). If scientists ditch those old dogmas and approach the genome expecting to find reasons for things, they often do.

To-may-to or to-mah-to? The British write flavour; the Americans write flavor, but generally each understands the other without too much difficulty. Genomes, too, have alternate ways of spelling things: GGU and GGC in messenger RNA both spell glycine. No big deal, thought geneticists; these silent mutations cause no change in the resulting protein. At the University of Notre Dame, however, biochemists are finding that the differences in spelling are not just background noise; they alter the proteins folding. Is that good or bad?

Synonymous mutations were long considered to be genomic background noise, but we found they do indeed lead to altered protein folding, and in turn impair cell function, said Patricia Clark, the Rev. John Cardinal OHara professor of biochemistry at the University of Notre Dame, and lead author of the study. Our results show that synonymous variations in our DNA sequences which account for most of our genetic variation can have a significant impact on shaping the fitness level of cellular proteins.

Surely many of these mutations are harmful, as are random mutations in humans that cause genetic disease. But E. coli has been around for a long time. Wouldnt the species have gone extinct by now with the accumulation of defective spellings if they are always deleterious? Other work has suggested a secret code in synonymous variations that fine-tunes expression rates or regulates the supply of a given protein based on environmental conditions. The news release only mentions impairments caused by synonymous variations, but Notre Dame teams paper in PNAS suggests some possible advantages:

Synonymous codon substitutions alter the mRNA coding sequence but preserve the encoded amino acid sequence. For this reason, these substitutions were historically considered to be phenotypically silent and often disregarded in studies of human genetic variation. In recent years, however, it has become clear that synonymous substitutions can significantly alter protein function in vivo through a wide variety of mechanisms that can change protein level, translational accuracy, secretion efficiency, the final folded structure and posttranslational modifications. The full range of synonymous codon effects on protein production is, however, still emerging, and much remains to be learned regarding the precise mechanisms that regulate these effects. [Emphasis added.]

A design perspective would consider every possible function before rendering a judgment that all synonymous variations reduce fitness.

Keeping the genome accurate to a high degree preserves it from collapsing due to error catastrophe. At the time of cell division, proofreading enzymes (what a concept!) perform this vital function. Chelsea R. Bulock et al., writing in PNAS, have found one duplication enzyme that proofreads itself while proofreading its partner! DNA polymerase proofreads errors made by DNA polymerase , the paper is titled.

Pol and Pol are the two major replicative polymerases in eukaryotes, but their precise roles at the replication fork remain a subject of debate. A bulk of data supports a model where Pol and Pol synthesize leading and lagging DNA strands, respectively. However, this model has been difficult to reconcile with the fact that mutations in Pol have much stronger consequences for genome stability than equivalent mutations in Pol. We provide direct evidence for a long-entertained idea that Pol can proofread errors made by Pol in addition to its own errors, thus, making a more prominent contribution to mutation avoidance. This paper provides an essential advance in the understanding of the mechanism of eukaryotic DNA replication.

In other words, Pol is a proofreader of a proofreader. The paper says that Pol is a versatile extrinsic proofreading enzyme. One could think of it as a supervisor checking the work of a subordinate, or better yet, as an auditor or inspector able to fix errors before they cause harm to the product. Why would this be necessary during replication? The authors see a seniority system:

Thus, the high efficiency of Pol at correcting errors made by Pol may result from a combination of two factors: the high proclivity of Pol to yield to another polymerase and the greater flexibility and robustness of Pol when associating with new primer termini.

One proofreader is amazing to consider evolving by a Darwinian mechanism. A proofreader of a proofreader is astonishing. Consider, too, that this proofreading operation occurs in the dark by feel, automatically, without eyes to see.

Now that genetics is long past the heady days of finding that DNA forms a code that is translated, additional discoveries continue to show additional codes and factors that contribute to genomic function. One factor is the high-order structure of DNA. Researchers at South Koreas UNIST center have explored further into the formation of this structure, which involves chromatin wrapping around histone proteins so that long strands of DNA can fit within the compact space of the cell nucleus. As with everything else in genomics, the structure doesnt just happen. It requires a lot of help.

Regulation of histone proteins allows the DNA strands become more tightly or loosely coiled during the processes of DNA replication and gene expression. However, problems may arise when histones clump together or when DNA strands intertwine. Indeed, the misregulation of chromatin structures could result in aberrant gene expression and can ultimately lead to developmental disorders or cancers.

Histone chaperones are those proteins, responsible for adding and removing specific histones [found] at the wrong time and place during the DNA packaging process. Thus, they also play a key role in the assembly and disassembly of chromatin.

Cryo-EM imaging allowed the team to envision the molecular structure of some of these chaperone proteins. Their paper in Nature Communications begins, The fundamental unit of chromatin, the nucleosome, is an intricate structure that requires histone chaperones for assembly. Their cryo-EM images of one particular chaperone named Abo1 reveals a six-fold symmetry with precise locations for docking to histones, its hexameric ring thus creating a unique pocket where histones could bind with energy from ATP. Not only is Abo1 distinct as a histone chaperone, they write, but Abo1 is also unique compared to other canonical AAA+protein structures. Like Lego blocks, Abo1 features tight knob-and-hole packing of individual subunits plus linkers and other binding sites, such as for ATP. And unlike static blocks, these blocks undergo conformational changes as they work.

Such sophistication is far beyond the old picture of DNA as a master molecule directing all the work. It couldnt work without the help of many precision machines like this.

These stories are mere samples from a vast and growing literature indicating higher order in the genome than expected. Here are some more samples readers may wish to investigate:

Researchers at the University of Seville found additional factors involved in the repair of DNA strand breaks. These repairs are essential for the maintenance of genome integrity. The factors they discovered help maintain the right tension in cohesin molecules that hold the chromosomes together until the right time to separate. The news was relayed by EurekAlert!and published in Nature Communications.

Remember Paleys Watch? Researchers at the University of Basel discovered that Inner clockwork sets the time for cell division in bacteria. In PNAS and in Nature Communications, the Basel team elucidates the structure and function of a small signaling molecule that starts the clock, which then informs the cell about the right time to reproduce. They report in the news release:

A team at the Biozentrum of the University of Basel, led by Prof. Urs Jenal has now identified a central switch for reproduction in the model bacteriumCaulobacter crescentus: the signaling molecule c-di-GMP. In their current study,published in the journalNature Communications,they report that this molecule initiates a clock-like mechanism, which determines whether individual bacteria reproduce.

Proteins must fold properly to perform their functions. Small proteins usually fold successfully on their own, but large ones can fall into several misfolding traps that are equally likely as the canonical fold. It appears that the sequence of the sequence in a gene has something to do with this. Interestingly, many of these proteins sequences contain conserved rare codons that may slow down synthesis at this optimal window, explain Amir Bitran et al. in a January 21 paper in PNAS, discovering that Cotranslational folding (i.e., folding that begins as the polypeptide exits the ribosome) allows misfolding-prone proteins to circumvent deep kinetic traps.

Design advocates and evolutionists need to fathom what they are dealing with when discussing origins. Theres nothing like some low-level detail to put the challenge in perspective.

Image credit: Caulobacter crescentus, by University of Basel, Swiss Nanoscience Institute/Biozentrum, via EurekAlert!

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More Hints of Order in the Genome - Discovery Institute

An epidemiologist answers the biggest questions she's getting about coronavirus. Wochit

SAN FRANCISCO At least eight strains of the coronavirus are making their way around the globe, creating a trail of death and disease that scientistsare tracking by their genetic footprints.

While much is unknown, hidden in the virus's unique microscopic fragments are clues to the origins of its original strain, how it behaves as it mutates and which strains are turning into conflagrations while others are dying out thanksto quarantine measures.

Huddled in once bustling and now almost empty labs, researchers who oversaw dozens of projects are instead focused on one goal:tracking the currentstrains of the SARS-CoV-2 virus that cause the illness COVID-19.

Labs around the world are turning their sequencing machines, most about the size of a desktop printer, to the task ofrapidly sequencing the genomes of virus samples taken frompeople sick with COVID-19.The information is uploaded to a website called NextStrain.org that shows how the virus is migrating and splitting into similarbut new subtypes.

Investigation:How federal health officials mislead states and derailed the best chance at containment.

While researcherscaution they'reonly seeing the tip of the iceberg, the tiny differences between the virus strains suggest shelter-in-place orders are working in some areas and thatno one strain of the virus ismore deadly than another. They also say it does not appear the strains will grow more lethal as theyevolve.

The virus mutates so slowly that the virus strains are fundamentally very similar to each other, said Charles Chiu, a professor of medicine and infectious disease at the University of California, San Francisco School of Medicine.

A map of the main known genetic variants of the SARS-CoV-2 virus that causes COVID-19 disease. The map is being kept on the nextstrain.org website, which tracks pathogen evolution.(Photo: nextstrain.org)

The SARS-CoV-2 virusfirst began causing illness in China sometimebetween mid-November and mid-December. Its genome is made up of about 30,000 base pairs. Humans, by comparison, have more than 3 billion. So fareven in the virus's most divergent strainsscientists have found only 11 base pair changes.

That makes iteasy to spot new lineages as they evolve, said Chiu.

The outbreaks are trackable. We have the ability to do genomic sequencing almost in real-time to see what strains or lineages are circulating, he said.

So far, mostcases on the U.S. West Coast are linked to a strainfirst identified in Washington state. It may have come from a man who had been in Wuhan, China, the virus epicenter, and returned home on Jan. 15. It is only three mutations away from the original Wuhan strain, according to work done early in the outbreakby Trevor Bedford, a computational biologist at Fred Hutch, a medical research center in Seattle.

On the East Coast there are several strains, including the one from Washington and others that appear to have made their way from China to Europe and then to New York and beyond, Chiu said.

Death rate soars in New Orleans coronavirus 'disaster' that could define city for generations

Charles Chiu, MD, PhD, director of the UCSF-Abbott Viral Diagnostics and Discovery Center, inserts a tray of Universal Transport Medium (UTM) or vials for the collection, transport, maintenance and long term freeze storage of viruses into a Biomatrix sorter that the Chiu Lab will be using, starting Monday to study the genes of the Coronavirus.(Photo: Susan Merrell/UCSF)

This isnt the first time scientists have scrambled to do genetic analysis of a virus in the midst of an epidemic. They did it with Ebola, Zika and West Nile, but nobodyoutside the scientific community paid much attention.

This is the first time phylogenetic trees have been all over Twitter, said Kristian Andersen, a professor at Scripps Research, a nonprofit biomedical science research facility in La Jolla, California, speaking of the diagrams that show the evolutionary relationships between different strains of an organism.

The maps are available on NextStrain, an online resource for scientists that uses data from academic, independent and government laboratories all over the world to visually track the genomics of the SARS-CoV-2 virus. It currently represents genetic sequences of strains from 36 countries on six continents.

While the maps are fun, they can also be little dangerous said Andersen. The trees showing the evolution of the virus are complex and its difficult even for experts to draw conclusions from them.

Remember, were seeing a very small glimpse into the much larger pandemic. We have half a million described cases right now but maybe 1,000 genomes sequenced. So there are a lot of lineages were missing, hesaid.

The basics on the coronavirus: What you need to know as the US becomes the new epicenter of COVID-19

COVID-19 hitspeople differently, with some feeling only slightly under the weather for a day, others flat on their backs sick for two weeks and about 15% hospitalized. Currently, an estimated1% of those infected die. The rate varies greatly by country and experts say it is likely tied to testing rates rather than actual mortality.

Chiu says it appears unlikely the differences are related to people being infected withdifferent strains of the virus.

The current virus strains are still fundamentally very similar to each other, he said.

The COVID-19 virus does not mutate very fast. It does so eightto 10 times more slowly than the influenza virus, said Anderson, making its evolution rate similar to other coronaviruses such as Ebola, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS).

Its also not expected tospontaneously evolve into a form more deadly than it already is to humans. The SARS-CoV-2 is so good at transmitting itself between human hosts,said Andersen,it is under no evolutionary pressure to evolve.

Chius analysis shows Californias strict shelter in place efforts appear to beworking.

Over half of the 50 SARS-CoV-2 virus genomes his San Francisco-based lab sequenced in the past two weeks are associated with travel from outside the state. Another 30% are associated with health care workers and families of people who have the virus.

Only 20% are coming from within the community. Its not circulating widely, he said.

Thats fantastic news, he said, indicating the virus has not been able to gain aserious foothold because of social distancing.

It's like a wildfire, Chiu said. A few sparks might fly off the fire and land in the grass and start new fires. But if the main fire is doused and itsembers stomped out, you can kill offan entire strain.In California, Chiu sees a lot of sparks hitting the ground, most coming from Washington,but they're quickly being put out.

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An example wasa small cluster of cases in Solano County, northeast of San Francisco. Chius team did a genetic analysis of the virus that infected patients there and found it was most closely related to a strain from China.

At the same time, his lab was sequencing a small cluster of cases in the city of Santa Clara in Silicon Valley. They discovered the patients there had the same strain as those in Solano County. Chiu believes someone in that cluster had contact with a traveler who recently returned from Asia.

This is probably an example of a spark that began in Santa Clara, may have gone to Solano County but then was halted, he said.

The virus, he said, can be stopped.

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China is an unknown

So far researchers dont have a lot of information about the genomics of the virus inside China beyond the fact that it first appeared in the city of Wuhan sometime between mid-November and mid-December.

The viruss initial sequence was published on Jan. 10 by professor Yong-Zhen Zhang at the Shanghai Public Health Clinical Center. But Chiu says scientists dont know if there was justone strain circulating in China or more.

It may be that they havent sequenced many cases or it may be for political reasons they havent been made available, said Chiu. Its difficult to interpret the data because were missing all these early strains.

Researchers in the United Kingdom who sequenced the genomes of viruses found in travelers from Guangdong in south China found those patients strains spanned the gamut of strains circulating worldwide.

That could mean several of the strains were seeing outside of China first evolved there from the original strain, or that there are multiple lines of infection. Its very hard to know, said Chiu.

There's a new symptom of coronavirus, docs say: Sudden loss of smell or taste

While there remain many questions about the trajectory of the COVID-19 disease outbreak, one thing is broadly accepted in the scientific community: Thevirus was not created in a lab but naturally evolved in an animal host.

SARS-CoV-2s genomic molecular structure thinkthe backbone of the virus is closest to a coronavirus found in bats. Parts of its structure also resemble a virus found in scaly anteaters, according to a paper published earlier this month in the journal Nature Medicine.

Someone manufacturing a virus targetingpeople would have started with one that attacked humans, wrote National Institutes of Health Director Francis Collinsin an editorial that accompanied the paper.

Andersen was lead author on the paper. He said it could have been a one-time occurrence.

Its possible it was a single event, from a single animal to a single human, and spread from there.

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8 strains of the coronavirus are circling the globe. Here's what clues they're giving scientists. - USA TODAY

Credit: B.C. Centre for Disease Control

B.C. researchers with ready-to-launch projects applicable to combatting the COVID-19 pandemic are being urged to tap into a new funding avenue that could deliver as much as $250,000.

Genome BC, a non-profit known for facilitating genomics research across the province, launched a rapid-response funding program Thursday (March 26) that could get funds approved for projects within days.

Researchers, scientists and innovators based on the West Coast will be prioritized for funding, but Genome BC is not closing the door on any out-of-province projects that are endorsed by another regional genome centre.

The initiative is optimized for speed while maintaining high review standards and balanced decision-making, Pascal Spothelfer, president and CEO of Genome BC, said in a statement.

By investing in ideas to deliver short-term impacts, we increase our chances to overcome challenges of this pandemic more quickly.

Genome BC has been funding COVID-19 research since at least February, supporting thelaunch of a $150,000, six-month pilot studywith the B.C. Centre for Disease Control.

That project integrates genomic analysis into the BCCDCs own coronavirus tracking methods.

The goal is to turn around genome sequences from patients within 24-48 hours, which would allow B.C. experts to quickly determine if the strain has a close relative thats already appeared in the province or if its a new introduction already documented in another country or province.

So it really helps us understand transmission and that can be really important information when investigating a cluster of cases or trying to understand how an organism is spreading throughout the community, Natalie Prystajecky, a BCCDC microbiologist overseeing COVID-19 test development, toldBusiness in Vancouverlast month.

torton@biv.com

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Ready-to-launch COVID-19 projects can tap $250k from Genome BC - Business in Vancouver

The cerebral cortex is the relatively thin, folded, outer gray matter layer of the brain crucial for thinking, information processing, memory, and attention. Not much has been revealed about the genetic underpinnings that influence the size of the cortexs surface area and its thickness, both of which have previously been linked to various psychiatric traits, including schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder (ADHD), and autism.Now, for the first time, more 360 scientists from 184 different institutions including UNC-Chapel Hill have contributed to a global effort to find more than 200 regions of the genome and more than 300 specific genetic variations that affect the structure of the cerebral cortex and likely play important roles in psychiatric and neurological conditions.

The study was led by co-senior authors Jason Stein, PhD, assistant professor in the Department of Genetics at the UNC School of Medicine; Sarah Medland, PhD, senior research fellow at the QIMR Berghofer Medical Research Institute in Australia; and Paul Thompson, PhD, associate director of the Mark and Mary Stevens Neuroimaging and Informatics Institute at the University of Southern California. Ten years ago, these scientists cofounded the ENIGMA Consortium, an international research network that has brought together hundreds of imaging genomics researchers to understand brain structure, function, and disease based on brain imaging and genetic data.

This study was only possible due to a huge scientific collaboration of more than 60 sites involved in MRI scanning and genotyping participants, Stein said. This study is the crown jewel of the ENIGMA Consortium, so far.

The researchers studied MRI scans and DNA from more than 50,000 people to identify 306 genetic variants that influence brain structure in order to shed light on how genetics contribute to differences in the cerebral cortex of individuals. Genetic variants or variations are simply the slight genetic differences that make us unique. Generally speaking, some variants contribute to differences such as hair color or blood type. Some are involved in diseases. Most of the millions of genetic variants, though, have no known significance. This is why pinpointing genetic variants associated with cortex size and structure is a big deal. Stein and colleagues consider their new genetic roadmap of the brain a sort of Rosetta stone that will help translate how some genes impact physical brain structure and neurological consequences for individuals.

Among the findings of the research:

Most of our previous understanding of genes affecting the brain are from model systems, like mice, Stein said. With mice, we can find genes, knock out genes, or over express genes to see how they influence the structure or function of the brain. But there are a couple of problems with this.One problem is, quite simply, a mouse is not a human. There are many human-specific features that scientists can only study in the human brain.

The genetic basis for a mouse is very different than the genetic basis for humans, Stein said, especially in in the noncoding regions of the genome.

Genes contain DNA, the basic human code that, when translated into action, creates proteins that do things, such as help your finger muscles type or your heart beat or your liver process toxins. But only about 3 percent of the human genome codes for proteins. The vast majority of the human genome is called the noncoding genome. Much of this region is not shared between mice and humans. This noncoding genome consists of tiny molecular switches that can modulate the expression of other genes. These switches dont directly alter the function of a protein, but they can affect the amounts of a protein that is expressed. Turns out, most genetic variants associated with psychiatric disorders are found in the noncoding region of the genome.

These findings can now be a resource for scientists to help answer important questions about the genetic influences on the brain and how they relate to numerous conditions.ReferenceGrasby et al. (2020) The genetic architecture of the human cerebral cortex. Science. DOI: https://doi.org/10.1126/science.aay6690

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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The First Genetic Map of the Cerebral Cortex - Technology Networks