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More Genetic Clues to COVID-19 Susceptibility and Severity

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DNA with coronavirus. A doctor tends to a woman patient in a hospital bed.

Many factors influence our risk of illness from SARS-CoV-2, the coronavirus responsible for COVID-19. That includes being careful to limit our possible exposures to the virus, as well as whether we have acquired immunity from a vaccine or an earlier infection. But once a person is infected, a host of other biological factors, including age and pre-existing medical conditions, will influence one’s risk of becoming severely ill.

While earlier studies have tied COVID-19 severity to genetic variations in a person’s antiviral defenses and blood type, we still have a lot to learn about how a person’s genetic makeup influences COVID-19 susceptibility and severity. So, I was pleased to see the recent findings of an impressive global effort to map the genetic underpinnings of SARS-CoV-2 infection and COVID-19 severity, which involved analyzing the genomes of many thousands of people with COVID-19 around the globe.

This comprehensive search led to the identification of 13 regions of the human genome that appear to play a role in COVID-19 infection or severity. Though more research is needed to sort out these leads, they represent potentially high-quality clues to the pathways that this virus uses to cause illness, and help to explain why some people are more likely to become infected with SARS-CoV-2 or to develop severe disease.

The international effort, known as The COVID-19 Host Genetics Initiative, is led by Andrea Ganna, Institute for Molecular Medicine Finland, Helsinki, and colleagues in the United States and around the world. Teasing out those important genetic influences is no easy task. It requires vast amounts of data, so Ganna reached out to the scientific community via Twitter to announce a new COVID-19 gene-hunting effort and ask for help. Thousands of researchers around the world answered his call. The new study, published in the journal Nature, includes data collected through the initiative as of January 2021, and represents nearly 50,000 COVID-19 patients and another 2 million uninfected controls [1].

In search of common gene variants that may influence who becomes infected with SARS-CoV-2 and how sick they will become, Ganna’s international team turned to genome-wide association studies (GWAS). As part of this, the team analyzed patient genome data for millions of so-called single-nucleotide polymorphisms, or SNPs. While these single “letter” nucleotide substitutions found all across the genome are generally of no health significance, they can point the way to the locations of gene variants that turn up more often in association with particular traits or conditions—in this case, COVID-19 susceptibility or severity. To find them, the researchers compared SNPs in people with COVID-19 to those in about 2 million healthy blood donors from the same population groups. They also looked for variants that turned up significantly more often in people who became severely ill.

Their analyses uncovered a number of gene variants associated with SARS-CoV-2 infection or severe COVID-19 in 13 regions of the human genome, six of which were new. Four of the 13 affect a person’s risk for becoming infected with SARS-CoV-2. The other nine influence a person’s risk for developing severe illness following the infection.

Interestingly, some of these gene variants already were known to have associations with other types of lung or autoimmune diseases. The new findings also help to confirm previous studies suggesting that the gene that determines a person’s blood type may influence a person’s susceptibility to SARS-CoV-2 infection, along with other genes that play a role in immunity. For example, the findings show overlap with variants within a gene called TYK2, which was earlier shown to protect against autoimmune-related diseases. Some of the variants also point to the need for further work to study previously unexplored biological processes that may play potentially important roles in COVID-19.

Two of the new variants associated with disease severity were discovered only by including individuals with East Asian ancestry, highlighting the value of diversity in such analyses to gain a more comprehensive understanding of the biology. One of these newfound variants is close to a gene known as FOXP4, which is especially intriguing because this gene is known to play a role in the airways of the lung.

The researchers continue to look for more underlying clues into the biology of COVID-19. In fact, their latest unpublished analysis has increased the number of COVID-19 patients from about 50,000 to 125,000, making it possible to add another 10 gene variants to the list.

Reference:

[1] Mapping the human genetic architecture of COVID-19. COVID-19 Host Genetics Initiative. Nature. 2021 Jul 8.

Links:

COVID-19 Research (NIH)

The COVID-19 Host Genetics Initiative


Understanding Neuronal Diversity in the Spinal Cord

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Cross-section image of spinal cord showing glowing green and magenta neurons.
Credit: Salk Institute, La Jolla, CA

The spinal cord, as a key part of our body’s central nervous system, contains millions of neurons that actively convey sensory and motor (movement) information to and from the brain. Scientists have long sorted these spinal neurons into what they call “cardinal” classes, a classification system based primarily on the developmental origin of each nerve cell. Now, by taking advantage of the power of single-cell genetic analysis, they’re finding that spinal neurons are more diverse than once thought.

This image helps to visualize the story. Each dot represents the nucleus of a spinal neuron in a mouse; humans have a very similar arrangement. Most of these neurons are involved in the regulation of motor control, but they also differ in important ways. Some are involved in local connections (green), such as those that signal outward to a limb and prompt us to pull away reflexively when we touch painful stimuli, such as a hot frying pan. Others are involved in long-range connections (magenta), relaying commands across spinal segments and even upward to the brain. These enable us, for example, to swing our arms while running to help maintain balance.

It turns out that these two types of spinal neurons also have distinctive genetic signatures. That’s why researchers could label them here in different colors and tell them apart. Being able to distinguish more precisely among spinal neurons will prove useful in identifying precisely which ones are affected by a spinal cord injury or neurodegenerative disease, key information in learning to engineer new tissue to heal the damage.

This image comes from a study, published recently in the journal Science, conducted by an NIH-supported team led by Samuel Pfaff, Salk Institute for Biological Studies, La Jolla, CA. Pfaff and his colleagues, including Peter Osseward and Marito Hayashi, realized that the various classes and subtypes of neurons in our spines arose over the course of evolutionary time. They reasoned that the most-primitive original neurons would have gradually evolved subtypes with more specialized and diverse capabilities. They thought they could infer this evolutionary history by looking for conserved and then distinct, specialized gene-expression signatures in the different neural subtypes.

The researchers turned to single-cell RNA sequencing technologies to look for important similarities and differences in the genes expressed in nearly 7,000 mouse spinal neurons. They then used this vast collection of genomic data to group the neurons into closely related clusters, in much the same way that scientists might group related organisms into an evolutionary family tree based on careful study of their DNA.

The first major gene expression pattern they saw divided the spinal neurons into two types: sensory-related and motor-related. This suggested to them that one of the first steps in spinal cord evolution may have been a division of labor of spinal neurons into those two fundamentally important roles.

Further analyses divided the sensory-related neurons into excitatory neurons, which make neurons more likely to fire; and inhibitory neurons, which dampen neural firing. Then, the researchers zoomed in on motor-related neurons and found something unexpected. They discovered the cells fell into two distinct molecular groups based on whether they had long-range or short-range connections in the body. Researches were even more surprised when further study showed that those distinct connectivity signatures were shared across cardinal classes.

All of this means that, while previously scientists had to use many different genetic tags to narrow in on a particular type of neuron, they can now do it with just two: a previously known tag for cardinal class and the newly discovered genetic tag for long-range vs. short-range connections.

Not only is this newfound ability a great boon to basic neuroscientists, it also could prove useful for translational and clinical researchers trying to determine which specific neurons are affected by a spinal injury or disease. Eventually, it may even point the way to strategies for regrowing just the right set of neurons to repair serious neurologic problems. It’s a vivid reminder that fundamental discoveries, such as this one, often can lead to unexpected and important breakthroughs with potential to make a real difference in people’s lives.

Reference:

[1] Conserved genetic signatures parcellate cardinal spinal neuron classes into local and projection subsets. Osseward PJ 2nd, Amin ND, Moore JD, Temple BA, Barriga BK, Bachmann LC, Beltran F Jr, Gullo M, Clark RC, Driscoll SP, Pfaff SL, Hayashi M. Science. 2021 Apr 23;372(6540):385-393.

Links:

What Are the Parts of the Nervous System? (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)

Spinal Cord Injury (National Institute of Neurological Disorders and Stroke/NIH)

Samuel Pfaff (Salk Institute, La Jolla, CA)

NIH Support: National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Eunice Kennedy Shriver National Institute of Child Health and Human Development


Tracking the Evolution of a ‘Variant of Concern’ in Brazil

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P.1 Variant of SARS-CoV-2 in the center of standard SARS-CoV-2. Arrows move out from the variant

By last October, about three out of every four residents of Manaus, Brazil already had been infected with SARS-CoV-2, the virus that causes COVID-19 [1]. And yet, despite hopes of achieving “herd immunity” in this city of 2.2 million in the Amazon region, the virus came roaring back in late 2020 and early 2021 to cause a second wave of illness and death [2]. How is this possible?

The answer offers a lesson in viral evolution, especially when an infectious virus such as SARS-CoV-2 replicates and spreads through a population largely unchecked. In a recent study in the journal Science, researchers tied the city’s resurgence of SARS-CoV-2 to the emergence and rapid spread of a new SARS-CoV-2 “variant of concern” known as P.1 [3]. This variant carries a unique constellation of mutations that allow it not only to sneak past the human immune system and re-infect people, but also to be about twice as transmissible as earlier variants.

To understand how this is possible, consider that each time the coronavirus SARS-CoV-2 makes copies of itself in an infected person, there’s a chance a mistake will be made. Each mistake can produce a new variant that may go on to make more copies of itself. In most cases, those random errors are of little to no consequence. This is evolution in action.

But sometimes a spelling change can occur that benefits the virus. In the special case of patients with suppressed immune systems, the virus can have ample opportunity to accrue an unusually high number of mutations. Variants carrying beneficial mutations can make more copies of themselves than other variants, allowing them to build their numbers and spread to cause more infection.

At this advanced stage of the COVID-19 pandemic, such rapidly spreading new variants remain cause for serious concern. That includes variants such as B.1.351, which originated in South Africa; B.1.1.7 which emerged in the United Kingdom; and now P.1 from Manaus, Brazil.

In the new study, Nuno Faria and Samir Bhatt, Imperial College London, U.K., and Ester Cerdeira Sabino, Universidade de Sao Paulo, Brazil, and their colleagues sequenced SARS-CoV-2 genomes from 184 patient samples collected in Manaus in November and December 2020. The research was conducted under the auspices of the Brazil-UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE), a project focused on viral genomics and epidemiology for public health.

Those genomic data revealed the P.1 variant had acquired 17 new mutations. Ten were in the spike protein, which is the segment of the virus that binds onto human cells and the target of current COVID-19 vaccines. In fact, the new work reveals that three of these spike protein mutations make it easier for the P.1 spike to bind the human ACE2 receptor, which is SARS-CoV-2’s preferred entry point.

The first P.1 variant case was detected by genomic surveillance on December 6, 2020, after which it spread rapidly. Through further evolutionary analysis, the team estimates that P.1 must have emerged, undetected for a brief time, in mid-November 2020.

To understand better how the P.1 variant led to such an explosion of new COVID-19 cases, the researchers developed a mathematical model that integrated the genomic data with mortality data. The model suggests that P.1 may be 1.7 to 2.4 times more transmissible than earlier variants. They also estimate that a person previously infected with a variant other than P.1 will have only 54 percent to 79 percent protection against a subsequent infection with P.1.

The researchers also observed an increase in mortality following the emergence of the P.1 variant. However, it’s not yet clear if that’s an indication P.1 is inherently more deadly than earlier variants. It’s possible the increased mortality is related primarily to the extra stress on the healthcare system in Manaus from treating so many people with COVID-19.

These findings are yet another reminder of the importance of genomic surveillance and international data sharing for detecting and characterizing emerging SARS-CoV-2 variants quickly. It’s worth noting that at about the same time this variant was detected in Brazil, it also was reported in four individuals who had traveled to Brazil from Japan. The P.1 variant continues to spread rapidly across Brazil. It has also been detected in more than 37 countries [4], including the United States, where it now accounts for more than 1 percent of new cases [5].

No doubt you are wondering what this means for vaccines, such as the Pfizer and Moderna mRNA vaccines, that have been used to immunize (at least one dose) over 140 million people in the United States. Here the news is encouraging. Serum from individuals who received the Pfizer vaccine had titers of neutralizing antibodies that were only slightly reduced for P.1 compared to the original SARS-CoV-2 virus [6]. Therefore, the vaccine is predicted to be highly protective. This is another example of a vaccine providing more protection than a natural infection.

The United States has made truly remarkable progress in combating COVID-19, but we must heed this lesson from Manaus: this terrible pandemic isn’t over just yet. While the P.1 variant remains at low levels here for now, the “U.K. variant” B.1.1.7 continues to spread rapidly and now is the most prevalent variant circulating in the U.S., accounting for 44 percent of new cases [6]. Fortunately, the mRNA vaccines also work well against B.1.1.7.

We must continue to do absolutely everything possible, individually and collectively, to prevent these new SARS-CoV-2 variants from slowing or even canceling the progress made over the last year. We need to remain vigilant for just a while longer, while encouraging our friends, neighbors, and loved ones to get vaccinated.

References:

[1] Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic. Buss, L. F., C. A. Prete, Jr., C. M. M. Abrahim, A. C. Dye, V. H. Nascimento, N. R. Faria and E. C. Sabino et al. (2021). Science 371(6526): 288-292.

[2] Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence. Sabino EC, Buss LF, Carvalho MPS, Prete Jr CCA, Crispim MAE, Fraiji NA, Pereira RHM, Paraga KV, Peixoto PS, Kraemer MUG, Oikawa MJ, Salomon T, Cucunuba ZM, Castro MC, Santos AAAS, Nascimento VH, Pereira HS, Ferguson NM, Pybus OG, Kucharski A, Busch MP, Dye C, Faria NR Lancet. 2021 Feb 6;397(10273):452-455.

[3] Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Faria NR, Mellan TA, Whittaker C, Claro IM, Fraiji NA, Carvalho MDPSS, Pybus OG, Flaxman S, Bhatt S, Sabino EC et al. Science. 2021 Apr 14:eabh2644.

[4] GRINCH Global Report Investigating novel coronavirus haplotypes. PANGO Lineages.

[5] COVID Data Tracker. Variant Proportions. Centers for Disease Control and Prevention.

[6] Antibody evasion by the P.1 strain of SARS-CoV-2. Dejnirattisai W, Zhou D, Supasa P, Liu C, Mongkolsapaya J, Ren J, Stuart DI, Screaton GR, et al. Cell. 2021 Mar 30:S0092-8674(21)00428-1.

Links:

COVID-19 Research (NIH)

Brazil-UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE)

Nuno Faria (Imperial College, London, U.K.)

Samir Bhatt (Imperial College)

Ester Cerdeira Sabino (Universidade de Sao Paulo, Brazil)

NIH Support: National Institute of Allergy and Infectious Diseases


Infections with ‘U.K. Variant’ B.1.1.7 Have Greater Risk of Mortality

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One coronavirus in a group looks different and is labeled B.1.1.7 variant. Lines radiate from Britain on a map.

Since the genome sequence of SARS-CoV-2, the virus responsible for COVID-19, was first reported in January 2020, thousands of variants have been reported. In the vast majority of cases, these variants, which arise from random genomic changes as SARS-CoV-2 makes copies of itself in an infected person, haven’t raised any alarm among public health officials. But that’s now changed with the emergence of at least three variants carrying mutations that potentially make them even more dangerous.

At the top of this short list is a variant known as B.1.1.7, first detected in the United Kingdom in September 2020. This variant is considerably more contagious than the original virus. It has spread rapidly around the globe and likely accounts already for at least one-third of all cases in the United States [1]. Now comes more troubling news: emerging evidence indicates that infection with this B.1.1.7 variant also comes with an increased risk of severe illness and death [2].

The findings, reported in Nature, come from Nicholas Davies, Karla Diaz-Ordaz, and Ruth Keogh, London School of Hygiene and Tropical Medicine. The London team earlier showed that this new variant is 43 to 90 percent more transmissible than pre-existing variants that had been circulating in England [3]. But in the latest paper, the researchers followed up on conflicting reports about the virulence of B.1.1.7.

They did so with a large British dataset linking more than 2.2 million positive SARS-CoV-2 tests to 17,452 COVID-19 deaths from September 1, 2020, to February 14, 2021. In about half of the cases (accounting for nearly 5,000 deaths), it was possible to discern whether or not the infection had been caused by the B.1.1.7 variant.

Based on this evidence, the researchers calculated the risk of death associated with B.1.1.7 infection. Their estimates suggest that B.1.1.7 infection was associated with 55 percent greater mortality compared to other SARS-CoV-2 variants over this time period.

For a 55- to 69-year-old male, this translates to a 0.9-percent absolute, or personal, risk of death, up from 0.6 percent for the older variants. That means nine in every 1,000 people in this age group who test positive with the B.1.1.7 variant would be expected to die from COVID-19 a month later. For those infected with the original virus, that number would be six.

The U.S. percentage of B.1.1.7 started near zero on January 2, 2021 but by March 13 was over 20%.
Adapted from Centers for Disease Control and Prevention

These findings are in keeping with those of another recent study reported in the British Medical Journal [4]. In that case, researchers at the University of Exeter and the University of Bristol found that the B.1.1.7 variant was associated with a 64 percent greater chance of dying compared to earlier variants. That’s based on an analysis of data from more than 100,000 COVID-19 patients in the U.K. from October 1, 2020, to January 28, 2021.

That this variant comes with increased disease severity and mortality is particularly troubling news, given the highly contagious nature of B.1.1.7. In fact, Davies’ team has concluded that the emergence of new SARS-CoV-2 variants now threaten to slow or even cancel out improvements in COVID-19 treatment that have been made over the last year. These variants include not only B1.1.7, but also B.1.351 originating in South Africa and P.1 from Brazil.

The findings are yet another reminder that, while we’re making truly remarkable progress in the fight against COVID-19 with increasing availability of safe and effective vaccines (more than 45 million Americans are now fully immunized), now is not the time to get complacent. This devastating pandemic isn’t over yet.

The best way to continue the fight against all SARS-CoV-2 variants is for each one of us to do absolutely everything we can to stop their spread. This means that taking the opportunity to get vaccinated as soon as it is offered to you, and continuing to practice those public health measures we summarize as the three Ws: Wear a mask, Watch your distance, Wash your hands often.

References:

[1] US COVID-19 Cases Caused by Variants. Centers for Disease Control and Prevention.

[2] Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. Davies NG, Jarvis CI; CMMID COVID-19 Working Group, Edmunds WJ, Jewell NP, Diaz-Ordaz K, Keogh RH. Nature. 2021 Mar 15.

[3] Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Davies NG, Abbott S, Barnard RC, Jarvis CI, Kucharski AJ, Munday JD, Pearson CAB, Russell TW, Tully DC, Washburne AD, Wenseleers T, Gimma A, Waites W, Wong KLM, van Zandvoort K, Silverman JD; CMMID COVID-19 Working Group; COVID-19 Genomics UK (COG-UK) Consortium, Diaz-Ordaz K, Keogh R, Eggo RM, Funk S, Jit M, Atkins KE, Edmunds WJ.
Science. 2021 Mar 3:eabg3055.

[4] Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva-Atanasova K, Danon L. BMJ. 2021 Mar 9;372:n579.

Links:

COVID-19 Research (NIH)

Nicholas Davies (London School of Hygiene and Tropical Medicine, U.K.)

Ruth Keogh (London School of Hygiene and Tropical Medicine, U.K.)


On-the-Spot Gene Readouts Offer Clues to How Cells Work

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Credit: MIT and Harvard Medical School, Cambridge, MA

Just as two companies can merge to expand their capabilities, two technologies can become more powerful when integrated into one. That’s why researchers recently merged two breakthrough technologies into one super powerful new method called ExSeq. The two-in-one technology enables researchers for the first time to study an intact tissue sample and track genetic activity on the spot within a cell’s tiniest recesses, or microenvironments—areas that have been largely out of reach until now.

ExSeq, which is described in a paper in the journal Science [1], will unleash many new experimental applications. Beyond enabling more precise analysis of the basic building blocks of life, these applications include analyzing tumor biopsies more comprehensively and even unlocking mysteries of how the brain works. The latter use is on display in this colorful cross-section of a mouse’s hippocampus, a region of the brain involved in the memory of facts and events.

Here you can see in precise and unprecedented detail the areas where genes are activated (magenta) in the brain’s neurons (green). In this particular example, the genes are working within subregions of the hippocampus called the CA1 and dentate gyrus regions (white, bottom and top left).

ExSeq is a joint effort from NIH grantees Ed Boyden, Massachusetts Institute of Technology (MIT), Cambridge, and George Church, Harvard Medical School, Boston. The new method combines a technology called tissue expansion with an in situ sequencing approach.

Tissue expansion swells the contents of tissue sections up to 100 times their normal size but retains their same physical structure [2]. It’s sort of like increasing the font size and line spacing on a hard-to-read document. It makes cellular details that were outside the resolution range of the light microscope suddenly accessible.

With the information inside cells now easier to see, the next step involves a technique called FISSEQ (fluorescent in situ sequencing), which generates readouts of thousands of mRNA molecules in cells [3]. FISSEQ works by detecting individual RNA molecules where they are inside cells and amplifying them into “nanoballs,” or rolled-up copies of themselves. Each nanoball can be read using standard sequencing methods and a fluorescence microscope.

Using the combined ExSeq approach, the team can analyze precisely where gene activity changes within tiny cellular microenvironments. Or, it can compile a more-comprehensive readout of gene activity within cells by analyzing as many gene readouts as detectable. When used in the hippocampus, this untargeted, “agnostic” approach led to some surprises—revealing unusual forms of RNA and, by association, genes for proteins not previously linked with communication between neurons.

Like many technology developments, the scientists envision that ExSeq can be used in many ways, including for more precise analysis of tumor biopsies. To illustrate this point, the researchers analyzed breast cancer metastases, which are cells from breast tumors that have spread to other areas in the body. Metastases contain many different cell types, including cancer cells and immune cells.

Using ExSeq, Boyden and Church learned that these distinct cell types can behave differently depending on where they are inside a tumor. They discovered, for example, that immune B cells near tumor cells expressed certain inflammatory genes at a higher level than immune B cells that were further away. Precise information about a tumor’s composition and activity may lead to development of more targeted approaches to attack it.

Many discoveries come on the heels of transformative new technologies. ExSeq shines a much brighter light on the world of the very small. And that should help us better understand how different parts of cells work together, as well as how cells work with each other in the brain, in cancer, and throughout the body.

References:

[1] Expansion sequencing: Spatially precise in situ transcriptomics in intact biological systems. Alon S, Goodwin DR, Sinha A, Wassie AT, et al. Science. 2021 Jan 29;37:eaax2656.

[2] Expansion microscopy. Chen F, Tillberg PW, Boyden ES. Science. 2015;347:543-548.

[3]. Highly multiplexed subcellular RNA sequencing in situ. Lee JH, Daugharthy ER, Scheiman J, Kalhor R, et al. Science. 2014;343:1360-1363.

Links:

Ribonucleic Acid (RNA) (National Human Genome Research Institute/NIH)

Synthetic Neurobiology Group (Massachusetts Institute of Technology, Cambridge)

George Church (Harvard Medical School, Boston)

NIH Support: National Human Genome Research Institute; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke


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