Skip to main content

genome

A New View of the 3D Genome

Posted on by

Caption: 3D model of a chromatin “forest.” Each sphere represents a tree-shaped domain of about 10 nucleosomes, the basic structural unit of DNA packaging. Larger domains are green; smaller ones are red. Credit: Northwestern University, Evanston, IL

 

This lush panoply of color might stir up daydreams of getting away to explore a tropical rain forest. But what you see here is a new model that’s enabling researchers to explore something equally amazing: how a string of DNA that measures 6 feet long can be packed into the microscopic nucleus of a human cell. Fitting that much DNA in a nucleus is like fitting a thread the length of the Empire State building underneath your fingernail!

Scientists have known for a while that that the answer lies in how DNA is folded onto spool-like complexes called chromatin, but many details of the process still remain to be worked out. Recently, an NIH-funded team, led by Vadim Backman and Igal Szleifer, Northwestern University, Evanston, IL, developed this new model of chromatin folding by pairing sophisticated mathematical modeling and optical imaging.In a study published in the journal Science Advances [1], the team found that chromatin is folded into a variety of tree-like domains along a chromatin backbone, which they liken to an aggregation of trees growing from the forest floor. The colorful spheres you see above represent trees of varying sizes.

Earlier models of chromatin folding had suggested that DNA folds into regular and orderly fibers. In the new study, the Northwestern researchers used their own specially designed Partial Wave Spectroscopic microscope. This high-powered system, coupled with electron imaging, allowed them to peer deep inside living cells to “sense” real-time alterations in chromatin packing. What makes their new view on chromatin so interesting is it suggests our DNA is packaged in a way that’s much more disorderly and unpredictable than initially thought.

Chromatin Forest
Caption: Schematic shows the interplay between transcription and chromatin packing. Inactive high DNA density (blue) regions and active low DNA density (red). The horizontal chromatin backbone includes RNA polymerase (green), activating factors (yellow), and repressing factors (purple). Credit: Huang et al., Sci. Adv. 2020

As Backman notes, it is reasonable to assume that a forest would be filled with trees of varying sizes and shapes. But you couldn’t predict the exact location of each tree or its particular size and configuration. The same appears to be true of these tree-like structures within chromatin. Their precise location and size vary, seemingly unpredictably, from cell to cell.

This apparently random DNA packing structure might seem surprising given chromatin’s importance in influencing the expression and function of our genes. But the researchers think such variability likely has its advantages.

Here’s the idea: If all of our cells responded to stressful conditions (such as heat or a toxic exposure) in exactly the same way and that way happened to be suboptimal, the whole tissue or organ might fail. But if differences in chromatin structure lead each cell to respond somewhat differently to the same stimulus, then some cells might be more likely to survive or even thrive under the stress. It’s a built-in way for cells to hedge their bets.

These new findings offer a fundamentally new three-dimensional view of the human genome. They might also inspire innovative strategies to understand and fight cancer, as well as other diseases. And, while most of us probably won’t be venturing off into the rain forest anytime soon, this work does give us all something to think about next time we’re enjoying the great outdoors in our own neck of the woods. 

Reference:

[1] Physical and data structure of 3D genome. Huang K, Li Y, Shim AR, Virk RKA, Agrawal V, Eshein A, Nap RJ, Almassalha LM, Backman V, Szleifer I. Sci Adv. 2020 Jan 10;6(2):eaay4055.

Links:

Deoxyribonucleic Acid (DNA) (National Human Genome Research Institute/NIH)

4D Nucleome (Common Fund/NIH)

Vadim Backman (Northwestern University, Evanston, IL)

Igal Szleifer (Northwestern University, Evanston, IL)

NIH Support: National Cancer Institute


Genes, Blood Type Tied to Risk of Severe COVID-19

Posted on by

SARS-CoV-2 virus particles
Caption: Micrograph of SARS-CoV-2 virus particles isolated from a patient.
Credit: National Institute of Allergy and Infectious Diseases, NIH

Many people who contract COVID-19 have only a mild illness, or sometimes no symptoms at all. But others develop respiratory failure that requires oxygen support or even a ventilator to help them recover [1]. It’s clear that this happens more often in men than in women, as well as in people who are older or who have chronic health conditions. But why does respiratory failure also sometimes occur in people who are young and seemingly healthy?

A new study suggests that part of the answer to this question may be found in the genes that each one of us carries [2]. While more research is needed to pinpoint the precise underlying genes and mechanisms responsible, a recent genome-wide association (GWAS) study, just published in the New England Journal of Medicine, finds that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death.

The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system. In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.

These new findings—the first to identify statistically significant susceptibility genes for the severity of COVID-19—come from a large research effort led by Andre Franke, a scientist at Christian-Albrecht-University, Kiel, Germany, along with Tom Karlsen, Oslo University Hospital Rikshospitalet, Norway. Their study included 1,980 people undergoing treatment for severe COVID-19 and respiratory failure at seven medical centers in Italy and Spain.

In search of gene variants that might play a role in the severe illness, the team analyzed patient genome data for more than 8.5 million so-called single-nucleotide polymorphisms, or SNPs. The vast majority of these single “letter” nucleotide substitutions found all across the genome are of no health significance, but they can help to pinpoint the locations of gene variants that turn up more often in association with particular traits or conditions—in this case, COVID-19-related respiratory failure. To find them, the researchers compared SNPs in people with severe COVID-19 to those in more than 1,200 healthy blood donors from the same population groups.

The analysis identified two places that turned up significantly more often in the individuals with severe COVID-19 than in the healthy folks. One of them is found on chromosome 3 and covers a cluster of six genes with potentially relevant functions. For instance, this portion of the genome encodes a transporter protein known to interact with angiotensin converting enzyme 2 (ACE2), the surface receptor that allows the novel coronavirus that causes COVID-19, SARS-CoV-2, to bind to and infect human cells. It also encodes a collection of chemokine receptors, which play a role in the immune response in the airways of our lungs.

The other association signal popped up on chromosome 9, right over the area of the genome that determines blood type. Whether you are classified as an A, B, AB, or O blood type, depends on how your genes instruct your blood cells to produce (or not produce) a certain set of proteins. The researchers did find evidence suggesting a relationship between blood type and COVID-19 risk. They noted that this area also includes a genetic variant associated with increased levels of interleukin-6, which plays a role in inflammation and may have implications for COVID-19 as well.

These findings, completed in two months under very difficult clinical conditions, clearly warrant further study to understand the implications more fully. Indeed, Franke, Karlsen, and many of their colleagues are part of the COVID-19 Host Genetics Initiative, an ongoing international collaborative effort to learn the genetic determinants of COVID-19 susceptibility, severity, and outcomes. Some NIH research groups are taking part in the initiative, and they recently launched a study to look for informative gene variants in 5,000 COVID-19 patients in the United States and Canada.

The hope is that these and other findings yet to come will point the way to a more thorough understanding of the biology of COVID-19. They also suggest that a genetic test and a person’s blood type might provide useful tools for identifying those who may be at greater risk of serious illness.

References:

[1] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. Wu Z, McGoogan JM, et. al. 2020 Feb 24. [published online ahead of print]

[2] Genomewide association study of severe Covid-19 with respiratory failure. Ellinghaus D, Degenhardt F, et. a. NEJM. June 17, 2020.

Links:

The COVID-19 Host Genetics Initiative

Andre Franke (Christian-Albrechts-University of Kiel, Germany)

Tom Karlsen (Oslo University Hospital Rikshospitalet, Norway)


Uncovering a Hidden Zika Outbreak in Cuba

Posted on by

Zika Virus in Cuba
Credit: Sharon Isern, steampunkphage.com.

When Brazilian health officials discovered four years ago that the mosquito-borne Zika virus could cause severe birth defects and other serious health problems, it prompted a major effort across the Americas to curb the infection by controlling mosquitoes and issuing travel advisories. By mid-2017, the hard work seemed to have paid off, and reports of new Zika infections had nearly stopped.

But it turns out Zika may be tougher to control than once thought. New research shows that a large, previously hidden outbreak of Zika virus disease occurred in Cuba, just when it looked like the worst of the epidemic was over. The finding suggests that the Zika virus can linger over long periods, and that mosquito control efforts alone may slow, but not necessarily stop, the march of this potentially devastating infectious disease.

When combating global epidemics, it’s critical to track the spread of dangerous viruses from one place to the next. But some viruses can be tougher to monitor than others, and that certainly has been the case with Zika in the Americas. Though the virus can harm unborn children, many people infected with Zika never feel lousy enough to go to the doctor. Those who do often have symptoms that overlap with other prevalent tropical diseases, such as dengue and chikungunya fever, making it hard to recognize Zika.

That’s why in Brazil, where Zika arrived in the Americas by early 2014, this unexpected viral intruder went undetected for well over a year. By then, it had spread unnoticed to Honduras, circulating rapidly to other Central American nations and Mexico—likely by late 2014 and into 2015.

In the United States, even with close monitoring, a small local outbreak of Zika virus in Florida also went undetected for about three months in 2016 [1]. Then, in 2017, Florida officials began noticing something strange: new cases of Zika infection in people who had traveled to Cuba.

This came as a real surprise because Cuba, unlike most other Caribbean islands, was thought to have avoided an outbreak. What’s more, by then the Zika epidemic in the Americas had slowed to a trickle, prompting the World Health Organization to delist it as a global public health emergency of international concern.

Given the Cuban observation, some wondered whether the Zika epidemic in the Americas was really over. Among them was an NIH-supported research team, including Nathan Grubaugh, Yale School of Public Health, New Haven, CT; Sharon Isern and Scott Michael, Florida Gulf Coast University, Fort Myers; and Kristian Andersen, The Scripps Research Institute, La Jolla, CA, who worked closely with the Florida Department of Health, including Andrea Morrison.

As published in Cell, the team was able to document a previously unreported outbreak in Cuba after the epidemic had seemingly ended [2]. Interestingly, another research group in Spain also recently made a similar observation about Zika in Cuba [3].

In the Cell paper, the researchers show that between June 2017 and October 2018, all but two of 155 cases—a whopping 98 percent of travel-associated Zika infections—traced back to Cuba. Further analysis suggests that the outbreak in Cuba was likely of similar magnitude to outbreaks that occurred in other Caribbean nations.

Their estimates suggest there were likely many thousands of Zika cases in Cuba, and more than 5,000 likely should have been diagnosed and reported in 2017. The only difference was the timing. The Cuban outbreak of Zika virus occurred about a year after infections subsided elsewhere in the Caribbean.

To fill in more of the blanks, the researchers relied on Zika virus genomes from nine infected Florida travelers who returned from Cuba in 2017 and 2018. The sequencing data support multiple introductions of Zika virus to Cuba from other Caribbean islands in the summer of 2016.

The outbreak peaked about a year after the virus made its way to Cuba, similar to what happened in other places. But the Cuban outbreak was likely delayed by a year thanks to an effective mosquito control campaign by local authorities, following detection of the Brazilian outbreak. While information is lacking, including whether Zika infections had caused birth defects, it’s likely those efforts were relaxed once the emergency appeared to be over elsewhere in the Caribbean, and the virus took hold.

The findings serve as yet another reminder that the Zika virus—first identified in the Zika Forest in Uganda in 1947 and for many years considered a mostly inconsequential virus [4]—has by no means been eliminated. Indeed, such unrecognized and delayed outbreaks of Zika raise the risk of travelers innocently spreading the virus to other parts of the world.

The encouraging news is that, with travel surveillance data and genomic tools —enabled by open science—it is now possible to detect such outbreaks. By combining resources and data, it will be possible to develop even more effective and responsive surveillance frameworks to pick up on emerging health threats in the future.

In the meantime, work continues to develop a vaccine for the Zika virus, with more than a dozen clinical trials underway that pursue a variety of vaccination strategies. With the Zika pandemic resolved in the Americas, these studies can be harder to conduct, since proof of efficacy is not possible without active infections. But, as this paper shows, we must remain ready for future outbreaks of this unique and formidable virus.

References:

[1] Genomic epidemiology reveals multiple introductions of Zika virus into the United States. Grubaugh et al. Nature. 2017 Jun 15;546(7658):401-405.

[2] Travel surveillance and genomics uncover a hidden Zika outbreak during the waning epidemic. Grubaugh ND, Saraf S, Gangavarapu K, Watts A, Tan AL, Oidtman RJ, Magnani DM, Watkins DI, Palacios G, Hamer DH; GeoSentinel Surveillance Network, Gardner LM, Perkins TA, Baele G, Khan K, Morrison A, Isern S, Michael SF, Andersen .KG, et. al. Cell. 2019 Aug 22;178(5):1057-1071.e11.

[3] Mirroring the Zika epidemics in Cuba: The view from a European imported diseases clinic. Almuedo-Riera A, Rodriguez-Valero N, Camprubí D, Losada Galván I, Zamora-Martinez C, Pousibet-Puerto J, Subirà C, Martinez MJ, Pinazo MJ, Muñoz J. Travel Med Infect Dis. 2019 Jul – Aug;30:125-127.

[4] Pandemic Zika: A Formidable Challenge to Medicine and Public Health. Morens DM, Fauci AS. J Infect Dis. 2017 Dec 16;216(suppl_10):S857-S859.

Links:

Video: Uncovering Hidden Zika Outbreaks (Florida Gulf Coast University, Fort Myers)

Zika Virus (National Institute of Allergy and Infectious Diseases/NIH)

Zika Virus Vaccines (NIAID)

Zika Free Florida (Florida Department of Health, Tallahassee)

Grubaugh Lab (Yale School of Public Health, New Haven, CT)

Andersen Lab (The Scripps Research Institute, La Jolla, CA)

NIH Support: National Institute of Allergy and Infectious Diseases; National Center for Advancing Translational Sciences


Biomedical Research Highlighted in Science’s 2018 Breakthroughs

Posted on by

Science Breakthroughs of the Year 2018

A Happy New Year to one and all! While many of us were busy wrapping presents, the journal Science announced its much-anticipated scientific breakthroughs of 2018. In case you missed the announcement [1], it was another banner year for the biomedical sciences.

The 2018 Breakthrough of the Year went to biomedical science and its ability to track the development of life—one cell at a time—in a variety of model organisms. This newfound ability opens opportunities to understand the biological basis of life more systematically than ever before. Among Science’s “runner-up” breakthroughs, more than half had strong ties to the biomedical sciences and NIH-supported research.

Sound intriguing? Let’s take a closer look at some of the amazing science conducted in 2018, starting with Science’s Breakthrough of the Year.

Development Cell by Cell: For millennia, biologists have wondered how a single cell develops into a complete multicellular organism, such as a frog or a mouse. But solving that mystery was almost impossible without the needed tools to study development systematically, one cell at a time. That’s finally started to change within the last decade. I’ve highlighted the emergence of some of these powerful tools on my blog and the interesting ways that they were being applied to study development.

Over the past few years, all of this technological progress has come to a head. Researchers, many of them NIH-supported, used sophisticated cell labeling techniques, nucleic acid sequencing, and computational strategies to isolate thousands of cells from developing organisms, sequence their genetic material, and determine their location within that developing organism.

In 2018 alone, groundbreaking single-cell analysis papers were published that sequentially tracked the 20-plus cell types that arise from a fertilized zebrafish egg, the early formation of organs in a frog, and even the creation of a new limb in the Axolotl salamander. This is just the start of amazing discoveries that will help to inform us of the steps, or sometimes missteps, within human development—and suggest the best ways to prevent the missteps. In fact, efforts are now underway to gain this detailed information in people, cell by cell, including the international Human Cell Atlas and the NIH-supported Human BioMolecular Atlas Program.

An RNA Drug Enters the Clinic: Twenty years ago, researchers Andrew Fire and Craig Mello showed that certain small, noncoding RNA molecules can selectively block genes in our cells from turning “on” through a process called RNA interference (RNAi). This work, for the which these NIH grantees received the 2006 Nobel Prize in Physiology or Medicine, soon sparked a wave of commercial interest in various noncoding RNA molecules for their potential to silence the expression of a disease-causing gene.

After much hard work, the first gene-silencing RNA drug finally came to market in 2018. It’s called Onpattro™ (patisiran), and the drug uses RNAi to treat the peripheral nerve disease that can afflict adults with a rare disease called hereditary transthyretin-mediated amyloidosis. This hard-won success may spark further development of this novel class of biopharmaceuticals to treat a variety of conditions, from cancer to cardiovascular disorders, with potentially greater precision.

Rapid Chemical Structure Determination: Last October, two research teams released papers almost simultaneously that described an incredibly fast new imaging technique to determine the structure of smaller organic chemical compounds, or “small molecules“ at atomic resolution. Small molecules are essential components of molecular biology, pharmacology, and drug development. In fact, most of our current medicines are small molecules.

News of these papers had many researchers buzzing, and I highlighted one of them on my blog. It described a technique called microcrystal electron diffraction, or MicroED. It enabled these NIH-supported researchers to take a powder form of small molecules (progesterone was one example) and generate high-resolution data on their chemical structures in less than a half-hour! The ease and speed of MicroED could revolutionize not only how researchers study various disease processes, but aid in pinpointing which of the vast number of small molecules can become successful therapeutics.

How Cells Marshal Their Contents: About a decade ago, researchers discovered that many proteins in our cells, especially when stressed, condense into circumscribed aqueous droplets. This so-called phase separation allows proteins to gather in higher concentrations and promote reactions with other proteins. The NIH soon began supporting several research teams in their groundbreaking efforts to explore the effects of phase separation on cell biology.

Over the past few years, work on phase separation has taken off. The research suggests that this phenomenon is critical in compartmentalizing chemical reactions within the cell without the need of partitioning membranes. In 2018 alone, several major papers were published, and the progress already has some suggesting that phase separation is not only a basic organizing principle of the cell, it’s one of the major recent breakthroughs in biology.

Forensic Genealogy Comes of Age: Last April, police in Sacramento, CA announced that they had arrested a suspect in the decades-long hunt for the notorious Golden State Killer. As exciting as the news was, doubly interesting was how they caught the accused killer. The police had the Golden Gate Killer’s DNA, but they couldn’t determine his identity, that is, until they got a hit on a DNA profile uploaded by one of his relatives to a public genealogy database.

Though forensic genealogy falls a little outside of our mission, NIH has helped to advance the gathering of family histories and using DNA to study genealogy. In fact, my blog featured NIH-supported work that succeeded in crowdsourcing 600 years of human history.

The researchers, using the online profiles of 86 million genealogy hobbyists with their permission, assembled more than 5 million family trees. The largest totaled more than 13 million people! By merging each tree from the crowd-sourced and public data, they were able to go back about 11 generations—to the 15th century and the days of Christopher Columbus. Though they may not have caught an accused killer, these large datasets provided some novel insights into our family structures, genes, and longevity.

An Ancient Human Hybrid: Every year, researchers excavate thousands of bone fragments from the remote Denisova Cave in Siberia. One such find would later be called Denisova 11, or “Denny” for short.

Oh, what a fascinating genomic tale Denny’s sliver of bone had to tell. Denny was at least 13 years old and lived in Siberia roughly 90,000 years ago. A few years ago, an international research team found that DNA from the mitochondria in Denny’s cells came from a Neanderthal, an extinct human relative.

In 2018, Denny’s family tree got even more interesting. The team published new data showing that Denny was female and, more importantly, she was a first generation mix of a Neanderthal mother and a father who belonged to another extinct human relative called the Denisovans. The Denisovans, by the way, are the first human relatives characterized almost completely on the basis of genomics. They diverged from Neanderthals about 390,000 years ago. Until about 40,000 years ago, the two occupied the Eurasian continent—Neanderthals to the west, and Denisovans to the east.

Denny’s unique genealogy makes her the first direct descendant ever discovered of two different groups of early humans. While NIH didn’t directly support this research, the sequencing of the Neanderthal genome provided an essential resource.

As exciting as these breakthroughs are, they only scratch the surface of ongoing progress in biomedical research. Every field of science is generating compelling breakthroughs filled with hope and the promise to improve the lives of millions of Americans. So let’s get started with 2019 and finish out this decade with more truly amazing science!

Reference:

[1] “2018 Breakthrough of the Year,” Science, 21 December 2018.

NIH Support: These breakthroughs represent the culmination of years of research involving many investigators and the support of multiple NIH institutes.


Building a 3D Map of the Genome

Posted on by

3D Genome Map

Credit: Chen et al., 2018

Researchers have learned a lot in recent years about how six-plus feet of human DNA gets carefully packed into a tiny cell nucleus that measures less than .00024 of an inch. Under those cramped conditions, we’ve been learning more and more about how DNA twists, turns, and spatially orients its thousands of genes within the nucleus and what this positioning might mean for health and disease.

Thanks to a new technique developed by an NIH-funded research team, there is now an even more refined view [1]. The image above features the nucleus (blue) of a human leukemia cell. The diffuse orange-red clouds highlight chemically labeled DNA found in close proximity to the tiny nuclear speckles (green). You’ll need to look real carefully to see the nuclear speckles, but these structural landmarks in the nucleus have long been thought to serve as storage sites for important cellular machinery.


Next Page