Published by
Stanford Medicine

Category

Genetics

Evolution, Genetics, Research, Science, Stanford News

Kennewick Man’s origins revealed by genetic study

Kennewick Man's origins revealed by genetic study

K man - 560

One day in 1996, on the banks of the Columbia River near Kennewick, Washington, two men found a human skull about ten feet from shore. Eventually, the nearly complete skeleton of an adult man was unearthed and found to be nearly 9,000 years old.

Since that find, controversy has swirled as to whether the man was an ancestor of Native American tribes living in the area, or was more closely related to other population groups around the Pacific Rim. A study published in 2014, based in part on anatomical measurements, concluded that the skeleton, known as the Kennewick Man, was more likely related to indigenous Japanese or Polynesian peoples.

Now Stanford geneticists Morten Rasmussen, PhD, and Carlos Bustamante, PhD, working with Eske Willerslev, PhD, and others at the University of Copenhagen’s Centre for GeoGenetics have studied tiny snippets of ancient DNA isolated from a hand bone. They’ve compared these DNA sequences with those of modern humans and concluded that the Kennewick Man (known to many Native Americans as the Ancient One) is more closely related to Native American groups than to any other population in the world.

The findings are published today online in Nature, and they’re likely to reignite an ongoing controversy as to the skeleton’s origins and to whom the remains belong.

As Rasmussen said in our press release:

Due to the massive controversy surrounding the origins of this sample, the ability to address this will be of interest to both scientists and tribal members. […]

Although the exterior preservation of the skeleton was pristine, the DNA in the sample was highly degraded and dominated by DNA from soil bacteria and other environmental sources. With the little material we had available, we applied the newest methods to squeeze every piece of information out of the bone.

Increasingly, such methods of isolating and sequencing ancient DNA are being used to solve millennia-old mysteries, including those surrounding Otzi the Iceman and a young child known as the Anzick boy buried more than 12,000 years ago in Montana.

Bustamante explained in the release:

Advances in DNA sequencing technology have given us important new tools for studying the great human diasporas and the history of indigenous populations. Now we are seeing its adoption in new areas, including forensics and archeology. The case of Kennewick Man is particularly interesting given the debates surrounding the origins of Native American populations. Morten’s work aligns beautifully with the oral history of native peoples and lends strong support for their claims. I believe that ancient DNA analysis could become standard practice in these types of cases since it can provide objective means of assessing both genetic ancestry and relatedness to living individuals and present-day populations.

Previously: Caribbean skeletons hold slave trade secrets,  Melting pot or mosaic? International collaboration studies genomic diversity in Mexico and  On the hunt for ancient DNA, Stanford researchers improve the odds
Photo, of bust showing how Kennewick Man may have looked, by Brittany Tatchell/Smithsonian (bust by StudioEIS; forensic facial reconstruction by sculptor Amanda Danning)

Biomed Bites, Evolution, Genetics, Research, Science, Videos

One mutation, two people and two (or more) outcomes: What gives?

One mutation, two people and two (or more) outcomes: What gives?

Welcome to Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative researchers. 

Tweak a piano string and you’ve created a different note. Tweak a gene and no one knows exactly what might happen. Perhaps the resultant protein is completely defective. Perhaps the same change does nothing in me but turns your world upside down. Who knows?

One Stanford researcher is working to demystify some of that variability, an endeavor that could lead to big changes in the development of therapies for diseases such as cancer. Daniel Jarosz, PhD, assistant professor of chemical and systems biology and of developmental biology, describes his work in the video above:

We all know there are many mutations associated with disease, for example, that give rise to that disease in some patients, yet there are other patients that have the same mutations and don’t have any effects. We’d really like to understand that…

The clinical benefits of this work are potentially very large.

For example, Jarosz said he and his team study why some tumor genes are able to evolve rapidly to evade chemotherapy. With a greater understanding of what conditions cause rapid evolution — and drug resistance — they can more easily evaluate new therapies.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: From finches to cancer: A Stanford researcher explores the role of evolution in disease, Computing our evolution and Whole genome sequencing: The known knowns and the unknown unknowns

Genetics, HIV/AIDS, Infectious Disease, Research, Stanford News

Study shows toothed whales have persisted millions of years without two common antiviral proteins

Study shows toothed whales have persisted millions of years without two common antiviral proteins

1821221135_4a6cd4e8f8_z

Our ability to fend off the flu, HIV and other viruses is enhanced when proteins are produced by two “immune genes,” called MX1 and MX2. Other mammals also have these genes, but little is known about the role they play in the immune responses of these animals.

Now a study comparing the genomes and Mx genes of 60 mammal species has revealed a surprising finding: Every species in the study has functioning Mx1 and Mx2 genes except for dolphins, whales and orcas — species from a lineage of toothed whales that’s persisted for roughly 33 million years.

Gill Bejerano, PhD, a geneticist and developmental biologist, graduate student Benjamin Braun and their team wanted to know more about the status and function of Mx genes in non-human mammals. To do this, they examined and compared the part of the genome that contains the Mx genes in 60 different species including humans, cows, whales, dolphins and orcas.

I think this will open up very exciting research avenues, either to better protect the compromised whales, or to study their different viral defenses, and someday add them to our own arsenal.

The study, published this week in the Proceedings of National Sciences, showed that the Mx1 and Mx2 genes in the toothed whales (bottlenose dolphin, orca, Yangtze river dolphin and sperm whale) they tested were non-functional, and couldn’t produce the proteins that help fight viral infections. Bejerano explained the significance of this finding in our press release:

Given how important the Mx genes seem to be in fighting off disease in humans and other mammals, it’s striking to see a species lose them both and go about its business for millions of years.

To find out when in evolutionary history these genes became inactive the researchers compared the genomes of toothed whales to that of their closest ancestors, the baleen whales and hoofed mammals (ungulates). They found that the Mx genes function in baleen whales and hoofed mammals, but not in toothed whales. This means that some — perhaps all — toothed whales likely lost use of their Mx genes when this lineage split off from these ancestors about 33 million years ago (see Fig. 1).

Continue Reading »

Genetics, Imaging, Neuroscience, Research, Stanford News

From phrenology to neuroimaging: New finding bolsters theory about how brain operates

From phrenology to neuroimaging: New finding bolsters theory about how brain operates

phrenologyNeuroscience has come a long way since the days of phrenology, when lumps on the outside of the skull were believed to denote enhanced size and strength of the particular brain region responsible for particular individual functions. Today’s far more advanced neuroimaging technologies allow scientists to peer deep into the living brain, revealing not only its anatomical structures and the tracts connecting them but, in recent years, physiological descriptions of the brain at work.

Visualized this way, the brain appears to contain numerous “functional networks:” clusters of remote brain regions that are connected directly via white-matter tracts or indirectly through connections with mediating regions. These networks’ tightly coupled brain regions not only are wired together, but fire together. Their pulses, purrs and pauses, so to speak, are closely coordinated in phase and frequency.

Well over a dozen functional networks, responsible for brain operations such as memory, language processing, vision and emotion, have been identified via a technique called resting-state functional magnetic resonance imaging. In a resting-state fMRI scan, the individual is asked to simply lie still, eyes closed, for several minutes and relax. These scans indicate that even at rest, the brain’s functional networks continue to hum along — albeit at lower volumes — at distinguishable frequencies and phases, like so many different radio stations playing simultaneously on the same radio.

But whether the images obtained via resting-state fMRI truly reflect neuronal activity or are some kind of artifact has been controversial. Now, a new study led by neuroscientist Michael Greicius, MD, and just published in Science, has found genetic evidence that convincingly bolsters neuroimaging-based depictions of these brain-activity patterns.

Continue Reading »

Biomed Bites, Genetics, Infectious Disease, Research, Videos

Why are viruses so wily? One researcher thinks she knows — and is working to thwart them

Why are viruses so wily? One researcher thinks she knows — and is working to thwart them

Welcome to Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative researchers. 

Some of the world’s best known viruses use RNA, rather than DNA, to code for proteins, including polio, measles and hepatitis C. There are a few differences:  RNA uses a component not used in DNA, and RNA is usually single-stranded, rather than the familiar double helix of DNA.

RNA viruses change rapidly, evading efforts to develop vaccines and therapies. But the change is uneven — some genes evolve with nearly every replication, others stay the same for generations. Molecular biologist Karla Kirkegaard, PhD, wondered why. The chair of Stanford’s Department of Microbiology and Immunology explains her discovery in the video above:

The answer was unusual. It turns out that there are different kinds of selective pressures on these regions, and it is very hard for new variants to arise in certain regions because their family members around them poison their advantage.

Alone, for example, a mutated gene might perform better than one that is unaltered. But when it is mixed with other genes, it might make the resultant virus less competitive.

That offers valuable insight for drug development, she said. Consider the interaction of genes and viruses together, rather than aiming to disable a single player, Kirkegaard advises:

My quest right now is to convince people who target antivirals for the common cold, West Nile virus and SARS to think about those processes the viruses have to cooperate on so we won’t have such a big problem with drug resistance.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: Ending enablers: Stanford researcher examines genes to find virus helpers, A conversation on West Nile virus and its recent California surge and Exploring the role of extracellular RNA communication in human disease

Big data, Cancer, Genetics, Research, Science, Stanford News

Stanford researchers suss out cancer mutations in genome’s dark spots

Stanford researchers suss out cancer mutations in genome's dark spots

lighted pathOnly a small proportion of our DNA contains nucleotide sequences used to make proteins. Much of the remainder is devoted to specifying how, when and where those proteins are made. These rules are encoded in our DNA as regulatory elements, and they’re what makes one cell type different from another, and keep them from running wild like children in an unattended classroom. When things go awry, the consequences (like rampant growth and cancers) can be severe.

Geneticist Michael Snyder, PhD, and postdoctoral scholar Collin Melton, PhD, recently combined information from The Cancer Genome Atlas, a national effort to sequence and identify mutations in the genomes of many different types of cancers, with data from the national ENCODE Project, which serves as an encyclopedia of DNA functional regions, or elements. Their aim was to better understand the roles that mutations in regulatory regions may play in cancer development.

Snyder and Melton found that fewer than one of every thousand mutations in each cancer type occurs in the coding region of a gene. In contrast, more than 30 percent of the mutations occur in regulatory regions. The study was published this morning in Nature Genetics.

As Snyder explained to me:

Until recently, many mutations outside the coding regions of genes have been mostly invisible to us. Cancer researchers largely focused on identifying changes within coding regions. Using ENCODE data, we’ve been able to define some important regions of the genome and found that certain regulatory regions are often enriched for mutations. This opens up a whole new window for this type of research.

Snyder, who leads Stanford’s genetics department and directs the Stanford Center for Genomics and Personalized Medicine, likens looking for cancer-causing mutations only in coding regions as “looking under the lamppost” for keys lost at night. Until recently, the coding regions of genes were the most well-studied, and unexpected mutations stood out like a sore thumb. We’ve known there’s a lot more of the genome outside the coding regions, but until the ENCODE project was largely completed in 2012, researchers were often in the dark as to where, or even how, they should look.

Continue Reading »

Genetics, Microbiology, Research, Science

Make it or break it — or both: New research reveals RNA’s dual role

Make it or break it — or both: New research reveals RNA's dual role

7314255232_8ee9474b2e_zBehind every big biomedical breakthrough lies boatloads of basic biology. In that vein, a new finding published today in Cell shakes up a fundamental view of RNA, the bridging material necessary to convert genes into proteins.

Previously, it was well known that RNA is degraded, broken down into its constituent parts so it could be used again. Otherwise, used RNA would accumulate in the cell, clogging it up. But everyone assumed that RNA was degraded only after it had transmitted its message to build a protein.

Now, a team of researchers led by Lars Steinmetz, PhD, professor of genetics, have discovered that RNA is broken down while it’s communicating the blueprint for protein assembly, a process known as translation. One end of the RNA is still making proteins while the other is being dismantled.

“In the bigger picture, decaying RNA was thought to be of little interest biologically,” Steinmetz said. “Our findings show that it contains hallmarks of the translation process.”

That finding could change the way researchers examine gene expression in live cells. Current methods use drugs that “freeze” the translation process, but that artificial interference alters the measurements of protein creation. A new method — which involves looking at the products of the RNA degradation — simplifies that process and produces more accurate results, said Wu Wei, PhD, a senior research scientist in biochemistry who worked on the research.

“People think that RNA is translated or degraded, but actually they can happen at the same time,” Wei said.

The researchers made the discovery almost accidently, when they spotted an unusual pattern in the byproducts of RNA that remained in the cell.

So far, their work has been in living yeast cells, but Wei said the team plans to move next to examining RNA degradation in human cells.

“Our approach provides a simple and straightforward way to measure ribosome dynamics in living cells. Both this study and research performed by our collaberators have proven that it is a powerful tool to investigate the regulation of translation, said Vicent Pelechano, PhD, who is based in Steinmetz’s laboratory at the European Molecular Biology Laboratory and designed the experimental aspects of the study.

Previously: The politics of destruction: Short-lived RNA helps stem cells turn on a dime, Step away from DNA? Circulating *RNA* in blood gives dynamic information about pregnancy, health and RNA Rosetta stone? Molecules’ second, structural language predicted from their first, linear one
Image by AJ Cann

Evolution, Genetics, HIV/AIDS, Immunology, Infectious Disease, Research, Stanford News

Study: Chimps teach people a thing or two about HIV resistance

Study: Chimps teach people a thing or two about HIV resistance

I, personally, have never had trouble distinguishing a human being from a chimp. I look, and I know.

But I’m not a molecular biologist. Today’s sophisticated DNA-sequencing technologies show that the genetic materials of the two species, which diverged only 5 million or so years ago (an eye-blink in evolutionary time), are about 98 percent identical. Think about that next time you eat a banana.

One major exception to that parallelism: a set of three genes collectively called the major histocompatibility complex, or MHC. These genes code for proteins that sit on the surfaces of each cell in your body, where they serve as jewel cases that display bits of proteins that were once inside that cell but have since been chopped into pieces by molecular garbage disposals, transported to the cell surface and encased in one or another of the MHC proteins. That makes the protein bits highly visible to roving immune cells patrolling our tissues to see if any of the cells within are harboring any funny-looking proteins. If those roving sentry cells spot a foreign-looking protein bit, they flag the cell on whose surface it’s displayed as possibly having been infected by a virus or begun to become cancerous.

Viruses replicate frequently and furiously, so they evolve super-rapidly. If they can evade immune detection, that’s groovy from their perspective. So our MHC has to evolve rapidly, too, and as a result, different species’ MHC genes  diverge relatively quickly.  To the extent they don’t, there’s probably a good reason.

Stanford immunologist and evolutionary theorist Peter Parham, PhD, pays a lot of attention to the MHC genes. In a new study in PLOS Biology, he and his colleagues have made a discovery that may prove relevant to AIDS research, by analyzing genetic material found in chimp feces. Not zoo chimps. Wild Tanzanian chimps. As I noted in a news release about the study:

The wild chimps inhabit Gombe Stream National Park, a 13.5-square-mile preserve where they have been continuously observed from afar since famed primatologist Jane Goodall, PhD, began monitoring them more than 50 years ago.

One thing that sets the Gombe chimps apart from captive chimps, unfortunately, is a high rate of infection by the simian equivalent of HIV, the virus responsible for AIDS.

The study’s lead author, postdoc Emily Wroblewski, PhD, set up shop in a corner of Parham’s lab and extracted DNA from fecal samples legally obtained by other researchers (close contact with the animals is prohibited). Each sample could be tied to a particular Gombe-resident chimp. RNA extracted from the same sample indicated that chimp’s infection status.

Parham, Wroblewski and their colleagues found that one particular MHC gene came in 11 different varieties – astounding diversity for such a small collection of chimps (fewer than 125 of them in the entire Gombe). Surprisingly, one small part of one of those 11 gene variants was nearly identical to a piece of a protective version of its human counterpart gene, a version that seems to protect HIV- infected people slowing HIV progression to full-blown AIDS.

Why is that important? Because any piece of an MHC gene that has maintained its sequence in the face of 5 million years of intense evolutionary pressure must be worth something.

Sure enough, fecal samples from chimps with that MHC gene variant, so strikingly analogous to the protective human variant, had lower counts of virus that those from infected chimps carrying other versions of the gene.

You can believe that scientists will be closely examining the DNA sequence contained in both the human and chimp gene variant, as well as the part of the MHC protein that DNA sequence codes for. Because it must be doing something right.

Previously: Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease, Our species’ twisted family tree and Humans share history – and a fair amount of genetic material – with Neanderthals
Photo by Emily Wroblewski

Biomed Bites, Cancer, Genetics, Microbiology, Research, Videos

Packed and ready to go: The link between DNA folding and disease

Packed and ready to go: The link between DNA folding and disease

Welcome to Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative researchers.

In cells, DNA doesn’t make a lovely, languid helix as popularly depicted. It’s scrunched up, bound with proteins that smoosh one meter of DNA into just one micrometer, a millionth of its size. DNA wound around proteins form a particle called a nucleosome.

Yahli Lorch, PhD, associate professor of structural biology, has studied nucleosomes since they were first discovered more than 20 years ago, as she mentions in the video above:

When I began working on the nucleosome, it was a largely neglected area since most people considered it just a packaging and nothing beyond that.

Since I discovered that it has a role and a very important role in the regulation of gene expression, the field has grown many fold and it’s one of the largest areas in biology now.

Many diseases have been linked to the packaging of DNA, including neurodegenerative diseases, autoimmune diseases and several types of cancer such as some pancreatic cancers. Enhancing the understanding of the basic biology of DNA folding is leading to new and improved treatments for these conditions, Lorch says.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: DNA origami: How our genomes fold, DNA architecture fascinates Stanford researcher — and dictates biological outcomes and More than shiny: Stanford’s new sculpture by Alyson Shotz

Big data, BigDataMed15, Events, Genetics, Research, Technology

Big Data in Biomedicine panelists: Genomics’ future is bright, thanks to data-science tools

Big Data in Biomedicine panelists: Genomics' future is bright, thanks to data-science tools

Jill HagenkordStanford’s annual Big Data in Biomedicine began this morning with a “breathtaking set of talks,” as described by Russ Altman, MD, PhD, a Stanford professor of bioengineering, genetics and of medicine.

The first panel focused on genomics, with the speakers presenting a dizzying forecast of a future where biomedical data is standardized and easily accessible to researchers, yet carefully guarded to protect privacy.

“How do we build this in a way that allows you to spend time working on your science, and not spend your time to worry about reinventing the plumbing?,” asked David Glazer, director of engineering at Google and a speaker on the panel.

His team is hard at work ensuring the infrastructure of the Google Cloud Platform can withstand the rigorous demands of a slew of big data projects, including the Million Veteran Program and MSSNG, an effort to understand the genetics of autism.

For panelist Heidi Rehm, PhD, associate professor of pathology at Harvard Medical School and director of the Partners Laboratory for Molecular Medicine, a key hurdle is standardizing definitions and ensuring that supporting evidence is available for system users. For example, data developers should be able to demonstrate why a particular gene variant has been deemed benign, and what definition of “benign” they are using, she said.

Her team has developed a star system, which rates sources of data by their credibility, giving results submitted by expert panels more stars than data submitted by a single researcher.

Rehm also addressed the pros and cons of various models to share data. Rather than collecting it all centrally, she said she expects data will be shared through a small number of hubs, which each have the ability to connect with each other, similar to an airline trafficking model.

Individuals are not standing in the way of research advances, reported panelist Jill Hagenkord, MD, chief medical officer of the personal genetics company 23andMe. She said that of their 950,000 customers, nearly 80 percent have agreed to share their data for research. Participants are also eager to provide additional information when asked, Hagenkord said. It becomes almost a philanthropic effort, they feel grateful that someone is interested in their conditions, she said.

Continue Reading »

Stanford Medicine Resources: