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Evolution, Genetics, Global Health, Public Health, Research, Stanford News

Melting pot or mosaic? International collaboration studies genomic diversity in Mexico

Melting pot or mosaic? International collaboration studies genomic diversity in Mexico

6626429111_df791cbb8d_zMexico is a vast country with a storied past. Indigenous Native American groups across the country maintain their own languages and culture, while its cosmopolitan residents of large cities are as globally connected as anywhere on Earth. But Mexicans and Mexican Americans are usually lumped together as “Latinos” for the purposes of genetic or medical studies.

Now an international collaboration headed by Stanford geneticist Carlos Bustamante, PhD, and the University of California, San Francisco pulmonologist and public-health expert Esteban Burchard, MD, MPH, has assessed the breadth and depth of genomic diversity in Mexico for the first time. Their work was published today in Science. As I explain in our release:

The researchers compared variation in more than 1 million single nucleotide polymorphisms, or SNPs, among 511 people representing 20 indigenous populations from all over Mexico. They compared these findings with SNP variation among 500 people of mixed Mexican, European and African descent (a category called mestizos) from 10 Mexican states, a region of Guadalajara and Los Angeles, as well as with SNP variation among individuals from 16 European populations and the Yoruba people of West Africa.

The researchers found that Mexico’s indigenous populations diverge genetically along a diagonal northwest-to-southeast axis, with differences becoming more pronounced as the ethnic groups become more geographically distant from one another. In particular, the Seri people along the northern mainland coast of the Gulf of California and a Mayan people known as the Lacandon found near the country’s southern border with Guatemala are as genetically different from one another as Europeans are from Chinese.

Surprisingly, this pattern of diversity is mirrored in the genomes of Mexican individuals with mixed heritage (usually a combination of European, Native American and African):

Consistent with the history of the Spanish occupation and colonization of Mexico, the researchers found that the European portion of the mixed-individuals’ genomes broadly corresponded to that of modern-day inhabitants of the Iberian Peninsula. The Native American portion of their genomes, however, was more likely to correspond to that of local indigenous people. A person in the Mexican state of Sonora, for example, was likely to have ancestors from indigenous groups in the northern part of the country, whereas someone from Yucatan was more likely to have a southern native component in their genome, namely Mayan.

“We were really fascinated by these results because we had expected that 500 years of population movements, immigration and mixing would have swamped the signal of pre-Columbian population structure,” said Bustamante

Finally, the researchers found that the origin of the Native America portion of an individual’s genome affected a clinical measure of lung function abbreviated FEV1:

The researchers drew on data that calculated the predicted normal FEV1 for each subject based on age, gender, height and ethnicity (in this case, the reference was a standard used for all people of Mexican descent). To understand implications of these results within Mexico, they modeled the predicted lung function across Mexico, accounting for differences in local Native American ancestry for a large cohort of mestizos from eight states. The model predicts a marked difference across the country, with the average predicted FEV1 for a person from the northern state of Sonora and another from the state of Yucatan differing by about 7.3 percent. (That is, the population from Sonora has predicted values that were slightly higher than the average for the country, and those from the Yucatan were slightly lower.)

“There’s a definite predicted difference that’s due only to an individual’s Native American ancestry,” said Gignoux. “Variations in genetic composition clearly give a different physiological response.”

The researchers emphasize that a lower FEV1 does not necessarily mean a particular ethnic group has impaired lung function. Disease analysis takes place in the context of standardized values of matched populations, and the study points out how it is necessary to match people correctly to their ethnic backgrounds before making clinical decisions.

Stanford’s Andres Moreno Estrada, MD, PhD, and Christopher Gignoux, PhD, share first authorship of the study with Juan Carlos Fernandez Lopez, a researcher at Mexico’s National Institute of Genomic Medicine.

Previously: Roots of disease may vary with ancestry, according to Stanford geneticist, Recent shared ancestry between southern Europe and North Africa identified by Stanford researchers, and Caribbean genetic diversity explored by Stanford/University of Miami researchers
Photo by DL

Evolution, Genetics, Research, Science, Stanford News, Stem Cells

It’s a blond thing: Stanford researchers suss out molecular basis of hair color

It's a blond thing: Stanford researchers suss out molecular basis of hair color

blond hair, brighter

It’s all over the news today: Blonds aren’t stupid.

Well, that’s what most of the media would have you believe is the take-home message of the latest research by developmental biologist David Kingsley, PhD. And although I’m happy to see such great coverage, I’m hoping that readers realize that Kingley’s study on human hair color, which was published yesterday in Nature Genetics (subscription required), describes something much more subtle, and less superficial. From our release:

The study describes for the first time the molecular basis for one of our most noticeable traits. It also outlines how tiny DNA changes can reverberate through our genome in ways that may affect evolution, migration and even human history.

Kingsley, who is known for his study of a tiny fish called the threespine stickleback, is interested in learning how organism adapt to new environments by developing new traits. He’s found that this type of adaptation is most-often accomplished by changes in DNA regulatory regions that affect when, where and how a gene is expressed, rather than through (possibly disruptive) changes in the genes themselves.

In this case, he and his colleagues turned his attention to the blond hair common to many northern European and Icelanders. A previous study had shown that a single nucleotide change on human chromosome 12 was a major driver in hair color. As explained in the release:

The researchers found that the blond hair commonly seen in Northern Europeans is caused by a single change in the DNA that regulates the expression of a gene that encodes a protein called KITLG, also known as stem cell factor. This change affects how much KITLG is expressed in the hair follicles without changing how it’s expressed in the rest of the body. Introducing the change into normally brown-haired laboratory mice yields an animal with a decidedly lighter coat — not quite Norma Jeane to Marilyn Monroe, but significant nonetheless.

The involvement of KITLG, with its critical role in stem cell biology, is certainly interesting. But there’s also a more global lesson about the specificity of gene expression their effect on phenotype:

The study shows that even small, tissue-specific changes in the expression of genes can have noticeable morphological effects. It also emphasizes how difficult it can be to clearly connect specific DNA changes with particular clinical or phenotypic outcomes. In this case, the change is subtle: A single nucleotide called an adenine is replaced by another called a guanine on human chromosome 12. The change occurs over 350,000 nucleotides away from the KITLG gene and only alters the amount of gene expression about 20 percent — a relatively tiny blip on a biological scale more often assessed in terms of gene expression being 100 percent “on” or “off.”

“What we’re seeing is that this regulatory region exercises exquisite control over where, and how much, KITLG expression occurs,” said Kingsley. “In this case, it controls hair color. In another situation — perhaps under the influence of a different regulatory region — it probably controls stem cell division. Dialing up and down the expression of an essential growth factor in this manner could be a common mechanism that underlies many different traits.”

And now, the hook that excited most of the news media:

[Kingsley] added: “It’s clear that this hair color change is occurring through a regulatory mechanism that operates only in the hair. This isn’t something that also affects other traits, like intelligence or personality. The change that causes blond hair is, literally, only skin deep.”

Previously: Something fishy: Threespine stickleback genome published by Stanford researchers, Hey guys, sometimes less really is more , Tickled by stickle(backs) and Blond hair evolved more than once, and why it matters
Photo by Traci Lawson

Behavioral Science, Evolution, Medicine and Society, Ophthalmology, Research

Looks of fear and disgust help us to see threats, study shows

Looks of fear and disgust help us to see threats, study shows

disgustedNext time someone throws you a look, don’t take it personally: In a study of fear and disgust (the facial expressions), researchers have shown how those reactions to threat have helped us survive. Scientists studied the effects of eyes widening in fear, admitting more light and broading a participant’s field of vision, or narrowing in disgust, focusing more precisely on an object. As two-dozen undergraduate volunteers mimicked each emotion, scientists tracked their vision using using standard eye-exam equipment.

From a recent Los Angeles Times article:

Although some scientists have proposed that emotional expressions are intended primarily to communicate information, study authors argued that expressions of fear and disgust seem to perform different visual functions.

“Eye widening may improve detection and localization of a potential threat that requires enhanced vigilance, which would be consistent with the hypothesized function of fear,” wrote senior author Adam Anderson, [PhD,] a professor of human development at Cornell University. (The research was conducted by Anderson and his colleagues at the University of Toronto.)

“Conversely, eye narrowing may improve perceptual discrimination to discern different kinds of threats, such as disease vectors and contaminated foods, avoidance of which is a hypothesized function of disgust,” Anderson and his colleagues wrote.

The study was published in the journal Psychological Science.

Previously: Botox: frozen face = chilled emotional response? and Compassion, Darwin, facial expressions, the Dalai Lama – and counterterrorism?
Photo by Rachael Towne

Evolution, Immunology, Infectious Disease, Men's Health, Research, Stanford News

In men, a high testosterone count can mean a low immune response

In men, a high testosterone count can mean a low immune response

alpha maleMen have deeper voices and tons more facial and body hair than women. They are (usually) bigger, stronger, and much more likely to risk their lives on a whim. I, for example, have been known to bite a full-sized salami in half with a single snap of my jaws when hungry, angry or threatened. Or just for the hell of it.

But when it comes to immune response, men are wimps. It’s well documented that, for reasons that aren’t clear, men are more susceptible to bacterial, viral, fungal and parasitic infection than women are and that men’s immune systems don’t respond as strongly as women’s to vaccinations against influenza, yellow fever, measles, hepatitis and many other infectious diseases.

A new study just published in the Proceedings of the National Academy of Sciences by immunologist Mark Davis, PhD, who directs Stanford’s Institute for Immunity, Transplantation and Infection, and his colleagues may explain why. The same steroid hormone that makes a man’s beard, bones and muscles grow operates – albeit it in a slightly indirect way – to shrink immune responsiveness. Yep, we’re talking about (sigh…) that much-maligned male molecule, testosterone. In a nutshell, high circulating testosterone levels boost the activity of a clutch of genes that, among other things, dial down the aggressiveness with which our immune systems fight back against invading pathogens.

Now why, we ask ourselves, would evolution be so perverse as to have designed a hormone that on the one hand enhances classic male secondary sexual characteristics such as muscle strength, beard growth (or antler size, as the case may be) and risk-taking propensity – the very hallmarks of the alpha male – but on the other hand wussifies men’s immune systems?

Here’s what I got from talking at length (and, I admit, in an uncharacteristically high-pitched voice) to Davis in preparation for the news release I wrote about the study:

The evolutionary selection pressure for male characteristics ranging from peacocks’ plumage to deer’s antlers to fighter pilots’ heroism is pretty obvious: Females, especially at mating-cycle peaks, prefer males with prodigious testosterone-driven traits. Davis speculates that high testosterone may provide another, less obvious evolutionary advantage… Men are prone to suffer wounds from their competitive encounters, not to mention from their traditional roles in hunting, defending kin and hauling things around, increasing their infection risk. While it’s good to have a decent immune response to pathogens, an overreaction to them — as occurs in highly virulent influenza strains, SARS, dengue and many other diseases — can be more damaging than the pathogen itself. Women, with their robust immune responses, are twice as susceptible as men to death from the systemic inflammatory overdrive called sepsis. So perhaps, Davis suggests, having a somewhat weakened (but not too weak) immune system can prove more lifesaving than life-threatening for a dominant male in the prime of life.

Previously: Best thing since sliced bread? A (potential) new diagnostic for celiac disease, Deja Vu: Adults’ immune systems “remember” microscopic monsters they’ve seen before, Immunology escapes from the mouse trap and Immunology meets infotech
Photo by Craig Sunter *Click-64*

Evolution, Genetics, History, Myths, Research, Stanford News

New genetic study: More evidence for modern Ashkenazi Jews’ ancient Hebrew patrimony

New genetic study: More evidence for modern Ashkenazi Jews' ancient Hebrew patrimony

IsraelI hail from the so-called Ashkenazi branch of Jews, who account for the great majority of all Jews in the world today. Ashkenazis are distinguished by the historical fact that, over the last couple of thousand years or so, they propagated throughout Europe, generating and maintaining tens of thousands of distinctly Jewish communities in diverse countries spanning the entire continent. My dad was born in Lithuania; my mom’s mom came from an Eastern European region that has belonged to any one of about a half-dozen countries, depending on what particular year you happen to be talking about; and my mom’s dad grew up in Russia, near the Black Sea.

Tradition holds, though, that Ashkenazi Jews ultimately trace their origins straight back to ancient Israel, whence most Jews were expelled en masse in 70 CE by their Roman conquerors and sent skittering to all parts of the globe. (Jews who initially fled to Spain and Portugal are referred to as Sephardic. Those who took up residence in Iran, Turkey, Iraq and Northern Africa, are designated as Mizrahi.)

But in the late 1970s I read what was then a recent book titled The Thirteenth Tribe, written by polymath Arthur Koestler, advancing a theory that today’s Ashkenazis descend not from the Holy Land but, rather, from Khazaria, a medieval Turkic empire in the Causasus region whose royals, caught between the rock of Islam and the hard place of Christendom, chose the politically expedient course of converting to Judaism. That hypothesis has become highly politicized, with some groups holding that Ashkenazis, who constitute half of Israel’s current population, are colonialist interlopers with zero historical claim to the land of Israel.

Plausible at the time, the Khazar-origin premise has crumbled under the onslaught of modern molecular genetics. The latest volley: a study published this week in Nature Communications. The study’s senior author, Stanford geneticist Peter Underhill, PhD, works in the lab of  Carlos Bustamante, PhD, whose high-resolution techniques have highlighted the historical hopscotch of other migratory peoples.

Underhill, Bustamante and their co-authors analyzed the Y chromosome – a piece of the human genome invariably handed down father-to-son – of a set of Ashkenazi men claiming descent from Levi,  the founder of one of the Twelve Tribes of Israel. (Names such as Levy, Levine and Levitt, for example, bespeak a Levite heritage.)

If Ashkenazis were the spawn of Khazar royals, their DNA would show it. But those Y chromosomes were as Levantine as a levant sandwich. The same genetic “signature” popped up on every Levite sampled (as well as a significant number of non-Levite Ashkenazis), strongly implying descent from a single common ancestor who lived in the Fertile Crescent between 1,500 and 2,500 years ago. That signature is absent in the Y chromosomes of modern European non-Jewish men, and in male inhabitants of what was once Khazaria.

Yes, 2,000 years is a long time, and a fellow gets lonely. Genetic studies of mitochrondria – tiny intracellular power packs that have their own dollop of DNA and are always inherited matrilineally – have conflicted (contrast this with this) but, in combination with broader studies of entire genomes, suggest that a bit of canoodling transpired between Ashkenazi men and local European women, in particular Italian women, early in that two-millenia European sojourn.

I can relate. My wife is 100 percent Italian by heritage, and my daughter by my first marriage is half-Italian.

Previously: Caribbean genetic diversity explored by Stanford/University of Miami researchers, Stanford study investigates our most-recent common ancestors and Stanford study identifies molecular mechanism that triggers Parkinson’s
Photo by cod_gabriel

Evolution, Genetics, History, Research, Science, Stanford News

On the hunt for ancient DNA, Stanford researchers improve the odds

On the hunt for ancient DNA, Stanford researchers improve the odds

110427-N-YY9999-002On the surface, it’s perfect Halloween fodder: Ancient Peruvian mummies, Bronze and Iron Age human teeth from Bulgaria and a thousands-of-years old hair sample from Denmark. In fact, one attendee of Stanford geneticist Carlos Bustamante’s talk this morning at the annual conference of the American Society of Human Genetics in Boston quipped that his introduction sounded like “the start of a joke.”

But really old human DNA (we’re talking thousands of years) holds amazing secrets about our distant past. What did we look like? Where did our ancestors come from? What diseases may we have had? Unfortunately, it’s much more difficult than it seems to unlock these mysteries.

Stanford postdoctoral scholar Meredith Carpenter, PhD, explained the problem in an e-mail to me yesterday:

From Neandertals to mammoths to Otzi the Iceman, discoveries in ancient DNA sequencing have been making headlines.  But what you might not realize is that most of the ancient genomes sequenced to date have come from exceptionally well-preserved specimens – Otzi, for example, was literally frozen in ice for 5000 years.

Ancient DNA specimens from temperate environments, in contrast, are much trickier to sequence because they contain high levels of environmental contamination, primarily derived from bacteria and other microbes inhabiting the ancient bone. This contamination often makes it too expensive to sequence the tiny amounts of endogenous DNA (which degrades over the years due to exposure to the elements) remaining in a sample.

Now, Carpenter and Bustamante, PhD, and their colleagues have hit upon a way to enrich, or increase the proportion of ancient human DNA in an environmental sample from about 1.2 percent to nearly 60 percent–rendering it vastly easier to sequence and analyze. They do so by exposing the sample to a genome-wide panel of human-specific RNA molecules to which the degraded DNA in the sample can bind. The effect is somewhat like stirring a pile of iron-rich dirt with a powerful magnet to isolate the metal from the soil.

This isn’t Bustamante’s first foray into the secrets of ancient DNA. Last year he published very interesting results showing that the ancestors of the famous Iceman likely came not from mainland Italy, as previously thought, but instead from the islands of Corsica or Sardinia. This new technique should enable researchers to learn even more about our ancestors, including those oh-so-intriguing mummies.

According to Carpenter:

We hope that this new method will enable ancient DNA researchers to more cheaply sequence a larger number of specimens, providing broader insight into historical populations rather than just a few well-preserved individuals.

The research is published online today in the American Journal of Human Genetics. If you’re interested in following tweets from the conference, which goes through tomorrow, you can do so by following hashtag #ASHG2013.

Previously: Iceman’s origins discovered at Stanford, Stanford study investigates our most-recent common ancestors  and Recent shared ancestry between Southern Europe and North Africa identified by Stanford researchers.
Photo by Official US Navy Imagery

Evolution, In the News, Science

419 million year-old fish fossil may reveal origins of the human jaw

6971051776_9c4c9a71a6_nAs a kid, I used to ponder the origins of my unusually square jawline while looking in the bathroom mirror. After reading this story in Nature News, I wonder if I should have pondered my jaw’s origins while walking the halls of the nearest aquarium instead. Researchers from the Chinese Academy of Sciences in Beijing discovered a well-preserved 419 million year-old fossil that suggests the armor-plated fish, called Entelognathus primordialis, may be the earliest known species with a jaw like ours.

From Nature News:

Entelognathus primordialis is a new addition to the placoderms, a class of armour-plated fishes that lived from about 430 million to 360 million years ago. Like most vertebrates, including mammals, placoderms had a bony skull and jaw, but most of them had simple beak-like jaws built out of bone plates.

If you’re stifling a yawn, consider this: Researchers have seen fossils of this fish species before, but they were in less than pristine shape. Based on these fossils, most scientists concluded that this species was unrelated to humans.

Now, the discovery of this well-preserved fossil described in the journal Nature by paleontologist Min Zhu, PhD, and his team may upend this view of our family tree. Eliot Barford of Nature News explains:

There is a serious possibility that the modern bony visage originated with E. primordialis’s ancestors. This would mean that humans look more like the last common ancestor of living jawed vertebrates than we thought, and that sharks are less primitive than palaeontologists assumed, having done away with their bones as an adaptation.

However, the rearranged family tree is not yet quite conclusive, write the authors of a related News & Views article. There remains a chance that E. primordialis evolved its jaw independently from the bony fish, so that we did not inherit it, and the resemblance is an illusion.

Holly MacCormick is a writing intern in the medical school’s Office of Communication & Public Affairs. She is a graduate student in ecology and evolutionary biology at University of California-Santa Cruz.

Previously: Stanford study investigates our most-recent common ancestorsRecent shared ancestry between Southern Europe and North Africa identified by Stanford researchers and Stanford engineer studies bones that aid hearing
Photo by cuatrok77

Evolution, otolaryngology, Research, Stanford News

Stanford engineer studies bones that aid hearing

Stanford engineer studies bones that aid hearing

What distinguishes us from the dinosaurs? Three middle ear bones, for starters. Stanford mechanical engineer Sunil Puria, PhD, studies inner- and middle-ear biomechanics and the role of bone conduction in hearing, and he’s among a number of scientists who are curious why we have the tiny malleus, incus and stapes but reptiles and birds don’t.

Read more from Stanford Report on what Puria’s research on bone conduction hearing could mean for treating hearing loss, enhancing sound technology, and understanding evolutionary biology.

Previously: Battling hearing loss on and off the battlefield and Hearing loss patient discusses why Stanford research gives her hope for an eventual cure

Evolution, Genetics, Research, Stanford News

Stanford study investigates our most-recent common ancestors

Stanford study investigates our most-recent common ancestors

skullsGenealogy buffs know the thrill that comes with identifying ancestors further and further up the family tree. Reaching back through the sands of time to learn when, where and how our relatives lived is like a very personal treasure hunt.

Now geneticist Carlos Bustamante, PhD, and his colleagues have done something similar for our Y-chromosomal “Adam” and mitochondrial “Eve”: two individuals who have passed down a portion of their genomes to the vast expanse of humanity. These people are known as our most-recent common ancestors, or MRCAs. From our release:

“Previous research has indicated that the male MRCA lived much more recently than the female MRCA,” said Bustamante… “But now our research shows that there’s no discrepancy.” Previous estimates for the male MRCA ranged from between 50,000 to 115,000 years ago.

Bustamante’s research indicates the two MRCAs roughly overlapped during evolutionary time: from between 120,000 to 156,000 years ago for the man, and between 99,000 and 148,000 years ago for the woman. More from the release :

Despite the Adam and Eve monikers, which evoke a single couple whose children peopled the world, it is extremely unlikely that the male and female MRCAs were exact contemporaries. And they weren’t the only man and woman alive at the time, or the only people to have present-day descendants. These two individuals simply had the good fortune of successfully passing on specific portions of their DNA, called the Y chromosome and the mitochondrial genome, through the millennia to most of us, while the corresponding sequences of others have largely died out due to natural selection or a random process called genetic drift.

The researchers used high-throughput sequencing technology to sequence the Y chromosomes of 69 men from nine globally distinct regions. They identified about 11,000 differences among the sequences, which allowed them to determine phylogentic relationships and timelines with unprecedented accuracy. As graduate student and study co-author David Poznik described:

Essentially, we’ve constructed a family tree for the Y chromosome. Prior to high-throughput sequencing, the tree was based on just a few hundred variants. Although these variants had revealed the main topology, we couldn’t say much about the length of any branch — the number of variants shared by all of its descendants. We now have a more complete structure, including meaningful branch lengths, which are proxies for the periods of time between specific branching events.

Previously: Recent shared ancestry between Southern Europe and North Africa identified by Stanford researchers, Cracking the code of 1000 (make that 1092!) genomes and Blond hair evolved more than once-and why it matters
Photo by tup wanders

Evolution, Research, Stanford News

Mammals can “choose” the sex of their offspring, Stanford study finds

Mammals can "choose" the sex of their offspring, Stanford study finds

monkey and mama

A Stanford researcher and his colleagues have produced a surprising new study which shows that mammals can effectively “choose” the sex of their offspring and they’re doing it for their own selfish reasons – so they can have more grandchildren.

The researchers used data on more than 2,300 animals at the San Diego Zoo to track three generations for nearly 200 mammal species. Their numbers confirm what evolutionary biologists have theorized for decades – that females are strategically evaluating their options and making decisions that will serve their own reproductive interests, said Joseph Garner, PhD, associate professor of comparative medicine at Stanford and senior author of the study. Garner told me:

You can think of this as being girl power at work in the animal kingdom. We like to think of reproduction as being all about the males competing for females, females dutifully picking the winner. But in reality females have much more invested than males, and they are making highly strategic decisions about their reproduction based on the environment, their condition, and the quality of their mate. Amazingly, the female is somehow picking the sperm that will produce the sex that will serve her interests the most: the sperm are really just pawns in a game that plays out over generations.

What the researchers found is that grandparents could strategically choose to give birth to sons, if the sons would be of high enough quality to give them more grandchildren. In fact, they found that when females did have mostly sons, those sons had 2.7 times more children per capita than those who had equal numbers of male and female offspring. The same was true for male grandparents, with the study showing that when grandfathers produced mostly sons, those sons on average had 2.4 times more children per capita. But again, it’s most likely the females controlling the process, Garner said.

How they do it remains a bit of a mystery, he said, though one theory is that females control the sperm as it moves through the reproductive tract, selectively slowing down or speeding up the sperm they want to select.

Garner noted that there have been studies showing some similar patterns among humans. For instance, one found that billionaires are more likely to have sons than daughters because sons tend to retain the family’s wealth, or so the theory goes.

To read more on this tantalizing subject, see the study, which appears online today in PLOS ONE.

Photo by EvaSwensen

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