Through the millennia wave after wave of migrants – often in the form of invading armies – have descended upon the British Isles.

The first people to arrive after the Ice Age were hunter-gatherers who followed their prey north from southern Europe about 12,000 years ago. The Celts came from central Europe about 3,000 years ago. Then came the Romans, followed by the Anglo-Saxons, Vikings and finally the Normans in 1066 AD.

With each successive invasion, the previous people were either absorbed by the invaders, or retreated to the isolated corners of the Isles. Often called the “Celtic Fringe,” these regions have been studied as a window into the ancient history of the British Isles. Some scholars even propose that the present-day people of the fringe could be direct descendants of the earliest humans to arrive on the Isles after the Ice Age.

But despite exhaustive research into the history and genetics of the Celtic Fringe, its prehistory remains mysterious, forcing scientists to think outside the box. In the September 30 issue of the Proceedings of the Royal Society B: Biological Sciences, biologist Jeremy Searle and his research team did just that, devising an unconventional method to study the prehistoric peopling of the British Isles.

They could have examined the DNA of the Celts themselves. But that’s already been tried, so Searle and his colleagues turned their research underfoot.

Earlier analysis found similar genetic patterns in populations of both common shrews and humans inhabiting the Celtic Fringe. Using those results as a benchmark, Searle and his team expanded the genetic analysis to the pygmy shrew as well as two species of voles.

Searle reasoned that if these shrews and voles had similar immigration patterns to early humans, perhaps those patterns would show up in their DNA. Specifically, he believes that “this study can help us understand why humans in the British Isles form a Celtic Fringe.”

Interestingly, Searle and his colleagues’ analysis revealed a division in DNA types for the shrews and voles similar to that separating the people of the Celtic Fringe and the rest of the British population. Further analysis revealed that the DNA types for the mammals living in the Celtic Fringe were quite old. So old, in fact, that Searle and his team propose that the arrival of these mammals traces all the way back to the post-Ice Age arrival of humans 12,000 years ago.

If the mammals living in the Celtic Fringe date back 12,000 years, the people living there could as well.

There is one problem with this hypothesis. The Celts themselves only arrived from mainland Europe 3,000 years ago, not 12,000 years ago. Conventional wisdom states that the Celtic Fringe only evolved after the Celts were pushed back following the invasion of the Romans and Anglo-Saxons.

How does Searle explain this discrepancy? He and his team argue that the Celtic Fringe is not actually Celtic in origin. Rather, its presence predates the arrival of the Celts and their arrival only ‘reinforced’ a pre-existing division that was already there.

In that case, it would have been the Celts themselves whose arrival pushed earlier inhabitants to the isolated corners of the British Isles. Subsequent migrations would have pushed the Celts into these same corners, which is why the language and culture of these regions are inherently Celtic. And that would also explain why the languages, culture, and history of the pre-Celtic people of Britain have mostly been lost to time.

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Malaria is one of the leading causes of death in the developing world, claiming nearly a million victims each year. The great majority of them are African children below the age of five. The illness is caused by a single-celled parasite called Plasmodium that is transmitted by mosquito bites to humans. In a paper published today in Nature Genetics, a group of African and British doctors and scientists report on their study of the genetic roots of malaria susceptibility. They found no new smoking gun with this effort, but learned much about how to improve African genetic studies in the future.

The researchers gathered the SNP genotypes of 2,500 children, with the consent of their parents, from a small region in The Gambia. About 1,000 of the children had been admitted to the hospital with a case of severe malaria — the other 1,500 were newborns. In a genomewide association study, the researchers checked each of a half-million SNPs (single nucleotide polymorphisms) for sharp differences in genetic composition between the group of children suffering from malaria and the group of newborns, who served as an approximation of a malaria-free group. If one version of an individual SNP was seen at high frequency among the malaria victims, but at low frequency in the newborns, then the difference might be because the SNP tends to cause malaria or is nearby one that does.

Upon scanning their data, the researchers came up more or less empty-handed: by the usual standards of the field, none of the 500,000 SNPs would pass muster.

This deflating result stands at odds with what is known already about the genetics of malaria susceptibility. Most people who have taken a biology class learn that human populations in malarial regions have developed a natural immunity to malaria infection, not through their immune systems, but through a genetic modification of hemoglobin. Hemoglobin is a molecule charged with ferrying oxygen from your lungs (and the lungs of most life forms that have them) to all your cells, an essential task. Biologists have traced hemoglobin-based malaria resistance to a change at a single DNA base pair on chromosome 11 — wouldn’t we expect at least this SNP to light up as significant?

In truth, the failure wasn’t so surprising; it arises from the interplay of genetics with our species’ history. Humans first arose in Africa, so that’s where genetic variation has had the longest time to build up. Modern-day Asian, European, and Native American people descend from people who emigrated from Africa about 50,000 years ago. These migrants carried just a subset of the African gene pool with them, so non-African populations today have much less “well-mixed” genomes than African populations. The present study uses genotyping chips developed for use in European populations, and its failure to find the known hemoglobin SNP (which isn’t even genotyped by the chip) and other known genetic contributors to malaria resistance is essentially due to the fact that you’d need more like two million SNPs than half a million to do the job right.

The solution, you’d think, is just to make a chip with a lot of markers for specific use in Africa, and be done with it. But the authors show that African genomes appear to be mixed so well that no single such chip could be designed. Instead, they propose an alternative approach: use a good but inevitably suboptimal African SNP chip in your full study sample, then obtain full genome sequences from a small number of the members of that sample. Then, using a powerful statistical method called imputation, you use the full sequences of the smaller group to fill in the full genomes of the entire study sample based on their SNP genotypes. This approach, as the authors demonstrate convincingly in the case of hemoglobin-based malaria resistance, would provide a statistically powerful and economically viable means of tracking down the causes of some of the most challenging health problems of our time.

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For an insightful and thought-provoking essay on the present and future of personal genomics, as well as the role that 23andMe is playing in its advancement, check out Steven Pinker’s essay “My Genome, My Self” in this week’s New York Times magazine.

Pinker, who is a 23andMe customer himself and also a participant in George Church’s Personal Genome Project, recommends taking genetic data with a grain of salt. Because as we often point out on The Spittoon, genetics is not fate and the science is still evolving.

Pinker, for example, has discovered that he has a genetic variation that increases his chances of going bald. Considering the man’s trademark thick and curly tresses, that one genetic toggle is not the whole story.

Pinker recommends personal genomics if you’re curious about how the countless genetic discoveries that are being made almost daily may apply to you personally, and might be relevant to your health down the road. And, we might add, becoming part of the 23andMe community also gives you the opportunity to help advance genetic research into diseases, conditions or traits that interest you. Combined with our community features, which let you find people with whom you share elements of nature AND nurture, personal genomics has great potential to become a tool not just for utilizing scientific advancements but making new ones as well.

As Pinker makes it clear however, personal genomics is not about to supplant, or even supplement, preventive medicine any time soon. “If you want to know whether you are at risk for high cholesterol, have your cholesterol measured,” he rightly recommends. (For some other takes on the Pinker piece and the state of personal genomics, check in with our colleagues at Gene Expression and Genetic Future.)

One of the most fascinating, albeit technical, parts of the essay is Pinker’s prediction that personal genomics will have more success elucidating the genetic underpinnings of personality than intelligence. Assuming from an evolutionary standpoint that it’s better to be smarter (it also kind of depends on how you define intelligence, but we won’t dwell on that), then over the millennia natural selection has done the work of deleting any genetic variations that substantially decrease intelligence but left intact hundreds or thousands that have negligible influence. Thanks to their tiny effect, those variations will prove very difficult to identify.

Evolution appears to foster large personality differences, on the other hand, because different types of people tend to thrive as the environment changes. Consider the recent history of the world’s financial markets — it’s easy to see how both pessimists and optimists could do well, though not necessarily at the same time. And it’s also easy to see how the number of bulls and bears could oscillate as first one side, then the other, got the upper hand. If you’re smart (and lucky) enough, you can make money in the market using either approach.

Evolutionary biologists call it balancing selection when two opposing traits are maintained in this way. And geneticists have had considerable success identifying genetic variations that have been subject to balancing selection, just as they have ones that make some people more adventurous, or prone to depression.

“It’s still a messy science, with plenty of false alarms, contradictory results and tiny effects. But consumers will probably learn of genes linked to personality before they see any that are reliably connected to intelligence,” Pinker contends.

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In a way, organ transplantation is the one branch of medicine that has already been personalized, because doctors must carefully match the immune systems of donor and recipient to prevent rejection.

Now transplant physicians in Germany have taken that procedure a step further by engineering not just a successful bone marrow transplant, but one that appears to have cured their patient’s HIV infection as well. The doctor who conceived the operation has suggested that in principle, the accomplishment could inspire a gene therapy for HIV. But it will take much more research, and a lot of luck, for that to happen.

This week Dr. Gero Huetter and his colleagues at the Charite Hospital in Berlin announced that they were treating a 42-year-old patient who required a bone marrow transplant for leukemia, but had also been HIV-positive for a decade.

The doctors knew of a gene, CCR5, that confers resistance to the most common form of HIV. People who have a particular mutation, known as Delta32, on both copies of CCR5 can be exposed repeatedly to HIV-1 without becoming infected.

23andMe customers can learn their CCR5 status by referring to the Resistance to HIV/AIDS report in our Health and Traits section.

The doctors reasoned that if they could find a donor who was not only immune compatible with their patient, but also had two copies of the Delta32 mutation in the CCR5 gene, perhaps they could simultaneously eradicate his leukemia and his HIV infection.

Remarkably, such a donor existed. And 600 days after his bone marrow transplant, the patient is both leukemia- and HIV-free.

Is this a cure for AIDS? Not a chance. Doctors do not consider the procedure a potential treatment for HIV, because bone marrow transplants are expensive and risky — about one patient in four does not survive the procedure. But the case does provide inspiration and hope for researchers who are working on ways to harness the resistance conferred by CCR5Delta32 to treat the infection.

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Like many Americans, Vincent Vizachero knew only bits and pieces about his family history.  He knew, for instance, that his paternal grandfather emigrated to America from Italy in 1914. But because his grandfather died long before he was born, Vincent did not hear a lot of family stories growing up.  So he had to dig them up himself.  In his research, Vincent discovered that many people with his surname seemed to have come from the same small region in Italy.  He wanted to find out if all people with the Vizachero surname are somehow closely related.

The more he dug, however, the more roadblocks appeared in his way.  Three generations of civil and parish records in his grandfather’s hometown from the late 19th century were destroyed during World War II.   There was a gap between 1860 and 1910 where no information existed.

Problems like these often arise with genealogical research. But instead of giving up, Vincent decided to turn to another method — genetics.

As it turns out, Vincent is not alone.  Many genealogy buffs use genetics to enhance their research on family history.  In 2005, a group of genealogists formed the International Society of Genetic Genealogy (ISOGG), kicking off a grass roots effort to incorporate genetic data into the fold of genealogy.  By this time, companies like Ancestry.com and Family Tree DNA had been offering genetic testing for about five years, giving genealogists who had pored over historical records for years a completely new kind of information.

Many used DNA from the Y-chromosome, which is passed from father to son the same way surnames are passed down from one generation to the next.  Communities began to form, taking genetic data and trying to relate it to their own family histories rather than the broader scale addressed by academic researchers.  ISOGG began developing a ‘family tree’ based on genetic data from thousands of Y-chromosomes from hundreds of families around the world.  Some genealogists, like Adriano Squecco, have worked tirelessly to organize these data together into a sharable format for anyone to view.

As data from thousands of individuals began rolling in, communities realized that many of the results coming back were quite similar – most people were being classified within very common branches of the Y-chromosome tree.  The people with the most interesting or unique DNA were usually not getting themselves tested.

Instead of waiting for academic researchers to find and genotype these individuals, a few enterprising genealogists, including Vincent Vizachero, decided to take matters into their own hands.  They started a fundraising effort, where people can donate money to buy the 23andMe Personal Genome Service for individuals with potentially interesting or unique genetic ancestry.  At first they tested more people of western European ancestry, to add detail in that already well-known part of the Y-chromosome tree. Now they are focusing their efforts on testing people of African descent, in an attempt to flesh out the genetic ancestry of the notoriously under-studied continent.  The major organizers of the effort have set up a website to keep track of their fundraising, along with periodic updates on their progress.

But why have Vincent and the other organizers chosen 23andMe’s Personal Genome Service^TM , when there are so many different companies that test genetic ancestry?  “The decision was really about cost-effectiveness,” says Vincent.  “23andMe is including over 1,800 usable Y-SNPs for less than $400.  So the 23andMe service allows us to cover a lot of ground much more quickly than any other method of testing would allow.”

In addition, 23andMe allows customers to download their raw data.  While the casual customer may not use this feature, genetic genealogists relish the fact that their raw data is available for them to examine and manipulate.

What’s more, 23andMe provides other hereditary information that can be of interest to genealogists.  Some are using 23andMe to examine hereditary health and traits issues within their family trees.  And with the Family Inheritance feature, customers can see how various traits have been passed from generation to generation.

For genealogists, a thriving community is vital.  Such communities have been the cornerstone of traditional genealogical research for many years, and the addition of genetic data has only compounded their importance. Genealogists have even been able to contribute to science by helping identify new branches to the genetic family tree.  As their fundraising project continues to gain steam, Vincent and the other project organizers are pleased with the amount of information they have been able to extract, and how important the genealogy community is in fostering its development.  We at 23andMe recognize the importance of working with the genetic genealogy community and ISOGG to provide our customers, and we are thrilled that we can help this community flourish!

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When 23andMe launched last November, we set out to make genetics accessible to everyone – not just the experts.  So we created a series of education videos called Genetics 101. These videos educated viewers on the basics of genetics:  What is a gene, what is a SNP, how genes are inherited from generation to generation, and a host of other useful topics.

But understanding your genetic code is only part of what the 23andMe Personal Genome Service^TM offers its customers.  We also want our customers to understand their genetics in the context of human evolution:  How did our species evolve, how did we come to populate the globe, and how can we account for the diversity of peoples living today on our planet?

Those questions are the basis for a new series of videos, dubbed Human Prehistory 101. Using the same creative team as with Genetics 101 (led by chief illustrator Ariana Killoran), we developed a series of videos that tell the human story, from the birth of our species to present day.  The first installment, the Prologue, was released last week on 23andMe’s website.

The Prologue sets the stage for the human story, beginning with our closest living relatives, the chimpanzee.  We then see how the earliest humans lived in Africa nearly 200,000 years ago, and follow some of our fossil ancestors such as Homo erectus — who ventured into Asia long before we did.  We also learn that our evolutionary cousins, the Neanderthals, were not so very different from early humans; they cared for their sick and even buried their dead.

This installment will soon be followed by others, each tackling a key chapter in the evolution of our species.  Future videos will explain how and when humans ventured out of Africa for the first time, how they survived the Last Ice Age, and how they came to populate so many parts of the world. So be sure to stay tuned for more Human Prehistory 101!

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The practice of monogamy – the most popular mating practice on the planet today – is nothing new. In fact, anthropologists have found evidence of monogamous relationships in Homo erectus, a human ancestor that lived nearly 2 million years ago.

But the alternative to monogamy – polygamy – though not nearly as popular in today’s world, has long been a part of our species’ history as well. In this week’s issue of PLoS Genetics, human geneticist Michael Hammer and his team have found evidence that polygamy — and specifically polygyny, the practice of one man taking multiple wives — was widespread enough in the ancient past to leave its mark in the human genome.

The X chromosome is a very important bit of DNA. Having one versus two copies of the X chromosome determines whether you are a boy or a girl, and many famous diseases can be traced to the inheritance patterns on X. Scientists have often assumed that because the X gets passed down at a slightly lower rate than the 22 paired chromosomes (women inherit two X chromosomes, but men get only one) it would be proportionately less diverse.

Upon closer examination however, the opposite appears to be the case. As part of the study, researchers examined the DNA of isolated populations around the world, including the Biaka Pygmies of Central Africa and French Basque from the Pyrenees Mountains. What they found was that there is in fact more genetic diversity worldwide of the X chromosome compared to the biparentally inherited parts of the genome. Not only that, the authors found that this genetic diversity is heavily skewed towards females.

Hammer and his team propose that this high amount of X chromosome diversity can be directly related to polygyny. Their reasoning:

In polygynous societies, because single men have children by multiple wives, the number of males contributing to the genome is lower than it would be if each woman chose a different mate.

The effect of that decrease in genetic diversity should be roughly equal for the 22 biparentally inherited chromosomes, because half of the DNA they contain comes from the paternal side.

But that’s not true of the X, because although girls get one X from each parent, boys get only one — and it comes from mom. So all other things being equal, the X chromosome is a primarily “female” chromosome. Any decrease in genetic diversity due to the under-representation of men in the breeding population will have less of an effect on it compared to the rest of the chromosomes.

This is exactly what Hammer and his colleagues have found — increased genetic diversity on the X chromosome compared to the rest of the genome. That pattern, they argue, is a smoking gun that proves the existence of polygyny in the human past.

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A good diet and plenty of exercise are important for maintaining a healthy weight, but they’re not the whole story. Studies have shown that there’s a substantial genetic component to body mass index. Research published today in Archives of Internal Medicine demonstrates, however, that in people with a genetic predisposition for obesity, DNA is not necessarily destiny.

Scientists studying about 700 Old Order Amish men and women in Pennsylvania found that SNPs in a gene called FTO were associated with being obese or overweight. These associations, however, applied only to people with low physical activity levels. In people categorized as highly active for their age and sex, their FTO variants didn’t make a difference.

(A SNP in FTO, distinct from the variants described in this new research, is featured in the 23andMe My Health and Traits article on obesity.)

The high and low activity groups differed by about 900 kcal/day in their energy expenditures — the equivalent of three or four extra hours of moderately intensive physical activity like brisk walking, house cleaning, or gardening. While this might seem like a lot of activity, the authors point out that it’s typical for the lifestyle of the Old Order Amish, who farm without the aid of modern machinery.

Additional research is needed to determine the lower bound of how much exercise is really needed to negate the effect of an FTO-related genetic predisposition to weight gain. And then comes the hard part – figuring out exactly how the FTO gene influences weight and why physical activity seems to modulate its effect.

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As science types, we’re often mystified — and maybe just a little exasperated — by the details of health care policy. But 23andMe director Esther Dyson has a very interesting post on the blog of the policy journal Health Affairs that we recommend.

It’s very interesting to hear what Esther, a person who often seems to be thinking a few steps ahead of the rest of us, has to say about what will happen as consumers take a more active role in their own health care:

Years ago, Intuit’s Quicken let people manage a checkbook online and print out checks. As the world moved online, Intuit built interfaces to the online banking services of certain major banks so that users could upload and download their financial information. Pretty soon after that, the less-popular banks built their own interfaces to Quicken in order to capture or regain market share. None of them really wanted to let users mingle data from one source with data from another . . . but of course it happened. And now, users can use Mint or Wesabe [a company that Esther invests in] not just to mingle data but to analyze it, to compare their own spending patterns with others’ and (here’s the business model) to receive “offers” from other financial institutions based on those spending patterns.

I expect exactly the same thing to happen with health information. And, just as banks compete (mostly with success) to keep customers’ money and data safe, so will the organizations that handle users’ medical information. This doesn’t actually require any legislation or standards to happen. Companies are already emerging that will provide interfaces to the IT systems of market-leading health care and insurance providers; eventually, the laggards will adapt to the market standards set by the leaders.

Once those standards are in place, Esther predicts that our health care system will benefit greatly from the availability of all that data. For one thing, the availability of data will enable research that leads to better treatment. But perhaps most provocative is the prospect that health providers could be rewarded not just for going through the motions, but actually improving their patients’ lives.

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Last weekend I attended Science Foo Camp, a sort of grown-up summer camp for scientists sponsored by Google (an investor in 23andMe), Nature Magazine and O’Reilly Media.

Aside from the science itself (which is worth many blog posts on its own), one question really grabbed my attention: What motivates people to do science in the first place?

23andMe Director Esther Dyson weightless.

In two different sessions, I felt that scientists were ignoring one critical element of the equation — themselves.

Compelled by Curiosity

Many scientists say they do what they do out of a thirst for knowledge. Yet in the 23andMe session, I found that many researchers don’t recognize curiosity as a motivating factor when it extends to oneself.

There was a sense that of course scientists are interested in scientific data. But why would “normal people” want to use 23andMe for anything other than health care information? Many scientists at the session seemed to think that if you’re motivated by personal curiosity rather than “serious health concerns,” your curiosity is somehow less legitimate. Ironically, this is at a time when we are all struggling with how to get kids interested in science. Why not appeal to people’s innate curiosity and fascination with themselves?

I’m lucky enough to have about 30 family members plus another 80-odd people in my personal circle of friends. I love combing through the data to see how everyone compares to me and one another. (You’re welcome to add yourself! My user name is edyson, and I will accept an invitation at whatever level you set. NOTE: I will freely disclose your overall similarity to others, and your ancestry painting, but not the health information unless you give permission.)

At SciFoo, I encountered a 23andMe customer who was adopted. “The first time I saw a blood relative was when my first baby was born,” she said. “I wanted to know more about my own kids.” Did she find out anything “serious” or actionable? No, but she satisfied a lot of curiosity … and indeed, she now knows something about health issues her child may face down the road.

Data = notches on your belt

In addition to curiosity there’s money, which scientists mostly hate to discuss in public, but which is fairly well understood as a motivator for some scientists – not to mention for all the engineers, applied scientists and others who turn scientific insights into useful technology and products. 

But there’s another motivator that seems to be less understood or acknowledged. I’m not sure of the best word to describe it, but it’s an interest in being part of the effort and being acknowledged for it, sometimes leavened by fascination with one’s own data (either alone or compared with others’).

This came up in a session I attended about data-sharing. The focus was mostly data about insect species, viruses and human medical records, but it could just as easily have been genetic data.

The discussion reflected how science has changed over time. In the past, much of it was about individual discovery and experiments. But increasingly we need lots of data, collected by lots of people, to make progress. Yet scientists, and even more so scientific institutions, often operate in a climate of secrecy – at least until their results are published in a peer-reviewed journal. But what if you need the data before you can produce the results?

In science as in sports, teamwork can mean the difference between victory and defeat. At the Beijing Olympics, one of the big stories is how Michael Phelps swam to victory by following a teammate who let him swim in his wake until the final sprint, when Phelps was able to use the energy he had not expended earlier in the race to win it. That’s a benefit of collaboration.

There’s also the odd but totally understandable fact that Olympians tend to set records in competition, when they’re trying to beat another person. (I know I personally always swim faster when there’s someone about my speed in the next lane.)

Scientists aren’t immune to such effects. Biologist Dan Janzen and medical researcher/doctor Scott Layne both talked about how scientists like to add data to the pot in a way that gets them recognition for their contributions – karma points so to speak. On Flickr, you post photos. In science, you post data … and you can measure your contribution to the general welfare not just in citations, but in page views, reuse, whatever. The tools for doing that are still being developed. Meanwhile, through 23andMe and PatientsLikeMe, a social network for patients with ALS or Parkinson’s, even individuals can play by contributing their own data (medical or genetic) rather than isolating enzymes in a lab or bugs in a hospital.

Scientists may scoff, but I’m sure the evidence will show that social recognition can do a lot for science.

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