Here’s how it goes for me: a few afternoons a year, usually when I haven’t slept or eaten right, but sometimes for no apparent reason, I begin to sense a pressure behind my left eyebrow and to feel queasy. By now I know what’s coming, and I resign myself to another miserable evening and a coming day or two lost to indistinctness. I rush home and secrete myself in the coolest, darkest spot I can find, because for each of my senses the volume seems to have been cranked to amphitheater-level. I lie there for four or five hours, a dog on a leash, thinking grim thoughts and, despite myself, yelping every now and again when the pain ratchets up. Perhaps you know somebody with migraine and are familiar with the vocabulary they use to capture the experience: ‘throbbing’, ‘nauseating’, ‘excruciating’ and the like. All true. Respite comes only when my stomach has had too much and returns my lunch — normally one wants to avoid this outcome, but here I welcome it, court it even, which I’ve always found darkly funny. Then I fall into a dreamless sleep. While some don’t have it as bad as me, many have it far worse.

With the launch of our new migraine headache survey today, we at 23andMe invite you all to share your headache experiences, whether you’re one of the lucky few who’s never had even a little one or someone who must deal with the threat of migraine pain on a daily basis.  You needn’t be a 23andMe customer to take the survey (although we recommend it). All you need is a free 23andMe account.

Migraine headaches are nasty things. The common feature is a terrible pulsing pain emanating from inside the skull, usually just on one side, but apart from this everyone experiences them a bit differently. Some unlucky folks get them every day, while others get them just once a year. Migraines can last for a few hours or can pound on for days at a time. Then there is the menagerie of symptoms that can accompany the headaches, including nausea, vomiting, visual or aural illusions, and aversion to light, smell, touch and/or sound. Perhaps most variable across people are the causes of the headache, or triggers. For one person the triggers might be red wine or nuts, for another they might be stress, bright lights, or noise.

There is a wide array of treatment options for migraine. With guidance from their doctors, most migraine sufferers nowadays are able to find partial or full relief from their headaches. Despite the effectiveness of these treatments, the basic biology of the disease is not well-understood¹,  and migraine continues to exact a tremendous physical and economic toll on our society².

Two prominent migraine researchers have suggested that the blame for the slow progress in understanding migraine lies with a systemic lack of public funding for migraine research. They argue that the relatively recent, and incomplete, acceptance of migraine by the medical and research communities as a genuine medical problem, as opposed to mere melodrama, has led migraine’s funding to lag well behind that for diseases of similar impact. For example, they estimate that while $13.80 is spent for each sufferer of asthma, just 36 cents of federal research funds are spent per migraine sufferer.

The genetics of migraine are also only partially understood. That’s where our new survey comes in. Our community-based research program 23andWe seeks to empower the public to engage in genetic research from the ground up. We know our efforts cannot substitute for proper federal support of migraine research, but evidence of great public interest, plus a new finding or two, would add to our understanding of the disease and potentially send a message to Washington.

With all haste, then, please head over to the new migraine survey and be counted!

Footnotes:

1. What is understood of its biology and chemistry is fascinating, and summarized well here.
2. Nearly 40 million people in the US, and a similar number in Europe, suffer from migraine, roughly one in every ten people. Migraine occurs in women about three times more commonly than in men. Migraine is estimated to cost  around $23BN/year in the US and Euro27BN/year in Europe in direct medical costs and in indirect costs, such as lost productivity.

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Mutations are bad, right?

Not always.  Some DNA changes are completely neutral. That’s how the human genome came to have so many variations. And some mutations are actually advantageous.

A case in point is the PCSK9 gene. So-called “loss-of-function” mutations that prevent the protein encoded by this gene from functioning properly actually lead to lower cholesterol levels.

Researchers at several pharmaceutical companies have taken inspiration from these PCSK9 mutations. They are now developing drugs that would block its function in people with non-mutated forms of the gene.  These drugs, though still in the early stages of testing, may offer a new way for the tens of millions of Americans with high cholesterol to get their levels under control.

The PCSK9 protein binds to LDL cholesterol receptors on the surface of cells.  Once cholesterol binds to the receptor too, the whole complex is internalized into the cell, and the receptor is degraded.  When PCSK9 function is missing, the LDL receptor is able to recycle back to the cell’s surface after dropping off its cholesterol cargo in the cells, allowing it to sop up more “bad” cholesterol from the bloodstream.  There doesn’t seem to be any downside to the cholesterol-lowering PCSK9 mutations, suggesting that targeting the protein with drugs could be safe and effective way of reducing cholesterol.

One company, Amgen, is tackling the problem with antibodies that attach to the PCSK9 protein outside of cells, targeting it for destruction by the immune system.  Two others, Isis and Alnylam, are using small pieces of RNA designed to go inside cells and keep the PCSK9 protein from being made in the first place.  All three companies have shown reductions of LDL cholesterol in early animal experiments.  A review of their findings appeared recently in Nature Publishing Group’s Science-Business eXchange.

People who need to lower their cholesterol but can’t tolerate statins stand to benefit most from any PCSK9 inhibitors that are developed.  But these drugs might be good for those taking statins too.  High doses of statins can actually increase the amount of PCSK9 in the body.  Taking a PCSK9 inhibitor along with a statin could help cut off this potentially backtracking side effect.  Unfortunately, unlike statins, none of the PCSK9 inhibitors under development can be taken orally.  They all need to be delivered through an injection.

Many years of clinical trials are ahead for each of these drugs.  Researchers will need to assess both their safety and efficacy.  But it’s exciting to see a genetics discovery be so quickly translated into an idea that could help millions of people.

What This Means For You
23andMe customers can check their data for two (there are others) PCSK9 loss-of-function mutations:

• The T version of rs11591147 and the A version of rs28362286 have both been associated with decreased LDL levels.  Each copy of these variants leads to lower LDL cholesterol.

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It may be you’ve heard a rumor that males are on the brink of extinction.

Whatever you may think of that prospect, the rumor is false. But over the past decade, numerous studies have hinted that the Y chromosome, a male necessity, is going the way of the dodo.

Though other studies have suggested this idea may be a bit of an exaggeration, a new report this week suggests that the Y chromosome may indeed be endangered.

In most mammals, such as us humans, two chromosomes determine the sex of each individual organism:  the X and the Y.  If an individual’s cells contain two copies of the X chromosome, then they will be genetically female.  If they contain one copy of the X and another of the Y, they will be male.

Yet even though these aptly named sex chromosomes have a similar duty — to confer sex — the X and the Y could not be more different.  The most striking difference between the two is their size; the Y is less than half as big as the X, and contains only 78 genes, compared to the more than 2,000 found along the X chromosome.  The evolutionary history of the two sex chromosomes and the question as to why they are so different from each other has been the subject of heated debate for many years.  Now scientists at Pennsylvania State University believe they’ve found a way to uncover not only the difference between the X and Y, but how and why it arose and what this means for the future of the small, but essential, Y chromosome.  Their results are reported in the July 17 issue of PLOS Genetics.

The research team, led by biologists Kateryna Makova and Melissa Wilson, believes the key to understanding the origins and future of the Y chromosome lie in some of our most distant mammalian relatives.  There are three classes of mammals: egg-layers like the platypus, marsupials like the kangaroo, and the eutherians, which includes humans and thousands of other similar species.  While there are many differences between the three groups, one of the most striking is the difference in the organization of the sex chromosomes.  As Makova explained, “In eutherian mammals, the sex chromosomes contain an additional region of DNA whereas, in the marsupials and egg layers, this additional region of DNA [is not on a distinct chromosome, but] is [a region of] the non-sex chromosomes.”

The authors argue that the key to the origins of the X and the Y chromosomes may lie in this fundamental difference.  By analyzing the X and Y of humans compared to the sex-determining regions of marsupials and egg-laying mammals, Makova and Wilson found that the X and Y split from the other chromosomes about 80 to 130 million years ago.

But that is not all they found.  The authors also examined how fast the X and Y mutated over time, and noticed a startling change that occurred at about the same time as the split.  “Our research revealed that the Y-specific DNA began to evolve rapidly at the same time that the DNA region split into two entities, while the X-specific DNA maintained the same evolutionary rate as it had previously,” Makova explained.

In other words, as soon as the X and the Y split their own distinct chromosomes, the Y began to evolve much more quickly than its counterpart, mutating at a much higher rate with each new generation.  The faster the Y evolved, the faster its genes disappeared.  Whereas at one point the Y may have contained thousands of genes, that number has dwindled to the mere 78.

The disappearance of these genes over time and the small number of those remaining on the Y begs the question:  will the Y chromosome ever disappear entirely?  The authors believed this was an important question to answer as well, and began additional analysis to determine the fate of the Y.

Makova and Wilson reasoned that there must be some utility to the Y, or else it surely would have disappeared by now.  As Wilson states, “we know that a few of the genes on the Y chromosome are important, such as the ones involved in the formation of sperm … .  Although there is evidence that the Y chromosome is still degrading, some of the surviving genes on the Y chromosome may be essential.”  By performing additional tests, they found that there were indeed some genes on the Y that will probably never disappear entirely.  But they also found several genes that were already disappearing, and were likely to be gone many generations from now.

Some recent studies have produced evidence that the genes on the Y may not be disappearing as fast as was initially thought. But, according to Makova, the Y chromosome may not be out of the woods just yet. “We still think there is a chance that the Y chromosome eventually could disappear,” she says.  “[But] if this happens, it won’t be the end of males.”  Instead, she believes that a new pair of sex chromosomes will arise from the genome, latching on to those few remaining genes, keeping alive the genes necessary for male survival.

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The exact causes of Crohn’s disease remain a mystery, but scientists do know that genetic factors play an important part. More than 30 variations have been associated with increased risk for the disease, but changes in one gene, NOD2, have been found to be especially critical.  Three different variants in this gene have been associated with significantly increased risk for developing the disease.  It’s estimated that 10-15% of people with Crohn’s disease have two copies of one of these variants.

Because changes in NOD2 are associated with so many cases of Crohn’s disease, medications made to interact with the protein the gene encodes would seem to be obvious candidates for drug development.  But the NOD2 protein doesn’t have the type of function that can be modified by a drug.

A new avenue of drug research may have been opened, however, thanks to a study from Derek Abbott and colleagues at Case Western Reserve University.  In a paper appearing in the August issue of Current Biology, they show for the first time that a protein called ITCH can influence NOD2 biological pathways.  This is important because, in the parlance of pharmaceutical development, ITCH is a  “druggable” target.

NOD2 binds to bacteria that make their way into cells, setting off signals that activate the immune system. Research has shown that the Crohn’s disease-associated NOD2 variants decrease the signals that go through a particular protein called NFkB.  Abbott’s lab found that ITCH also decreases NOD2-dependent NFkB signals.  This is significant because studies have shown that increased NFkB signaling can help slow down the progression of Crohn’s disease.

“The thought is that if you could identify patients with NOD2 polymorphisms who also displayed early gastrointestinal trouble, you could block ITCH to increase NFkB signaling and not let the Crohn’s disease get to the acute stage,” Abbott said in an email.

Abbott and his fellow researchers are in the very early stages of looking for drugs that could be used to inhibit ITCH and possibly be useful in treating Crohn’s disease.  But the road to drug discovery is a long one.  ITCH interacts with many other proteins in cells and it’s not yet clear if blocking it would have unwanted effects on other important biological pathways. However, in the future this research could lead to a valuable drug against Crohn’s disease — at least for the 10 to 15% of patients who have variants that cause decreased NOD2 signaling.

(23andMe customers can check their data for three distinct NOD2 SNPs, as well as nine other Crohn’s disease associated variants, in the Crohn’s Disease Clinical Report.)

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My surname — Holden — has gone through many incarnations since it originated in England nearly 700 years ago.  Letters were added, then dropped.  Some branches of my family added an extra “u” in the middle, while others changed the pronunciation entirely.  Then, when my ancestors arrived in America over 200 years ago, the name went through a whole new set of changes.  It seems my surname has been in a constant state of change since its inception.

But the story of my surname is not unique.  Millions of Americans have similar stories about ancestors who, upon arriving in the New World, actively changed their names to sound more “American.” German immigrants named Blum became Bloom, Küsters became Custers, and Kÿfers became Coopers. Immigrants from Italy, Sweden, France, and countless other countries underwent similar transformations.  After just a few generations, the original spelling or pronunciation was lost.

Just as our surnames have changed over the centuries, little by little, so too has our DNA.  In fact, some regions of the human genome acquire mutations in such a way that researchers can trace the changes back through time – much like tracing a surname back for generations in a family tree.  And one region in particular, the Y-chromosome, happens to be passed down from father to son, the same way surnames are inherited in Western culture. That provides a wealth of opportunities for scientists from a variety of disciplines to use the Y-chromosome to unlock history’s secrets, unravel family trees, and even solve crimes.

The Genetic Legacy of the Vikings

The histories of Scandinavia and the British Isles have been entwined since Vikings from Norway and Denmark landed on the eastern coast of England in the year 792.  Successful raiding parties eventually led to settlements along the eastern half of England.  Today there are remnants of Viking settlements in this region in the form of place names, unique vocabulary, and even surnames.  Last year, British geneticists took surname information from an area formerly settled by Vikings to see if men living there today who had Scandinavian surnames also had evidence of Scandinavian (aka Viking) genetic ancestry.  They analyzed the Y-chromosomes of several hundred men, and, not surprisingly, found that those with Scandinavian surnames did indeed have Scandinavian DNA, at least on the Y-chromosome.  Similar studies of Irish men have also found a modest connection between surnames and Y-chromosome types.

Surname DNA Projects

As we reported several weeks ago, the field of genealogy has been invigorated by the increasing use of genetic testing to fill in the missing branches of a person’s family tree.  Genealogists are now comparing their Y-chromosomes to those of others with the same surname, to see if a shared surname is also an indication of the shared ancestry.  Within the past few years, surname DNA projects have sprung up all across the world – with hundreds of genetic genealogists digging deep into their genes as they piece together their detailed family trees.

Surnames and Forensics

By far one of the most interesting applications for surname and Y-chromosome comparison is in the field of forensic science.  In 2006, British geneticists found that – for some of the more rare surnames such as Maloy or Rivis, there was a strong connection between surname and Y-chromosome haplogroup.  The authors reasoned that, if DNA were to be recovered from a crime scene, forensic investigators might be able to narrow down the possible perpetrators to a specific subset of surnames.

However, there are several limitations to this idea – namely the fact that most men in the UK have rather common surnames, such as Smith, Green, and Adams.  Men with these surnames have a wide range of Y-chromosome DNA types, so it would nearly impossible for investigators to use the Y-chromosome to locate a suspect.  However, on principle this idea has merit, and further advances along these lines may someday allow investigators to exploit the DNA-surname connection.

One final note: 23andMe customers need not worry that their data will be used in this way — our research database does not include surnames and our terms of service do not allow us to share data with law enforcement unless we are legally compelled to. And even if such a situation did arise, we have publicly committed to resisting legal requests for customer data.

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23andMe is all about empowering you to really get to know your own DNA. But we also have tools that let you share and compare your data with family and friends.

All you need to do to share your genome with another person is send an invitation from the Genome Sharing page of your account. You’ll need a person’s username, which can be found by searching with a first name, last name, or email address.

(Only people who have added their full name to their public profiles will be searchable. If you know someone who’s signed up with 23andMe but isn’t searchable, you can just ask for his or her username directly.)

Not sure whom to share with? Why not start with 23andMe founders Anne Wojcicki and Linda Avey? Both are ready and waiting to accept your invitation to share genomes at the Basic level.

23andMe board member Esther Dyson is also willing to share. She’s accepting both Basic and Extended sharing invitations. She’d like to hear about who you are and why you’re interested in sharing. Drop her a line at edyson@boxbe.com and be sure to put 23andMe in the subject line.

At the end of this post, there’s a list of more people looking to share.

If you’re interested in sharing your genome with friends you just haven’t met yet, leave a comment here at The Spittoon. Include your full name, the level of sharing you’re comfortable with, and a little bit about yourself or what you hope to learn. And make sure to add your name to your public profile so people can find you! (While you’re at it, why not also add a profile picture so you’re not just another gray silhouette?)

• Matt Crenson
  Basic
  “I’m looking for people who might be distantly related to me, especially on the paternal side. Unfortunately, my paternal haplogroup is the incredibly common R1b1c.”
• Iram Mirza
  Basic
  “I’m maternal haplogroup U5, I love my Ancestry Painting, and I can’t stay up past 9 pm!”
• Anne Holden
  Basic
  “I have a very rare maternal haplogroup (H11) and I’m really interested in finding other H11’s so we can see how our ancestries compare!”
• Alex Coonce
  Basic
  “I’m interested in seeing the true power of sharing.”
• Becca Ling
  Basic
  “It’s fun to compare ancestry!”
• Andro Hsu
  Basic
  “I’m looking for fellow Asians, and for any long-lost Spanish relatives.”
• Rachel Cohen
  Basic
  “I am interested in finding others with my maternal haplogroup, K2a2a. Specifically, I’ve heard that Ashkenazi Jews often have half identical segments on the Genome Comparison Feature. I want to see if anyone shares segments with me.”
• Lawrence Hon
  Basic
• Rajiv Mahadevan
  Basic
• Erin Davis
  Basic
• Denali Lumma
  Extended
  “I am happy to share my genetic data because it is simply what I was given at birth, not what I have made of myself. I would also be curious to see the genetic data of others willing to share.”
• Oliver Ryan
  Extended
• Jonathan Hansen
  Extended

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Consider Erin Mendel, a member of the family whose data is visible both to customers and holders of free demo accounts. Using the Compare Genes feature (reproduced below), you can see that among the genes associated with pigmentation Erin is closest to her brothers and mother, and less like her father Greg.

The Cards You’re Dealt

Assign each of your grandparents a suit – spades, hearts and so on – in a deck of cards. In the game of inheritance, their chromosomes (or chunks of genes) are shuffled (or recombined) and then dealt to their children so that each grandparent contributes one chromosome out of each pair. Your dad then ends up with 23 chromosomes of one suit from his father, and 23 of another from his mother. Your mom has a similar set of paired chromosomes from her two parents. So when your parents’ chromosomes

are shuffled, mixed together and dealt in turn to you and your siblings, you end up with a mix of chromosomes bearing all four of your grandparents’ suits. The illustration on the right shows the proportion of her genes that Erin inherited from each grandparent.

Since each child’s genetic information is produced by shuffling and dealing a new hand from the same genetic deck, there are going to be segments on their chromosomes where siblings are completely identical (having gotten the same suits from mom and dad). If a pair of siblings got the same chromosomal segment from one parent, but not from the other, they will be what geneticists call “half-identical.” In general, parents are half-identical to their children everywhere, because they passed their offspring one out of each pair of chromosomes. The exception is when two parents are related to each other.

Family Comparisons
Using the Family Inheritance option, Erin can see which segments she shares in common with various members of her family.

On the Genome-Wide Comparison chart, bars representing the 22 chromosomes and both X and Y chromosomes can be dark blue (representing a full match), light blue (“half-identity”), white (no match) and gray (not enough information). Below is a comparison of Erin and her father, showing only the first six chromosomes. Erin is only half-identical to her dad throughout her genome because one of her chromosomes out of each pair came from her mom Lilly.

So what does this all mean? Let’s consider the following example. When Erin compares herself to other people at the immune system compatibility trait, she sees red triangles above a region of chromosome 6 known as the MHC, or major histocompatibility complex. The human MHC is known as the HLA (human lymphocyte antigen) system. These genes determine how the immune system recognizes and distinguishes bacteria and other foreign invaders from the body’s own tissues. Aside from tests to verify that the blood types of donor and recipient match, the HLA system is what gets checked to minimize the chances that a transplant recipient’s immune system will reject the organ or tissue donated.

Because they are unrelated, Erin’s parents Greg and Lilly have no identical segments in the HLA system so they probably wouldn’t be a good match for each other. One’s histocompatibility, as this gene harmony matching process is known, is inherited.

On the other hand, Erin might decide to make sure her brother Ian gets great birthday and Christmas presents from now on. When Erin does the one-on-one comparison with Ian using the Family Inheritance option, the results on the right suggest that he might be the best match for her if she ever needs a new kidney or some bone marrow. With “completely identical” HLA systems, the chances are good that they could donate marrow or a kidney to each other without immune rejection.

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Neanderthal and Homo sapiens skeletons side by side. The thicker femurs, different eye sockets and barrel-shaped chest of our distant relatives are prominent in this comparison.

Mining the past: The Neanderthal Genome Project
The first invited speaker at the SMBE 2008 conference was Svante Pääbo of the Max Planck Institute for Anthropology in Germany. Pääbo and colleagues continue their incredible project to sequence the Neanderthal genome. Neanderthals are especially interesting in understanding our own history; they were another animal that walked upright, hunted with weapons, used clothes, and had culture, traits we consider very “human.” Pääbo presented some new findings that may change the way we think about our own history and that of our distant cousins, who went extinct around 25,000 years ago.

So far, the project has sequenced more than 3 billion Neanderthal DNA base pairs. The figure sounds impressive, and it is. However, sequencing ancient DNA is subject to contamination and in fact more than 99% of the DNA Paabo’s group extracts from Neanderthal bones is from bacteria, fungi or other organisms – including modern humans.

Scientists have debated for decades whether Neanderthals and humans interbred. So far, the Neanderthal genome does not show any evidence of having human ancestry. But the recent split between humans and Neanderthals has resulted in some sharing of genetic material between the species. That is, some people may share versions of SNPs with Neanderthals, but this sharing traces to a common ancestor who lived before the two species split about 800,000 years ago.

One especially interesting finding by Paabo’s group was in the so-called “language gene,” FOXP2. Humans have a very different version of FOXP2 than most other mammals, birds, and reptiles. Rare deletions in the gene cause people to have trouble with speaking and comprehension, providing support that the gene is important for language. Interestingly, other verbal mammals also have changes in FOXP2.
Scientists had thought the “human” version of FOXP2 arose within the last 200,000 years, since the origin of Homo sapiens and long after the human lineage split from Neanderthals. However, it turns out Neanderthals share the human version of FOXP2. These results indicate that something else happened in human history to make FOXP2 appear younger than it really is; and that this may not be related to the unique version of the gene shared by humans and Neanderthals.
So, is FOXP2 the gene that makes us unique from other animals? No. But could it still have played an important part in our own history? Probably. Just one of the many mysteries that evolutionary geneticists hope to answer.

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Art Nouveau architecture at the Codorníu winery outside of Barcelona.

So much new research was discussed in Barcelona it’s hard to decide which were the most notable presentations. But here are a few of the ones I found most interesting:
Were humans shaped more by history or local environment?
A major debate in the human evolutionary genetics talks and posters considered the origin of the genetic differences seen in humanity today: Were they shaped more by populations splitting apart and coming together, or evolutionary adaptation to local environments? Interestingly, people from the lab of our SAB member Jonathan Pritchard presented arguments on both sides. Both talks presented strong evidence using similar data sets. Perhaps one phenomenon has more impact locally and the other more regionally. Certainly the debate continues.

James Cai and coauthors from Stanford (including our very own R&D scientist Mike Macpherson) and The Hebrew University of Jerusalem showed that the history of the human genome cannot be explained simply by neutral variants – variants that do not cause a functional change. All across the genome there is evidence of “selective sweeps” where an advantageous version of a gene quickly increased in frequency in a population or species. For example, the gene FOXP2 has undergone a selective sweep in all humans within the past several hundred thousand years and may have contributed to our ability to use advanced language. More recent selective sweeps in the Duffy and Lactase genes (both have variants that 23andMe customers or demo account holders can read more about in My Gene Journal (now called Health and Traits)) happened after human populations diverged and thus didn’t sweep across the entire globe but are confined to specific regions: primarily western Africa for the Duffy-0 variant and Europe, the Near East, eastern Africa, and southern Asia for Lactose Tolerance.

Selective sweeps tend leave evidence in the form of nearby DNA that gets dragged along with the variant as it sweeps across a population. Similarly, new variants that are disadvantageous (or become disadvantageous when, say, moving into a new environment) can leave these similar signals as they are dragged out of the population. However, it is often difficult to separate out effects of population history from these selective forces. By using a novel statistic that controls for population history, Cai and colleagues show that many locations on the human genome have been affected by these selective sweeps. While previous scans for positive selection required these selective sweeps to be incomplete (see here and here, for example), the authors use a metric which can go back even further to look at the timing and strength of selective sweeps which have affected the entire human population, even going back as far as one million years. This work is an extension of previous research on Drosophila.

Interestingly, one of the data sets used for this work was the complete genome of Jim Watson, who co-discovered the structure of DNA.

Population Structure, History, and Migrations
Sarah Tishkoff of U. Penn gave a talk on her incredible data set of sub-Saharan African populations. So much of the world’s genetic diversity is located in this region, yet its inhabitants have been relatively under-sampled so far. Tishkoff’s data, in the context of global variation, makes it apparent just how important it is to understand the history of sub-Saharan populations in order to understand the history of our species. In one example, Tishkoff used a technique known as Principal Components Analysis (PCA) to collapse all their genetic data into three dimensions. Individuals near each other in PCA are more similar. In her plot, a hunter-gatherer population from Tanzania known as the Hadza can be found in their own dimension on the plot, which suggests that the Hadza, while having a small population size, have been isolated for a long, long time and are quite divergent from other populations, even including the 52 in the CEPH-HGDP data.
Tishkoff also showed how difficult it is to extrapolate from one African population to the next, even if they neighbor each other. One example of this is in parts of western Africa where the Fulani have increased malaria resistance compared to other groups such as the Mossi and Rimaibe – even within the same town.
Several talks and posters looked at the new lactase persistence variants discovered last year in sub-Saharan Africa and the Near East. These variants are functionally the same as their much more common counterparts, which allows Europeans and South Asians to drink milk into adulthood without experiencing lactose intolerance (23andMe customers can look up their genotype for this variant in My Gene Journal (now called Health and Traits)). But because they differ genetically, these newly discovered variants illustrate the importance of milk digestion for populations that relied on herding in their past. Multiple research groups showed that the eastern African persistence variants made their way down to the San Bushmen and neighboring populations of southern Africa.
When normal inheritance breaks down

Genomic imprinting in action. Here, the color of the offspring comes from the father, regardless of which genotype he has.

Andrew Clark of Cornell has been looking at versions of genes in mice that change the traits of offspring depending on whether they are inherited from the mother or father. This phenomenon, called Genomic Imprinting, has been detected in many mammals before, including humans, although interestingly it isn’t found in marsupials or the egg-laying monotremes like the Platypus. However, the traits affected by genomic imprinting have not been surveyed using a genome-wide approach.
Clark and colleagues used the Solexa sequencing platform to look for differences in the mouse brain between mice crossed from two different strains. By switching the strains of the mother and father researchers can detect traits that derive exclusively, or “imprint on”, one parent.
It turns out a good number of genes exhibit genomic imprinting Genes imprinted on the father tend to show only the trait of the father. Genes imprinted on the mother tend to let some of the father’s trait come through, albeit at much lower numbers. In addition, the researchers found differences in the organs affected by imprinting: genes imprinted on the mother were more likely to be expressed in the reproductive organs and those imprinted on the father were found more in the brain.
It appears that imprinting has no immediate benefit for offspring and may have originated in mammals completely by accident, a quirk of our histories. But learning about how imprinting evolved will help us understand how they came to be.

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The Stormtroopers in Star Wars were modeled after these air vents at La Pedrera in Barcelona.

Part One: Benvinguts a Barcelona!

The pace of genetics research has increased dramatically over the past few years. What was possible only in a large, well-funded lab a few years ago can now be done by a solitary grad student on a laptop.
Many people at the conference were studying large publicly available sets of genetic data, such as the 23andMe-sponsored data set of 650,000 SNPs from 1,000 individuals in 52 populations (data available here, for those interested). Others were taking advantage of next-generation sequencing platforms (such as 454 and Solexa) to investigate everything from differences in protein expression in different strains of mice to the genetic makeup of extinct organisms – even Neanderthals.
Over the next few posts in this series I’ll discuss some of the most interesting talks and topics; but I’ll start with why we went to Barcelona.

Maternal history of populations

We were happy to present research we’ve done that puts a date on every major branch point in the human mitochondrial DNA tree. Because mitochondrial DNA is passed directly from mothers to their offspring, it can be used to trace the maternal ancestry of every person on the planet (for customers and demo account holders, that’s the maternal line feature). We used more than 4,000 publicly available complete mitochondrial genomes from Genbank, assigned to maternal haplogroups using their full sequence, to accomplish this goal.
Why would we want to do this? Well, calculating the dates of common ancestors allows us to tell someone how long ago he or she shared a maternal relative with a friend, coworker, or even a celebrity. Our study is the first time all the haplogroups on the tree (or at least over 550 of them) have been dated all at once. For example, thanks to our research 23andMe can state confidently that Jesse James and Jimmy Buffett can both trace their female lineages back to a single woman who lived 60,000 years ago, probably somewhere in the Near East.

In addition, by looking at dates of common ancestors across the entire maternal tree we can fill in some details relating to the history of our species. We know that everyone living on Earth today descends from a woman who lived in Africa around 175,000 years ago. But each lineage that connects back to that woman has had a different history of mutations. Looking at this mutation history can tell us about the different groups of humans that expanded from eastern Africa to settle across the planet. For instance, we might be able to tell if certain groups were large or small when they split off from the tree, or whether they faced different environmental challenges that led to their rise or fall.
Interestingly, we see an increase in mutation rates along certain mitochondrial DNA lineages that arose after the out-of-Africa expansion around 50-60,000 years ago, but before the glaciers retreated in the last Ice Age (around 18,000 years ago). This contradicts previous work – maybe because we used much more data than previous studies and it was gathered from a much more diverse set of people. Whether the increased mutation rates were due to natural selection as humans moved into different environments or other events in the history of our ancestors remains to be seen – we’re working towards resolving the importance of various evolutionary processes in the history of the human maternal lineage.
In the next installment, I’ll blog some more about other interesting topics and presentations at the SMBE conference.

Adéu for now!

Click here for a PDF of our poster entitled: “How do you date all humans at once? The use of complete genomes to date nodes on the human mitochondrial tree.”

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