Early human history was characterized by many rapid, long-distance migrations. But despite our beginnings as travelers, genetic evidence published online last Sunday in Nature indicates that after expanding to all corners of the earth people (at least those in Europe) tended to stay close to home.

Close on the heels of similar research published just a few weeks ago (and covered in The Spittoon), John Novembre and colleagues have created a genetic “map” of Europe that closely mirrors the geographic map. Their results will allow scientists to better understand how geography contributes to genetic variation, which is important for both genome-wide association studies and ancestry analyses.

Figure 1: The genetic map of Europe using PCA, with the geographic map of Europe for reference. Figure 2: The same map, but zoomed in on Switzerland. Swiss individuals tend to cluster with countries that speak the same language. (Courtesy: John Novembre, UCLA)

The researchers used a mathematical technique called principle components analysis (PCA) to collapse large amounts of SNP data for 3,192 people drawn from throughout Europe into a two-dimensional “map” of their genetic distances from one another. (Figure 1)

When the researchers looked at the DNA of any two individuals, they found that the number of genetic differences between them was proportional to the geographic distance that separates their respective home countries. Even within countries the researchers saw that groups with similar cultural histories shared similar genetics. For example, Italian-speakers from southern Switzerland tended to cluster together with other Italian-speakers and apart from other Swiss groups. (Figure 2)

Using only genetic data, the researchers were able to assign, on average, 50% of European individuals to within 400 kilometers of their correct country of origin. But there was one caveat: all four grandparents of an individual had to come from the same European country for the assignment to be correct. People with mixed European ancestry tended to show up between the locations of their ancestors.

The accuracy of assignment varied greatly from country to country: some people, like the Swedes and Portuguese, were placed on the map with less precision than other groups like the Polish and Belgians.

As in earlier research that constructed a genetic map of Europe, the results of this study show that genetic variations between people tend to follow a northwest to southeast path. This may reflect an ancient migration after the Last Ice Age when glacial sheets extended down from northern Europe. Human groups (not to mention grasshoppers, hedgehogs, etc.) were forced to take refuge in warm southern locations like the Italian and Iberian Peninsulas. But after the glaciers melted about 15,000 years ago, humans began to re-colonize Europe, moving from south to north.

In the past, genome-wide association studies have been hampered by the effects of geography on genetics. For example, a study looking for DNA variants associated with height found spurious evidence of linkage to SNPs that are actually linked to lactose tolerance, because both traits vary along the same NW/SE axis in Europe. The results of this study current study and others like it will help scientists make corrections in their data and increase their ability to detect true associations.

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It should be no surprise that in general, we are more genetically similar to our neighbors than to people living far away. The reason is fairly simple — until recently in human history it was fairly rare for people from widely separated geographic regions to even meet, much less reproduce.

This pattern, known as isolation-by-distance, has been observed in a number of studies over the past several decades. This week, it has been confirmed in Europe by the largest study of its kind to date.

The researchers produced a two-dimensional map, like the one below, that preserves the genetic similarities between individuals as far as possible; in other words, the closer two dots (people) are on the map, the more closely related they are genetically.

Two dimensional genetic similarity map of Europeans showing the northern and southern clusters. Each colored symbol in the plot on the left represents a single person’s genotype. Note the similar placement of symbols on the plot to the left and the geographic legend to the right. Adapted from Tian et al., Plos Genetics, (2008).

In the figure above, each individual was labeled with their country of origin after the mapmaking procedure was run. If Europe were genetically homogeneous, you would expect the different nationalities to appear in a jumble. Instead, they  separate into clusters that, remarkably, roughly recapitulate the geography of Europe.

Northern vs. Southern Europe

Even though Europe has been occupied for only a relatively short time compared to other parts of the world, different populations within the continent have had time to differentiate from one another. Scientists have known for a long time that certain traits, like lactase persistence and light-colored eyes and hair are more common in northern than in southern Europe. Likewise, there are certain diseases such as sickle cell anemia that, although rare across Europe, are found more in the south than in the north. Height and skin color also vary from northern to southern Europe: both vary gradually with latitude rather than in quick jumps.
Early genetic studies (such as those in the landmark population genetics text History and Geography of Human Genes) showed that this north-south cline was also a genetic one: even though Europeans of different nationalities did not fit into simple clusters, there was an overarching north-south difference. Newer studies have increased the number of people typed, and the number of markers, to approach the genome-wide level of hundreds of thousands of SNPs we use here at 23andMe — which brings us to this week’s paper.

A summary of genome-wide findings

The Lao et al. study out this week obtained genotypes from more than 2,500 individuals of known European ancestry. Each of the genotypes consists of about half a million SNPs typed on the Affymetrix 500K, a chip similar in size to the Illumina 550K used here at 23andMe. They confirm the findings of several recent but smaller European studies (Seldin et al, PLoS Genetics (2006); Bauchet et al, AJHG (2007); Tian et al, PLoS Genetics (2008); Price et al, PLoS Genetics (2008); Paschou et al, PLoS Genetics (2008)), namely:

• Over all SNPs, Europeans are very genetically similar.
• There is a small set of SNPs that does allow European populations to be distinguished — at least when used among people whose ancestors are all from the same part of Europe — and they are surprisingly effective.
• Most of the genetic variation in Europe is found along the north-south axis, which is consistent with archaeological knowledge. The next most prominent axis of genetic variation runs roughly east-west.
• More isolated populations tend to exist at the extremes of these plots. In the case of this current paper the Finns are the only nationality completely distinct from the rest of the European samples. The Finns speak a different kind of language from much of the rest of Europe, and are the only Scandinavian population represented.

There’s plenty of action in the blogosphere on this one. For more discussion check out dienekes’ anthropology blog, anthropology.net, gene expression, and genetic future.

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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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