It is estimated that there are up to 8,000 distinct languages spoken around the world today.  At birth, the human mind is capable of learning and understanding any of these languages; an impressive feat given how uniquely complex they are.  The fact that humans are able to understand and communicate with one another in such a way that even our closest primate relatives cannot has long been supposed to be the result of some sort of genetic distinction separating us from the rest of the animal kingdom. 

In 2002, scientists believed they had found this genetic distinction in the form of a gene called FOXP2.  Their early studies suggested that FOXP2 was linked to the development of language in humans, and in humans’ ability to manipulate the brain, lungs, and vocal chords to make the complicated suite of sounds and movements resulting in speech.

However, the expression of FOXP2 in humans – and its presence in other species – is anything but simple.  Research has revealed that FOXP2 isn’t expressed just in the brain, but in a host of other tissues and organs throughout the body.  Moreover, FOXP2 isn’t unique to humans, but is found in many species, from chimpanzees to field mice.  It’s the version of FOXP2 we humans carry that is distinct from those of other species.  So it is the differences in FOXP2 across species that has been at the heart of scientific research into the origins of complex language.

A few years after the FOXP2 gene’s possible role in promoting complex language skills was announced in 2002, scientists analyzing ancient DNA extracted from Neanderthals, our closest fossil ancestors, found that they had the same version of FOXP2 as humans.  This discovery was revolutionary, as it meant that humans may not have been the first species capable of complex speech and language. It also pushed back the appearance of this version of FOXP2 to at least 350,000 years ago.

Recently, the focus of genetic research into FOXP2 has focused on the specific role FOXP2 plays in our language ability.  Was it involved in enhancing our cognitive abilities?  Our motor skills? Our breathing patterns?  The results of scientists’ most recent effort to uncover the answers to these questions are in the May 29th issue of Cell, in a paper published by researchers from the Max-Planck Institute of Evolutionary Anthropology.

In order to advance our understanding of FOXP2, the scientists chose to examine its expression in mice, a surprisingly strong model for many human biological systems.  The chief difference in FOXP2 between humans and many other species such as mice boils down to two changes in the gene.  At some point in human prehistory, these changes arose and quickly became universal in the FOXP2 of humans.

To see what effect those changes might have had, the Max Planck scientists altered the copies of FOXP2 in mice to be identical to the copies of FOXP2 in humans.  They then examined any changes that took place surrounding the cognition and vocal skills of the genetically altered mice, to see how they might be affected by the supposedly advanced copy of FOXP2.  And, while the linguistic skills of the mice failed to rival our own, the scientists did see some surprising changes.  First, they found that the altered mice showed changes in their brain circuitry that bore some similarity to that of humans.  And perhaps most intriguing, the altered mice had distinct ultrasonic vocalizations that differed from their unmodified brethren.  Ultrasonic vocalizations, sometimes referred to as chirps or squeaks, are used by mice to communicate to each other, such as to warn of a predator.  When the young altered mice were separated from their mothers, something that usually elicits many such squeaks, they emitted ultrasonic vocalizations that were distinctly different in intensity and frequency than their counterparts.  The authors argue that the altered FOXP2 in the mice was influencing the type of squeaks that they were making when separated from their mothers.  And the scientists therefore believe there is some kind of connection to language development.

But what does all this mean to humans?  The past several years of research into FOXP2 has revealed that human patients who carry at least one non-functional version of the gene (i.e., the version of the gene found in species other than humans) have problems producing the facial movements necessary to form words.  It had been thought that part of the function of FOXP2 in humans was to develop motor control needed to articulate our mouths, vocal chords, and esophagus to produce complex language.  Many experts have also proposed that FOXP2 in humans plays a role in the development of both the lungs and the esophagus – both of which are vital to speech.  This most recent study shows that by simply tweaking FOXP2 in mice, we see a noticeable change in how they communicate.

Clearly, there is much more work to be done and many more questions to be answered.  In the future, these researchers envision going even further to understand exactly how FOXP2 influences our ability to communicate with each other.  Their next goal?  To understand the exact mechanics behind the version of FOXP2 found in humans, so that they can finally piece together its importance in giving us the power of speech.

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Most children have mastered the complexities of spoken language by age six or seven,. But about 5% of otherwise healthy children struggle with either expressing themselves, understanding what others are saying or both, a disorder known as specific language impairment (SLI).

In a report published online yesterday by the New England Journal of Medicine, researchers from the Wellcome Trust Centre for Human Genetics at the University of Oxford present evidence that a gene called CNTNAP2 is involved in specific language impairment.

“It has long been suspected that inherited factors play an important role in childhood language disorders,” Simon Fisher, senior author of the study, said in a statement. “But this is the first time that we have been able to implicate variants of a specific gene in common forms of language impairment.”

Several previous studies have linked broad regions of DNA with SLI, but there has yet to be any consensus on the true genetic underpinnings of the disorder.

The researchers narrowed in on the role of CNTNAP2 in SLI because it interacts with FOXP2, another gene implicated in the development of language skills. Some people with rare speech disorders have mutations in FOXP2, but variations in this gene have not been associated with more typical forms of language impairment.

In a study of children from 184 families with at least one child affected by SLI, the researchers found that each G at rs17236239 decreased the score on a test that measures the ability to hear and repeat nonsense words like “brufid” and “contramponist” by 5.53 points on average. Previous studies have indicated that this test is a good indicator of SLI.

Each G also decreased a child’s score on the standardized Expressive Language Score, which measures the ability to communicate through spoken language, by an average 3.21 points. Scores can range from 46 to 141 for the nonsense word test, and 50 to 150 for the expressive language test. Most children in the general population get a score between 85 and 115 on both.

(23andMe customers can check their data for rs17236239 using the Browse Raw Data feature.)

Variants in the same region of CNTNAP2 as rs17236239 have also been linked to delayed speech in children with autism. Some experts suggest that the different components of autism-spectrum disorders, such as communication problems, impaired social interaction, and repetitive behaviors, could be due to different genetic influences. Fisher and colleagues suggest that alterations in CNTNAP2 could be a shared mechanism for pure SLI and language problems associated with autism.

The research team plans to investigate whether variants of CNTNAP2 are linked to natural variations in linguistic abilities in the general population. They also plan to investigate other genes that interact with FOXP2.

“Genes like CNTNAP2 and FOXP2 are giving us an exciting new molecular perspective on speech and language development, one of the most fascinating but mysterious aspects of being human,” said Fisher. “This work promises to shed light on how networks of genes help to build a language-ready brain.”

In an accompanying editorial in NEJM, Karin Stromswold, who was not associated with the research, said that the findings of the British study and others like it could someday help tease apart the genetic and environmental factors that affect language and language disorders. Stromswold questioned, however, why others studies of SLI have never implicated the DNA region where CNTNAP2 is found, even when the same group of children was studied.

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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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