Discovering how we evolved – Evolving genes lead to more evolving genes

Two of the three sets of FOXP2-regulated genes identified by genomic screens in mouse brain and human brain show signals of positive selection in Europeans, illustrated by the green bars extending above the critical threshold (dotted line). As a control, FOXA2-regulated genes, whose expression is regulated by a different transcription factor, do not show such a signal of positive selection in any population. [doi: 10.1016/j.ajhg.2013.03.019]

Two of the three sets of FOXP2-regulated genes identified by genomic screens in mouse brain and human brain show signals of positive selection in Europeans, illustrated by the green bars extending above the critical threshold (dotted line). As a control, FOXA2-regulated genes, whose expression is regulated by a different transcription factor, do not show such a signal of positive selection in any population. [doi: 10.1016/j.ajhg.2013.03.019]

21 May 2013

By Qasim Ayub

As a researcher in the Human Evolution Team at the Wellcome Trust Sanger Institute, I am interested in understanding how humans evolved and adapted to local environments as they established themselves in and out of Africa.  It’s an exciting time to be working in this area: the huge number of whole-genome sequences from a diverse range of human populations that are available give us an unprecedented opportunity to study the natural selection of beneficial traits in humans over time.

Advantageous adaptations – such as the ability to digest certain types of food or developing our capacity for language – result from changes in the DNA sequences of the genome. These changes leave signatures that we can search for in modern-day genomes. My work is rather like that of an archaeologist, but instead of searching for the tell-tale signs of previous events in the landscape, I am looking for the signatures of evolutionary selection in people’s genomes.

Unfortunately there is a problem: the signatures I am searching for can be mimicked by fluctuations in population sizes over time. In the absence of functional evidence that confirms the role of a genetic region in development, it is difficult to be sure which areas of the human genome have really undergone selection. This difficulty has been discussed extensively in the scientific literature.

I have developed a strategy to look at sets of genes for selection signatures by comparing them with control genes matched for gene size, GC content and average recombination rate. The idea came out of a brain storming session at one of our team retreats and I worked on it with help from Yuan Chen, our team’s bioinformatician and other team members.

We wanted to test our method to see if it worked or not, so we looked at genes that are controlled by FOXP2, a regulatory protein. Defects in this gene have been associated with speech and language disorders and have received substantial press coverage.  We know that altered versions of the FOXP2 gene have been selected for at least twice during human evolution and we wondered whether or not evolutionary changes in FOXP2 had resulted in selection of any of the genes it regulates.

Initially I had intended to use just two published sets of FOXP2-regulated genes that had been identified in humans using a technique called ChIP-chip, that involved chromatin immunoprecipitation and hybridization with microarrays.  A fortuitous meeting in Cambridge with Simon Fisher led to a collaboration. Simon’s research group had been studying FOXP2-controlled genes in mouse models  and he kindly provided us with his, much more comprehensive, list. We then compared all three sets of FOXP2-regulated genes with matched controls using our method.

A surprise finding was the strong evidence for selection of some FOXP2-regulated genes in Europeans, but not in Asians, or Africans. This was reinforced when we found FOXP2 binding motif variants that were enriched in the European populations only for a subset of the selected genes . Does this mean that Europeans have improved speech or language compared with people from other continents, or is this enrichment conferring a different advantage?

The FOXP2-regulated genes that were selected in Europeans are highly expressed in the brain and some have been implicated in neurodevelopmental disorders, which might suggest that they are related to brain function. In my opinion, the selection signal is probably not related to brain function, and almost certainly not linked to speech or language. A gene often has more than one role in the body and these genes are no different: The selected genes have multiple roles in cellular development, signalling, reproduction and immunity. Selection of these genes in Europeans is more likely to reflect local population adaptations to the climate, diet or pathogens that they encountered as their ancestors spread across Europe after splitting from the ancestors of Asian populations.

The study was recently published in the May 2013 issue of The American Journal of Human Genetics.  It highlights the complexity of biology and how genes have evolved and adapted to different roles during human evolution.  The method that we developed can be used universally to test for evolutionary adaption in any chosen set of genes.  It can aid identification of gene sets that show evidence for positive selection in comparison with matched controls, and thus highlight genes for further functional studies. We are already using this method to search for  signatures of positive selection in other gene sets.

Qasim Ayub works in the Human Evolution research group led by Dr Chris Tyler-Smith more…

Research paper

Qasim Ayub, Bryndis Yngvadottir, Yuan Chen, Yali Xue, Min Hu, Sonja C. Vernes, Simon E. Fisher, Chris Tyler-Smith. FOXP2 targets show evidence of positive selection in European populations.American Journal of Human Genetics 2013. DOI: 10.1016/j.ajhg.2013.03.019

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