Inferring the evolutionary history and the genetic basis of small stature in African Pygmies from whole-genome sequencing data. M. Sikora1, E. Patin2, H. Costa1, K. Siddle2, B. M. Henn1,6, J. M. Kidd1,7, R. Kita1, M. C. Yee1, P. Verdu3, L. Barreiro4, J. M. Hombert5, E. Heyer3, C. D. Bustamante1, L. Quintana-Murci2 1) Department of Genetics, Stanford University, Stanford, CA; 2) Institut Pasteur, Unit of Human Evolutionary Genetics, CNRS URA3012, Paris, France; 3) CNRS-MNHN-Universite Paris 7, UMR 7206 Eco-anthropologie et Ethnobiologie, Paris, France; 4) CHU Sainte-Justine, Universite de Montreal, Montreal, Canada; 5) Laboratoire Dynamique Du Langage, CNRS UMR 5596 Universite Lumière Lyon 2, Lyon, France; 6) Present address: Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY, USA; 7) Present address: Departments of Human Genetics and Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.

   The Pygmy populations of the Central African rainforests are some of the last remaining hunter-gatherers among present-day human populations. They are characterized by distinct cultural and physical characteristics such as short stature, which are thought to be a consequence of the unique environment they inhabit. Here we present the results of a population genomic study investiagting the demographic and adaptive history of these populations using whole-genome sequencing data. We sequenced 47 individuals from two Pygmy populations (Western Baka, Eastern Mbuti), as well as one non-Pygmy farmer population (Nzebi) to a median sequencing depth of 5.5x. Multi-sample SNP calling followed by stringent QC filters resulted in a final dataset of >17 million SNPs. Analyses of population structure and pairwise identity-by-descent (IBD) sharing patterns revealed varying levels of farmer-related admixture in the Baka. Both Pygmy populations showed increased within-population IBD sharing and relatedness, consistent with recent genetic isolation. Demographic inference using the pairwise-sequential Markov Coalescent (psmc) showed that Pygmy populations diverged from the Nzebi around 50,000 years ago, with a subsequent split between the Mbuti and Baka starting 30,000 years ago. We also found evidence for a population expansion unique to the Baka after their divergence from the Mbuti. In order to investigate the genetic basis of small stature in the Pygmies, we scanned the genome for highly differentiated regions using the population-specific branch length method (PBS). Highly differentiated SNPs were annotated with a rich set of both coding and non-coding annotations from a variety of sources in order to identify variants of interest. We found that while GWAS SNPs previously associated with height do not show higher frequencies for the small allele in Pygmies, the chromosomal regions around those SNPs show significantly increased differentiation in Pygmies compared to random GWAS regions. Furthermore, we identified SNPs in genes of the growth hormone / IGF1 axis that are rare worldwide but common in Pygmies, and associated with regulatory features such as DNase hypersensitivity sites. These candidate SNPs were followed up in a larger replication panel of around 300 individuals from diverse ethnic groups, including phenotypic data on height. Our study provides an unprecedented view of the evolutionary history and the genetic basis of small stature in African Pygmies.

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