The population structure and demographic history of Sardinia in relationship to neighboring populations. J. Novembre1, C. Chiang2, J. Marcus1, C. Sidore3, 4, 5, M. Zoledziewska3, M. Steri3, H. Al-asadi1, G. Abecasis4, D. Schlessinger6, F. Cucca3, 5 1) Dept of Human Genetics, University of Chicago, Chicago, IL; 2) Deptartment of Ecology and Evolution, University of California - Los Angeles, Los Angeles, CA; 3) Instituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy; 4) Center for Statistical Genetics University of Michigan Ann Arbor, MI; 5) Universita degli Studi di Sassari Sassari, Italy; 6) Laboratory of Genetics National Institute on Aging National Institutes of Health Baltimore, MD.

   Numerous studies have made clear that Sardinian populations are relatively isolated genetically from other populations of the Mediterranean, and more recently, intriguing connections between Sardinian ancestry and early Neolithic ancient DNA samples have been made. In this study, we analyze a whole-genome low-coverage sequencing dataset from 2120 Sardinians to more fully characterize patterns of genetic diversity in Sardinia. The study contains one subsample that contains individuals from across Sardinia and a second subsample that samples 4 villages from the more isolated Ogliastra region. We also merge the data with published reference data from Europe and North Africa. Overall Fst values of Sardinia to other European populations are low (<0.015); however using a novel method for visualizing genetic differentiation on a geographic map, we formally show how Sardinia is more differentiated than would be expected given its geographic distance from the mainland, consistent with periods of isolation. Applications of the software Admixture show how Sardinia populations differ in the levels of recent admixture with mainland European populations and that there are only minor contributions from North African populations to Sardinian ancestry. Notably the Sardinians from Ogliastra contain a distinct genetic cluster with minimal evidence of recent admixture with mainland Europe. We found frequency-based f3 tests and the tree-based algorithm Treemix both also show minimal evidence of recent admixture. Given the relative isolation, one might expect to see a unique demographic history from neighboring populations. Using coalescent-based approaches, we find Sardinian populations have had more constant effective sizes over the past several thousand years than mainland European populations, which typically show evidence for rapid growth trajectories in the recent past. This unique demographic history has consequences for the abundance of putatively damaging and deleterious variants, and we use our data to address the prediction that the genetic architecture of disease traits is expected to involve fewer loci with a greater proportion of variants at common frequencies in Sardinia.

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