Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations

Yali Xue (), Massimo Mezzavilla, Marc Haber, Shane McCarthy, Yuan Chen, Vagheesh Narasimhan, Arthur Gilly, Qasim Ayub, Vincenza Colonna, Lorraine Southam, Christopher Finan, Andrea Massaia, Himanshu Chheda, Priit Palta, Graham Ritchie, Jennifer Asimit, George Dedoussis, Paolo Gasparini, Aarno Palotie, Samuli Ripatti, Nicole Soranzo, Daniela Toniolo, James F. Wilson, Richard Durbin, Chris Tyler-Smith and Eleftheria Zeggini ()
Additional contact information
Yali Xue: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Massimo Mezzavilla: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Marc Haber: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Shane McCarthy: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Yuan Chen: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Vagheesh Narasimhan: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Arthur Gilly: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Qasim Ayub: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Vincenza Colonna: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Lorraine Southam: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Christopher Finan: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Andrea Massaia: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Himanshu Chheda: Institute for Molecular Medicine Finland (FIMM), University of Helsinki
Priit Palta: Institute for Molecular Medicine Finland (FIMM), University of Helsinki
Graham Ritchie: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Jennifer Asimit: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
George Dedoussis: Harokopio University Athens
Paolo Gasparini: Medical Genetics, DSM, University of Trieste and IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Burlo Garofolo Children Hospital
Aarno Palotie: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Samuli Ripatti: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Nicole Soranzo: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Daniela Toniolo: San Raffaele Scientific Institute
James F. Wilson: MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital
Richard Durbin: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Chris Tyler-Smith: The Wellcome Trust Sanger Institute, Wellcome Genome Campus
Eleftheria Zeggini: The Wellcome Trust Sanger Institute, Wellcome Genome Campus

Nature Communications, 2017, vol. 8, issue 1, 1-7

Abstract: Abstract The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.

Date: 2017
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DOI: 10.1038/ncomms15927

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