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 RipattiNicole Soranzo, Toniolo Daniela, James Wilson, Richard Durbin, Chris Tyler-Smith, Eleftheria Zeggini

Research output: Contribution to journalArticlepeer-review

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 3059 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.
Original languageEnglish
JournalNature Communications
Early online date23 Jun 2017
DOIs
Publication statusE-pub ahead of print - 23 Jun 2017

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