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Nat Commun. 2017 Jun 23;8:15927. doi: 10.1038/ncomms15927.

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

Author information

1
The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
2
Institute for Maternal and Child Health, IRCCS Burlo Garofolo, University of Trieste, 34137 Trieste, Italy.
3
Consiglio Nazionale delle Ricerche, Istituto di Genetica e Biofisica 'Adriano Buzzati-Traverso', via Pietro Castellino 111, 80131 Napoli, Italy.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
5
National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
6
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Tukholmankatu 8, 00290 Helsinki, Finland.
7
Estonian Genome Center, University of Tartu, 23B Riia Street, 51010 Tartu, Estonia.
8
European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
9
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
10
Department of Nutrition and Dietetics, Harokopio University Athens, Athens, Eleftheriou Venizelou 70, Kallithea 176 76, Greece.
11
Medical Genetics, DSM, University of Trieste and IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Burlo Garofolo Children Hospital, Via dell'Istria, 65, 34137 Trieste, Italy.
12
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
13
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02114, USA.
14
The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02114, USA.
15
Psychiatric &Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
16
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
17
Department of Public Health, University of Helsinki, Helsinki FI-00014, Finland.
18
Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
19
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy.
20
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG Scotland, UK.

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.

PMID:
28643794
PMCID:
PMC5490002
DOI:
10.1038/ncomms15927
[Indexed for MEDLINE]
Free PMC Article

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