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

Author

Listed:
  • Yali Xue

    (The Wellcome Trust Sanger Institute, Wellcome Genome Campus)

  • Massimo Mezzavilla

    (The Wellcome Trust Sanger Institute, Wellcome Genome Campus
    Institute for Maternal and Child Health, IRCCS Burlo Garofolo, University of Trieste)

  • 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
    Consiglio Nazionale delle Ricerche, Istituto di Genetica e Biofisica ‘Adriano Buzzati-Traverso’)

  • Lorraine Southam

    (The Wellcome Trust Sanger Institute, Wellcome Genome Campus
    Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Christopher Finan

    (The Wellcome Trust Sanger Institute, Wellcome Genome Campus)

  • Andrea Massaia

    (The Wellcome Trust Sanger Institute, Wellcome Genome Campus
    National Heart and Lung Institute, Imperial College London)

  • Himanshu Chheda

    (Institute for Molecular Medicine Finland (FIMM), University of Helsinki)

  • Priit Palta

    (Institute for Molecular Medicine Finland (FIMM), University of Helsinki
    Estonian Genome Center, University of Tartu)

  • Graham Ritchie

    (The Wellcome Trust Sanger Institute, Wellcome Genome Campus
    European Bioinformatics Institute, Wellcome Genome Campus
    MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital)

  • 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
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki
    Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard)

  • Samuli Ripatti

    (The Wellcome Trust Sanger Institute, Wellcome Genome Campus
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki
    University of Helsinki)

  • Nicole Soranzo

    (The Wellcome Trust Sanger Institute, Wellcome Genome Campus
    University of Cambridge)

  • Daniela Toniolo

    (San Raffaele Scientific Institute)

  • James F. Wilson

    (MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital
    Usher Institute of Population Health Sciences and Informatics, University of Edinburgh)

  • 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)

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.

Suggested Citation

  • Yali Xue & Massimo Mezzavilla & Marc Haber & Shane McCarthy & Yuan Chen & Vagheesh Narasimhan & Arthur Gilly & Qasim Ayub & Vincenza Colonna & Lorraine Southam & Christopher Finan & Andrea Massaia & H, 2017. "Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations," Nature Communications, Nature, vol. 8(1), pages 1-7, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15927
    DOI: 10.1038/ncomms15927
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    Cited by:

    1. Isabel Alves & Joanna Giemza & Michael G. B. Blum & Carolina Bernhardsson & Stéphanie Chatel & Matilde Karakachoff & Aude Pierre & Anthony F. Herzig & Robert Olaso & Martial Monteil & Véronique Gallie, 2024. "Human genetic structure in Northwest France provides new insights into West European historical demography," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Mihail Halachev & Viktoria-Eleni Gountouna & Alison Meynert & Gannie Tzoneva & Alan R. Shuldiner & Colin A. Semple & James F. Wilson, 2024. "Regionally enriched rare deleterious exonic variants in the UK and Ireland," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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