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; Eleftheria Zeggini

doi:10.1038/ncomms15927

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, Daniela Toniolo, James F. Wilson, Richard Durbin, Chris Tyler-Smith, Eleftheria Zeggini

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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.

Original language	English
Article number	15927
Number of pages	7
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15927
Publication status	Published - 23 Jun 2017
Externally published	Yes

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344996301-oaFinal published version, 834 KBLicence: CC BY

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Xue, Y., Mezzavilla, M., Haber, M., McCarthy, S., Chen, Y., Narasimhan, V., Gilly, A., Ayub, Q., Colonna, V., Southam, L., Finan, C., Massaia, A., Chheda, H., Palta, P., Ritchie, G., Asimit, J., Dedoussis, G., Gasparini, P., Palotie, A., ... Zeggini, E. (2017). Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations. Nature Communications, 8, Article 15927. https://doi.org/10.1038/ncomms15927

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

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.",

author = "Yali Xue and Massimo Mezzavilla and Marc Haber and Shane McCarthy and Yuan Chen and Vagheesh Narasimhan and Arthur Gilly and Qasim Ayub and Vincenza Colonna and Lorraine Southam and Christopher Finan and Andrea Massaia and Himanshu Chheda and Priit Palta and Graham Ritchie and Jennifer Asimit and George Dedoussis and Paolo Gasparini and Aarno Palotie and Samuli Ripatti and Nicole Soranzo and Daniela Toniolo and Wilson, {James F.} and Richard Durbin and Chris Tyler-Smith and Eleftheria Zeggini",

year = "2017",

month = jun,

day = "23",

doi = "10.1038/ncomms15927",

language = "English",

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Xue, Y, Mezzavilla, M, Haber, M, McCarthy, S, Chen, Y, Narasimhan, V, Gilly, A, Ayub, Q, Colonna, V, Southam, L, Finan, C, Massaia, A, Chheda, H, Palta, P, Ritchie, G, Asimit, J, Dedoussis, G, Gasparini, P, Palotie, A, Ripatti, S, Soranzo, N, Toniolo, D, Wilson, JF, Durbin, R, Tyler-Smith, C & Zeggini, E 2017, 'Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations', Nature Communications, vol. 8, 15927. https://doi.org/10.1038/ncomms15927

TY - JOUR

T1 - Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations

AU - Xue, Yali

AU - Mezzavilla, Massimo

AU - Haber, Marc

AU - McCarthy, Shane

AU - Chen, Yuan

AU - Narasimhan, Vagheesh

AU - Gilly, Arthur

AU - Ayub, Qasim

AU - Colonna, Vincenza

AU - Southam, Lorraine

AU - Finan, Christopher

AU - Massaia, Andrea

AU - Chheda, Himanshu

AU - Palta, Priit

AU - Ritchie, Graham

AU - Asimit, Jennifer

AU - Dedoussis, George

AU - Gasparini, Paolo

AU - Palotie, Aarno

AU - Ripatti, Samuli

AU - Soranzo, Nicole

AU - Toniolo, Daniela

AU - Wilson, James F.

AU - Durbin, Richard

AU - Tyler-Smith, Chris

AU - Zeggini, Eleftheria

PY - 2017/6/23

Y1 - 2017/6/23

N2 - 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.

AB - 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.

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DO - 10.1038/ncomms15927

M3 - Article

C2 - 28643794

AN - SCOPUS:85021419267

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 15927

ER -

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

Abstract

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