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

Research output: Contribution to journal › Article › peer-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 language	English
Journal	Nature Communications
Early online date	23 Jun 2017
DOIs	https://doi.org/10.1038/ncomms15927
Publication status	E-pub ahead of print - 23 Jun 2017

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Enrichment of low-frequency functional variants revealed byAccepted author manuscript, 1.95 MBLicence: Creative Commons: Attribution (CC-BY)
Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations.Final published version, 974 KBLicence: Creative Commons: Attribution (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. https://doi.org/10.1038/ncomms15927

Xue, Yali ; Mezzavilla, Massimo ; Haber, Marc ; McCarthy, Shane ; Chen, Yuan ; Narasimhan, Vagheesh ; Gilly, Arthur ; Ayub, Qasim ; Colonna, Vincenza ; Southam, Lorraine ; Finan, Christopher ; Massaia, Andrea ; Chheda, Himanshu ; Palta, Priit ; Ritchie, Graham ; Asimit, Jennifer ; Dedoussis, George ; Gasparini, Paolo ; Palotie, Aarno ; Ripatti, Samuli ; Soranzo, Nicole ; Daniela, Toniolo ; Wilson, James ; Durbin, Richard ; Tyler-Smith, Chris ; Zeggini, Eleftheria. / Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations. In: Nature Communications. 2017.

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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 comprehensiveinvestigation 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.",

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 Toniolo Daniela and James Wilson and Richard Durbin and Chris Tyler-Smith and Eleftheria Zeggini",

year = "2017",

month = jun,

day = "23",

doi = "10.1038/ncomms15927",

language = "English",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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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, Daniela, T, Wilson, J, 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. https://doi.org/10.1038/ncomms15927

Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations. / Xue, Yali; Mezzavilla, Massimo; Haber, Marc; McCarthy, Shane; Chen, Yuan; Narasimhan, Vagheesh; Gilly, Arthur; Ayub, Qasim; Colonna, Vincenza; Southam, Lorraine; Finan, Christopher; Massaia, Andrea; Chheda, Himanshu; Palta, Priit; Ritchie, Graham; Asimit, Jennifer; Dedoussis, George ; Gasparini, Paolo; Palotie, Aarno; Ripatti, Samuli; Soranzo, Nicole; Daniela, Toniolo; Wilson, James; Durbin, Richard; Tyler-Smith, Chris; Zeggini, Eleftheria.

In: Nature Communications, 23.06.2017.

Research output: Contribution to journal › Article › peer-review

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 - Daniela, Toniolo

AU - Wilson, James

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 comprehensiveinvestigation 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.

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 comprehensiveinvestigation 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.

U2 - 10.1038/ncomms15927

DO - 10.1038/ncomms15927

M3 - Article

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

ER -

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

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