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

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

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

Abstract

© 2017 The Author(s). 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
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15927
Publication status	Published - Jun 23 2017

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Xue, Y., Mezzavilla, M., Mezzavilla, M., Haber, M., McCarthy, S., Chen, Y., Narasimhan, V., Gilly, A., Ayub, Q., Colonna, V., Colonna, V., Southam, L., Southam, L., Finan, C., Massaia, A., Massaia, A., Chheda, H., Palta, P., Palta, P., ... Zeggini, E. (2017). Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations. Nature Communications, 8. 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; Mezzavilla, Massimo; Haber, Marc; McCarthy, Shane; Chen, Yuan; Narasimhan, Vagheesh; Gilly, Arthur; Ayub, Qasim; Colonna, Vincenza; Colonna, Vincenza; Southam, Lorraine; Southam, Lorraine; Finan, Christopher; Massaia, Andrea; Massaia, Andrea; Chheda, Himanshu; Palta, Priit; Palta, Priit; Ritchie, Graham; Ritchie, Graham; Ritchie, Graham; Asimit, Jennifer; Dedoussis, George; Gasparini, Paolo; Palotie, Aarno; Palotie, Aarno; Palotie, Aarno; Palotie, Aarno; Palotie, Aarno; Palotie, Aarno; Palotie, Aarno; Ripatti, Samuli; Ripatti, Samuli; Ripatti, Samuli; Soranzo, Nicole; Soranzo, Nicole; Toniolo, Daniela; Wilson, James F.; Wilson, James F.; Durbin, Richard; Tyler-Smith, Chris; Zeggini, Eleftheria.

In: Nature Communications, Vol. 8, 23.06.2017.

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

Xue, Y, Mezzavilla, M, Mezzavilla, M, Haber, M, McCarthy, S, Chen, Y, Narasimhan, V, Gilly, A, Ayub, Q, Colonna, V, Colonna, V, Southam, L, Southam, L, Finan, C, Massaia, A, Massaia, A, Chheda, H, Palta, P, Palta, P, Ritchie, G, Ritchie, G, Ritchie, G, Asimit, J, Dedoussis, G, Gasparini, P, Palotie, A, Palotie, A, Palotie, A, Palotie, A, Palotie, A, Palotie, A, Palotie, A, Ripatti, S, Ripatti, S, Ripatti, S, Soranzo, N, Soranzo, N, Toniolo, D, Wilson, JF, 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. https://doi.org/10.1038/ncomms15927

Xue, Yali ; Mezzavilla, Massimo ; Mezzavilla, Massimo ; Haber, Marc ; McCarthy, Shane ; Chen, Yuan ; Narasimhan, Vagheesh ; Gilly, Arthur ; Ayub, Qasim ; Colonna, Vincenza ; Colonna, Vincenza ; Southam, Lorraine ; Southam, Lorraine ; Finan, Christopher ; Massaia, Andrea ; Massaia, Andrea ; Chheda, Himanshu ; Palta, Priit ; Palta, Priit ; Ritchie, Graham ; Ritchie, Graham ; Ritchie, Graham ; Asimit, Jennifer ; Dedoussis, George ; Gasparini, Paolo ; Palotie, Aarno ; Palotie, Aarno ; Palotie, Aarno ; Palotie, Aarno ; Palotie, Aarno ; Palotie, Aarno ; Palotie, Aarno ; Ripatti, Samuli ; Ripatti, Samuli ; Ripatti, Samuli ; Soranzo, Nicole ; Soranzo, Nicole ; Toniolo, Daniela ; Wilson, James F. ; Wilson, James F. ; 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 ; Vol. 8.

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abstract = "{\textcopyright} 2017 The Author(s). 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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AU - Ripatti, Samuli

AU - Soranzo, Nicole

AU - Toniolo, Daniela

AU - Wilson, James F.

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