Diversity in non-repetitive human sequences not found in the reference genome

Birte Kehr; Anna Helgadottir; Pall Melsted; Hakon Jonsson; Hannes Helgason; Adalbjörg Jonasdottir; Aslaug Jonasdottir; Asgeir Sigurdsson; Arnaldur Gylfason; Gisli H. Halldorsson; Snaedis Kristmundsdottir; Gudmundur Thorgeirsson; Isleifur Olafsson; Hilma Holm; Unnur Thorsteinsdottir; Patrick Sulem; Agnar Helgason; Daniel F. Gudbjartsson; Bjarni V. Halldorsson; Kari Stefansson

doi:10.1038/ng.3801

Diversity in non-repetitive human sequences not found in the reference genome

Birte Kehr, Anna Helgadottir, Pall Melsted, Hakon Jonsson, Hannes Helgason, Adalbjörg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Arnaldur Gylfason, Gisli H. Halldorsson, Snaedis Kristmundsdottir, Gudmundur Thorgeirsson, Isleifur Olafsson, Hilma Holm, Unnur Thorsteinsdottir, Patrick Sulem, Agnar Helgason, Daniel F. Gudbjartsson, Bjarni V. Halldorsson^*, Kari Stefansson

^*Corresponding author for this work

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

33 Citations (Scopus)

Abstract

Genomes usually contain some non-repetitive sequences that are missing from the reference genome and occur only in a population subset. Such non-repetitive, non-reference (NRNR) sequences have remained largely unexplored in terms of their characterization and downstream analyses. Here we describe 3,791 breakpoint-resolved NRNR sequence variants called using PopIns from whole-genome sequence data of 15,219 Icelanders. We found that over 95% of the 244 NRNR sequences that are 200 bp or longer are present in chimpanzees, indicating that they are ancestral. Furthermore, 149 variant loci are in linkage disequilibrium (r 2 > 0.8) with a genome-wide association study (GWAS) catalog marker, suggesting disease relevance. Additionally, we report an association (P = 3.8 × 10^-8, odds ratio (OR) = 0.92) with myocardial infarction (23,360 cases, 300,771 controls) for a 766-bp NRNR sequence variant. Our results underline the importance of including variation of all complexity levels when searching for variants that associate with disease.

Original language	English
Pages (from-to)	588-593
Number of pages	6
Journal	Nature Genetics
Volume	49
Issue number	4
DOIs	https://doi.org/10.1038/ng.3801
Publication status	Published - 30 Mar 2017

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Kehr, B., Helgadottir, A., Melsted, P., Jonsson, H., Helgason, H., Jonasdottir, A., Jonasdottir, A., Sigurdsson, A., Gylfason, A., Halldorsson, G. H., Kristmundsdottir, S., Thorgeirsson, G., Olafsson, I., Holm, H., Thorsteinsdottir, U., Sulem, P., Helgason, A., Gudbjartsson, D. F., Halldorsson, B. V., & Stefansson, K. (2017). Diversity in non-repetitive human sequences not found in the reference genome. Nature Genetics, 49(4), 588-593. https://doi.org/10.1038/ng.3801

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title = "Diversity in non-repetitive human sequences not found in the reference genome",

abstract = "Genomes usually contain some non-repetitive sequences that are missing from the reference genome and occur only in a population subset. Such non-repetitive, non-reference (NRNR) sequences have remained largely unexplored in terms of their characterization and downstream analyses. Here we describe 3,791 breakpoint-resolved NRNR sequence variants called using PopIns from whole-genome sequence data of 15,219 Icelanders. We found that over 95% of the 244 NRNR sequences that are 200 bp or longer are present in chimpanzees, indicating that they are ancestral. Furthermore, 149 variant loci are in linkage disequilibrium (r 2 > 0.8) with a genome-wide association study (GWAS) catalog marker, suggesting disease relevance. Additionally, we report an association (P = 3.8 × 10-8, odds ratio (OR) = 0.92) with myocardial infarction (23,360 cases, 300,771 controls) for a 766-bp NRNR sequence variant. Our results underline the importance of including variation of all complexity levels when searching for variants that associate with disease.",

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doi = "10.1038/ng.3801",

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Kehr, B, Helgadottir, A, Melsted, P, Jonsson, H, Helgason, H, Jonasdottir, A, Jonasdottir, A, Sigurdsson, A, Gylfason, A, Halldorsson, GH, Kristmundsdottir, S, Thorgeirsson, G , Olafsson, I, Holm, H, Thorsteinsdottir, U, Sulem, P, Helgason, A, Gudbjartsson, DF, Halldorsson, BV & Stefansson, K 2017, 'Diversity in non-repetitive human sequences not found in the reference genome', Nature Genetics, vol. 49, no. 4, pp. 588-593. https://doi.org/10.1038/ng.3801

TY - JOUR

T1 - Diversity in non-repetitive human sequences not found in the reference genome

AU - Kehr, Birte

AU - Helgadottir, Anna

AU - Melsted, Pall

AU - Jonsson, Hakon

AU - Helgason, Hannes

AU - Jonasdottir, Adalbjörg

AU - Jonasdottir, Aslaug

AU - Sigurdsson, Asgeir

AU - Gylfason, Arnaldur

AU - Halldorsson, Gisli H.

AU - Kristmundsdottir, Snaedis

AU - Thorgeirsson, Gudmundur

AU - Olafsson, Isleifur

AU - Holm, Hilma

AU - Thorsteinsdottir, Unnur

AU - Sulem, Patrick

AU - Helgason, Agnar

AU - Gudbjartsson, Daniel F.

AU - Halldorsson, Bjarni V.

AU - Stefansson, Kari

PY - 2017/3/30

Y1 - 2017/3/30

N2 - Genomes usually contain some non-repetitive sequences that are missing from the reference genome and occur only in a population subset. Such non-repetitive, non-reference (NRNR) sequences have remained largely unexplored in terms of their characterization and downstream analyses. Here we describe 3,791 breakpoint-resolved NRNR sequence variants called using PopIns from whole-genome sequence data of 15,219 Icelanders. We found that over 95% of the 244 NRNR sequences that are 200 bp or longer are present in chimpanzees, indicating that they are ancestral. Furthermore, 149 variant loci are in linkage disequilibrium (r 2 > 0.8) with a genome-wide association study (GWAS) catalog marker, suggesting disease relevance. Additionally, we report an association (P = 3.8 × 10-8, odds ratio (OR) = 0.92) with myocardial infarction (23,360 cases, 300,771 controls) for a 766-bp NRNR sequence variant. Our results underline the importance of including variation of all complexity levels when searching for variants that associate with disease.

AB - Genomes usually contain some non-repetitive sequences that are missing from the reference genome and occur only in a population subset. Such non-repetitive, non-reference (NRNR) sequences have remained largely unexplored in terms of their characterization and downstream analyses. Here we describe 3,791 breakpoint-resolved NRNR sequence variants called using PopIns from whole-genome sequence data of 15,219 Icelanders. We found that over 95% of the 244 NRNR sequences that are 200 bp or longer are present in chimpanzees, indicating that they are ancestral. Furthermore, 149 variant loci are in linkage disequilibrium (r 2 > 0.8) with a genome-wide association study (GWAS) catalog marker, suggesting disease relevance. Additionally, we report an association (P = 3.8 × 10-8, odds ratio (OR) = 0.92) with myocardial infarction (23,360 cases, 300,771 controls) for a 766-bp NRNR sequence variant. Our results underline the importance of including variation of all complexity levels when searching for variants that associate with disease.

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U2 - 10.1038/ng.3801

DO - 10.1038/ng.3801

M3 - Article

C2 - 28250455

AN - SCOPUS:85014090196

SN - 1061-4036

VL - 49

SP - 588

EP - 593

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

Diversity in non-repetitive human sequences not found in the reference genome

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