Identification of a large set of rare complete human knockouts

Patrick Sulem; Hannes Helgason; Asmundur Oddson; Hreinn Stefansson; Sigurjon A. Gudjonsson; Florian Zink; Eirikur Hjartarson; Gunnar Th Sigurdsson; Adalbjorg Jonasdottir; Aslaug Jonasdottir; Asgeir Sigurdsson; Olafur Th Magnusson; Augustine Kong; Agnar Helgason; Hilma Holm; Unnur Thorsteinsdottir; Gisli Masson; Daniel F. Gudbjartsson; Kari Stefansson

doi:10.1038/ng.3243

Identification of a large set of rare complete human knockouts

Patrick Sulem^*, Hannes Helgason, Asmundur Oddson, Hreinn Stefansson, Sigurjon A. Gudjonsson, Florian Zink, Eirikur Hjartarson, Gunnar Th Sigurdsson, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Olafur Th Magnusson, Augustine Kong, Agnar Helgason, Hilma Holm, Unnur Thorsteinsdottir, Gisli Masson, Daniel F. Gudbjartsson, Kari Stefansson

^*Corresponding author for this work

Faculty of Sociology, Anthropology and Folkloristics

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

144 Citations (Scopus)

Abstract

Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10-261).

Original language	English
Pages (from-to)	448-452
Number of pages	5
Journal	Nature Genetics
Volume	47
Issue number	5
DOIs	https://doi.org/10.1038/ng.3243
Publication status	Published - 30 May 2015

Bibliographical note

Publisher Copyright:
© 2015 Nature America, Inc.

Access to Document

10.1038/ng.3243

Cite this

Sulem, P., Helgason, H., Oddson, A., Stefansson, H., Gudjonsson, S. A., Zink, F., Hjartarson, E., Sigurdsson, G. T., Jonasdottir, A., Jonasdottir, A., Sigurdsson, A., Magnusson, O. T., Kong, A., Helgason, A., Holm, H., Thorsteinsdottir, U., Masson, G., Gudbjartsson, D. F., & Stefansson, K. (2015). Identification of a large set of rare complete human knockouts. Nature Genetics, 47(5), 448-452. https://doi.org/10.1038/ng.3243

@article{23ac97e96a504b84916a3b0c9ee7f5ab,

title = "Identification of a large set of rare complete human knockouts",

abstract = "Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10-261).",

author = "Patrick Sulem and Hannes Helgason and Asmundur Oddson and Hreinn Stefansson and Gudjonsson, {Sigurjon A.} and Florian Zink and Eirikur Hjartarson and Sigurdsson, {Gunnar Th} and Adalbjorg Jonasdottir and Aslaug Jonasdottir and Asgeir Sigurdsson and Magnusson, {Olafur Th} and Augustine Kong and Agnar Helgason and Hilma Holm and Unnur Thorsteinsdottir and Gisli Masson and Gudbjartsson, {Daniel F.} and Kari Stefansson",

note = "Publisher Copyright: {\textcopyright} 2015 Nature America, Inc.",

year = "2015",

month = may,

day = "30",

doi = "10.1038/ng.3243",

language = "English",

volume = "47",

pages = "448--452",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

}

Sulem, P, Helgason, H, Oddson, A, Stefansson, H, Gudjonsson, SA, Zink, F, Hjartarson, E, Sigurdsson, GT, Jonasdottir, A, Jonasdottir, A, Sigurdsson, A, Magnusson, OT, Kong, A, Helgason, A, Holm, H, Thorsteinsdottir, U, Masson, G, Gudbjartsson, DF & Stefansson, K 2015, 'Identification of a large set of rare complete human knockouts', Nature Genetics, vol. 47, no. 5, pp. 448-452. https://doi.org/10.1038/ng.3243

TY - JOUR

T1 - Identification of a large set of rare complete human knockouts

AU - Sulem, Patrick

AU - Helgason, Hannes

AU - Oddson, Asmundur

AU - Stefansson, Hreinn

AU - Gudjonsson, Sigurjon A.

AU - Zink, Florian

AU - Hjartarson, Eirikur

AU - Sigurdsson, Gunnar Th

AU - Jonasdottir, Adalbjorg

AU - Jonasdottir, Aslaug

AU - Sigurdsson, Asgeir

AU - Magnusson, Olafur Th

AU - Kong, Augustine

AU - Helgason, Agnar

AU - Holm, Hilma

AU - Thorsteinsdottir, Unnur

AU - Masson, Gisli

AU - Gudbjartsson, Daniel F.

AU - Stefansson, Kari

PY - 2015/5/30

Y1 - 2015/5/30

N2 - Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10-261).

AB - Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10-261).

UR - http://www.scopus.com/inward/record.url?scp=84929133372&partnerID=8YFLogxK

U2 - 10.1038/ng.3243

DO - 10.1038/ng.3243

M3 - Article

C2 - 25807282

AN - SCOPUS:84929133372

SN - 1061-4036

VL - 47

SP - 448

EP - 452

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Identification of a large set of rare complete human knockouts

Abstract

Bibliographical note

Access to Document

Fingerprint

Cite this