Open Access

Science

, volume 335 , issue 6070 , pages 823-828

A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes

Daniel G. MacArthur ^{1, 2}

Suganthi Balasubramanian ^{3, 4}

Adam Frankish ¹

Ni Huang ¹

James Morris ¹

Klaudia Walter ¹

Luke Jostins ¹

Lukas Habegger ^{3, 4}

Joseph K. Pickrell ⁵

Stephen B. Montgomery ^{6, 7}

Cornelis A Albers ^{1, 8}

Zhengdong D Zhang ⁹

Donald F Conrad ¹⁰

Lunter Gerton ¹¹

Hancheng Zheng ¹²

Qasim Ayub ¹

Mark A Depristo ¹³

Eric BANKS ¹³

Min Hu ¹

Robert E Handsaker ^{13, 14}

Jeffrey A Rosenfeld ¹⁵

Menachem Fromer ¹³

Mike Jin ³

Xinmeng Jasmine Mu ^{3, 4}

Ekta Khurana ^{3, 4}

Kai Ye ¹⁶

Mike Kay ¹

Gary Ian Saunders ¹

Marie-Marthe Suner ¹

Toby Hunt ¹

If H. A. Barnes ¹

Clara Amid ^{1, 17}

Denise R Carvalho Silva ¹

Alexandra H Bignell ¹

Catherine Snow ¹

Bryndis Yngvadottir ¹

Suzannah Bumpstead ¹

David N. Cooper ¹⁸

Yali Xue ¹

Irene Gallego Romero ^{1, 5}

Jun Wang ¹²

Yingrui Li ¹²

Richard A. Gibbs ¹⁹

Steven A. McCarroll ^{13, 14}

Emmanouil T. Dermitzakis ⁷

Jonathan K Pritchard ^{5, 20}

Jeffrey C. Barrett ¹

Jennifer Harrow ¹

Matthew E. Hurles ¹

Mark B Gerstein ^{3, 4, 21}

Chris TYLER-SMITH ¹

Hide authors affiliations Show authors affiliations: 21 affiliations

Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. |

Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW 2006, Australia. |

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA. |

⁴

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA. |

⁵

Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. |

⁶

Departments of Pathology and Genetics, Stanford University, Stanford, CA 94305–5324, USA. |

⁷

Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva 4, Switzerland. |

⁸

Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge CB2 0PT, UK. |

⁹

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. |

¹⁰

Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, USA. |

¹¹

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. |

¹²

BGI-Shenzhen, Shenzhen 518083, China. |

¹³

Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. |

¹⁴

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. |

¹⁵

IST/High Performance and Research Computing, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA. |

¹⁶

Molecular Epidemiology Section, Leiden University Medical Center, 2300 RC Leiden, Netherlands. |

¹⁷

The European Nucleotide Archive, European Molecular Biology Laboratory–European Bioinformatics Institute, Hinxton CB10 1SD, UK. |

¹⁸

Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. |

¹⁹

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. |

²⁰

Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.

University of Chicago

Howard Hughes Medical Institute

²¹

Department of Computer Science, Yale University, New Haven, CT, USA. |

Publication type: Journal Article

Publication date: 2012-02-17

American Association for the Advancement of Science (AAAS)

Science

scimago Q1

wos Q1

SJR: 10.416

CiteScore: 48.4

Impact factor: 45.8

ISSN: 00368075, 10959203

DOI: 10.1126/science.1215040

Copy DOI

PubMed ID: 22344438

Multidisciplinary

Abstract

Defective Gene Detective

Identifying genes that give rise to diseases is one of the major goals of sequencing human genomes. However, putative loss-of-function genes, which are often some of the first identified targets of genome and exome sequencing, have often turned out to be sequencing errors rather than true genetic variants. In order to identify the true scope of loss-of-function genes within the human genome, MacArthur et al. (p. 823 ; see the Perspective by Quintana-Murci ) extensively validated the genomes from the 1000 Genomes Project, as well as an additional European individual, and found that the average person has about 100 true loss-of-function alleles of which approximately 20 have two copies within an individual. Because many known disease-causing genes were identified in “normal” individuals, the process of clinical sequencing needs to reassess how to identify likely causative alleles.

Found

2 citations

Potapova Nadezhda

🤝

19 publications, 82 citations

h-index: 6

Immanuel Kant Baltic Federal University

Irkutsk State University

Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Research interests

Bioinformatics

Evolutionary genomics

Genetics

1 citation

Fedrigo Olivier

62 publications, 5 452 citations

h-index: 23

Rockefeller University

University of Nottingham

International Livestock Research Institute (Kenya)

1 citation

Kutsenko Vladimir

PhD in Physics and Mathematics

155 publications, 4 411 citations

h-index: 15

Lomonosov Moscow State University

National Research Center for Therapy and Preventive Medicine

Research interests

Biostatistics

Epidemiology

Quantitative genetics

1 citation

Poulin Elie

156 publications, 3 046 citations, 11 reviews

h-index: 31

Universidad de Chile

1 citation

Chew Emily

623 publications, 72 799 citations, 13 reviews

h-index: 103

National Eye Institute

1 citation

Sousa Mário

53 publications, 575 citations, 13 reviews

1 citation

Marongiu Michele

96 publications, 10 404 citations, 3 reviews

h-index: 28

1 citation

GENSINI FRANCESCA

86 publications, 2 181 citations

h-index: 29

University of Florence

1 citation

Yarovaya Elena

194 publications, 1 311 citations

h-index: 20

National Research Center for Therapy and Preventive Medicine

Lomonosov Moscow State University

National Medical Research Center of Cardiology

Steklov Mathematical Institute of Russian Academy of Sciences

Top-30

Journals

	5 10 15 20 25 30 35
American Journal of Human Genetics	American Journal of Human Genetics, 31, 2.92% American Journal of Human Genetics 31 publications, 2.92%
Nature Communications	Nature Communications, 25, 2.35% Nature Communications 25 publications, 2.35%
PLoS ONE	PLoS ONE, 24, 2.26% PLoS ONE 24 publications, 2.26%
PLoS Genetics	PLoS Genetics, 22, 2.07% PLoS Genetics 22 publications, 2.07%
Nature	Nature, 21, 1.98% Nature 21 publications, 1.98%
Nature Genetics	Nature Genetics, 18, 1.69% Nature Genetics 18 publications, 1.69%
Scientific Reports	Scientific Reports, 16, 1.51% Scientific Reports 16 publications, 1.51%
BMC Genomics	BMC Genomics, 16, 1.51% BMC Genomics 16 publications, 1.51%
Human Mutation	Human Mutation, 16, 1.51% Human Mutation 16 publications, 1.51%
Nature Reviews Genetics	Nature Reviews Genetics, 15, 1.41% Nature Reviews Genetics 15 publications, 1.41%
Science	Science, 15, 1.41% Science 15 publications, 1.41%
Frontiers in Genetics	Frontiers in Genetics, 14, 1.32% Frontiers in Genetics 14 publications, 1.32%
Genome Medicine	Genome Medicine, 14, 1.32% Genome Medicine 14 publications, 1.32%
Genome Research	Genome Research, 14, 1.32% Genome Research 14 publications, 1.32%
Human Genetics	Human Genetics, 13, 1.22% Human Genetics 13 publications, 1.22%
Cell	Cell, 13, 1.22% Cell 13 publications, 1.22%
Bioinformatics	Bioinformatics, 13, 1.22% Bioinformatics 13 publications, 1.22%
Human Molecular Genetics	Human Molecular Genetics, 13, 1.22% Human Molecular Genetics 13 publications, 1.22%
Molecular Biology and Evolution	Molecular Biology and Evolution, 11, 1.03% Molecular Biology and Evolution 11 publications, 1.03%
eLife	eLife, 10, 0.94% eLife 10 publications, 0.94%
Nucleic Acids Research	Nucleic Acids Research, 10, 0.94% Nucleic Acids Research 10 publications, 0.94%
Proceedings of the National Academy of Sciences of the United States of America	Proceedings of the National Academy of Sciences of the United States of America, 10, 0.94% Proceedings of the National Academy of Sciences of the United States of America 10 publications, 0.94%
Genes	Genes, 9, 0.85% Genes 9 publications, 0.85%
npj Genomic Medicine	npj Genomic Medicine, 8, 0.75% npj Genomic Medicine 8 publications, 0.75%
European Journal of Human Genetics	European Journal of Human Genetics, 8, 0.75% European Journal of Human Genetics 8 publications, 0.75%
Genome Biology	Genome Biology, 8, 0.75% Genome Biology 8 publications, 0.75%
Circulation Cardiovascular Genetics	Circulation Cardiovascular Genetics, 7, 0.66% Circulation Cardiovascular Genetics 7 publications, 0.66%
Molecular Psychiatry	Molecular Psychiatry, 7, 0.66% Molecular Psychiatry 7 publications, 0.66%
Advances in Experimental Medicine and Biology	Advances in Experimental Medicine and Biology, 7, 0.66% Advances in Experimental Medicine and Biology 7 publications, 0.66%
	5 10 15 20 25 30 35

Publishers

	50 100 150 200 250 300 350
Springer Nature	Springer Nature, 304, 28.6% Springer Nature 304 publications, 28.6%
Elsevier	Elsevier, 171, 16.09% Elsevier 171 publications, 16.09%
Cold Spring Harbor Laboratory	Cold Spring Harbor Laboratory, 134, 12.61% Cold Spring Harbor Laboratory 134 publications, 12.61%
Oxford University Press	Oxford University Press, 82, 7.71% Oxford University Press 82 publications, 7.71%
Wiley	Wiley, 81, 7.62% Wiley 81 publications, 7.62%
Public Library of Science (PLoS)	Public Library of Science (PLoS), 56, 5.27% Public Library of Science (PLoS) 56 publications, 5.27%
MDPI	MDPI, 25, 2.35% MDPI 25 publications, 2.35%
Frontiers Media S.A.	Frontiers Media S.A., 24, 2.26% Frontiers Media S.A. 24 publications, 2.26%
Ovid Technologies (Wolters Kluwer Health)	Ovid Technologies (Wolters Kluwer Health), 24, 2.26% Ovid Technologies (Wolters Kluwer Health) 24 publications, 2.26%
American Association for the Advancement of Science (AAAS)	American Association for the Advancement of Science (AAAS), 21, 1.98% American Association for the Advancement of Science (AAAS) 21 publications, 1.98%
Taylor & Francis	Taylor & Francis, 12, 1.13% Taylor & Francis 12 publications, 1.13%
Annual Reviews	Annual Reviews, 11, 1.03% Annual Reviews 11 publications, 1.03%
eLife Sciences Publications	eLife Sciences Publications, 10, 0.94% eLife Sciences Publications 10 publications, 0.94%
Proceedings of the National Academy of Sciences (PNAS)	Proceedings of the National Academy of Sciences (PNAS), 10, 0.94% Proceedings of the National Academy of Sciences (PNAS) 10 publications, 0.94%
F1000 Research	F1000 Research, 8, 0.75% F1000 Research 8 publications, 0.75%
American Chemical Society (ACS)	American Chemical Society (ACS), 8, 0.75% American Chemical Society (ACS) 8 publications, 0.75%
BMJ	BMJ, 6, 0.56% BMJ 6 publications, 0.56%
American Medical Association (AMA)	American Medical Association (AMA), 6, 0.56% American Medical Association (AMA) 6 publications, 0.56%
SAGE	SAGE, 5, 0.47% SAGE 5 publications, 0.47%
Massachusetts Medical Society	Massachusetts Medical Society, 4, 0.38% Massachusetts Medical Society 4 publications, 0.38%
The Company of Biologists	The Company of Biologists, 3, 0.28% The Company of Biologists 3 publications, 0.28%
Institute of Electrical and Electronics Engineers (IEEE)	Institute of Electrical and Electronics Engineers (IEEE), 3, 0.28% Institute of Electrical and Electronics Engineers (IEEE) 3 publications, 0.28%
Cambridge University Press	Cambridge University Press, 3, 0.28% Cambridge University Press 3 publications, 0.28%
American Society of Hematology	American Society of Hematology, 3, 0.28% American Society of Hematology 3 publications, 0.28%
Mary Ann Liebert	Mary Ann Liebert, 2, 0.19% Mary Ann Liebert 2 publications, 0.19%
PeerJ	PeerJ, 2, 0.19% PeerJ 2 publications, 0.19%
Royal Society of Chemistry (RSC)	Royal Society of Chemistry (RSC), 2, 0.19% Royal Society of Chemistry (RSC) 2 publications, 0.19%
Pleiades Publishing	Pleiades Publishing, 2, 0.19% Pleiades Publishing 2 publications, 0.19%
American Association for Cancer Research (AACR)	American Association for Cancer Research (AACR), 2, 0.19% American Association for Cancer Research (AACR) 2 publications, 0.19%
	50 100 150 200 250 300 350

We do not take into account publications without a DOI.
Statistics recalculated weekly.

Are you a researcher?

Create a profile to get free access to personal recommendations for colleagues and new articles.

PDF

Metrics

1.1k

Cite this

GOST |

Cite this

GOST Copy

MacArthur D. G. et al. A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes // Science. 2012. Vol. 335. No. 6070. pp. 823-828.

GOST all authors (up to 50) Copy

MacArthur D. G. et al. A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes // Science. 2012. Vol. 335. No. 6070. pp. 823-828.

RIS |

Cite this

RIS Copy

TY - JOUR

DO - 10.1126/science.1215040

UR - https://doi.org/10.1126/science.1215040

TI - A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes

T2 - Science

AU - MacArthur, Daniel G.

AU - Balasubramanian, Suganthi

AU - Frankish, Adam

AU - Huang, Ni

AU - Morris, James

AU - Walter, Klaudia

AU - Jostins, Luke

AU - Habegger, Lukas

AU - Pickrell, Joseph K.

AU - Montgomery, Stephen B.

AU - Albers, Cornelis A

AU - Zhang, Zhengdong D

AU - Conrad, Donald F

AU - Gerton, Lunter

AU - Zheng, Hancheng

AU - Ayub, Qasim

AU - Depristo, Mark A

AU - BANKS, Eric

AU - Hu, Min

AU - Handsaker, Robert E

AU - Rosenfeld, Jeffrey A

AU - Fromer, Menachem

AU - Jin, Mike

AU - Mu, Xinmeng Jasmine

AU - Khurana, Ekta

AU - Ye, Kai

AU - Kay, Mike

AU - Saunders, Gary Ian

AU - Suner, Marie-Marthe

AU - Hunt, Toby

AU - Barnes, If H. A.

AU - Amid, Clara

AU - Carvalho Silva, Denise R

AU - Bignell, Alexandra H

AU - Snow, Catherine

AU - Yngvadottir, Bryndis

AU - Bumpstead, Suzannah

AU - Cooper, David N.

AU - Xue, Yali

AU - Romero, Irene Gallego

AU - Wang, Jun

AU - Li, Yingrui

AU - Gibbs, Richard A.

AU - McCarroll, Steven A.

AU - Dermitzakis, Emmanouil T.

AU - Pritchard, Jonathan K

AU - Barrett, Jeffrey C.

AU - Harrow, Jennifer

AU - Hurles, Matthew E.

AU - Gerstein, Mark B

AU - TYLER-SMITH, Chris

PY - 2012

DA - 2012/02/17

PB - American Association for the Advancement of Science (AAAS)

SP - 823-828

IS - 6070

VL - 335

PMID - 22344438

SN - 0036-8075

SN - 1095-9203

ER -

BibTex |

Cite this

BibTex (up to 50 authors) Copy

@article{2012_MacArthur,

author = {Daniel G. MacArthur and Suganthi Balasubramanian and Adam Frankish and Ni Huang and James Morris and Klaudia Walter and Luke Jostins and Lukas Habegger and Joseph K. Pickrell and Stephen B. Montgomery and Cornelis A Albers and Zhengdong D Zhang and Donald F Conrad and Lunter Gerton and Hancheng Zheng and Qasim Ayub and Mark A Depristo and Eric BANKS and Min Hu and Robert E Handsaker and Jeffrey A Rosenfeld and Menachem Fromer and Mike Jin and Xinmeng Jasmine Mu and Ekta Khurana and Kai Ye and Mike Kay and Gary Ian Saunders and Marie-Marthe Suner and Toby Hunt and If H. A. Barnes and Clara Amid and Denise R Carvalho Silva and Alexandra H Bignell and Catherine Snow and Bryndis Yngvadottir and Suzannah Bumpstead and David N. Cooper and Yali Xue and Irene Gallego Romero and Jun Wang and Yingrui Li and Richard A. Gibbs and Steven A. McCarroll and Emmanouil T. Dermitzakis and Jonathan K Pritchard and Jeffrey C. Barrett and Jennifer Harrow and Matthew E. Hurles and Mark B Gerstein and others},

title = {A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes},

journal = {Science},

year = {2012},

volume = {335},

publisher = {American Association for the Advancement of Science (AAAS)},

month = {feb},

url = {https://doi.org/10.1126/science.1215040},

number = {6070},

pages = {823--828},

doi = {10.1126/science.1215040}

}

MLA

Cite this

MLA Copy

MacArthur, Daniel G., et al. “A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes.” Science, vol. 335, no. 6070, Feb. 2012, pp. 823-828. https://doi.org/10.1126/science.1215040.

Publisher

American Association for the Advancement of Science (AAAS)

Journal

Science

scimago Q1

wos Q1

SJR

10.416

CiteScore

48.4

Impact factor

45.8

ISSN

00368075 (Print)

10959203 (Electronic)