A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes-Reference-Cited by-同舟云学术

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

Published:2012-02-17 Issue:6070 Volume:335 Page:823-828
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

MacArthur Daniel G.¹²,Balasubramanian Suganthi³⁴,Frankish Adam¹,Huang Ni¹,Morris James¹,Walter Klaudia¹,Jostins Luke¹,Habegger Lukas³⁴,Pickrell Joseph K.⁵,Montgomery Stephen B.⁶⁷,Albers Cornelis A.¹⁸,Zhang Zhengdong D.⁹,Conrad Donald F.¹⁰,Lunter Gerton¹¹,Zheng Hancheng¹²,Ayub Qasim¹,DePristo Mark A.¹³,Banks Eric¹³,Hu Min¹,Handsaker Robert E.¹³¹⁴,Rosenfeld Jeffrey A.¹⁵,Fromer Menachem¹³,Jin Mike³,Mu Xinmeng Jasmine³⁴,Khurana Ekta³⁴,Ye Kai¹⁶,Kay Mike¹,Saunders Gary Ian¹,Suner Marie-Marthe¹,Hunt Toby¹,Barnes If H. A.¹,Amid Clara¹¹⁷,Carvalho-Silva Denise R.¹,Bignell Alexandra H.¹,Snow Catherine¹,Yngvadottir Bryndis¹,Bumpstead Suzannah¹,Cooper David N.¹⁸,Xue Yali¹,Romero Irene Gallego¹⁵,Wang Jun¹²,Li Yingrui¹²,Gibbs Richard A.¹⁹,McCarroll Steven A.¹³¹⁴,Dermitzakis Emmanouil T.⁷,Pritchard Jonathan K.⁵²⁰,Barrett Jeffrey C.¹,Harrow Jennifer¹,Hurles Matthew E.¹,Gerstein Mark B.³⁴²¹,Tyler-Smith Chris¹,

Affiliation:

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

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

3. 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.

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

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference70 articles.

1. Genetic Variation in an Individual Human Exome

2. A map of human genome variation from population-scale sequencing

3. The Characterization of Twenty Sequenced Human Genomes

4. Loss-of-function variants in the genomes of healthy humans

5. Gene inactivation and its implications for annotation in the era of personal genomics

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