A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes: - Enviado mediante la barra Google

Science 17 February 2012:
Vol. 335 no. 6070 pp. 823-828
DOI: 10.1126/science.1215040

• Research Article

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

1. Daniel G. MacArthur¹,²,*,
2. Suganthi Balasubramanian³,⁴,
3. Adam Frankish¹,
4. Ni Huang¹,
5. James Morris¹,
6. Klaudia Walter¹,
7. Luke Jostins¹,
8. Lukas Habegger³,⁴,
9. Joseph K. Pickrell⁵,
10. Stephen B. Montgomery⁶,⁷,
11. Cornelis A. Albers¹,⁸,
12. Zhengdong D. Zhang⁹,
13. Donald F. Conrad¹⁰,
14. Gerton Lunter¹¹,
15. Hancheng Zheng¹²,
16. Qasim Ayub¹,
17. Mark A. DePristo¹³,
18. Eric Banks¹³,
19. Min Hu¹,
20. Robert E. Handsaker¹³,¹⁴,
21. Jeffrey A. Rosenfeld¹⁵,
22. Menachem Fromer¹³,
23. Mike Jin³,
24. Xinmeng Jasmine Mu³,⁴,
25. Ekta Khurana³,⁴,
26. Kai Ye¹⁶,
27. Mike Kay¹,
28. Gary Ian Saunders¹,
29. Marie-Marthe Suner¹,
30. Toby Hunt¹,
31. If H. A. Barnes¹,
32. Clara Amid¹,¹⁷,
33. Denise R. Carvalho-Silva¹,
34. Alexandra H. Bignell¹,
35. Catherine Snow¹,
36. Bryndis Yngvadottir¹,
37. Suzannah Bumpstead¹,
38. David N. Cooper¹⁸,
39. Yali Xue¹,
40. Irene Gallego Romero¹,⁵,
41. 1000 Genomes Project Consortium,
42. Jun Wang¹²,
43. Yingrui Li¹²,
44. Richard A. Gibbs¹⁹,
45. Steven A. McCarroll¹³,¹⁴,
46. Emmanouil T. Dermitzakis⁷,
47. Jonathan K. Pritchard⁵,²⁰,
48. Jeffrey C. Barrett¹,
49. Jennifer Harrow¹,
50. Matthew E. Hurles¹,
51. Mark B. Gerstein³,⁴,²¹,^†,
52. Chris Tyler-Smith¹,^†

+ Author Affiliations

1. ¹Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
2. ²Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW 2006, Australia.
3. ³Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
4. ⁴Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
5. ⁵Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
6. ⁶Departments of Pathology and Genetics, Stanford University, Stanford, CA 94305–5324, USA.
7. ⁷Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva 4, Switzerland.
8. ⁸Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge CB2 0PT, UK.
9. ⁹Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
10. ¹⁰Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
11. ¹¹Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
12. ¹²BGI-Shenzhen, Shenzhen 518083, China.
13. ¹³Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
14. ¹⁴Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
15. ¹⁵IST/High Performance and Research Computing, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
16. ¹⁶Molecular Epidemiology Section, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
17. ¹⁷The European Nucleotide Archive, European Molecular Biology Laboratory–European Bioinformatics Institute, Hinxton CB10 1SD, UK.
18. ¹⁸Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
19. ¹⁹Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
20. ²⁰Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
21. ²¹Department of Computer Science, Yale University, New Haven, CT, USA.

1. ↵*To whom correspondence should be addressed. E-mail: macarthur@atgu.mgh.harvard.edu

1. ↵† These authors contributed equally to this work.

Abstract

Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease–causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

• Received for publication 10 October 2011.
• Accepted for publication 11 January 2012.