Journal article

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

Daniel G MacArthur, Suganthi Balasubramanian, Adam Frankish, Ni Huang, James Morris, Klaudia Walter, Luke Jostins, Lukas Habegger, Joseph K Pickrell, Stephen B Montgomery, Cornelis A Albers, Zhengdong D Zhang, Donald F Conrad, Gerton Lunter, Hancheng Zheng, Qasim Ayub, Mark A DePristo, Eric Banks, Min Hu, Robert E Handsaker Show all

Science | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2012


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-t..

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University of Melbourne Researchers


Awarded by Wellcome Trust

Awarded by Netherlands Organisation for Scientific Research (NWO)

Awarded by National Basic Research Program of China (973 program)

Awarded by National Natural Science Foundation of China

Awarded by Chinese 863 program

Awarded by Shenzhen Municipal Government of China

Awarded by Biotechnology and Biological Sciences Research Council

Awarded by British Heart Foundation



Funding Acknowledgements

T. Shah provided the Pyvoker software used for manual assignment of genotypes based on intensity clusters; S. Edkins was involved in the Sequenom validation; and the genotyping groups at Illumina, the Wellcome Trust Sanger Institute, and The Broad Institute of Harvard and MIT provided raw intensity data for the three Illumina arrays used for genotyping validation. The work performed at the Wellcome Trust Sanger Institute was supported by Wellcome Trust grant 098051; D. G. M. was supported by a fellowship from the Australian National Health and Medical Research Council; G. L. by the Wellcome Trust (090532/Z/09/Z); E. T. D. and S. B. M. by the Swiss National Science Foundation, the Louis Jeantet Foundation, and the NIH-National Institute of Mental Health GTEx fund; K.Y. by the Netherlands Organisation for Scientific Research (NWO) VENI grant 639.021.125; and H.Z., Y.L., and J.W. by a National Basic Research Program of China (973 program no. 2011CB809200), the National Natural Science Foundation of China (30725008, 30890032, 30811130531), the Chinese 863 program (2006AA02A302, 2009AA022707), the Shenzhen Municipal Government of China (grants JC200903190767A, JC200903190772A, ZYC200903240076A, CXB200903110066A, ZYC200903240077A, and ZYC200903240080A), and the Ole Romer grant from the Danish Natural Science Research Council, as well as funding from the Shenzhen Municipal Government and the Local Government of Yantian District of Shenzhen. M. B. G. and C.T.-S. contributed equally to this work as senior authors. J.K.P. is on the scientific advisory board of 23andMe, and R. A. G. has a shared investment in Life Technologies. Raw sequence data for the 1000 Genomes pilot projects are available from, and a curated list of the loss-of-function variants described in this manuscript is provided in the supporting online material.