Loss of Function Variants

This page contains material relevant to loss-of-function polymorphisms in human protein-coding genes, a key interest of our group.

Science paper 2012
Our major publication in this field has just been published in Science:

MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K, Jostins L, Habegger L, Pickrell JK, Montgomery SB, Albers CA, Zhang Z, Conrad DF, Lunter G, Zheng H, Ayub Q, DePristo MA, Banks E, Hu M, Handsaker R, Habegger L, Fromer M, Jin M, Mu X, Khurana E, Ye K, Kay M, Saunders GI, Suner M.-M., Hunt T, Barnes IHA, Amid C, Carvalho-Silva DR, Bignell AH, Snow C, Yngvadottir B, Bumpstead S, Cooper DN, Xue Y, Gallego Romero I, 1000 Genomes Project Consortium, Wang J, Li Y, Gibbs RA, McCarroll SA, Dermitzakis ET, Pritchard JK, Barrett JC, Harrow J, Hurles ME, Gerstein M, Tyler-Smith C. (2012) A systematic survey of loss-of-function polymorphisms in human protein-coding genesScience. 335:823-828.

This was a very large collaborative project involving researchers at the Sanger Institute, Yale University, and a number of other institutions, and used data made available by the 1000 Genomes Project

Manuscript and data
A pre-formatted version of the manuscript is available here, and the supplementary data file is here.

You can download the complete list of all candidate LoF SNPs and indels (with additional annotation) here, and the predicted probability of recessive disease causation, P(rec), for all assayable protein-coding genes in the human genome here. All of the genotyping validation data used in this study (from three custom Illumina arrays and 819 custom Sequenom assays) have been formatted for analysis with Evoker, and are available as a zipped archive here.

Media and online coverage
Lluis Quintana-Murci, Science perspective: Gene losses in the human genome
Darren Burgess, Nature Reviews Genetics: How pervasive are defective genes? [subscription required]
Joy Yang, National Human Genome Research Institute, Genome Advance of the Month: Discovering the mutants among us
Jocelyn Kaiser, ScienceNOW: The case of the missing genes
Tina Hesman Saey, ScienceNews: All genes aren't indispensable
Nature Research Highlight: Loss-of-function found in droves
Alzheimer Research Forum: Are broken genes commin in humans?
Jennifer Welsh, LiveScience: Humans have about 100 broken genes each

Previous literature on loss-of-function variants
Balasubramanian S, Habegger L, Frankish A, MacArthur DG, Harte R, Tyler-Smith C, Harrow J, Gerstein M. (2011) Gene inactivation and its implications for annotation in the era of personal genomicsGenes Dev. 25(1):1-10.

1000 Genomes Project Consortium. (2010) A map of human genome variation from population-scale sequencingNature. 467(7319):1061-1073.

MacArthur DG, Tyler-Smith C. (2010) Loss-of-function variants in the genomes of healthy humansHum Mol Genet. 19(R2):R125-130. 
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Daniel MacArthur,
17 Feb 2012 16:27
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Daniel MacArthur,
17 Feb 2012 16:28
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Daniel MacArthur,
17 Feb 2012 17:45
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Daniel MacArthur,
16 Feb 2012 11:40
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Daniel MacArthur,
16 Feb 2012 11:35