Loss of function variants

loss-of-function variants

We’re interested in the detection and interpretation of loss-of-function (LoF) variants – genetic changes predicted to completely disrupt the function of protein-coding genes. We are developing an automated pipeline for the sensitive detection and filtering of LoF variants from large-scale exome and genome sequencing data. We are also involved in a number of collaborative projects linking LoF variation to human phenotypes and disease risk, including large-scale studies in the Finnish population and consanguineous individuals living in the UK.

Our work on investigating LoF variants in human genes – which we’re calling the Human Knockout Project – was recently highlighted 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
Daniel MacArthur, Genomes Unzipped: All genomes are dysfunctional: broken genes in healthy individuals
Lluis Quintana-Murci, Science perspective: Gene losses in the human genome
Darren Burgess, Nature Reviews GeneticsHow 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
Andrea Anderson, GenomeWeb: Researchers catalog loss-of-function variants in protein-coding genes
Tina Hesman Saey, ScienceNews: All genes aren’t indispensable
Nature Research Highlight: Loss-of-function found in droves
Kate Jelland, Chicago Tribune: Study finds one percent of human genes switched off
David Brown, Washington Post: Genome news flash: we’re all a little bit broken
Alzheimer Research Forum: Are broken genes commin in humans?
Jennifer Welsh, LiveScience: Humans have about 100 broken genes each
John Hawks: When genes break: validating loss-of-function variants
Razib Khan, Gene Expression: Extraordinary mutations require extraordinary evidence
Emily Singer, SFARI: Major errors in genome can be harmless
Emily Singer, SFARI: Major errors in genome can be harmless

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.