My group has a long-standing interest in the detection and interpretation of loss-of-function (LoF) variants – genetic changes predicted to completely disrupt the function of protein-coding genes. We have developed an automated pipeline, LOFTEE, for the sensitive detection and filtering of LoF variants from large-scale exome and genome sequencing data. We have also been deeply 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 and Pakistan.
Our work investigating LoF variants in human genes – which we’re calling the Human Knockout Project – was highlighted in Science in 2014. We have a recent paper in Nature exploring the distribution of LoF variants in the gnomAD dataset of over 140,000 exomes and genomes, an accompanying manuscript describing principles for using LoF variants to validate drug targets, and a case study in Nature Medicine using these variants to validate LRRK2 as a likely safe inhibitory therapeutic target for Parkinson’s disease.