A new study using a ‘reverse genetics’ approach to understanding gene function has enabled researchers to assess the phenotype of loss-of-function mutations in humans. The research, reported in this week’s Nature, lays the foundations for a large-scale study into human gene function.
Traditionally, researchers have unpicked gene function by knocking out key genes in model animals then studying the changes that follow. Sekar Kathiresan and colleagues apply a reverse approach. After sequencing the gene-encoding regions of 10,503 people living in Pakistan, they identified around 50,000 mutations predicted to cause loss of function of 1,317 genes in at least one participant and then determined whether these changes were associated with any of 200 or so traits measured in blood samples. In a proof-of-principle study, they show an example of recalling patients who carried a particular mutation, and then carried out further tests to show that this particular genetic change improved the ability to clear dietary fat from the circulation.
The study demonstrates the potential of this reverse genetics approach, setting the stage for a ‘Human Knockout Project’ to include assessment of more biochemical as well as clinical phenotypes, including disease, of loss-of-function mutations for genes across the human genome. This particular initial study benefitted from its unique choice of participants. The Pakistani population displays high rates of consanguinity, meaning that individuals are more likely to have loss of function in both copies of a particular gene, which can then be detected.