Although humans have about 20,000 genes, exactly what most of them do inside our body’s cells is still murky. One way to learn more is to find people who lack a working copy of a particular gene and see how that affects their health. Such so-called knockouts are scarce in the general population. But a new study points to a more efficient way to find them: Search the DNA of people from a culture in which marrying a relative is common.
The study, which scoured the genomes of more than 3200 British-Pakistanis, has found hundreds of genes that we can apparently live without, including one that scientists had assumed based on animal studies would make a person sterile. And it paves the way for finding more healthy human “knockouts,” some of whom could also be a boon for developing new drugs. The new work “is a beautiful exemplar of how having a catalogue of gene knockouts for humans will be useful in testing our current understanding of human biology and revealing new biology," says geneticist Molly Przeworski of Columbia University, who was not involved in the research.
Scientists often knock out, or disable, a gene in mice to learn about its function, yet the results don’t necessarily translate into humans. With cheap DNA sequencing, it has become feasible to sequence the genomes of large numbers of people and find individuals who naturally lack a working version of certain genes—“a gift of nature for us to study,” says human geneticist David van Heel of Queen Mary University of London. Last year, for example, a project studying Icelanders’ genomes reported on a batch of knocked out genes. And complete knockouts—people whose two copies of a specific gene are both disabled—should be even more abundant in groups in which parents are often related because this increases a person’s chances of inheriting the same chunk of DNA from both parents. For that reason, Van Heel, Richard Durbin of the Wellcome Trust Sanger Institute in Cambridge, U.K., and co-workers sequenced the protein-coding DNA of 3222 relatively healthy British adults of Pakistani heritage, many of whose parents were first cousins.
Today in Science, the U.K. team reports that this British-Pakistani group did indeed have a lot of missing genes. Among them were 781 rare, missing genes (where these variants are found in less than 1% of the population) in about 821 individuals, about half of which had not been described before. (Rare knockouts are more interesting than ones due to common variants because the missing gene is more likely to have some effect on biological function—if a knocked-out gene has no effects, it is free to accumulate in populations instead of being weeded out by natural selection.)
Thirty-eight people lacked genes whose absence was thought to cause serious diseases. But only nine of the people clearly had the disease; often those carrying these so-called Mendelian genes weren’t at all sick, suggesting that missing these genes don’t always cause as much harm as the medical literature suggests.
And one healthy mother completely lacked a gene called PRDM9 that is involved in shuffling chromosomes during the formation of eggs and sperm. Mice lacking the gene are sterile, although dogs don’t carry the gene and do fine. That humans apparently have other genes that compensate for the loss of PRDM9 is “puzzling” and suggests that mice may be “more the exception than the rule,” Przeworski says. It also shows that as sequencing people’s genomes becomes routine, doctors will need to be cautious about concluding that a missing gene causes harm, Van Heel says.
The U.K. researchers are still analyzing their data, but they also expect to find examples of missing genes that protect against disease. A drug blocking such a gene should be safe because the gene isn’t essential, notes Robert Plenge, Vice President of Merck Research Laboratories in Boston. He predicts the study and others like it, including the 1-million-person Precision Medicine Initiative study gearing up in the United States, “will transform our approach to drug R&D.”
Van Heel’s team is now recruiting volunteers—more than 8000 so far—for a health study of 100,000 South Asians in East London that should find more rare knockouts. And co-author Daniel MacArthur of the Broad Institute in Cambridge, Massachusetts, is heading an effort to compile all available data on human knockouts in a database that will open up to researchers by mid-summer. “The goal is to say, for any given gene in the genome, is it sensitive to disruption?” MacArthur says. For now, he says, “we’re still only scratching the surface” of the universe of human knockouts.