Making gene knockouts has long been one of researchers’ favorite ways to determine the function of a gene. If you eliminate a particular gene and it kills the organism, the thinking goes, then that gene must be pretty darn important. Less dramatic ramifications can be equally informative; knockouts have identified genes involved in things like growth, DNA repair, and limb formation.
Knockouts are usually generated in species that are laboratory standbys, like mice and yeast. Creating human knockouts has not really been done for the obvious ethical reasons, not to mention the technical ones (you have to wait 17 years between generations). But ultimately, the whole goal of these studies is to figure out what these genes are doing in humans.
Now a group of geneticists has decided that if you can't make them, you can find them. They've collected and studied human knockouts that have occurred naturally and reported the results in Science.
The subjects were 3,222 mostly healthy adults (some had type 2 diabetes) of Pakistani descent living in the United Kingdom. In this culture, marriage between first cousins is fairly frequent; about a third of the study participants came from such unions. If their mother and their father both have recessive mutations rendering a gene nonfunctional—a more likely scenario when that mother and father are cousins—then the odds of getting no functional copies of the gene are increased. Therefore, this population has functional knockouts for a relatively high number of genes.
The researchers found naturally occurring knockouts in 781 genes in 821 people (meaning some of the same genes were knocked out in more than one person). A hundred and seven of these genes had already been identified in a similar study of Icelanders, another famously interrelated group. The researchers speculate that these genes are either really dispensable or really mutation-prone.
Researchers found 13.7 percent fewer knockouts than they expected; they accounted for the discrepancy by concluding that the knockouts they didn’t see caused early lethality or severe disease. Their most noteworthy finding came from correlating their genetic data with health records, which showed that the adults harboring these knockouts were… totally fine.
One of the women in the study had complete loss of function from a gene called PRDM-9, which determines where maternal and paternal chromosomes recombine (exchange genetic material) during meiosis. As far as genetic fitness of a species is concerned, this recombination is probably the single best thing about reproducing sexually as opposed to any alternative. PRDM-9 knockout mice are sterile, but this woman was not.
Likewise, about a quarter of the genes that were lost in these subjects were fatal when knocked out in mice. The authors conclude by noting that as DNA sequencing is being more routinely offered to healthy adults, we need to interpret the sequence data very, very carefully. Not all mutations will have clinical consequences—even if mouse studies indicate that they might.