A common way for scientists to learn what a particular gene does is to breed animals with a mutation in that gene, then study what happens.
That is not an option in humans. But a powerful new study, whose leaders included scientists from the University of Pennsylvania, illustrates the next best option: taking what nature gives you.
Upon studying the genomes of more than 10,000 people in Pakistan, the authors said they had identified more than 1,800 "knockouts" – people in whom copies of a gene inherited from both their mother and father were deficient.
Among them were a man, a woman, and their nine children whose mutations resulted in abnormally low levels of triglycerides, likely protecting them against heart disease. This mutation also has been found in the insular Amish community in Lancaster County.
If drug companies could mimic beneficial effects caused by genetic knockouts (not all are beneficial), it could speed up the search for effective treatments, said Danish Saleheen, an assistant professor of epidemiology and biostatistics at Penn's Perelman School of Medicine.
"Instead of shooting arrows in the dark to find a drug that would be beneficial, we can now make an informed choice about the beneficial and harmful effects of pharmacological inhibition of a wide range of pathways," said Saleheen, one of the lead authors.
The study, published in the journal Nature, was the result of an international collaboration led by Penn, the Center for Non-Communicable Diseases in Pakistan, the Broad Institute, Harvard, and the University of Cambridge in England.
One of the study's two senior authors was Daniel J. Rader, chair of Penn's department of genetics.
The mutations identified in the study touch on so much human biology, from breaking down toxins in the lungs to metabolizing glucose, that it will take years to sort out what they all mean. Some of the genetic pathways could inform drug development, while others may simply guide the pursuit of science.
The scientists focused on Pakistan because of its high rate of marriage between first cousins. That means a greater chance that children are born with two identical copies of the same gene.
Geneticists study the Amish for a similar reason. Marriage between cousins is not practiced there, but certain genetic mutations can become concentrated. In Lancaster County, however, the triglyceride-lowering mutation was found in only one copy of the gene, and so levels of the fatty substance were not as low as in the Pakistani family.
In Pakistan, the scientists identified a total of 1,317 genes that were knocked out in at least one person. Some of the knockouts, such as the triglyceride ones, were present in more than one person, leading to the total of more than 1,800 people.
This was not the first study to identify people without functioning copies of a particular gene, but it is the largest to date.
Saleheen, who is from Pakistan, said the results published this week are just the beginning. He and his colleagues plan to test the genomes of 200,000 participants from his native country, potentially identifying up to 8,000 people with knocked-out genes.
Robert M. Plenge, a scientist at the drugmaker Merck & Co., wrote in the same issue of Nature that the effort by Saleheen's team is sure to yield results.
Animal studies will still be needed, Plenge wrote, but the study of these human knockouts "will change the nature of the scientific investigation of the genetic basis of human disease."