Mikko Mattila - Travel, Finland, Helsinki/Alamy
Finland offers geneticists a rich seam of variation.
For decades, biologists have studied gene function by inactivating the gene in question in mice and other lab animals, and then observing how it affects the organism. Now researchers studying such gene knockouts have another, ideal model at their disposal: humans.
The approach does not involve genetically engineering mutant people in the lab, as is done in mice. Instead, researchers scan the genomes of thousands or millions of people, looking for naturally occurring mutations that inactivate a particular gene. By observing how these mutations affect health, researchers hope to gain insight into basic biology and to unearth new disease treatments.
Geneticists discussed several such large-scale efforts during a packed session at the American Society of Human Genetics meeting in San Diego, California, last week. So much of what we know is based on mice and rats, and not humans, says Daniel MacArthur, a genomicist at Massachusetts General Hospital in Boston, whose team identified around 150,000 naturally knocked-out genes by trawling the protein-coding portion of the genome, or exome, in more than 90,000 people. Now we can find people who actually have a particular gene inactivated or somehow modified, and that allows us to test hypotheses directly.
On average, every person carries mutations that inactivate at least one copy of 200 or so genes and both copies of around 20 genes. However, knockout mutations in any particular gene are rare, so very large populations are needed to study their effects. These loss of function mutations have long been implicated in certain debilitating diseases, such as cystic fibrosis. Most, however, seem to be harmless and some are even beneficial to the persons carrying them. These are people were not going to find in a clinic, but theyre still really informative in biology, says MacArthur.
His group and others had been focusing on genome data, but they are now also starting to mine patient-health records to determine the sometimes subtle effects of the mutations. In a study of more than 36,000Finnish people, published in July (E.T.Lim etal. PLoS Genet. 10, e1004494; 2014), MacArthur and his team discovered that people lacking a gene called LPA might be protected from heart disease, and that another knockout mutation, carried in one copy of a gene by up to 2.4% of Finns, may cause fetuses to miscarry if it is present in both copies.
Bing Yu of the University of Texas Health Science Center in Houston told the meeting how he and his collaborators had compared knockout mutations found in more than 1,300people with measurements of around 300molecules in their blood. The team found that mutations in one gene, called SLCO1B1, were linked to high levels of fatty acids, a known risk factor for heart failure. And a team from the Wellcome Trust Sanger Institute in Hinxton, UK, reported that 43 genes whose inactivation is lethal to mice were found to be inactivated in humans who are alive and apparently well.
Following up on such insights will help researchers to unpick the functions of the thousands of human genes about which little or nothing is known, say MacArthur and others. It might even aid drug discovery by identifying genes or biological pathways that could protect against disease.
The poster child for human-knockout efforts is a new class of drugs that block a gene known as PCSK9 (see Nature 496, 152155; 2013). The gene was discovered in French families with extremely high cholesterol levels in the early 2000s. But researchers soon found that people with rare mutations that inactivate one copy of PCSK9 have low cholesterol and rarely develop heart disease. The first PCSK9-blocking drugs should hit pharmacies next year, with manufacturers jostling for a share of a market that could reach US$25 billion in five years.
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