Today researchers unveiled the largest ever set of full genomes from a single population: Iceland. The massive project, carried out by a private company in the country, deCODE genetics, has yielded new disease risk genes, insights into human evolution, and a list of more than 1000 genes that people can apparently live without.
The project also serves as a model for other countries’ efforts to sequence their people’s DNA for research on personalized medical care, says study leader Kári Stefánsson, deCODE’s CEO. For example, the United States is planning to sequence the genomes of 1 million Americans over the next few years and use the data to devise individualized treatments.
The deCODE whole genomes study is “an amazing piece of work” that “was impossible 5 years ago,” says human geneticist Daniel MacArthur of Massachusetts General Hospital in Boston and the Broad Institute in Cambridge, Massachusetts, who was not involved in the research.
DeCODE is the controversial Reykjavik company that 19 years ago set out to develop drugs by mining Icelanders’ genetic and medical data for disease genes. It failed to get access to the entire country’s health records, but recruited volunteers who now represent more than 40% of Iceland’s population of 323,000. The company eventually went bankrupt, reformed, then in late 2012 was bought by Amgen Inc. All along, deCODE has churned out papers on genetic variants commonly involved in schizophrenia, diabetes, cancer, and other diseases, mostly by comparing markers scattered along the genomes of healthy and sick people.
Now, thanks to cheap genome sequencing, deCODE has sequenced the entire genomes of 2636 Icelanders and combed them for much rarer mutations. By drawing on the country’s genealogy records and on already-collected marker data, the company also calculated who among more than 100,000 other people carries these variants. In an overview paper and three related papers published online today in Nature Genetics, deCODE offers a sampling of what these data revealed.
The company found several new disease genes, including mutations in one gene, ABCA7, that double the risk of developing Alzheimer’s disease in people of European ancestry. Genetic marker studies had pointed to this gene, but could not nail down specific high-risk variants. Another paper estimates how quickly the Y chromosome mutates. This analysis suggests the last common human ancestor traced through the male line lived about 239,000 years ago, almost 100,000 years more recently than had been thought. The new rate of Y chromosome mutation will help refine the dates of key events in human evolution and migration, says Agnar Helgason of deCODE.
Iceland’s genomes also yielded a bounty of so-called human knockouts—people who carry two nonfunctional copies of one of the roughly 20,000 human genes. Thus, their cells don’t make that gene’s protein. Such individuals could shed light on the function of many genes and point to new drug targets if the knocked-out gene somehow protects against disease. DeCODE found that just over 8000 Icelanders carried 1171 knocked-out genes. Many are probably redundant and not essential or don’t affect health—3% of the missing genes are involved in distinguishing smells, which may have mattered for ancient humans but not for modern ones. But others are potentially intriguing, including a couple that may be involved in hearing. The company now plans to ask some of the people lacking a functional gene to come in for clinical testing so researchers can figure out what the missing genes do.
“This is just sort of scratching the surface,” Stefánsson says. MacArthur says there are undoubtedly other findings that Amgen is keeping to itself for now: “It’s clear they’re not giving everything away in these papers,” he says.
Geneticists say large population databases will be essential to pin down what portion of people carrying potentially harmful mutations will develop disease, and if the effects can be mitigated by other genes, for example. That is also one goal of President Barack Obama’s proposed Precision Medicine Initiative, which centers on a genomics study of 1 million Americans. “The benefits are enormous,” MacArthur says.