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Imperfect. The average person may be walking around with about 20 inactive genes.

The Case of the Missing Genes

Jocelyn is a staff writer for Science magazine.

You might assume that if you're healthy, you have a normal, healthy genome. But there is no such thing as a normal genome—all of us carry a number of mutated and nonfunctioning genes. Now researchers have estimated exactly how many such genes there are in the average person: about 100, including 20 mutated and completely inactive genes. We probably don't need some of this DNA and in some cases could even be better off without it.

Soon after researchers began to sequence individual genomes 5 years ago, they realized that everyone's DNA seems to have major mutations that disable the protein for which the gene codes. But because DNA sequencing is prone to errors, many of these variants are likely to be mistakes in gene analysis. To figure out which mutations were real, postdoc Daniel MacArthur of Chris Tyler-Smith's group at the Wellcome Trust Sanger Institute in Hinxton, U.K., and colleagues from Yale University and other institutions started with 2951 possible "loss of function" variants found in the genomes of 185 anonymous people from various ethnic groups whose DNA is part of the international 1000 Genomes Project. MacArthur's team then winnowed the list by removing errors and genetic mistakes that don't alter the function of the corresponding protein.

They found that 1285 loss-of-function gene variants are likely genuine, about 100 of which appear in the genome of the average European, MacArthur's team reports today in the 17 February issue of Science. Some are mutations in known disease-causing genes and occur in only one copy of the gene, so the person's other copy probably compensates. But the average individual had lost both copies of roughly 20 genes, which means the gene is essentially missing—a surprisingly high number, MacArthur says. Many of these genes probably don't affect health, and his team's analysis suggests that lacking some genes might even be beneficial.

As more genomes are sequenced, "we know for sure that we will find a lot more" loss-of-function mutations, MacArthur says. A more complete catalog could help researchers track down the culprit genes in patients with rare, unexplained diseases. Knowing that many inactivated genes don't result in disease will also be important when sequencing genomes becomes routine in the clinic, MacArthur says. "This shows how careful we need to be when drawing inferences about such mutations," agrees geneticist Peter Visscher of the University of Queensland in Australia. Studying healthy people who are missing genes could also shed light on the function of genes that aren't well understood, MacArthur and his co-authors suggest.

Genome researcher Elaine Mardis of Washington University in St. Louis in Missouri cautions that because the 1000 Genomes Project participants' genomes weren't sequenced in depth and were done when next-generation sequencing technologies were very new, MacArthur's team may have missed some loss-of-function variants. Still, even if the numbers aren't definitive, the study is "important" because it "establishes a framework for thinking about loss-of-function mutations and how to prioritize them," she says.

Posted in Biology