Researchers have spent the past decade looking for tiny changes in common genes that predispose people to chronic diseases, such as asthma and diabetes. Now a new approach is starting to pay off: hunting for rare mutations in genes that are crucial to maintaining health.
In the latest example of this approach, researchers found faulty copies of a gene called sialic acid acetylesterase (SIAE) in 24 of 923 white subjects who suffered from autoimmune disorders, such as rheumatoid arthritis and lupus, compared with just 2 of 648 healthy white individuals.
The researchers knew that when the SIAE gene is switched off in mice, it allows components of the immune system called B cells to run wild and attack healthy tissue – the hallmark of autoimmune disease. They found signs of similar hyperactivity in the B cells of sick humans bearing the SIAE defects.
The study adds to a growing body of work suggesting that relatively rare gene mutations are at work in complex diseases, from heart disease to cancer to schizophrenia, said study researcher Shiv Pillai of Harvard Medical School. "It's the accumulation of maybe a dozen such defects which makes someone susceptible," he said.
"Someone gets the right number of them and things break down," Pillai said, usually with help from triggers in the environment such as diet, a sedentary lifestyle or exposure to a pathogen.
Past studies of twins and other close relatives imply that many common diseases are at least partially inherited (or "heritable"), possibly because of genes that influence the risk of getting ill.
After the first sequencing of a human genome 10 years ago, geneticists had to decide how to use their newfound data to try to understand that presumed heritability. Their first strategy, pursued in hundreds of studies since then, was to identify small, relatively easy-to-find differences in genetic sequences that we all share, like a best-selling book in which some copies have one set of typos and the rest have a different set of typos.
These typos are called single-nucleotide polymorphisms (SNPs), and although researchers have identified certain SNPs that are more frequent in sick individuals, the SNPs they've found don't seem to play much of a role in the diseases themselves. Pillai said that may be because SNPs arose thousands of years ago and anyone carrying harmful SNPs would not have survived to pass on the genetic "typos."
Looking for rare mutations
An alternative approach that is gaining momentum is to examine all of a single gene or the whole set of genes from numerous individuals, some sick and some healthy, to look for genetic mutations that strongly contribute to disease in at least a few individuals (rare mutations).
Among the diseases that have started to yield to this approach include heart disease, Type 1 diabetes, colorectal cancer and even tuberculosis. Given that the SNP approach has not been as successful, the findings suggest that rare mutations could be more important to disease.
The new work is impressive, because the mutations the researchers identified had not turned up before in scans of SNPs, said human geneticist Jay Shendure of the University of Washington, who was not involved in the study. "They were able to find these rare variants that were clearly associated with autoimmunity."
Shendure cautioned against getting too excited. "We should avoid the temptation to extrapolate this result into an expectation that rare variants are going to [explain] the rest of the missing heritability," he said. Common diseases may involve a huge number of genes working together, or genetics might be less important than we think, he said.
Rare mutations do have the virtue of illuminating specific biological pathways associated with a disease, such as the biochemical reactions that activate B cells in autoimmune patients, which might lead to new therapies, Shendure said. Ultimately, he said, "it's important to keep an eye on the ball, and the ball is interventions."
The research will be detailed in the June 17 issue of the journal Nature.