Rare Gene Glitch a Clue to Genomics Mystery
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The discovery of links between rare gene mutations and autoimmune disease could help solve one of modern medicine’s major dilemmas.
Common diseases have largely resisted genomic analysis, leaving scientists unable to explain genetic underpinnings of diseases that clearly have a hereditary component.
These analyses have focused on mutations that are relatively widespread and easy to see. It took new tools to notice mutations like those just found in the SIAE gene, which cause immune cells to go haywire during autoimmune disease. They were detected by ultra high-resolution analysis of a sort rarely used in genomics.
The findings’ implications extend beyond autoimmunity, and into the fundamental nature of complex disease.
“I think the hard-core genetic effects will come out of systematic studies of rare variants,” said Harvard University geneticist Shiv Pillai. “It’s probably not going to be everything, but it will be the major contribution. Rare variants will give you a much stronger link to disease.”
Pillai’s team’s findings, published June 16 in Nature, could hardly have been predicted a decade ago. Completion of the human genome’s sequence seemed to herald a new age in which scientists would soon use genetic tools to explain and cure killer diseases.
But the blueprint of life proved difficult to read. While a few diseases, such as sickle cell anemia and cystic fibrosis, are caused by easily detectable problems in single genes, scientists have had no such luck with Alzheimer’s, heart disease, cancer, diabetes and other common killers.
Genome-wide association studies — or GWAS, the gold standard of modern genomics, which compare thousands of genes in thousands of people — have helped provide targets for researchers and jump-started the investigation of disease mechanisms, but their predictive value is limited. For most complex diseases, known gene links account for about 5 percent of heritability measured in population-based studies. Genetics are involved, but we don’t know how.
Geneticists call this gap the “missing heritability,” and a top candidate for its location is in rare gene variants that may be, when their total numbers are combined, quite frequent but individually are so rare as to escape detection. The SIAE mutations identified by Pillai’s team are the most powerful rare variants to date, and may anticipate the future of genetics.
“We’ve done one gene. There are 20,000 genes. The methods are now coming together to sequence all these,” said Pillai. Rare variants are likely important in complex disease, and “we won’t learn about these until we sequence every single gene,” he said.
Earlier research had identified the role of SIAE in making an enzyme critical for regulating B cells, which manufacture antibodies used by the body to identify harmful bacteria and viruses. An SIAE-deficient mouse strain engineered by Ajit Varki, a University of California, San Diego geneticist and co-author of the latest study, developed a syndrome similar to lupus.
Intrigued by SIAE’s importance, the researchers studied the SIAE gene in 923 people with common autoimmune disorders — Crohn’s disease, type 1 diabetes, inflammatory bowel disease, multiple sclerosis, lupus and rheumatoid arthritis — and 648 unafflicted people.
In GWAS and most genome studies, researchers focus on a few DNA blocks in target genes. Concentrating on “hotspots” saves time and money, and narrows down an otherwise vast range variation. By contrast, Pillai’s team analyzed every single DNA unit of every SIAE gene.
They found 12 previously unidentified mutations. In the autoimmune disease group, 24 people had one of these mutations, compared to just two people in the control group. The mutations still accounted for only a fraction of autoimmune disease risk, but that risk “increases greatly with any one of these variations,” said Pillai.
The SIAE gene alone doesn’t cause disease, but likely works in tandem with other, as-yet-unidentified rare variants, said Pillai. If enough are combined, they produce a predisposition that’s later triggered by some environmental insult.
When the mutations were recreated in laboratory cell cultures, the researchers confirmed that the SIAE variants produced altered forms of their enzymes.
The findings “demonstrate the important point that many diseases are determined by a lot of different rare variants,” said Jackson Laboratory geneticist Elissa Chesler, who was not involved in the study. Traditional approaches to studying the genome “may never account for the variability of that,” she said.
In addition to rare variants, other factors likely contribute to the missing heritability. Epigenetic fluctuations — genes turning on and off at different times — appear to play a role in many diseases. So could duplicate copies of genes. Other cellular characteristics, such as abnormally folded chromosomes, may be involved.
But rare variants are the prime suspect. And though the task of conducting high-resolution studies of all 20,000 genes in thousands of people is daunting, the falling costs and rising speeds of DNA sequencing should make it possible in coming years.
“This paper is an example of what can be done,” said Chesler.
Image: Detail from a page of the printed genome./Wellcome Trust.
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Citation: “Functionally defective germline variants of sialic acid acetylesterase in autoimmunity.” By Ira Surolia, Stephan P. Pirnie, Vasant Chellappa, Kendra N. Taylor, Annaiah Cariappa, Jesse Moya, Haoyuan Liu, Daphne W. Bell, David R. Driscoll, Sven Diederichs, Khaleda Haider, Ilka Netravali, Sheila Le, Roberto Elia, Ethan Dow, Annette Lee, Jan Freudenberg, Philip L. De Jager, Yves Chretien, Ajit Varki, Marcy E. MacDonald, Tammy Gillis, Timothy W. Behrens, Donald Bloch, Deborah Collier, Joshua Korzenik, Daniel K. Podolsky, David Hafler, Mandakolathur Murali, Bruce Sands, John H. Stone, Peter K. Gregersen & Shiv Pillai. Nature, Vol. 465 No. 7300, June 16, 2010.