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Researchers Sequence Supercentenarian Genomes in Search of Rare, Longevity-related Variants

NEW YORK (GenomeWeb) – A whole-genome sequencing study of individuals over the age of 110 years old has yielded a collection of rare variants that's expected to serve as a resource for future studies of longevity.

Researchers from Stanford University and other centers in the US sequenced 17 so-called supercentenarians in the hopes of finding genetic clues to their exceptionally long lives. Their analyses of these genomes, described online today in PLOS One, did not uncover rare variants that were over-represented amongst the very elderly individuals.

The team did see a slight enrichment in alterations in a gene called TSHZ3 in the supercentenarian genomes, though that gene did not show significantly higher-than-usual levels of rare variation when screened in 99 more individuals over the age of 98 years old.

Still, investigators are continuing to follow up on this and other leads from the study with the goal of uncovering genetic contributors to long life and finding ways to use such information to extend middle age in other individuals.

"We want to extend the functional part of life and keep people healthy by being less [physiologically] old," senior author Stuart Kim, a developmental biology and genetic researcher at Stanford University, told GenomeWeb Daily News.

Past studies suggest that lower-than-usual risks of age-related conditions such as cancer, heart disease, and stroke have a hand in helping supercentenarians attain exceptionally long lifespans.

While a great deal of this disease dodging seems to be attributable to lifestyle and environmental factors, the researchers explained, genetics has a hand in the process, too. For instance, they noted that prior studies of twins have placed the genetic contribution to longevity at some 20 percent to 30 percent in the population as a whole. In families prone to reaching advanced age, that heritability appears to be even higher.

"We do think that there can be a pretty strong genetic effect," Kim said.

In an effort to build on past genetic studies of abnormally aged individuals, he and his colleagues sent DNA samples from 17 supercentenarians to Complete Genomics, where the genomes were sequenced to up to 40-fold coverage, including at least 20-fold coverage over more than 94 percent of each genome.

Participants in the study were recruited through an ongoing study of supercentenarians at the Gerontology Research Group, which is led by co-author Stephen Coles, executive director of that Los Angeles center.

The sequenced group included individuals who lived to a mean age of 112 years old — many of whom maintained unusually high levels of cognitive and physical function for much of their lifespan.

None of the participants had been diagnosed with heart disease, stroke, or diabetes, though one individual had Alzheimer's disease and another had survived cancer.

Through comparisons with ancestry information in nearly 1,200 HapMap samples, researchers verified self-reported ancestry information for the study participants. Two had Hispanic ancestry, 14 were European, and one was African American.

In searching for rare variants associated with longevity — as well as genes showing an over-representation of such variants in the supercentenarian cohort — the team focused much of its attention on 13 female Caucasian participants to avoid genetic confounders related to sex and ethnicity.

After removing common variants from the supercentenarian genomes via comparisons with the dbSNP database, data for European participants in the 1000 Genomes Project, and sequences for nearly three-dozen Caucasian participants in the Personal Genome Project, researchers were left with fewer than 14,000 rare protein-coding changes and about 10,500 rare variant-containing genes that were specific to the supercentenarian set.

Their analyses did not unearth any one variant or gene that was significantly more likely to differ in the supercentenarians, though a subsequent variant burden analysis pointed to a handful of genes with nominal ties to longevity.

The top candidate from the latter analysis was a transcription factor gene called TSHZ3, the study's authors explained. But there was no clear enrichment for alterations in the gene in older individuals when they compared data for 4,300 control exomes with TSHZ3 patterns in 99 individuals between the ages of 98 and 105 years old from the Georgia Centenarian Study.

The researchers unearthed a potentially pathogenic but poorly characterized alteration to the breast and ovarian cancer risk gene BRCA1 in one of the elderly individuals.

Another supercentenarian carried a gene mutation that's been linked to the heart condition arrhythmogenic right ventricular cardiomyopathy and is included on the American College of Medical Genetics and Genomics' list of clinically relevant alterations, which the organization recommends reporting if detected as incidental findings.

Nevertheless, that individual "lived to be the world's oldest man, with this bad disease gene," Kim said, noting that more work may be needed to understand how often risky mutations are present in individuals who never develop an associated disease.

The data generated for the study — including the list of rare protein-coding variants identified in the supercentenarian genomes — is available to other members of the research community in the hopes that it will aid other studies of exceptional longevity.

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