U.S. genetic researchers led by Dr Stuart Kim of Stanford University have sequenced the genomes of 17 supercentenarians to see if they could uncover the genetic basis for extreme human longevity.
Misao Okawa (born on March 5, 1898) and her relatives: she is a Japanese supercentenarian who is, at the age of 116 years, the world’s oldest living person; she married in 1919, has three children, four grandchildren and six great-grandchildren, and now lives in Osaka. Image credit: © Guinness World Records.
Supercentenarians are the world’s oldest people, living beyond 110 years of age. 74 are alive worldwide, with 22 living in the United States.
Dr Kim and his colleagues from Stanford University, the Institute for Systems Biology in Seattle, and the University of California Los Angeles, performed whole-genome sequencing on 17 supercentenarians to explore the genetic basis underlying their extreme longevity.
“For people born around 1900, the odds of living to 110 are estimated to be 1 in 10,000 people,” the scientists wrote in a paper in the journal PLoS ONE, “hence we assume that any genetic variant that contributes strongly to extreme longevity would also be rare.”
“One possibility is that a specific mutation could alter the protein-coding region in a gene and confer a significant increase in longevity. Such a mutation could act in a dominant or recessive fashion, and might be shared by a significant fraction of the supercentenarian genomes.”
“Another possibility is that there may be a gene that confers extreme longevity when it is altered by any one of a number of protein alterations.”
“Many of the supercentenarians may carry variants in the same gene, but the variant in each supercentenarian may be different. The variants could act in a dominant fashion and affect only one of the two alleles. Or else they could act in a recessive fashion such that both alleles would be affected, either with the same variant or with different mutations in each allele.”
The scientists analyzed rare protein-altering variants, but found no significant evidence of enrichment for a single rare protein-altering variant or for a gene harboring different rare protein altering variants in the supercentenarians compared to control genomes (379 European individuals from the 1000Genomes Project).
From the gene-based analysis, the gene showing the most enrichment for protein-altering variants in the supercentenarians compared to controls was the TSHZ3 transcription-factor gene.
“Because it was the top hit, we pursued this gene further in a study consisting of 99 genomes from subjects aged 98–105 years old. We found that TSHZ3 carried protein-altering variants in more of the long-lived subjects than the controls, although this difference was not statistically significant,” the scientists wrote.
The team also looked at whether the supercentenarians might carry pathogenic mutations.
“To do this, we analyzed all 17 supercentenarian genomes for the presence of pathogenic alleles as defined by the recent publication of the American College of Medical Genetics and Genomics.”
The scientists did find that one supercentenarian carries a variant associated with a heart condition, which had little or no effect on his/her health, as this person lived over 110 years.
“To our surprise, we discovered that one of our supercentenarians carried a known pathogenic allele in the DSC2 gene associated with arrhythmogenic right ventricular cardiomyopathy.”
The scientists added that it is recommended by the American College of Medical Genetics and Genomics to report the results to this individual as an incidental finding.
Although Dr Kim and his co-authors didn’t find significant association with extreme longevity of supercentenarians, they have publicly published the genomes, making them available as a resource for future studies.
_____
Gierman HJ et al. 2014. Whole-Genome Sequencing of the World’s Oldest People. PLoS ONE 9 (11): e112430; doi: 10.1371/journal.pone.0112430
