Whole-Genome Sequencing of the World’s Oldest People

Abstract

Supercentenarians (110 years or older) are the world’s oldest people. Seventy four are alive worldwide, with twenty two in the United States. We performed whole-genome sequencing on 17 supercentenarians to explore the genetic basis underlying extreme human longevity. We found no significant evidence of enrichment for a single rare protein-altering variant or for a gene harboring different rare protein altering variants in supercentenarian compared to control genomes. We followed up on the gene most enriched for rare protein-altering variants in our cohort of supercentenarians, TSHZ3, by sequencing it in a second cohort of 99 long-lived individuals but did not find a significant enrichment. The genome of one supercentenarian had a pathogenic mutation in DSC2, known to predispose to arrhythmogenic right ventricular cardiomyopathy, which is recommended to be reported to this individual as an incidental finding according to a recent position statement by the American College of Medical Genetics and Genomics. Even with this pathogenic mutation, the proband lived to over 110 years. The entire list of rare protein-altering variants and DNA sequence of all 17 supercentenarian genomes is available as a resource to assist the discovery of the genetic basis of extreme longevity in future studies.

Association between Age and the 7 Repeat Allele of the Dopamine D4 Receptor Gene

“…Moreover, there was no decline in the frequency of disease-associated genetic variants carried by centenarians as compared to the general population [7]. In addition, A GWAS study of a small sample of the world’s oldest people (17 people over 110 years, 13 of them females) concluded that there is no evidence for enrichment of genetic variants in female Caucasian supercentenarians compared to controls [8]. …”

Maximum reproductive lifespan correlates with CD33rSIGLEC gene number: Implications for NADPH oxidase‐derived reactive oxygen species in aging

“…[83][84][85] However, more variants that decrease gene function in the Teashirt Zinc Finger Homeobox 3 (TSHZ3) were observed in Centenarian and supercentenarian genomes (~110 years) than control genomes. 61 Considering these studies, we found that supercentenarians genomes did not contain an increased number of functional SIGLEC alleles in comparison to controls. Although the CD33 protective allele (also known as CD33m) helps reduce cognitive decline and Alzheimer's disease, the frequency of the variant was not significantly different between supercentenarian and control genomes which supports the conclusion that CD33rSIGLECs are not involved in regulating PRLS, but instead contribute to the regulation of reproductive lifespan.…”

Early life DNA methylation profiles are indicative of age-related transcriptome changes

“…Additionally, variation in transcriptional profiles with aging was reported between mouse strains from diverse genetic backgrounds [98], signifying the importance of the genome in determining transcriptional regulation with age. Genetic factors are also thought to underlie increased longevity in supercentenarians [99,100] and may contribute to age-related epigenetic drift [101]. Therefore, population differences in methylation early in life, in addition to genetic diversity may be associated with the variability in development of age-related neuropathologies, predisposition, and severity observed between individuals.…”