Whole-genome sequencing of the world's oldest people.
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.
Depts. of Developmental Biology and Genetics, Stanford University, Stanford, CA, United States of America.
Hinco J
HJ
Gierman
Depts. of Developmental Biology and Genetics, Stanford University, Stanford, CA, United States of America.
Kristen
K
Fortney
Institute for Systems Biology, Seattle, WA, United States of America.
Jared C
JC
Roach
Gerontology Research Group, Los Angeles, CA, United States of America; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America.
Natalie S
NS
Coles
Institute for Systems Biology, Seattle, WA, United States of America.
Hong
H
Li
Institute for Systems Biology, Seattle, WA, United States of America.
Gustavo
G
Glusman
Depts. of Developmental Biology and Genetics, Stanford University, Stanford, CA, United States of America.
Glenn J
GJ
Markov
Depts. of Developmental Biology and Genetics, Stanford University, Stanford, CA, United States of America.
Justin D
JD
Smith
Institute for Systems Biology, Seattle, WA, United States of America.
Leroy
L
Hood
Gerontology Research Group, Los Angeles, CA, United States of America; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America.
L Stephen
LS
Coles
Depts. of Developmental Biology and Genetics, Stanford University, Stanford, CA, United States of America.
Stuart K
SK
Kim
D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D051187:Desmocollins / Q000235:genetics; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA
C081561:DSC2 protein, human; D051187:Desmocollins; D018398:Homeodomain Proteins; C580600:TSHZ3 protein, human