Genome-wide analysis indicates association between heterozygote advantage and healthy aging in humans.
Balancing selection
Electronic health record
Fitness
Healthy aging
Heterozygote advantage
Human diseases
Journal
BMC genetics
ISSN: 1471-2156
Titre abrégé: BMC Genet
Pays: England
ID NLM: 100966978
Informations de publication
Date de publication:
02 07 2019
02 07 2019
Historique:
received:
31
10
2018
accepted:
20
06
2019
entrez:
4
7
2019
pubmed:
4
7
2019
medline:
6
2
2020
Statut:
epublish
Résumé
Genetic diversity is known to confer survival advantage in many species across the tree of life. Here, we hypothesize that such pattern applies to humans as well and could be a result of higher fitness in individuals with higher genomic heterozygosity. We use healthy aging as a proxy for better health and fitness, and observe greater heterozygosity in healthy-aged individuals. Specifically, we find that only common genetic variants show significantly higher excess of heterozygosity in the healthy-aged cohort. Lack of difference in heterozygosity for low-frequency variants or disease-associated variants excludes the possibility of compensation for deleterious recessive alleles as a mechanism. In addition, coding SNPs with the highest excess of heterozygosity in the healthy-aged cohort are enriched in genes involved in extracellular matrix and glycoproteins, a group of genes known to be under long-term balancing selection. We also find that individual heterozygosity rate is a significant predictor of electronic health record (EHR)-based estimates of 10-year survival probability in men but not in women, accounting for several factors including age and ethnicity. Our results demonstrate that the genomic heterozygosity is associated with human healthspan, and that the relationship between higher heterozygosity and healthy aging could be explained by heterozygote advantage. Further characterization of this relationship will have important implications in aging-associated disease risk prediction.
Sections du résumé
BACKGROUND
Genetic diversity is known to confer survival advantage in many species across the tree of life. Here, we hypothesize that such pattern applies to humans as well and could be a result of higher fitness in individuals with higher genomic heterozygosity.
RESULTS
We use healthy aging as a proxy for better health and fitness, and observe greater heterozygosity in healthy-aged individuals. Specifically, we find that only common genetic variants show significantly higher excess of heterozygosity in the healthy-aged cohort. Lack of difference in heterozygosity for low-frequency variants or disease-associated variants excludes the possibility of compensation for deleterious recessive alleles as a mechanism. In addition, coding SNPs with the highest excess of heterozygosity in the healthy-aged cohort are enriched in genes involved in extracellular matrix and glycoproteins, a group of genes known to be under long-term balancing selection. We also find that individual heterozygosity rate is a significant predictor of electronic health record (EHR)-based estimates of 10-year survival probability in men but not in women, accounting for several factors including age and ethnicity.
CONCLUSIONS
Our results demonstrate that the genomic heterozygosity is associated with human healthspan, and that the relationship between higher heterozygosity and healthy aging could be explained by heterozygote advantage. Further characterization of this relationship will have important implications in aging-associated disease risk prediction.
Identifiants
pubmed: 31266448
doi: 10.1186/s12863-019-0758-4
pii: 10.1186/s12863-019-0758-4
pmc: PMC6604157
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
52Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001114
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK098242
Pays : United States
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