Abstract
BackgroundGenetic 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Genetic diversity is known to confer survival advantage in many species across the tree of life
Principal component analysis (PCA) revealed that while majority of the Wellderly individuals overlapped with the CEU (Utah residents with Northern and Western ancestry) and GBR (British in England and Scotland) populations, Biobank individuals displayed higher diversity (Additional file 1: Figure S1), likely reflecting the distinct demographic of New York City
228,606 noncoding Single nucleotide polymorphism (SNP) passed the stringent quality control (QC), and the minor allele frequencies (MAF) were highly similar between the two cohorts (Additional file 3: Figure S3A), suggesting no systematic bias potentially introduced by difference in genotyping methods
Summary
Genetic diversity is known to confer survival advantage in many species across the tree of life. We hypothesize that such pattern applies to humans as well and could be a result of higher fitness in individuals with higher genomic heterozygosity. Genetic diversity within a population, often characterized by heterozygosity, is known to play an important role in conferring benefit for survival and reproduction [1]. Soy sheep with lower heterozygosity are more susceptible to parasite infection and exhibit lower fitness [7]. High genetic diversity of Major Histocompatibility Complex (MHC) region conveys robust pathogen resistance on the population level and, important for fighting against infectious diseases [8, 9]. The role of heterozygosity is less well studied in non-MHC regions, though interesting trends are emerging. People with higher heterozygosity are reported to exhibit better health-associated traits, such as lower blood pressure and
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