Genome-wide analysis indicates association between heterozygote advantage and healthy aging in humans

BMC Genetics

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[1] 0000 0001 0670 2351, grid.59734.3c, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0224 711X, grid.240871.8, Present Address: Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN, USA;0000 0001 0670 2351, grid.59734.3c, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 2151 2636, grid.215654.1, Present Address: ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA;0000 0001 0670 2351, grid.59734.3c, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, NY, USA;grid.418152.b, Present Address: Advanced Analytics Center, AstraZeneca, Gaithersburg, MD, USA;0000 0001 0670 2351, grid.59734.3c, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 0670 2351, grid.59734.3c, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA;0000 0001 2151 2636, grid.215654.1, Department of Biomedical Informatics, Arizona State University, Tempe, AZ, USA;0000 0001 2248 3398, grid.264727.2, Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA, USA;0000 0001 2248 3398, grid.264727.2, Department of Biology, Temple University, Philadelphia, PA, USA;0000 0001 0619 1117, grid.412125.1, Center for Excellence in Genome Medicine and Research, King Abdulaziz University, Jeddah, Saudi Arabia;

关键词: Heterozygote advantage;    Balancing selection;    Fitness;    Healthy aging;    Human diseases;    Electronic health record;   

DOI  :  10.1186/s12863-019-0758-4

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY