Inter-chromosomal level of genome organization and longevity-related phenotypes in humans
Abstract
Studies focusing on unraveling the genetic origin of health span in humans assume
that polygenic, aging-related phenotypes are inherited through Mendelian mechanisms
of inheritance of individual genes. We use the Framingham Heart Study (FHS) data to
examine whether non-Mendelian mechanisms of inheritance can drive linkage of loci
on non-homologous chromosomes and whether such mechanisms can be relevant to longevity-related
phenotypes. We report on genome-wide inter-chromosomal linkage disequilibrium (LD)
and on chromosome-wide intra-chromosomal LD and show that these are real phenomena
in the FHS data. Genetic analysis of inheritance in families based on Mendelian segregation
reveals that the alleles of single nucleotide polymorphisms (SNPs) in LD at loci on
non-homologous chromosomes are inherited as a complex resembling haplotypes of a genetic
unit. This result implies that the inter-chromosomal LD is likely caused by non-random
assortment of non-homologous chromosomes during meiosis. The risk allele haplotypes
can be subject to dominant-negative selection primary through the mechanisms of non-Mendelian
inheritance. They can go to extinction within two human generations. The set of SNPs
in inter-chromosomal LD (N = 68) is nearly threefold enriched, with high significance
(p = 1.6 × 10 -9), on non-synonymous coding variants (N = 28) compared to the entire
qualified set of the studied SNPs. Genes for the tightly linked SNPs are involved
in fundamental biological processes in an organism. Survival analyses show that the
revealed non-genetic linkage is associated with heritable complex phenotype of premature
death. Our results suggest the presence of inter-chromosomal level of functional organization
in the human genome and highlight a challenging problem of genomics of human health
and aging. © 2012 American Aging Association.
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https://hdl.handle.net/10161/14908Published Version (Please cite this version)
10.1007/s11357-011-9374-6Publication Info
Culminskaya, IV; Kulminski, Alexander; & Yashin, Anatoli I (2013). Inter-chromosomal level of genome organization and longevity-related phenotypes in
humans. Age, 35(2). pp. 501-518. 10.1007/s11357-011-9374-6. Retrieved from https://hdl.handle.net/10161/14908.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Alexander Kulminski
Associate Research Professor in the Social Science Research Institute
Anatoli I. Yashin
Research Professor in the Social Science Research Institute
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