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Inter-chromosomal level of genome organization and longevity-related phenotypes in humans

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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.

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Acknowledgments

AMK contributed to the study conception, design, statistical analysis, interpretation of the results, and writing the manuscript. IC contributed to the study design, conception, genetic analyses of inheritance, analysis of biological role, interpretation of the results, and writing the manuscript. AIY contributed to discussion and interpretation of the results and drafting the manuscript.

The research reported in this paper was supported, in part, by Award Number R01AG030612 from the National Institute on Aging. The FHS and the Framingham SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University. The Framingham SHARe data used for the analyses described in this manuscript were obtained through dbGaP (accession numbers phs000007.v7.p4 and phs000007.v14.p5). This manuscript was not prepared in collaboration with investigators of the FHS and does not necessarily reflect the opinions or views of the FHS, Boston University, or the NHLBI. We thank G. Martin for discussion of the results and drawing our attention to yeast-, worm-, and plant-based models of human diseases.

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  1. Center for Population Health and Aging, Duke University, Box 90408, Trent Hall, Room 002, Durham, NC, 27708, USA

    Alexander M. Kulminski, Irina Culminskaya & Anatoli I. Yashin

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  1. Alexander M. Kulminski
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  2. Irina Culminskaya
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  3. Anatoli I. Yashin
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Correspondence to Alexander M. Kulminski.

Electronic supplementary material

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Online resource 1

The 69 SNPs pre-selected at the first stage of the analyses according to potential association with prevalent cardiovascular disease (PDF 129 kb)

Online resource 2

Connections of the observed inter-chromosomal LD with phenotypes (PDF 267 kb)

Online resource 3

Detail map of perfect linkage disequilibrium among SNPs on non-homologous chromosomes from the Y and G sets for each sex (blue) (PDF 111 kb)

Online resource 4

Detail map of perfect linkage disequilibrium among SNPs on non-homologous chromosomes from the Y and G sets for the original and the offspring cohorts (PDF 111 kb)

Online resource 5

Genetic analysis of progeny of mating heterozygous and recessive (major allele) homozygous parents with information on live births and pregnancies included (PDF 111 kb)

Online resource 6

Evaluation of all theoretically possible contributions of genotypes with missing information, including those related to pregnancies and live births, to the explicitly observed genotypes for Tables 1 and Online resource 5 (PDF 77.7 kb)

Online resource 7

Linkage disequilibrium shown by each of the nine SNPs from the Y and G multi-locus inter-chromosomal complexes to SNPs within ±/− 1 Mb region on homologous chromosomes (PDF 131 kb)

Online resource 8

Maps showing chromosome-wide LD at the level r 2 ≥ 0.3 for the nine SNPs from the Y and G complexes (PDF 181 kb)

Online resource 9

Genotyping phases (PDF 141 kb)

Online resource 10

Survival of the genotyped and non-genotyped individuals (PDF 112 kb)

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Kulminski, A.M., Culminskaya, I. & Yashin, A.I. Inter-chromosomal level of genome organization and longevity-related phenotypes in humans. AGE 35, 501–518 (2013). https://doi.org/10.1007/s11357-011-9374-6

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  • DOI: https://doi.org/10.1007/s11357-011-9374-6

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