Mitochondrial DNA Haplogroup D4a Is a Marker for Extreme Longevity in Japan

Bilal1, Raul Rabadan2, Gabriela Alexe3, Noriyuki Fuku4, Hitomi Ueno4, Yutaka Nishigaki4, Yasunori Masafumi Ito5, Yasumichi Arai6, Nobuyoshi Hirose6, Andrei Ruckenstein7, Gyan Bhanot1,2,8, Tanaka4*

1BioMaPS Institute, Rutgers University, Piscataway, New Jersey, United States of America, 2Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, United States of America, 3Computational Biology and Bioinformatics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America, 4Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan, 5Department of Longevity and Aging Research, Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan, 6Department of Geriatric Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan, 7Department of Physics, Boston University, Boston, Massachusetts, United States of America, 8Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America

Abstract

supercentenarians (aged above 105 years) combined with previously published data from 96 patients in each of three non- disease phenotypes: centenarians (99–105 years of age), healthy non-obese males, obese young males and four disease phenotypes, diabetics with and without angiopathy, and Alzheimer’s and Parkinson’s disease patients. We analyze the correlation between mitochondrial polymorphisms and the longevity phenotype using two different methods. We first use an exhaustive algorithm to identify all maximal patterns of polymorphisms shared by at least five individuals and define a significance score for enrichment of the patterns in each phenotype relative to healthy normals. Our study confirms the correlations observed in a previous study showing enrichment of a hierarchy of haplogroups in the D clade for longevity. For the extreme longevity phenotype we see a single statistically significant signal: a progressive enrichment of certain ‘‘beneficial’’ patterns in centenarians and semi-supercentenarians in the D4a haplogroup. We then use Principal Component Spectral Analysis of the SNP-SNP Covariance Matrix to compare the measured eigenvalues to a Null distribution of eigenvalues on Gaussian datasets to determine whether the correlations in the data (due to longevity) arises from some property of the mutations themselves or whether they are due to population structure. The conclusion is that the correlations are entirely due to population structure (phylogenetic tree). We find no signal for a functional mtDNA SNP correlated with longevity. The fact that the correlations are from the population structure suggests that hitch-hiking on autosomal events is a possible explanation for the observed correlations.

Copyright:   2008 Bilal et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported in part by Grants-in-Aid for Scientific Research (A-15200051 to MT and C-18590317 to YN), and a Grant-in-Aid for Young Scientists (B-18700541 to NF) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, by a grant from the Third-Term Comprehensive 10-year Strategy for Cancer Control (to MT), by grant 17A-10 from the program Research Grants for Nervous and Mental Disorders of the Ministry of Health, Labour, and Welfare of Japan (to MT) as well as by a grant from Kao Research Council for the Study of Healthcare Science (to YN) and by grants from Takeda Science Foundation (I-2007 to MT and II-2007 to YN). The work of NH was supported by a grant for Longevity Science of Ministry of Health, Labour, and Welfare of Japan. The work of GB was supported by grants from the Cancer Institute of New Jersey and the NJ Commission for Cancer Research. The work of EB was supported by funds from the Center for Clinical and Translational Sciences at the Robert Wood Johnson Medical School, New Brunswick, NJ. RR was supported by the Simons Foundation, the Ambrose Monell Foundation, the Leon Levy Foundation, and the National Institutes of Health.

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: mtanaka@tmig.or.jp

Introduction

may either directly confer a selective advantage, or, they may compensate for deleterious mutations on other loci (associated with mtDNA or nuclear genes) or be detrimental (confer a selective disadvantage). Such polymorphisms are not limited to non- synonymous mutations alone. A synonymous mutation on mtDNA may also be a marker for longevity by hitch-hiking, where the mutation is a surrogate for amplification of a haplogroup due to a selective sweep from an autosomal event [4].

closest relatives, the chimpanzees [1]. Amongst humans, the Japanese are amongst the longest lived, with life expectancy of 79 years for males and 86 for females [2]. Whereas this longevity may arise from non-genetic factors such as better health care, diet, lifestyle, etc., it might also have a genetic component, particularly in very old people, who survive to longevity in spite of the lack of any evolutionary selection pressure (except perhaps the so called ‘grandmother effect [3]). In this paper, we focus on mtDNA mutations and analyze whether there is any evidence for their role in longevity. If mtDNA mutations affecting longevity exist, they

Ideally, genetic analysis should include SNPs on both mtDNA and autosomal chromosomes. This would allow a genome wide analysis to identify mutations and pathways associated with longevity and their correlation with geographic clustering and migration histories of population groups as inferred from mtDNA