It is known that population structure can introduce artificial correlations between SNPs and phenotypes, as seen in SNPs in the lactase gene that spuriously correlates with the height phenotype. These spurious correlations can be easily understood by considering a simple example: imagine one homogeneous population that splits into two. Each of these populations evolves independently and develops a set of SNPs (markers) that clearly differentiate them. All these SNPs appeared as linked because of the common ancestry of these populations. If, for any reason, one population has a different phenotype (height, disease, longevity) than the other, all these SNPs will correlate with the phenotype. However, this correlation doesIn this study, we analyzed the frequencies of enriched patterns in various haplogroups to determine the correlation between mtDNA SNPs and longevity in Japanese individuals. Our results confirm previous observations that the D4a haplogroup, along with many haplogroups in the D4 clade, is enriched for longevity. The significance scores for maximal patterns of mutations in the data are shown in Figure 2, while Figure 3 shows the significance score for the enrichment of SNPs in three data sets of centenarians and semi-supercentenarians compared to healthy normals.

We found that 45 mtSNPs were significantly correlated with longevity after correcting for multiple hypotheses. However, our analysis suggests that there are no functional mtSNPs significantly correlated with longevity and that all significant correlations seem to be associated only with population structure. This suggests that protective mutations on nuclear chromosomes, in addition to the defining mtDNA SNPs for D4a, are necessary for the longevity phenotype.

A limitation of our study is the small sample size and lack of direct correlation with SNPs on nuclear chromosomes. We are currently trying to mitigate this problem by identifying nuclear SNPs associated with our samples on the complexes formed by proteins encoded by mtDNA.

In conclusion, our results suggest a possible scenario for the evolution of a longevity phenotype, which may develop by combinations of protective mutations. The nuclear-mitochondrial interaction model for longevity may be an attractive working hypothesis to be examined by resequencing projects targeting Asian- or Japanese-specific nuclear genome variations. The resequencing projects focusing on mitochondrial genome in Japanese semi-supercentenarians reported here is a landmark for the start of investigation on longevity-associated nuclear genome polymorphisms.