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On the other hand, homozygotes for the minor allele of SNP2, SNP3, and SNP4 were found only among the younger controls. The frequency of the major haplotype is similar between centenarians and controls. A recently developed mathematical model suggests that centenarians show greater heterozygosity for stress-responder genes that drive the individual adaptive capacity than younger subjects [18]. Our data do not support this model, probably because SHC1 is not one of the genes affecting such adaptive capability.

While examining for differences between centenarians and controls, we found an interesting feature of SHC1. In our analysis the major allele showed a high frequency (>95%) in each polymorphism. Consequently the fre- quency of the major haplotype was also significantly high. In a recent study in which 50 genes were scanned across regions totaling 564 kb common SNPs, defined as ones with minor allele frequencies greater than 10%, were observed at a rate of one per 506 bp [19]. In our study no common SNPs were observed across the 10 kb region that comprised the SHC1 locus.

was unique for the Japanese population we additionally sequenced the same locus in samples from 24 African- Americans and 24 whites. This confirmed that this is indeed a characteristic of the SHC1 gene (data not shown), raising the possibility that this locus has been highly protected against mutations or highly preserved by natural selection throughout human evolution.

Although numerous studies have investigated the role of SHC1 as an adaptor protein functioning in the regulation of oxidative stress and apoptosis, few studies have focused on the associations between variations in the SHC1 locus and age-related disease in humans. Almind et al. [15] identified a M300V substitution in SHC1 and looked for any associations with birth weight, insulin sensitivity, or prevalence of type 2 diabetes mellitus. No such associa- tions were found. In our thorough investigation of the SHC1 locus in the Japanese population we found no significant association between allelotypes, genotypes, or haplotypes and longevity. However, we uncovered a unique feature of the SHC1 locus, which is monopolized by one major haplotype in the Japanese population. Further study is needed to elucidate the relationship between the characteristics of SHC1 and human longevity.