YTHDF2 intron 4 microsatellite polymorphism and longev- ity can be inferred by the genomic background surrounding the locus. The portion of the 1p35 chromosomal region around YTHDF2 is rich with genes (mostly involved in signal transduction, gene expression regulation, and cell division); the possibility of a linkage disequilibrium

YTHDF2 gene on longevity, suggested by the high expression level associated with the genetic variant in- creased in centenarians, are at present unknown, and the available data on this gene are scant. The protein sequence of the gene is highly conserved across vertebrates, suggesting a basic biological function. It contains a YTH

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between the considered (TG)n microsatellite and other functional polymorphisms in nearby genes should be carefully tested in future studies. Finally, it is important to remark that this locus lies in a genomic region with rare and atypical features. This polymorphism was originally iden- tified through the analysis of ‘‘anonymous’’ inter-Alu sequences much shorter than the 3 kb average (60) genomic inter-Alu distance, and the reasonable expectation was to find it located in a genomic region with higher than average Alu density. Indeed this locus is situated in a wide Alu-rich domain (1.6 Mb), and the 1 Mb region containing the YTHDF2 gene is the portion of chromosome 1 with the highest content of Alu elements (.40% of the sequence in this chromosomal region). In the whole genome, such a high Alu density is present in only four regions (of 1 Mb or more) which account for the 0.17% of the human genome, whereas two thirds of the genome show an Alu content about four times lower. This peculiarity in the genomic composition might affect the expression of YTHDF2 and other genes in the region, rendering it sensitive to Alu-induced epigenetic effects (18,23). Moreover, the very high Alu density could induce genomic instability, in germline as well as in somatic cells, due to unequal recombination events (18–20). Indeed, 1p35 has been described as one of the chromosomal sites most often involved in genomic instability in a variety of malignancies (61–63).

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