Gene Cluster Variants Predict Liver Telomere Length in Mice.

Variants in a gene cluster upstream-adjacent to on human chromosome 3, which includes genes , , and , have been associated with telomere length in several human populations. Currently, the mechanism by which variants in the gene cluster influence telomere length in humans is unknown. Given the proximity between the gene cluster and (~0.05 Mb) in humans, it is speculated that cluster variants are in linkage disequilibrium with a causal variant. In mice, the gene/ gene cluster are also located on chromosome 3; however, the gene cluster is located distantly downstream of (~60 Mb). Here, we initially aim to investigate the interactions between genotype and nicotine exposure on absolute liver telomere length (aTL) in a panel of eight inbred mouse strains. Although we found no significant impact of nicotine on liver aTL, this first experiment identified candidate single nucleotide polymorphisms (SNPs) in the murine gene cluster (within genes , and ) co-varying with aTL in our panel. In a second experiment, we tested the association of these gene cluster variants with liver aTL in an independent panel of eight inbred mice selected based on candidate SNP genotype. This supported our initial finding that gene cluster polymorphisms impact aTL in mice, consistent with data in human populations. This provides support for mice as a model for telomere dynamics, especially for studying mechanisms underlying the association between cluster variants and telomere length. Finally, these data suggest that mechanisms independent of linkage disequilibrium between the / gene cluster and the / gene mediate the cluster's regulation of telomere length.