Suggesting Better Genome Maintenance in Naked Mole-Rats

Naked mole-rats (NMRs) live nine times longer than other similarly sized rodent species and show comparatively few signs of degeneration in functional health along the way. There is considerable interest in understanding exactly why this is the case: what are the important differences in the biochemistry of this species? Progress on this front is probably not going to directly result in ways to extend healthy life in humans, but it will help to prioritize efforts to treat the causes of aging by understanding which of the possible contributions are most important.

Genome maintenance (GM) is an essential defense system against aging and cancer, as both are characterized by increased genome instability. Our study is the first step in a comparative genomics approach to study GM in relation to aging and cancer. Focusing on human, mouse, and NMR because of their contrasting aging phenotypes and the availability of high-quality genome sequences, we investigated copy number differences of GM genes and discovered that very few GM genes have been lost among these three species during evolution.

Interestingly, we found NMR to have a higher copy number of CEBPG, a regulator of DNA repair, and TINF2, a protector of telomere integrity. NMR, as well as human, was also found to have a lower rate of germline nucleotide substitution than the mouse. While we can only speculate whether the two genes with additional copies in the NMR, CEBPG and TINF2, confer a significant advantage, for example, through an increase in gene dosage, it is possible for a subtle difference at the genomic level to have a large phenotypic effect, such as increased lifespan.

The finding that the NMR has a slower nucleotide substitution rate is interesting, particularly in the context of their longevity, and suggests that GM in NMR is superior to GM in the mouse. As more genomes become sequenced and annotated to higher quality, these findings can be validated further, elucidating the role of genome maintenance in modulating lifespan. Our findings in this comparative analysis of GM in human, mouse, and NMR suggest that NMR has more robust GM than mouse, which could play a role in the former's extreme longevity.



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