Sequencing notably long-lived species has produced a number of interesting findings regarding the large variations in longevity between species. Long-lived species tend to exhibit one or more of exceptional DNA repair, exceptional cancer suppression mechanisms, exceptional regenerative and tissue maintenance capacity, exceptional control over inflammation, or the like. This short list is probably just scratching the surface, even given the great diversity of specific mechanisms in each category. For each of these discovered mechanisms it remains a question mark as to whether or not there is any way to safely port them over to humans, or whether they merely offer pointers to the areas of our biochemistry that researchers might prioritize when it comes to the development of rejuvenation therapies.
Comparative genomic analyses leverage the mechanisms of natural selection to find genes and biochemical pathways related to complex traits and processes. Multiple works have used these techniques with the genomes of long-lived mammals to shed light on the signalling and metabolic networks that might play a role in regulating age-related conditions. Similar studies on unrelated longevous organisms might unveil novel evolutionary strategies and genetic determinants of ageing in different environments. In this regard, giant tortoises constitute one of the few groups of vertebrates with an exceptional longevity: in excess of 100 years according to some estimates.
In this manuscript, we report the genomic sequencing and comparative genomic analysis of two long-lived giant tortoises: Lonesome George - the last representative of Chelonoidis abingdonii, endemic to the island of Pinta (Galapagos Islands, Ecuador) - and an individual of Aldabrachelys gigantea, endemic to the Aldabra Atoll and the only extant species of giant tortoises in the Indian Ocean. Comparison of these genomes with those of related species, using both unsupervised and supervised analyses, led us to detect lineage-specific variants affecting DNA repair genes, inflammatory mediators, and genes related to cancer development. Our study also hints at specific evolutionary strategies linked to increased lifespan, and expands our understanding of the genomic determinants of ageing.
This analysis singled out 43 genes with evidence of giant-tortoise-specific positive selection. This list includes genes with known roles in the dynamics of the tubulin cytoskeleton (TUBE1 and TUBG1) and intracellular vesicle trafficking (VPS35). Importantly, the analysis of genes showing evidence of positive selection also includes AHSG and FGF19, whose expression levels have been linked to successful ageing in humans. The list of genes with signatures of positive selection also features TDO2, whose inhibition has been proposed to protect against age-related diseases through regulation of tryptophan-mediated proteostasis. In addition, we found evidence for positive selection affecting several genes involved in immune system modulation, such as MVK, IRAK1BP1, and IL1R2. Taken together, these results identify proteostasis, metabolism regulation and immune response as key processes during the evolution of giant tortoises via effects on longevity and resistance to infection.
An important trait of large, long-lived vertebrates is their need for tighter cancer protection mechanisms, as illustrated by Peto's paradox. Therefore, we analysed more than 400 genes classified in a well-established census of cancer genes as oncogenes and tumour suppressors. We found that several putative tumour suppressors are expanded in turtles compared with other vertebrates. In addition, expansion of PRF1, together with the tortoise-specific duplication of PRDM1, suggests that immunosurveillance may be enhanced in turtles. Taken together, these results suggest that multiple gene copy-number alterations may have influenced the mechanisms of spontaneous tumour growth. Nevertheless, further studies are needed to evaluate the genomic determinants of putative giant-tortoise-specific cancer mechanisms.