The Evolution of Human Cancer Gene Duplications across Mammals

Abstract

Cancer is caused by genetic alterations that affect cellular fitness, and multicellular organisms have evolved mechanisms to suppress cancer such as cell cycle checkpoints and apoptosis.These pathways may be enhanced by the addition of tumor suppressor gene paralogs or deletion of oncogenes. To provide insights to the evolution of cancer suppression across the mammalian radiation, we estimated copy numbers for 548 human tumor suppressor gene and oncogene homologs in 63 mammalian genome assemblies. The naked mole rat contained the most cancer gene copies, consistent with the extremely low rates of cancer found in this species. We found a positive correlation between a species' cancer gene copy number and it's longevity, but not body size, contrary to predictions from Peto's Paradox. Extremely long-lived mammals also contained more copies of caretaker genes in their genomes, suggesting that the maintenance of genome integrity is an essential form of cancer prevention in long-lived species.We found the strongest association between longevity and copy numbers of genes that are both germline and somatic tumor suppressor genes, suggesting selection has acted to suppress both hereditary and sporadic cancers. We also found a strong relationship between the number of tumor suppressor genes and the number of oncogenes in mammalian genomes, suggesting complex regulatory networks mediate the balance between cell proliferation and checks on tumor progression. This study is the first to investigate cancer gene expansions across the mammalian radiation and provides a springboard for potential human therapies based on evolutionary medicine.

Somatic mutation rates scale with lifespan across mammals

“…Cows, giraffes and tigers weigh much more than an average human, and yet have somatic mutation rates several fold higher, in line with expectation from their lifespans but not their body mass. Altogether, the weak correlation between body mass and somatic mutation rates after correction for lifespan suggests that the evolution of larger body sizes may have relied on alternative or additional strategies to limit cancer risk, as has been speculated (Supplementary Note 2) 23,[49][50][51] . Of note, the low somatic mutation rate of naked mole-rats, unusual for their body mass but in line with their long lifespan (Fig.…”

Breaking the constraint on the number of cervical vertebrae in mammals: On homeotic transformations in lorises and pottos

“…Indeed, despite the remarkably high incidence of cervical ribs in lorisids, among 233 neonatal and juvenile deaths of lorisids in zoos, none was found to have a tumor (Simpson et al, 2018). Similarly, in manatees and sloths, cancer rates appeared to be exceptionally low (Galis & Metz, 2003;Tollis et al, 2020). The moderate use of the forelimbs of lorisids makes it unlikely that they will have TOS problems caused by pressure on the nerves and blood vessels.…”

Cross-species identification of cancer resistance–associated genes that may mediate human cancer risk

“…For example, Vicens and Posada ( 15 ) found that genes related to DNA repair and T cell proliferation have evolved under positive selection in mammals. Tollis et al ( 16 ) found that the number of paralogs of human cancer genes across mammals is positively correlated with the species’ life span but not body size. Vazquez and Lynch ( 17 ) reported widespread tumor suppressor gene (TSG) duplications across both large and small Afrotherian species.…”