Return to the Sea, Get Huge, Beat Cancer: An Analysis of Cetacean Genomes Including an Assembly for the Humpback Whale (Megaptera novaeangliae)

Abstract

Cetaceans are a clade of highly specialized aquatic mammals that include the largest animals that have ever lived. The largest whales can have ∼1,000× more cells than a human, with long lifespans, leaving them theoretically susceptible to cancer. However, large-bodied and long-lived animals do not suffer higher risks of cancer mortality than humans—an observation known as Peto’s Paradox. To investigate the genomic bases of gigantism and other cetacean adaptations, we generated a de novo genome assembly for the humpback whale (Megaptera novaeangliae) and incorporated the genomes of ten cetacean species in a comparative analysis. We found further evidence that rorquals (family Balaenopteridae) radiated during the Miocene or earlier, and inferred that perturbations in abundance and/or the interocean connectivity of North Atlantic humpback whale populations likely occurred throughout the Pleistocene. Our comparative genomic results suggest that the evolution of cetacean gigantism was accompanied by strong selection on pathways that are directly linked to cancer. Large segmental duplications in whale genomes contained genes controlling the apoptotic pathway, and genes inferred to be under accelerated evolution and positive selection in cetaceans were enriched for biological processes such as cell cycle checkpoint, cell signaling, and proliferation. We also inferred positive selection on genes controlling the mammalian appendicular and cranial skeletal elements in the cetacean lineage, which are relevant to extensive anatomical changes during cetacean evolution. Genomic analyses shed light on the molecular mechanisms underlying cetacean traits, including gigantism, and will contribute to the development of future targets for human cancer therapies.

Positive selection and gene duplications in tumour suppressor genes reveal clues about how cetaceans resist cancer

“…17 . In agreement with that, in the longest-living mammal, the bowhead whale ( Balaena mysticetus, lifespan ≈ 211 years, weight ≈ 100 tons) and the Humpback whale, the signal of positive selection were identified in genes involved in DNA repair, cell cycle regulation, resistance to ageing and cancer 18,19 .…”

Phylogeny, transposable element and sex chromosome evolution of the basal lineage of birds

“…Compared to the genomes of other smaller and volant birds, the ostrich genome is characterized with much lower rates of substitutions 9 and insertions/deletions, transposon removal 10 , and very few intrachromosomal rearrangements even when being compared with the distantly-related chicken 11 . This parallels the similar comparisons between elephants or whales vs. other mammals 10,[12][13][14] , and can be explained by the fact that species with a larger body size tend to have a longer generation time and a lower metabolic rate, hence a reduced mutation rate 12,15 .…”

The Evolution of Human Cancer Gene Duplications across Mammals

“…The genetic controls of cancer suppression in nature's giants has been the focus of much research (Abegglen et al 2015;Caulin et al 2015;Sulak et al 2016;Vazquez et al 2018;Tollis et al 2019), as well as in mammals with pronounced longevity such as naked mole rats (Heterocephalus glaber) (Seluanov et al 2009;Tian et al 2013). Low cancer mortality rates in elephants may be related to the redundancy provided by as many as 20 genomic copies of the tumor suppressor gene TP53 (Abegglen et al 2015;Caulin et al 2015;Sulak et al 2016), which is responsible for apoptosis, senescence, and cell-cycle arrest in the presence of damaged DNA (Kumari et al 2014).…”