Why do whales exist? cancer resistance in cetaceans

Thesis

Cancer is the inevitable fate for all multicellular organisms should they live long enough. However, if all mammalian cells have approximately equivalent probabilities of cancer-associated gene mutation then, all else being equal, the number of cells susceptible to transformation should scale with body size and longevity, implying larger, longer-lived mammals such as whales should be disproportionately more prone to cancer than smaller mammals, such as mice, simply due to cell number alone. Empirical evidence to date does not support this prediction, and the discrepancy between theory and observation is known as Peto’s paradox.

The mere existence of whales and other large mammals demands the evolution of a suite of cancer suppressive mechanisms in order to resolve the paradox; the establishment and understanding of which being the focus of this research.

First, cancer incidence rates across the animal kingdom are collected and assessed, quantitatively revealing the veracity of Peto’s paradox and the relationship between incidence risk and scaling basal metabolic rate. Next, computational models are developed to test the hypothesis that intrinsic metabolic scaling may itself be sufficient to explain Peto’s paradox. Results reveal that though incorporating scaling life-history traits into the narrative helps, they alone aren’t sufficient to explain cancer suppression in large mammals. Instead, genetic control is established as playing a crucial role. Finally, comparative analysis of the available cetacean genomes and transcriptomes uncovers several gene duplication events in key cancer-associated pathways, alongside lineage-specific and size-dependent selection in gene families associated with cancer resistance. This work demonstrates though there exists no singular explanation for Peto’s paradox, the disparate mechanisms that underlie the trajectory towards cancer resistance in independent lineages are all variations on a theme - the understanding of which may elucidate insight towards the development of future targets for human cancer therapies.

Authors: Speight, MAG

• DOI: 10.5287/ora-1rdrk1nj0
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Whales; Zoology; Genomics; Peto's Paradox; Cancer; Computational Biology; Cetaceans
• Subjects: Cancer; Zoology; Comparative genomics; Computational biology