Evolutionary Medicine

Introduction

Lifespan and maximum adult body size are fundamental life history traits that vary considerably between species (Healy et al., 2014). The maximum lifespan among vertebrates, for example, ranges from over 211 years in the bowhead whale (Balaena mysticetus) to only 59 days in the pygmy goby (Eviota sigillata) whereas body sizes ranges from 136,000 kg in the blue whale (Balaenoptera musculus) to 0.5 g in the Eastern red-backed salamander (Plethodon cinereus) (Healy et al., 2014). Similar to other life history traits, such as body size and metabolic rate or body size and age at maturation, body size and lifespan are strongly correlated such that larger species tend to live longer than smaller species (Figure 1A). While abiotic and biological factors have been proposed as major drivers of maximum body size evolution in animals, maximum body size within tetrapods appears to be largely determined by biology (Smith et al., 2010; Sookias et al., 2012).  Mammals, for example, likely share biological constraints on the evolution of very large body sizes with rare breaks in those constraints underlying the evolution of gigantism in some lineages (Sookias et al., 2012), such as Proboscideans (elephants and their and extinct relatives), Cetaceans (whales), and the extinct hornless rhinoceros Paraceratherium (‘Walter’).

Figure 1.jpg

Figure 1. Body size evolution in vertebrates. (A)  Relationship between body mass (g) and lifespan (years) among 2,556 vertebrates. Blue line shows the linear regression between log (body mass) and log (lifespan), R2=0.32. (B) Body size comparison between living (African and Asian elephants) and extinct (Steppe mammoth) Proboscideans, Cetaceans (Minke whale), and the extinct hornless rhinoceros Paraceratherium (‘Walter’), and humans.

A major constraint on the evolution of large body sizes in animals is an increased risk of developing cancer. If all cells have a similar risk of malignant transformation and equivalent cancer suppression mechanisms, organism with many cells should have a higher risk of developing cancer than organisms with fewer cells; Similarly organisms with long lifespans have more time to accumulate cancer-causing mutations than organisms with shorter lifespans and therefore should be at an increased risk of developing cancer, a risk that is compounded in large bodied, long-lived organisms . There are no correlations, however, between body size and cancer risk or lifespan and cancer risk across species , this lack of correlation is often referred to as ‘Peto’s Paradox’. Epidemiological studies in wild populations of Swedish roe deer (Capreolus capreolus) and beluga whales (Delphinapterus leucas) in the highly polluted St. Lawrence estuary, for example, found cancer accounted for only 2% (Aguirre et al., 1999)and 27% of mortality, respectively, much lower than expected given body size of these species.

            Among the mechanisms large, long lived animals may have evolved that resolve Peto’s paradox are a decrease in the copy number of oncogenes, an increase in the copy number of tumor suppressor genes, reduced metabolic rates leading to decreased free radical production, reduced  retroviral activity and load, increased immune surveillance, and selection for “cheater” tumors that parasitize the growth of other tumors, among many others. Naked mole rats (Heterocephalus glaber), for example, which have very long lifespans for a small-bodied organism evolved cells with extremely sensitive contact inhibition likely acting as a constraint on tumor growth and metastasis. Similarly long-lived blind mole rats (Splanx sp.) evolved an enhanced TP53-signaling and necrotic cell death mechanisms that also likely constrains tumor growth. Thus while some of the mechanisms that underlie cancer resistance in small long-lived mammals have been identified, the mechanisms by which large bodied animals evolved enhanced cancer resistance are unknown.

            We use evolutionary genomics and comparative cell biology to explore the mechanisms by which elephants, the largest extant land mammal (Figure 1B), have evolved enhanced resistance to cancer. For example, we have found that elephant cells have an enhanced response to DNA-damage that is mediated by a hyperactive TP53 signaling pathway, and that the elephant genome encodes numerous functional TP53 retrogenes (TP53RTGs). While TP53RTGs do not appear to be functionally equivalent with TP53, they do augment TP53 signaling. We are currently exploring the function of these TP53RTGs as well as other elephant specific changes that may be related to cancer resistance.