Abstract
Selective breeding of the domestic dog (Canis lupus familiaris) rigidly retains desirable features, and could inadvertently fix disease-causing variants within a breed. We combine phenotypic data from > 72,000 dogs with a large genotypic dataset to search for genes associated with cancer mortality and longevity in pedigree dog breeds. We validated previous findings that breeds with higher average body weight have higher cancer mortality rates and lower life expectancy. We identified a significant positive correlation between life span and cancer mortality residuals corrected for body weight, implying that long-lived breeds die more frequently from cancer compared to short-lived breeds. We replicated a number of known genetic associations with body weight (IGF1, GHR, CD36, SMAD2 and IGF2BP2). Subsequently, we identified five genetic variants in known cancer-related genes (located within SIPA1, ADCY7 and ARNT2) that could be associated with cancer mortality residuals corrected for confounding factors. One putative genetic variant was marginally significantly associated with longevity residuals that had been corrected for the effects of body weight; this genetic variant is located within PRDX1, a peroxiredoxin that belongs to an emerging class of pro-longevity associated genes. This research should be considered as an exploratory analysis to uncover associations between genes and longevity/cancer mortality.
Highlights
The World Health Organization predicts that the proportion of the world’s population over the age of 60 will nearly double from 12 to 22% between 2015 and 2050 (WHO 2016)
As demonstrated previously for cancer and other traits, the identification of novel genetic variants associated with complex conditions obtained from comparative mammalian models such as dogs has the potential to greatly advance our understanding of complex human conditions
Given the strong correlation between cancer mortality and body weight, and to avoid finding genetic associations with cancer merely due associations with body weight, a linear regression between body weight and cancer mortality was conducted to obtain cancer mortality residuals that were corrected for the effects of the correlation between cancer mortality and body weight (Fig. 1a and d)
Summary
The World Health Organization predicts that the proportion of the world’s population over the age of 60 will nearly double from 12 to 22% between 2015 and 2050 (WHO 2016). Ageing is the biggest risk factor for cancer (de Magalhães 2013), which is a leading cause of deaths worldwide. As demonstrated previously for cancer and other traits (for example, Sutter et al 2007; Paoloni et al 2009; Pinho et al 2012; Fenger et al 2014; Schiffman and Breen 2015), the identification of novel genetic variants associated with complex conditions obtained from comparative mammalian models such as dogs has the potential to greatly advance our understanding of complex human conditions. Artificial selection for specific traits circumvents Darwinian natural selection; desirable features are rigidly retained, undesirable disease-causing gene variants risk being inadvertently increased in frequency or even fixed in the gene pool. Selective breeding can direct the enrichment of disease-causing alleles which would reflect in the high rates of specific diseases in some breeds, disease-causing mutations could hitch-hike with a desirable phenotypic trait, or there may be a pleiotropic effect
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