Importance of metabolic rate to the relationship between the number of genes in a functional category and body size in Peto's paradox for cancer

Abstract

Elucidation of tumour suppression mechanisms is a major challenge in cancer biology. Therefore, Peto's paradox, or low cancer incidence in large animals, has attracted focus. According to the gene-abundance hypothesis, which considers the increase/decrease in cancer-related genes with body size, researchers evaluated the associations between gene abundance and body size. However, previous studies only focused on a few specific gene functions and have ignored the alternative hypothesis (metabolic rate hypothesis): in this hypothesis, the cellular metabolic rate and subsequent oxidative stress decreases with increasing body size. In this study, we have elected to explore the gene-abundance hypothesis taking into account the metabolic rate hypothesis. Thus, we comprehensively investigated the correlation between the number of genes in various functional categories and body size while at the same time correcting for the mass-specific metabolic rate (Bc). A number of gene functions that correlated with body size were initially identified, but they were found to be artefactual due to the decrease in Bc with increasing body size. By contrast, immune system-related genes were found to increase with increasing body size when the correlation included this correction for Bc. These findings support the gene-abundance hypothesis and emphasize the importance of also taking into account the metabolic rate when evaluating gene abundance–body size relationships. This finding may be useful for understanding cancer evolution and tumour suppression mechanisms as well as for determining cancer-related genes and functions.

A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage

“…While the ultimate resolution to Peto's paradox is that largebodied and/or long-lived species evolved enhanced cancer protection mechanisms, identifying and characterizing those mechanisms is essential for elucidating how enhanced cancer resistance and thus large bodies and long life spans evolved. Numerous and diverse mechanisms have been proposed to resolve Peto's paradox (Caulin and Maley, 2011;Dang, 2015;Katzourakis et al, 2014;Leroi et al, 2003;Maciak and Michalak, 2015;Nagy et al, 2007;Nunney, 1999;Takemoto et al, 2016), but discovering those mechanisms has been challenging because the ideal study system is one in which a large, long-lived species is deeply nested within a clade of smaller, short-lived species-all of which have sequenced genomes. Unfortunately, few lineages fit this pattern.…”

Exosomes in mammals with greater habitat variability contain more proteins and RNAs

“…Homologous genes in the same species whose E < 10 –5 and query coverage > 30% were defined as duplicated genes. We collected data on mass-specific metabolic rates B c (W g −1 ) and body mass M (g) from our previous studies [ 12 , 16 ]. The data for 32 mammalian species are available in the electronic supplementary material, table S1.…”

“…phylogenetic generalized least squares) for all 389 explanatory variables. However, we could not perform such an analysis in this study because of the combinatorial explosion in model selection and the multicollinearity that mainly arises from gene overlap among functional categories or the hierarchical organization of functional categories [ 12 , 16 ]. In fact, we were unable to perform the phylogenetic generalized least squares using the gls function in the R-package nlme (v. 3.1–128) because of singularities in the regression model.…”

“…These facts indicate the importance of taking into account (i.e. correcting for) the metabolic rate when evaluating relationships with genomic measures [ 16 ]. More importantly, metabolic rate and body size determine animal space use because they are related to the energy required for moving [ 25 ].…”

A zombieLIFgene in elephants is up-regulated by TP53 to induce apoptosis in response to DNA damage

“…While the ultimate resolution to Peto's paradox is that large bodied and/or long-lived species evolved enhanced cancer protection mechanisms, identifying and characterizing those mechanisms is essential for elucidating how enhanced cancer resistance and thus large bodies and long lifespans evolved. Numerous and diverse mechanisms have been proposed to resolve Peto's paradox (Caulin and Maley, 2011;Dang, 2015;Katzourakis et al, 2014;Leroi et al, 2003;Maciak and Michalak, 2015;Nagy et al, 2007;Nunney, 1999;Takemoto et al, 2016), but discovering those mechanisms has been challenging because the ideal study system is one in which a large, long-lived species is deeply nested within a clade of smaller, short-lived speciesall of which have sequenced genomes. Unfortunately, few lineages fit this pattern.…”