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 (B_c). 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 B_c 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 B_c. 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.

Keywords: Peto's paradox; body size; cancer; functional analysis of genome; metabolic rate.

Figure 1.

Distribution of the correlation coefficient between the NOGF and body mass (M). Mass-specific metabolic rate (B_c) correction was (a) not considered (b) considered. The filled area indicates the p-value of less than 0.05.

Figure 2.

Relationship between the NOGF, body mass (M) and mass-specific metabolic rate (B_c). Correlations of NOGF for fatty acid degradation with (a) log(M) and (b) log(B_c). (c) Scatter plot of the correlation coefficient (r) between NOGF and M versus r between NOGF and B_c.

Figure 3.

Change in the relationship between the NOGF and body mass (M). (a) NOGF–M correlation for taste transduction. (b) NOGF–M correlation for taste transduction corrected with the mass-specific metabolic rate (B_c). (c) Scatter plot for the determination of coefficient (R²) of NOGF–M correlation versus R² of NOGF–M correlation corrected with B_c. The solid line indicates the diagonal line.

Figure 4.

Scatter plot of the NOGF (residuals) versus log-transformed body mass (M) (residuals). (a) Toll-like receptor signalling pathway. (b) Regulation of autophagy.

Figure 5.

Enrichment of functional categories correlated with body size. The blue bars and red bars indicate the case that mass-specific metabolic rate (B_c) correction was not considered for evaluating the relationships between the NOGF and body mass (M) and the case that B_c correction was considered for evaluating NOGF–M correlations, respectively.