The bioenergetic costs of a gene

Abstract

An enduring mystery of evolutionary genomics concerns the mechanisms responsible for lineage-specific expansions of genome size in eukaryotes, especially in multicellular species. One idea is that all excess DNA is mutationally hazardous, but weakly enough so that genome-size expansion passively emerges in species experiencing relatively low efficiency of selection owing to small effective population sizes. Another idea is that substantial gene additions were impossible without the energetic boost provided by the colonizing mitochondrion in the eukaryotic lineage. Contrary to this latter view, analysis of cellular energetics and genomics data from a wide variety of species indicates that, relative to the lifetime ATP requirements of a cell, the costs of a gene at the DNA, RNA, and protein levels decline with cell volume in both bacteria and eukaryotes. Moreover, these costs are usually sufficiently large to be perceived by natural selection in bacterial populations, but not in eukaryotes experiencing high levels of random genetic drift. Thus, for scaling reasons that are not yet understood, by virtue of their large size alone, eukaryotic cells are subject to a broader set of opportunities for the colonization of novel genes manifesting weakly advantageous or even transiently disadvantageous phenotypic effects. These results indicate that the origin of the mitochondrion was not a prerequisite for genome-size expansion.

Keywords: cellular bioenergetics; evolutionary genomics; gene cost; transcription; translation.

Fig. 1.

(A) The costs associated with maintaining and producing a cell for a variety of bacteria (black) and unicellular eukaryotes (blue). The red points, which denote data for cultures of cells from multicellular species, are included for comparative purposes but were not used in the regressions. (B) Minimum cell-division times for unicellular species, normalized to 20 °C, with significant regression lines shown for individual phylogenetic groups. The upper dotted line denotes cell-division times that are expected to result in 50% of the cellular energy budget being allocated to maintenance; the dashed line demarcates the apparent absolute lower bound to volume-specific cell-division times across the tree of life. Data sources are provided in the tables in SI Appendix.

Fig. 2.

Numbers of protein and messenger RNA molecules per cell, with the five left-most points being for bacterial species, the intermediate two for yeasts, and the two right-most points for mammalian cells. Total numbers of molecules per cell (summed over all genes) are given by the closed points, with the solid-line regression. The brackets for numbers of molecules per gene denote the lower 2.5% and upper 97.5% cutoffs in the overall distributions; the dashed and dotted lines denote the regressions involving the means and medians. For transcripts, the total number per cell and the average number per active gene scale with cell volume (V) as $\mathrm{8,831}{V}^{0.36}$ ($r^2=0.97$) and $2.93V^{0.28}$ ($r^2=0.71$), respectively. For proteins, the total number per cell and the average number per active gene scale with cell volume (V) as $\mathrm{1,588,547}{V}^{0.93}$ ($r^2=0.98$) and $\mathrm{1,698}{V}^{0.66}$ ($r^2=0.96$), respectively.

Fig. 3.

Distribution of energy costs for the full sets of annotated genes in one bacterium (E. coli) and four eukaryotic species (Saccharomyces cerevisiae, C. elegans, and A. thaliana). The bottom axis shows the absolute costs in ATP units, and the upper axis shows the corresponding costs as the fraction of the cell’s lifetime energy budget. The dashed vertical lines denote key positions below which the energy cost is expected to be too low to be opposed by selection (in the absence of any additional advantages for the gene); for genes to the left of a particular vertical bar (with logarithmic value x on the upper axis), the energetic cost would be effectively neutral if the effective population size ($N_e$) were $>{10}^{-x}$. The three vertical lines in each plot provide the approximate range in which $N_e$ is likely to reside for species in the same broad taxonomic categories as the characterized species (2).

Fig. 4.

Fractional costs of average genes in bacteria and unicellular eukaryotes (relative to total cellular energy budgets), subdivided into components at the level of replication, transcription, and translation.