The Signature of Selection Mediated by Expression on Human Genes

Abstract

As the efficacy of natural selection is expected to be a function of population size, in humans it is usually presumed that selection is a weak force and hence that gene characteristics are mostly determined by stochastic forces. In contrast, in species with large population sizes, selection is expected to be a much more effective force. Evidence for this has come from examining how genic parameters vary with expression level, which appears to determine many of a gene's features, such as codon bias, amino acid composition, and size. However, not until now has it been possible to examine whether human genes show the signature of selection mediated by expression level. Here, then, to investigate this issue, we gathered expression data for >10,000 human genes from public data sets obtained by different technologies (SAGE and high-density oligonucleotide chip arrays) and compared them with gene parameters. We find that, even after controlling for regional effects, highly expressed genes code for smaller proteins, have less intronic DNA, and higher codon and amino acid biases. We conclude that, contrary to the usual supposition, human genes show signatures consistent with selection mediated by expression level

The Distribution of Fitness Effects of New Deleterious Amino Acid Mutations in Humans

“…Let us assume that synonymous mutations are neutral and that the distribution of fitness effects for nonsynonymous mutations is gamma. Although there is some evidence of selection on synonymous codon use in both murids and hominids (Keightley and Gaffney 2003;Urrutia and Hurst 2003;Chamary and Hurst 2004;Chimpanzee Sequencing and Analysis Consortium 2005), the level of selection seems to be small and quite similar in the two lineages; for example, the rate of synonymous substitution appears to be $70% of the intron substitution rate in both groups (Keightley and Gaffney 2003;Chimpanzee Sequencing and Analysis Consortium 2005). Further, let us assume that a small proportion of nonsynonymous mutations are advantageous and that these cause a proportion a of the nonsynonymous substitutions to be adaptive, the others being neutral or slightly deleterious.…”

Measuring and Detecting Molecular Adaptation in Codon Usage Against Nonsense Errors During Protein Translation

“…Most explanations of CUB involve a mixture of factors including mutational bias, intron splicing, recombination, gene conversion, DNA packaging, and selection for increased translational efficiency or accuracy (Bernardi and Bernardi 1986;Bulmer 1988Bulmer , 1991Shields et al 1988;Hey 1993, 1994;Akashi 1994Akashi , 2003Xia 1996Xia , 1998Akashi and Eyre-Walker 1998;Musto et al 1999Musto et al , 2003McVean and Charlesworth 1999;Ghosh et al 2000;Wagner 2000;Birdsell 2002;Comeron and Kreitman 2002;Elf et al 2003;Chen et al 2004;Chamary and Hurst 2005a,b;Comeron 2006;Lin et al 2006;Warnecke and Hurst 2007;Drummond and Wilke 2008;Warnecke et al 2008). As a result, CUB has played an important role in the neutralist-selectionist debate (e.g., Wolfe and Sharp 1993;Duret and Mouchiroud 1999;Musto et al 2001;Urrutia and Hurst 2003;Plotkin et al 2004;Sémon et al 2005;Chamary et al 2006;Lynch 2007), interpretations of molecular clocks (e.g., Long and Gillespie 1991;Tamura et al 2004;Xia 2009), and phylogenetics (e.g., Goldman and Yang 1994;Mooers and Holmes 2000;…”

Impact of Transcriptional Properties on Essentiality and Evolutionary Rate

“…Of particular importance, expression level has been believed to be the best indicator of the evolutionary rate of encoded proteins. Highly expressed genes were found to evolve slowly from bacteria to mammals (Sharp 1991;Duret and Mouchiroud 2000;Pal et al 2001;Herbeck et al 2003;Urrutia and Hurst 2003;Subramanian and Kumar 2004;Drummond et al 2005). In addition, it has recently emerged as a governing factor behind the apparent relationships between evolutionary rate and other important genomic features.…”