Comparative analysis of protein coding sequences from human, mouse and the domesticated pig

Abstract

Background: The availability of abundant sequence data from key model organisms has made large scale studies of molecular evolution an exciting possibility. Here we use full length cDNA alignments comprising more than 700,000 nucleotides from human, mouse, pig and the Japanese pufferfish Fugu rubrices in order to investigate 1) the relationships between three major lineages of mammals: rodents, artiodactyls and primates, and 2) the rate of evolution and the occurrence of positive Darwinian selection using codon based models of sequence evolution.

Results: We provide evidence that the evolutionary splits among primates, rodents and artiodactyls happened shortly after each other, with most gene trees favouring a topology with rodents as outgroup to primates and artiodactyls. Using an unrooted topology of the three mammalian species we show that since their diversification, the pig and mouse lineages have on average experienced 1.44 and 2.86 times as many synonymous substitutions as humans, respectively, whereas the rates of non-synonymous substitutions are more similar. The analysis shows the highest average dN/dS ratio in the human lineage, followed by the pig and then the mouse lineages. Using codon based models we detect signals of positive Darwinian selection in approximately 5.3%, 4.9% and 6.0% of the genes on the human, pig and mouse lineages respectively. Approximately 16.8% of all the genes studied here are not currently annotated as functional genes in humans. Our analyses indicate that a large fraction of these genes may have lost their function quite recently or may still be functional genes in some or all of the three mammalian species.

Conclusions: We present a comparative analysis of protein coding genes from three major mammalian lineages. Our study demonstrates the usefulness of codon-based likelihood models in detecting selection and it illustrates the value of sequencing organisms at different phylogenetic distances for comparative studies.

Figure 1

Phylogenetic tree of key mammalian species. A schematic drawing showing the topologies considered in our study compared to a recent study on human, chimpanzee and mouse trios [23]. Branch a shows the branch considered in the study by Clark et al (2003) while branch a+b represents the evolutionary time scale studied here.

Figure 2

Distribution of sequence alignment lengths. Histogram showing the distribution of sequence lengths in the three species alignments.

Figure 3

Conflicting mammalian phylogenies. A schematic drawing of the three conflicting bifurcating topologies (a-c) as well as a multifurcating alternative (d). The divergence times shown in (a) are million years from present [31].

Figure 4

Evolutionary rates. Histograms of key parameters in the codon models. (a-c) The rate of synonymous substitutions per synonymous site (dS) in the pig, human and mouse lineage respectively. (d-f) The rate of nonsynonymous substitutions per nonsynonymous site (dN) in the pig, human and mouse lineage respectively. (g-h) The ratio of nonsynonymous substitutions to synonymous substitutions (dN/dS ratio) in the pig, human and mouse lineage respectively. The horizontal line represents the mean of the distributions.