MOLPHY version 2.3 : programs for molecular phylogenetics based on maximum likelihood

We present here for the first time a comprehensive study based on the analysis of closely related organisms to provide an accurate determination of the nucleotide substitution rate in mammalian mitochondrial genomes. This study examines the evolutionary pattern of the different functional mtDNA regions as accurately as possible on the grounds of available data, revealing some important ``genomic laws.'' The main conclusions can be summarized as follows. (1) High intragenomic variability in the evolutionary dynamic of mtDNA was found. The substitution rate is strongly dependent on the region considered, and slow- and fast-evolving regions can be identified. Nonsynonymous sites, the D-loop central domain, and tRNA and rRNA genes evolve much more slowly than synonymous sites and the two peripheral D-loop region domains. The synonymous rate is fairly uniform over the genome, whereas the rate of nonsynonymous sites depends on functional constraints and therefore differs considerably between genes. (2) The commonly accepted statement that mtDNA evolves more rapidly than nuclear DNA is valid only for some regions, thus it should be referred to specific mitochondrial components. In particular, nonsynonymous sites show comparable rates in mitochondrial and nuclear genes; synonymous sites and small rRNA evolve about 20 times more rapidly and tRNAs about 100 times more rapidly in mitochondria than in their nuclear counterpart. (3) A species-specific evolution is particularly evident in the D-loop region. As the divergence times of the organism pairs under consideration are known with sufficient accuracy, absolute nucleotide substitution rates are also provided.

Nucleotide substitution rate of mammalian mitochondrial genomes.

The base composition of 25 complete mammalian mitochondrial (mt) genomes has been analyzed taking into account all three codon positions (P1230 and fourfold degenerate sites (P4FD) of H-strand genes. In the nontranscribed L strand, G is the less represented base and A is the most represented one in all cases, while C and T differ among species. H-strand protein-coding genes show an asymmetric distribution of the four bases between the two strands. The asymmetry indexes AT and GC skews on P4FD are much higher than those on P123, suggesting the existence of asymmetrical directional mutation pressure. Relationships between the compositional features and transcription of replication processes have been investigated in order to find a possible mechanism that could explain the origin of this asymmetry. AT and GC skews, the base composition in fourfold degenerate sites, and the number of variable sites for each gene are significantly correlated with the duration of single-stranded state of the H-stranded genes during replication. We tested different replication-related hypotheses, such as the existence of biased dNTP pools, gamma DNA polymerase mispairing, and the asymmetric replication itself. Most of them failed to explain the observed results, hydrolytic deaminations being the only one in agreement with our data. Thus, we hypothesize that one of the crucial processes for the origin of asymmetric and biased base composition of mammalian mitochondrial genomes is the spontaneous deamination of C and A in the H strand during replication.

Asymmetrical directional mutation pressure in the mitochondrial genome of mammals.

IN 1991 Graur et al. raised the question of whether the guinea-pig, Cavia porcellus, is a rodent1. They suggested that the guinea-pig and myomorph rodents diverged before the separation between myomorph rodents and a lineage leading to primates and artiodactyls. Several findings have since been reported, both for and against this phylogeny, thereby highlighting the issue of the validity of molecular analysis in mammalian phylogeny. Here we present findings based on the sequence of the complete mitochondrial genome of the guinea-pig, which strongly contradict rodent monophyly. The conclusions are based on the cumulative evidence provided by orthologically inherited genes and the use of three different analytical methods, none of which joins the guinea-pig with myomorph rodents. In addition to the phylogenetic conclusions, we also draw attention to several factors that are important for the validity of phylogenetic analysis based on molecular data.

The guinea-pig is not a rodent

The entire nucleotide sequence of the mitochondrial genome of the American opossum, Didelphis virginiana, was determined. Two major features distinguish this genome from those of other mammals. First, five tRNA genes around the origin of light strand replication are rearranged. Second, the anticodon of tRNA(Asp) is posttranscriptionally changed by an RNA editing process such that its coding capacity is altered. When the complete protein-coding region of the mitochondrial genome is used as an outgroup for placental mammals it can be shown that rodents represent an earlier branch among placental mammals than primates and artiodactyls and that artiodactyls share a common ancestor with carnivores. The overall rates of evolution of most of the mitochondrial genome of placentals are clock-like. Furthermore, the data indicate that the lineages leading to the mouse and rat may have diverged from each other as much as 35 million years ago.

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The marsupial mitochondrial genome and the evolution of placental mammals.

We have sequenced the mitochondrial cytochrome b gene from the guinea pig, the African porcupine, and a South American opossum. A phylogenetic analysis, which includes 22 eutherian and four other vertebrate cytochrome b sequences, indicates that the guinea pig and the porcupine constitute a natural clade (Hystricomorpha) that is not a sister group to the clade of mice and rats (Myomorpha). Therefore, the hypothesis that the Rodentia is paraphyletic receives additional support. The artiodactyls, the perissodactyls, and the cetaceans form a group that is separated from the primates and the rodents. The 26 sequences are used to study the structure/function relationships in cytochrome b, whose function is electron transport. Most of the amino acid residues involved in the two reaction centers are well conserved in evolution. The four histidines that are believed to ligate the two hemes are invariant among the 26 sequences, but their nearby residues are not well conserved in evolution. The eight transmembrane domains represent some of the most divergent regions in the cytochrome b sequence. The rate of nonsynonymous substitution is considerably faster in the human and elephant lineages than in other eutherian lineages; the faster rate might be due to coevolution between cytochrome b and cytochrome c.

Structure and evolution of opossum, guinea pig, and porcupine cytochrome b genes.

On the basis of 18 protein sequences totaling 2,413 aligned amino acid sites, it is suggested that the guinea pigs and the myomorphs (rat-like rodents) are not monophyletic. Rather, the evolutionary lineage leading to the guinea pig seems to have branched off prior to the divergence among myomorphs, lagomorphs, primates, chiropterans, artiodactyls, and carnivores. It is suggested therefore that the Caviomorpha (guinea pig-like rodents) and possibly the Hystricomorpha (porcupine-like rodents) should be elevated in taxonomic rank and conferred an ordinal status distinct from the Rodentia. This suggestion calls for a reevaluation of the morphological evolution of guinea pigs and further molecular studies on the possibility of paraphyly of the order Rodentia. If the monophyly of rodents holds, it must be concluded that the pattern of molecular evolution in many guinea pig genes has been extremely unusual and that the causes for this pattern should be sought. It is also suggested that claims of large differences in the rate of molecular evolution between guinea pigs and myomorphs may have been exaggerated in many cases as a result of an erroneous phylogenetic position for the guinea pig. The average rate of amino acid replacement in the guinea pig seems to be comparable to that in the rat and the mouse. However, the data indicate that myomorph and caviomorph genes evolve, on average, about two times faster than their human counterparts. Finally, our analysis provides evidence against the hypothesis that the gundi (an African rodent) represents the most ancient rodent lineage.

D. P. Ma

Papers

Structure and evolution of opossum, guinea pig, and porcupine cytochrome b genes.

The Molecular Taxonomy and Evolution of the Guinea Pig