Models of coding sequence evolution

Probabilistic models of sequence evolution are in widespreaduse in phylogenetics and molecular sequence evolution. Thesemodels have become increasingly sophisticated and combined withstatistical model comparison techniques have helped to shedlight on how genes and proteins evolve. Models of codon evolutionhave been particularly useful, because, in addition to providinga significant improvement in model realism for protein-codingsequences, codon models can also be designed to test hypothesesabout the selective pressures that shape the evolution of thesequences. Such models typically assume a phylogeny and canbe used to identify sites or lineages that have evolved adaptively.Recently some of the key assumptions that underlie phylogenetictests of selection have been questioned, such as the assumptionthat the rate of synonymous changes is constant across sitesor that a single phylogenetic tree can be assumed at all sitesfor recombining sequences. While some of these issues have beenaddressed through the development of novel methods, others remainas caveats that need to be considered on a case-by-case basis.Here, we outline the theory of codon models and their applicationto the detection of positive selection. We review some of themore recent developments that have improved their power andutility, laying a foundation for further advances in the modelingof coding sequence evolution.      

Network models for sequence evolution

We introduce a general class of models for sequence evolution that includes network phylogenies. Networks, a generalization of strictly tree-like phylogenies, are proposed to model situations where multiple lineages contribute to the observed sequences. An algorithm to compute the probability distribution of binary character-state configurations is presented and statistical inference for this model is developed in a likelihood framework. A stepwise procedure based on likelihood ratios is used to explore the space of models. Starting with a star phylogeny, new splits (nontrivial bipartitions of the sequence set) are successively added to the model until no significant change in the likelihood is observed. A novel feature of our approach is that the new splits are not necessarily constrained to be consistent with a treelike mode of evolution. The fraction of invariable sites is estimated by maximum likelihood simultaneously with other model parameters and is essential to obtain a good fit to the data. The effect of finite sequence length on the inference methods is discussed. Finally, we provide an illustrative example using aligned VPl genes from the foot and mouth disease viruses (FMDV). The different serotypes of the FMDV exhibit a range of treelike and network evolutionary relationships.Correspondence to: A. von Haeseler     

Coding nucleotide sequence of rat liver malic enzyme mRNA

The nucleotide sequence of the mRNA for malic enzyme ((S)-malate NADP+ oxidoreductase (oxaloacetate-decarboxylating, EC 1.1.1.40) from rat liver was determined from three overlapping cDNA clones. Together, these clones contain 2078 nucleotides complementary to rat liver malic enzyme mRNA. The single open reading frame of 1761 nucleotides codes for a 585-amino acid polypeptide with a calculated molecular mass of about 65,460 daltons. The cloned cDNAs contain the complete 3'-noncoding region of 301 nucleotides for the major mRNA species of rat liver and 16 nucleotides of the 5'-noncoding region. Amino acid sequences of seven tryptic peptides (67 amino acids) from the purified protein are distributed through the single open reading frame and show excellent correspondence with the translated nucleotide sequence. The putative NADP-binding site for malic enzyme was identified by amino acid sequence homology with the NADP-binding site of the enoyl reductase domain of fatty acid synthetase.     

A model of DNA sequence evolution

Statistical studies of gene populations on the purine/pyrimidine alphabet have shown that the mean occurrence probability of thei-motif YRY(N) _i YRY (R=purine, Y=pyrimidine, N=R or Y) is not uniform by varyingi in the range [1,99], but presents a maximum ati=6 in the following populations: protein coding genes of eukaryotes, prokaryotes, chloroplasts and mitrochondria, and also viral introns, ribosomal RNA genes and transfer RNA genes (Arquès and Michel, 1987b,J. theor. Biol. 128, 457–461). From the “universality” of this observation, we suggested that the oligonucleotide YRY(N)₆ is a primitive one and that it has a central function in DNA sequence evolution (Arquès and Michel, 1987b,J. theor. Biol. 128, 457–461). Following this idea, we introduce a concept of a model of DNA sequence evolution which will be validated according to a shema presented in three parts. In the first part, using the last version of the gene database, the YRY(N)₆YRY preferential occurrence (maximum ati=6) is confirmed for the populations mentioned above and is extended to some newly analysed populations: chloroplast introns, chloroplast 5′ regions, mitochondrial 5′ regions and small nuclear RNA genes. On the other hand, the YRY(N)₆YRY preferential occurrence and periodicities are used in order to classify 18 gene populations. In the second part, we will demonstrate that several statistical features characterizing different gene populations (in particular the YRY(N)₆YRY preferential occurrence and the periodicities) can be retrieved from a simple Markov model based on the mixing of the two oligonucleotides YRY(N)₆ and YRY(N)₃ and based on the percentages of RYR and YRY in the unspecified trinucleotides (N)₃ of YRY(N)₆ and YRY(N)₃. Several properties are identified and prove in particular that the oligonucleotide mixing is an independent process and that several different features are functions of a unique parameter. In the third part, the return of the model to the reality shows a strong correlation between reality and simulation concerning the presence of large alternating purine/pyrimidine stretches and of periodicities. It also contributes to a greater understanding of biological reality, e.g. the presence or the absence of large alternating purine/pyrimidine stretches can be explained as being a simple consequence of the mixing of two particular oligonucleotides. Finally, we believe that such an approach is the first step toward a unified model of DNA sequence evolution allowing the molecular understanding of both the origin of life and the actual biological reality.     

Mitochondrial genome sequence evolution in Chlamydomonas

The mitochondrial genomes of the Chlorophyta exhibit significant diversity with respect to gene content and genome compactness; however, quantitative data on the rates of nucleotide substitution in mitochondrial DNA, which might help explain the origin of this diversity, are lacking. To gain insight into the evolutionary forces responsible for mitochondrial genome diversification, we sequenced to near completion the mitochondrial genome of the chlorophyte Chlamydomonas incerta, estimated the evolutionary divergence between Chlamydomonas reinhardtii and C. incerta mitochondrial protein-coding genes and rRNA-coding regions, and compared the relative evolutionary rates in mitochondrial and nuclear genes. Synonymous and nonsynonymous substitution rates do not differ significantly between the mitochondrial and nuclear protein-coding genes. The mitochondrial rRNA-coding regions, however, are evolving much faster than their nuclear counterparts, and this difference might be explained by relaxed functional constraints on the mitochondrial translational apparatus due to the small number of proteins synthesized in Chlamydomonas mitochondria. Substitution rates at synonymous sites in a nonstandard mitochondrial gene (rtl) and at intronic and synonymous sites in nuclear genes expressed at low levels suggest that the mutation rate is similar in these two genetic compartments. Potential evolutionary forces shaping mitochondrial genome evolution in Chlamydomonas are discussed.     

Coding sequence polymorphisms among V beta T cell receptor genes

The four V beta gene segments, V beta 1, 3.1, 6, and 10, which previously have been shown by RFLP analyses to differ between TCR V beta a and V beta b haplotypes, were cloned and sequenced from V beta a SWR mice and compared with V beta b strains to define coding sequence polymorphisms distinguishing these haplotypes. V beta 3.1 and 6 alleles differed between strains by a single amino acid, whereas V beta 1 and 10 alleles differed by 4 and 6 amino acids, respectively. The overall interhaplotypic V beta polymorphisms appeared to be limited when based upon compilation of this information and previously published V beta sequences. One application of these data was to attempt to elucidate the molecular basis underlying the recently reported allele-specific autoimmune disease, collagen-induced arthritis. Based on the present structural data and the additional evidence, contrary to what was suggested, the V beta 6 gene does not appear to be the sole participant in anticollagen responses.     

Coding sequence polymorphism in avian mitochondrial genomes reflects population histories

Nucleotide sequence diversity at mitochondrial protein-coding loci from 72 species of birds from different geographical regions was analysed in order to test the hypothesis that temperate zone species show population genetic effects of past glaciation. Temperate zone species showed reduced nucleotide diversity in comparison to tropical mainland species, suggesting that the latter have long-term effective population sizes due to population bottleneck effects during the most recent glaciation. This hypothesis was further supported by evidence of an unusually high estimated rate of population growth in species breeding in North America and wintering in the New World tropics (Nearctic migrants), consistent with population expansion after a bottleneck. Nearctic migrants also showed evidence of an abundance of rare nonsynonymous (amino acid-altering) polymorphisms, a pattern suggesting that slightly deleterious polymorphisms drifted to high frequencies during a bottleneck and are now being eliminated by selection. Because the shape of the North American land mass limited the area available for refugia during glaciation, the bottleneck effects are predicted to have been particularly strong in Nearctic migrants, and this prediction was supported. The reduced genetic diversity of Nearctic migrants provides an additional basis for concern for the survival of these species, which are threatened by loss of habitat in the winter range and by introduced disease.     

Coding sequence and flanking regions of the mouse vimentin gene

Summary Using a polyclonal antibody, a cDNA clone coding for part of mouse vimentin was identified in a gt11 expression library. DNA from this clone was used to screen a genomic library from Ehrlich Ascites Tumor cells for the mouse vimentin gene. A clone was found which contained the whole coding sequence and a large part of the 5- and 3-untranslated sequences. It was used to prepare a construct equivalent to a full-length cDNA clone. Extensive homologies to the vimentin sequence from other species were found for the coding and 3-untranslated sequences and the promoter region.     

酶祖先序列重建与定向进化

酶祖先序列重建是指通过计算机算法推导来自灭绝生物的祖先酶的氨基酸序列的技术.通常可分为6个步骤,依次为现代酶的核酸/氨基酸序列收集、多序列比对、系统发育树构建、祖先酶序列的计算机推测、基因克隆、酶学性质表征.该方法广泛应用于研究分子在行星时间尺度上对环境条件不断变化的适应性和进化机制.随着酶在生物催化领域中扮演越来越重...     

Assessing site-interdependent phylogenetic models of sequence evolution

In recent works, methods have been proposed for applying phylogenetic models that allow for a general interdependence between the amino acid positions of a protein. As of yet, such models have focused on site interdependencies resulting from sequence-structure compatibility constraints, using simplified structural representations in combination with a set of statistical potentials. This structural compatibility criterion is meant as a proxy for sequence fitness, and the methods developed thus far can incorporate different site-interdependent fitness proxies based on other measurements. However, no methods have been proposed for comparing and evaluating the adequacy of alternative fitness proxies in this context, or for more general comparisons with canonical models of protein evolution. In the present work, we apply Bayesian methods of model selection-based on numerical calculations of marginal likelihoods and posterior predictive checks-to evaluate models encompassing the site-interdependent framework. Our application of these methods indicates that considering site-interdependencies, as done here, leads to an improved model fit for all data sets studied. Yet, we find that the use of pairwise contact potentials alone does not suitably account for across-site rate heterogeneity or amino acid exchange propensities; for such complexities, site-independent treatments are still called for. The most favored models combine the use of statistical potentials with a suitably rich site-independent model. Altogether, the methodology employed here should allow for a more rigorous and systematic exploration of different ways of modeling explicit structural constraints, or any other site-interdependent criterion, while best exploiting the richness of previously proposed models.     

Coding sequence and growth regulation of the human vimentin gene.

We have established the complete coding sequence of the human vimentin gene. It had 91% homology to the coding sequence of the Syrian hamster vimentin gene (Quax et al., Cell 35:215-223, 1983) and partial homology to several other sequences coding for intermediate filament proteins. The most striking difference between the Syrian hamster and human vimentin genes was in the 3' untranslated region, which was considerably longer in the Syrian hamster. Using RNA blots and a human vimentin cDNA clone from an Okayama-Berg library, we have established that expression of the vimentin gene was growth regulated. The steady-state levels of cytoplasmic vimentin mRNA in 3T3 cells were increased by serum and platelet-derived growth factor, but not by epidermal growth factor, insulin, or platelet-poor plasma. The increase in expression of the vimentin gene that occurred when G0-phase cells were stimulated to proliferate was detected in six different cell types from four different species. The expression of the vimentin gene was also increased when HL60 cells were induced to differentiate by phorbol esters; it decreased when differentiation was induced by retinoic acid.     

Modeling sequence evolution in acute HIV-1 infection

We describe a mathematical model and Monte Carlo (MC) simulation of viral evolution during acute infection. We consider both synchronous and asynchronous processes of viral infection of new target cells. The model enables an assessment of the expected sequence diversity in new HIV-1 infections originating from a single transmitted viral strain, estimation of the most recent common ancestor (MRCA) of the transmitted viral lineage, and estimation of the time to coalesce back to the MRCA. We also calculate the probability of the MRCA being the transmitted virus or an evolved variant. Excluding insertions and deletions, we assume HIV-1 evolves by base substitution without selection pressure during the earliest phase of HIV-1 infection prior to the immune response. Unlike phylogenetic methods that follow a lineage backwards to coalescence, we compare the observed data to a model of the diversification of a viral population forward in time. To illustrate the application of these methods, we provide detailed comparisons of the model and simulations results to 306 envelope sequences obtained from eight newly infected subjects at a single time point. The data from patients were in good agreement with model predictions, and hence compatible with a single-strain infection evolving under no selection pressure. The diversity of the samples from the other two patients was too great to be explained by the model, suggesting multiple HIV-1-strains were transmitted. The model can also be applied to longitudinal patient data to estimate within-host viral evolutionary parameters.     

Concerted evolution of sequence repeats inDrosophila mitochondrial DNA

Summary In the eightDrosophila species of themelanogaster subgroup, the mitochondrial DNA (mtDNA) contains an A+T-rich region in which replication originates. The length of this region, in contrast with that of the coding part of the genome, varies extensively among these species. The A+T-rich region ranges from about 1kbp inD. yakuba, D. teissieri, D. erecta, andD. orena to 5 kbp inD. melanogaster, D. simulans, D. mauritiana, andD. sechellia. The difference in size is due in part to the amplification, in the species with long genomes, of a 470-bp sequence that is present only once in each of the four species with short genomes.Usually three to six repeats of this sequence occur in direct tandem repetition in the species with long genomes. The sequence is characterized by the relative positions of the Hpa I and Acc I cleavage sites. Comparative study of the genomes found in the species with long mtDNA molecules reveals relative homogeneity of the repeat units within a given genome, which contrasts with the variability found among the repeats of different genomes. This result is suggestive of a process of a concerted evolution.The examination of heteroplasmic flies of three species (D. simulans, D. mauritiana, andD. sechellia) has shed light on this process. In most cases the molecular types of mtDNA present in a heteroplasmic individual differ by one repeat unit. Addition or deletion of this sequence appears to be the original mutational event generating transient heteroplasmy. Cycles of addition or deletion may consequently maintain the intragenomic homogeneity of the repeats.Finally, we have analyzed an exceptional isofemale line in which three molecular lengths of mtDNA are found (molecules with four, five, and six repeats, respectively). Individual offspring of this line carry from one to three of the molecular types, in all combinations. This indicates that the remodeling of the mitochondrial genome occurs through a mechanism that is at present unknown, but that is site specific and rather frequent.Presented at the FEBS Symposium on Genome Organization and Evolution, held in Crete, Greece, September 1–5, 1986