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PubMed1993

An examination of the generation-time effect on molecular evolution.

By using DNA sequences of 17 mammalian genes, the generation-time effect is estimated separately for synonymous substitutions and nonsynonymous substitutions. Star phylogenies composed of rodentia, artiodactyla, and primates are examined. The generation-time effect is found to be more conspicuous for synonymous substitutions than for non-synonymous substitutions, by using the methods of (i) Nei and Gojobori, (ii) Li, and (iii) Ina. The proportion of accepted amino acid substitutions in evolution is estimated to be about twice as large in the primate lineage as in the rodent lineage. This result is in accord with the nearly neutral theory of molecular evolution.

Animals↗
PubMed2002

Gene location and bacterial sequence divergence.

Previous comparison of a relatively small set of homologous genes from Escherichia coli and Salmonella typhimurium revealed that genes nearer to the origin of replication had substitution rates lower than genes closer to the replication terminus. The recently completed sequences of numerous bacterial genomes have allowed us to test whether this effect of distance from the replication origin on substitution rates, as observed for the E. coli-S. typhimurium comparison, is a general feature of bacterial genomes. Extending the analysis to all 3,000 E. coli-S. typhimurium homologs confirmed the significant association between chromosomal position and synonymous site divergence. However, the effect, though still significant, is not as dramatic as originally thought. A similar association between relative chromosomal location and synonymous substitution rate was detected in the majority of other bacterial species comparisons within alpha- and gamma- Proteobacteria, and Firmicutes but was absent in Chlamydiales. The opposite trend, i.e., a decrease in synonymous divergence with distance from the replication origin, was detected in Mycobacteria. Analysis of the patterns of nucleotide substitutions revealed that the distance effect is not affected by gene orientation and is mainly caused by an increase in rates of transversions, suggesting that this effect may not be caused by recombinational repair or biased gene conversion, as originally suggested.

Bacteria↗
PubMed2006

Selective constraint and genetic differentiation in geographically distant barley yellow dwarf virus populations.

Numerous studies have documented molecular variability in plant virus populations, but few have assessed the relative contribution of natural selection and genetic drift in generating the observed pattern of diversity. To this end, gene function, environment and phylogenetic history were examined to observe the effect on genetic diversity and population structure of the PAV and PAS species of Barley yellow dwarf virus (family Luteoviridae). Three functional classes of gene were analysed: transcription-related (RdRp), structural (CP) and movement-related (MP). The results indicate that there were no inherent differences, in terms of total diversity or diversity at synonymous or non-synonymous nucleotide sites, between functional classes of genes or populations. Rather, selective constraints on a gene may be more or less relaxed depending on its function and the phylogenetic history of the population sampled. The CP of the PAS species, but not the PAV species, was differentiated genetically between regions. This is probably due to genetic drift, as there was no evidence that any gene deviated from a neutral model of evolution or is under positive selection. In general, the MP was under considerably less functional constraint than structural or replication-related proteins and four positively selected codon sites were identified. Mutations at these sites differentiate species and geographical subpopulations, so presumably they have aided the virus in adaptation to its host environment and contributed to intra- and interspecies diversification.

Biological Evolution↗
PubMed2000

Comparative genomics of mitochondrial DNA in members of the Drosophila melanogaster subgroup.

In this study, a comparative genomics approach is employed to investigate the forces that shape evolutionary change in the mitochondrial DNA (mtDNA) of members of the Drosophila melanogaster subgroup. This approach facilitates differentiation of the patterns of variation resulting from processes acting at a higher level from those acting on a single gene. The mitochondrial genomes of three isofemale lines of D. simulans (siI, -II, and -III), two of D. melanogaster (Oregon R and a line from Zimbabwe), and D. mauritiana (maI and -II), and one of D. sechellia were sequenced and compared with that derived from D. yakuba. Data presented here indicate that at least three broad mechanisms shape the evolutionary dynamics of mtDNA in these taxa. The first set of mechanisms is intrinsic to the molecule. Dominant processes may be interpreted as selection for an increased rate of replication of the mtDNA molecule, biases in DNA repair, and differences in the pattern of nucleotide substitution among strands. In the genes encoded on the major strand (62% of the coding DNA) changes to or from C predominate, whereas on the minor changes to or from G predominate. The second set of mechanisms affects distinct lineages. There are evolutionary rate differences among lineages, possibly owing to population demographic changes or changes in mutational biases. This is supported by the heterogeneity found in synonymous, nonsynonymous, and silent substitutions. The third set of mechanisms differentially affects distinct genes. A maximum-likelihood sliding-window analysis detected four disjunct regions that have a significantly different nucleotide substitution process from that derived from the complete sequence. These data show the potential for comparative genomics to tease apart subtle forces that shape the evolution of DNA.

Animals↗
PubMed1995

Heterogeneity in Li-Fraumeni families: p53 mutation analysis and immunohistochemical staining.

We have screened two families for constitutional TP53 mutations, one family with Li-Fraumeni syndrome and the other with features of this syndrome. We report a germline mutation in exon 7 of the TP53 gene in the family with "Li-Fraumeni-like" syndrome. The mutation occurred at codon 245 and causes a Gly-Ser amino acid change. It was inherited by both affected and unaffected subjects. Malignant tumours from all members of this family showed strong positive nuclear immunohistochemical staining with antibodies CM-1 and DO1, directed against TP53. In contrast, no constitutional TP53 mutations were found in a "classic" Li-Fraumeni family. In this family positive staining was seen in both malignant and normal tissues. These results support previous findings that variants of the Li-Fraumeni syndrome exist since not all LFS families carry TP53 germline mutations. Secondly, immunohistochemical positivity is not synonymous with an underlying mutation and is therefore inadequate as an exclusive diagnostic marker.

Adolescent↗
PubMed2000

Detection of signature sequences in overlapping genes and prediction of a novel overlapping gene in hepatitis G virus.

In viruses an increased coding ability is provided by overlapping genes, in which two alternative open reading frames (ORFs) may be translated to yield two distinct proteins. The identification of signature sequences in overlapping genes is a topic of particular interest, since additional out-of-frame coding regions can be nested within known genes. In this work, a novel feature peculiar to overlapping coding regions is presented. It was detected by analysis of a sample set of 21 virus genomic sequences and consisted in the repeated occurrence of a cluster of basic amino acid residues, encoded by a frame, combined to a stretch of acidic residues, encoded by the corresponding overlapping frame. A computer scan of an additional set of virus sequences demonstrated that this feature is common to several other known overlapping ORFs and led to prediction of a novel overlapping gene in hepatitis G virus (HGV). The occurrence of a bifunctional coding region in HGV was also supported by its extremely lower rate of synonymous nucleotide substitutions compared to that observed in the other gene regions of the HGV genome. Analysis of the amino acid sequence that was deduced from the putative overlapping gene revealed a high content of basic residues and the presence of a nuclear targeting signal; these characteristics suggest that a core-like protein may be expressed by this novel ORF.

Algorithms↗
PubMed1999

Physicochemical optimization in the genetic code origin as the number of codified amino acids increases.

We have assumed that the coevolution theory of genetic code origin (Wong JT, Proc Natl Acad Sci USA 72:1909-1912, 1975) is essentially correct. This theory makes it possible to identify at least 10 evolutionary stages through which genetic code organization might have passed prior to reaching its current form. The calculation of the minimization level of all these evolutionary stages leads to the following conclusions. (1) The minimization percentages increased linearly with the number of amino acids codified in the codes of the various evolutionary stages when only the sense changes are considered in the analysis. This seems to favor the physicochemical theory of genetic code origin even if, as discussed in the paper, this observation is also compatible with the coevolution theory. (2) For the first seven evolutionary stages of the genetic code, this trend is less clear and indeed is inverted when we consider the global optimisation of the codes due to both sense changes and synonymous changes. This inverse correlation between minimization percentages and the number of amino acids codified in the codes of the intermediate stages seems to favor neither the physicochemical nor the stereochemical theories of genetic code origin, as it is in the early and intermediate stages of code development that these theories would expect minimization to have played a crucial role, and this does not seem to be the case. However, these results are in agreement with the coevolution theory, which attributes a role to the physicochemical properties of amino acids that, while important, is nevertheless subordinate to the mechanism which concedes codons from the precursor amino acids to the product amino acids as the primary factor determining the evolutionary structuring of the genetic code. The results are therefore discussed in the context of the various theories proposed to explain genetic code origin.

Algorithms↗
PubMed2001

Molecular evolution of transferrin: evidence for positive selection in salmonids.

Transferrins are iron-binding proteins that are involved in iron storage and resistance to bacterial disease. Previous work has shown that nonsynonymous-to-synonymous-site substitution ratios (d(n)/d(s) ratios) between transferrin genes from some salmonid species were significantly greater than 1.0, providing evidence for positive selection at the transferrin gene. The purpose of the current study was to put these earlier results in a broader evolutionary context by examining variation among 25 previously published transferrin sequences from fish, amphibians, and mammals. The results of the study show that evidence for positive selection at transferrin is limited to salmonids-d(n)/d(s) ratios estimated for nonsalmonid lineages were generally less than 1.0. Within the salmonids, approximately 13% of the transferrin codon sites are estimated to be subject to positive selection, with an estimated d(n)/d(s) ratio of approximately 7. The three- dimensional locations of some of the selected sites were inferred by comparing these sites to homologous sites in the bovine lactoferrin crystallographic structure. The selected sites generally fall on the outside of the molecule, within and near areas that are bound by transferrin-binding proteins from human pathogenic bacteria. The physical locations of sites estimated to be subject to positive selection support previous speculation that competition for iron from pathogenic bacteria could be the source of positive selection.

Amino Acid Substitution↗
PubMed2006

Selection on protein-coding genes of natural cyanobacterial populations.

We examined the distribution of synonymous and non-synonymous changes in 12 protein-coding genes of natural populations of cyanobacteria to infer changes in gene functionality. By comparing mutation distributions within and across species using the McDonald-Kreitman test, we found data sets to contain evidence for purifying selection (hetR of Trichodesmium, nifH of Cylindrospermopsis raceborskii and rpoC1 of Anabaena lemmermannii) and positive selection (kaiC of Microcoleus chthonoplastes and rbcX of Anabaena and Aphanizomenon sp.). Other genes from the same set of clonal isolates (petB and rbcL in M. chthonoplastes and Anabaena/Aphanizomenon, respectively) did not harbour evidence for either form of selection. The results of branch models of codon evolution agreed fully with the results of the McDonald-Kreitman test in terms of significance and absolute value of the dN/dS estimates. The high frequency of gene-specific mutation patterns and their association with branches that separate closely related cyanobacterial genera suggest that evolutionary tests are suited to uncover gene-specific selective differentiation in cyanobacterial genomes. At the same time, given the lack of information about the history of cyanobacteria, analysis of larger numbers of protein-coding genes of clonal cyanobacterial isolates will produce more detailed pictures of the effects of natural selection.

Bacterial Proteins↗
PubMed2006

Strong regional heterogeneity in base composition evolution on the Drosophila X chromosome.

Fluctuations in base composition appear to be prevalent in Drosophila and mammal genome evolution, but their timescale, genomic breadth, and causes remain obscure. Here, we study base composition evolution within the X chromosomes of Drosophila melanogaster and five of its close relatives. Substitutions were inferred on six extant and two ancestral lineages for 14 near-telomeric and 9 nontelomeric genes. GC content evolution is highly variable both within the genome and within the phylogenetic tree. In the lineages leading to D. yakuba and D. orena, GC content at silent sites has increased rapidly near telomeres, but has decreased in more proximal (nontelomeric) regions. D. orena shows a 17-fold excess of GC-increasing vs. AT-increasing synonymous changes within a small (approximately 130-kb) region close to the telomeric end. Base composition changes within introns are consistent with changes in mutation patterns, but stronger GC elevation at synonymous sites suggests contributions of natural selection or biased gene conversion. The Drosophila yakuba lineage shows a less extreme elevation of GC content distributed over a wider genetic region (approximately 1.2 Mb). A lack of change in GC content for most introns within this region suggests a role of natural selection in localized base composition fluctuations.

Animals↗
PubMed1989

Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection.

To study the mechanism of maintenance of polymorphism at major histocompatibility complex (MHC) loci, synonymous and nonsynonymous (amino acid-altering) nucleotide substitutions in the putative antigen-recognition site (included in the first domain of the MHC molecule) and other regions of human and mouse class II genes were examined. In the putative antigen-recognition site, the rate of nonsynonymous substitution was found to exceed that of synonymous substitution, whereas in the second domain the former was significantly lower than the latter. In light of a previous theoretical study and parallel findings in class I MHC loci, we conclude that the unusually high degree of polymorphism at class II MHC loci is caused mainly by overdominant selection (heterozygote advantage) operating in the antigen-recognition site.

Alleles↗
PubMed1998

Preponderance of slightly deleterious polymorphism in mitochondrial DNA: nonsynonymous/synonymous rate ratio is much higher within species than between species.

We estimated synonymous (dN) and nonsynonymous (dS) substitution rates for protein-coding genes of the mitochondrial genome from two individuals each of the species human, chimpanzee, and gorilla. The genes were analyzed both separately and in a combined data set. Pairwise sequence comparisons suggest that the dN/dS rate ratios are about 5-10 times higher in within-species comparisons than in between-species comparisons. This result is confirmed by a more rigorous likelihood ratio test, which rejected the null hypothesis that the dN/dS rate ratios are identical within and between species. The likelihood models account for the genetic code structure, transition/transversion rate ratio, and codon usage bias and are expected to produce more reliable results than the commonly used contingency test. Separate analyses of different genes show that the dN/dS rate ratios are higher within species than between species for all 13 mitochondrial genes, with the difference being statistically significant for all except three small or slowly evolving genes. Furthermore, in conserved genes, nonsynonymous rates within species tend to be higher than the between-species rates by a greater proportion than in fast-changing genes. Our findings confirm and extend earlier results obtained from smaller data sets and suggest the operation of slightly deleterious mutations throughout the mitochondrial genome in the hominoids. Implications of the results for evolutionary studies and, in particular, for studies of the origin of modern humans, are discussed.

Adenosine Triphosphatases↗
PubMed1996

The sequence and structure of the meadow grasshopper (Chorthippus parallelus) mitochondrial srRNA, ND2, COI, COII ATPase8 and 9 tRNA genes.

The nucleotide sequence of the mitochondrial ND2, COI, COII, ATPase8, srRNA and nine tRNA genes have been sequenced from two individual of the meadow grasshopper Chorthippus parallelus. Comparisons are made to other insects for which the same regions are completely sequenced. Percentage A + T is found to be relatively low in C. parallelus though consistent with that of the other Orthopteran, Locusta migratoria. The relative number of substitutions observed in the different protein-coding genes was analysed between pairs of insect species sharing different levels of relatedness. A clear change in this rate was observed between the within-genus and between-genera comparisons. This change is interpreted in terms of the functional constraints acting on these four different genes. The patterns seem to result from an early saturation of COI and COII genes with synonymous substitutions, and a tolerance of ND2 and ATPase8 function to high levels of amino acid replacements. This analysis highlights a need for further sequence studies and comparisons between taxa of different levels of divergence in order to understand the patterns of mtDNA evolution on which many evolutionary investigations are based.

Adenosine Triphosphatases↗
PubMed2006

Identification of variations in the human phosphoinositide 3-kinase p110delta gene in children with primary B-cell immunodeficiency of unknown aetiology.

Our recent study demonstrated that defects in p110delta result in B-cell immunodeficiency that is very similar to that observed in BTK-deficient mice. We revealed that the p110delta fit the B-cell signal transduction complex and played a non-redundant role in the development and function of B cells. In humans, most children with primary B-cell immunodeficiency have mutations in the BTK, whereas a few have defects in the components of the B-cell signal transduction complex. But little is known about the genetic variation of p110delta in children with defects in B-cell immunodeficiency of unknown aetiology. Sixteen patients from 15 unrelated families and 112 normal controls underwent sequence analysis to identify genetic variations of the p110delta. Allele frequency in each group was also analysed and compared. We identified five single base-pair polymorphic nucleotide exchanges in both patient and control groups with similar allele frequencies, which did not contribute to the immunodeficiency. Three of them are novel (m.953A>G, m.1200C>T and m.1561A>G), and the m.953A>G and m.1561A>G nucleotide exchanges are non-synonymous (N253S and T456A, respectively). The novel m.1561A>G was in complete linkage disequilibrium with the known m.873A>G in our study of Taiwanese group. In addition, one novel single base-pair missense mutation, m.3256G>A (E1021K), was identified in one boy with typical clinical features of primary B-cell immunodeficiency and could not be found in either his family or the normal control population. By atomic structural analysis of the amino acid as well as the alignment comparison between species, it resulted in the replacement of the negative-charged amino acid E with the positive-charged amino acid K at codon 1021, located in the highly conservative and important catalytic functional domain. Our findings could shed light on further understanding the polymorphisms of p110delta in B-cell immunodeficiency and different populations. Moreover, the 3256G>A missense mutation raised the attention and warranted further extensive analysis to elucidate the role of p110delta in human immunodeficiency.

Amino Acid Sequence↗
PubMed2005

The chloroplast genome of Phalaenopsis aphrodite (Orchidaceae): comparative analysis of evolutionary rate with that of grasses and its phylogenetic implications.

Whether the Amborella/Amborella-Nymphaeales or the grass lineage diverged first within the angiosperms has recently been debated. Central to this issue has been focused on the artifacts that might result from sampling only grasses within the monocots. We therefore sequenced the entire chloroplast genome (cpDNA) of Phalaenopsis aphrodite, Taiwan moth orchid. The cpDNA is a circular molecule of 148,964 bp with a comparatively short single-copy region (11,543 bp) due to the unusual loss and truncation/scattered deletion of certain ndh subunits. An open reading frame, orf91, located in the complementary strand of the rrn23 was reported for the first time. A comparison of nucleotide substitutions between P. aphrodite and the grasses indicates that only the plastid expression genes have a strong positive correlation between nonsynonymous (Ka) and synonymous (Ks) substitutions per site, providing evidence for a generation time effect, mainly across these genes. Among the intron-containing protein-coding genes of the sampled monocots, the Ks of the genes are significantly correlated to transitional substitutions of their introns. We compiled a concatenated 61 protein-coding gene alignment for the available 20 cpDNAs of vascular plants and analyzed the data set using Bayesian inference, maximum parsimony, and neighbor-joining (NJ) methods. The analyses yielded robust support for the Amborella/Amborella-Nymphaeales-basal hypothesis and for the orchid and grasses together being a monophyletic group nested within the remaining angiosperms. However, the NJ analysis using Ka, the first two codon positions, or amino acid sequences, respectively, supports the monocots-basal hypothesis. We demonstrated that these conflicting angiosperm phylogenies are most probably linked to the transitional sites at all codon positions, especially at the third one where the strong base-composition bias and saturation effect take place.

DNA, Chloroplast↗
PubMed2003

Relative rates of nucleotide substitution in frogs.

Accurate estimation of relative mutation rates of mitochondrial DNA (mtDNA) and single-copy nuclear DNA (scnDNA) within lineages contributes to a general understanding of molecular evolutionary processes and facilitates making demographic inferences from population genetic data. The rate of divergence at synonymous sites ( K(s)) may be used as a surrogate for mutation rate. Such data are available for few organisms and no amphibians. Relative to mammals and birds, amphibian mtDNA is thought to evolve slowly, and the K(s) ratio of mtDNA to scnDNA would be expected to be low as well. Relative K(s) was estimated from a mitochondrial gene, ND2, and a nuclear gene, c-myc, using both "approximate" and likelihood methods. Three lineages of congeneric frogs were studied and this ratio was found to be approximately 16, the highest of previously reported ratios. No evidence of a low K(s) in the nuclear gene was found: c-myc codon usage was not biased, the K(s) was double the intron divergence rate, and the absolute K(s) was similar to estimates obtained here for other genes from other frog species. A high K(s) in mitochondrial vs. nuclear genes was unexpected in light of previous reports of a slow rate of mtDNA evolution in amphibians. These results highlight the need for further investigation of the effects of life history on mutation rates.

Animals↗
PubMed1998

High sequence similarity within ras exons 1 and 2 in different mammalian species and phylogenetic divergence of the ras gene family.

We have determined the canine and feline N-, K-, and H-ras gene sequences from position +23 to +270 covering exons I and II which contain the mutational hot spot codons 12, 13, and 61. The results were used to assess the degree of similarity between ras gene DNA regions containing the critical domains affected in neoplastic disorders in different mammalian species. The comparative analyses performed included human, canine, feline, murine, rattine, and, whenever possible, bovine, leporine (rabbit), porcelline (guinea pig), and mesocricetine (hamster) ras gene sequences within the region of interest. Comparison of feline and canine nucleotide sequences with the corresponding regions in human DNA revealed a sequence similarity greater than 85% to the human sequence. Contemporaneous analysis of previously published ras DNA sequences from other mammalian species showed a similar degree of homology to human DNA. Most nucleotide differences observed represented synonymous changes without effect on the amino acid sequence of the respective proteins. For assessment of the phylogenetic evolution of ras gene family, a maximum parsimony dendrogram based on multiple sequence alignment of the common region of exons I and II in the N-, K-, and H-ras genes was constructed. Interestingly, a higher substitution rate among the H-ras genes became apparent, indicating accelerated sequence evolution within this particular clade. The most parsimonious tree clearly shows that the duplications giving rise to the three ras genes must have occurred before the mammalian radiation.

Animals↗
PubMed2001

Genome organization of the linear cytoplasmic element pPE1B from Pichia etchellsii.

The linear cytoplasmic element pPE1B from Pichia etchellsii CBS2011 (synonym Debaryomyces etchellsii) was totally sequenced. It consists of 12835 bp and has a remarkable high A+T content of 77.3%. The termini of pPE1B were found to consist of inversely orientated identical nucleotide repetitions 161 base pairs long, to which proteins are probably covalently linked at the 5' ends. Ten putative genes (open reading frames, ORFs) were identified, covering 96.5% of the total sequence. The predicted polypeptides correspond to proteins encoded by ORFs 2-11 of the linear plasmids pGKL2 of Kluyveromyces lactis and pSKL of Saccharomyces kluyveri. ORF1, existing on both latter elements, is lacking on pPE1B. An upstream conserved sequence motif (UCS) is located at the expected distance from the start codon of each of the 10 ORFs. As the arbitrarily chosen UCS6 was able to drive expression of a reporter gene in the heterologous pGKL-encoded killer system of K. lactis, extranuclear promoter function is probable. The almost congruent genome organization of pPE1B and other autonomous linear yeast plasmids sequenced so far, i.e. pGKL2 and pSKL, suggests a common, presumably viral, ancestor.

Base Sequence↗