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PubMed2004

Rapid evolution of mammalian X-linked testis-expressed homeobox genes.

Homeobox genes encode transcription factors that function in various developmental processes and are usually evolutionarily conserved in their sequences. However, two X-chromosome-linked testis-expressed homeobox genes, one from rodents and the other from fruit flies, are known to evolve rapidly under positive Darwinian selection. Here we report yet another case, from primates. TGIFLX is an X-linked homeobox gene that originated by retroposition of the autosomal gene TGIF2, most likely in a common ancestor of rodents and primates. While TGIF2 is ubiquitously expressed, TGIFLX is exclusively expressed in adult testis. A comparison of the TGIFLX sequences among 16 anthropoid primates revealed a significantly higher rate of nonsynonymous nucleotide substitution (d(N)) than synonymous substitution (d(S)), strongly suggesting the action of positive selection. Although the high d(N)/d(S) ratio is most evident outside the homeobox, the homeobox has a d(N)/d(S) of approximately 0.89 and includes two codons that are likely under selection. Furthermore, the rate of radical amino acid substitutions that alter amino acid charge is significantly greater than that of conservative substitutions, suggesting that the selection promotes diversity of the protein charge profile. More interestingly, an analysis of 64 orthologous homeobox genes from humans and mice shows substantially higher rates of amino acid substitution in X-linked testis-expressed genes than in other genes. These results suggest a general pattern of rapid evolution of mammalian X-linked testis-expressed homeobox genes. Although the physiological function of and the exact selective agent on TGIFLX and other rapidly evolving homeobox genes are unclear, the common expression pattern of these transcription factor genes led us to conjecture that the selection is related to one or more aspects of male reproduction and may contribute to speciation.

Amino Acid Sequence↗
PubMed1998

Enhanced expression of the yeast Ure2 protein in Escherichia coli: the effect of synonymous codon substitutions at a selected place in the gene.

The expression of the yeast Ure2 protein and its two N- and C-terminal HA-(YPYPVDYA) epitope and His-tag fusions has been enhanced in E. coli by selected silent mutagenesis of the URE2 gene. The two Arg-AGA codons at positions 253 and 254 of the URE2 gene coding sequence were exchanged by CGT codons accordingly. This has allowed an increased yield (up to 100-fold) of the full-length protein synthesized. Western blotting with HA-epitope-specific antibodies using N- and C-terminal Ure2p-HA(epitope)-His-tag fusion constructs confirmed the integrity of the recombinant proteins. The N-(C-) terminal tagged proteins were shown to possess biological activity of the natural Ure2 protein.

Amino Acid Sequence↗
PubMed2001

Positively selected amino acid sites in the entire coding region of hepatitis C virus subtype 1b.

To predict the amino acid sites important for the clearance of hepatitis C virus (HCV) subtype 1b in vivo, positively selected amino acid sites were detected by analyzing the sequence data collected from the international DNA databank. The rate of nonsynonymous substitutions per nonsynonymous site was compared with that of synonymous substitutions per synonymous site for each codon site in the entire coding region. As a result, 13 out of 3010 amino acid sites were found to be positively selected. Among the 13 positively selected amino acid sites, eight were located in the structural proteins and five were in the nonstructural proteins. Moreover, eight were located in B-cell epitopes and two were in T-cell epitopes. These observations suggest that both the antibody and the cytotoxic T lymphocyte are involved in the clearance of HCV subtype 1b in vivo. These positively selected amino acid sites represent candidate vaccination targets for HCV subtype 1b.

Amino Acids↗
PubMed2000

[Different evolution rule of SRY gene between hominoid and Old World monkey].

The complete SRY gene of P. nemaeus and M. arctiodes were amplified by using PCR and sequenced. Combined with the same regions of other primate animals, sequence analysis confirmed the conservation of HMGbox. In molecular phylogenetic tree constructed, we made the Ka/Ks value pairwise comparison of HMGbox flanking sequences both intra- and inter- Hominoid and the Old World monkey. To our interest, the pairwise comparison of species in Hominoid suggested a higher Ka/Ks ratio than that in the Old World monkey or between the Old World monkey and marmoset, which showed existent of different pattern of evolution. In addition, in Hominoid Ka/Ks ratio for HMGbox sequences was obviously on the increase. The rate of nonsynonymous substitutions per nonsynonymous site is faster than that of synonymous substitutions per synonymous site in Hominoid (driven by positive directional selection). Our analysis suggested that it might be resulted from functional change of this gene and the system error or the close relationship among Hominoid species. It is also supposed that the positive selection was functioned at the beginning of the divergence of Hominoid species.

Animals↗
PubMed1995

Evolution of immunoglobulin VH pseudogenes in chickens.

In chickens, there is a single functional gene (VH1) coding for the heavy chain variable region of immunoglobulins, and immunoglobulin diversity is generated by gene conversion of the VH1 gene by many variable region pseudogenes (psi VH's) that exist on the 5' side of the VH1 gene. To understand the evolution of this unique genetic system, we conducted statistical analyses of VH1 and psi VH genes together with functional VH genes from other higher vertebrate species. The results indicate, first, that chicken VH genes are all closely related to one another and were derived relatively recently from an ancestral gene belonging to one of the three major groups of VH genes in higher vertebrates. Second, the rate of nonsynonymous substitution is slightly higher than that of synonymous substitution in the complementarity-determining regions (CDRs), which suggests that diversity-enhancing selection has operated in the CDRs even for pseudogenes. However, both the rates of synonymous and nonsynonymous substitution are higher in the CDRs than in the framework regions (FRs), apparently because of an interaction between positive selection and meiotic gene conversion in the CDRs. Third, a dot matrix analysis of the psi VH genes and genomic diversity (D) genes has indicated that the 3' end of psi VH genes is attached by D-gene-like sequences, and this region of psi VH genes has high similarity with D gene sequences. This suggests that V and D genes were fused at some point of evolutionary time and this fused element multiplied by gene duplication. Finally, two alternative hypotheses of explaining the evolution of the chicken VH gene system are presented.

Animals↗
PubMed2004

Novel single nucleotide polymorphisms and haplotypes within the bovine CXCR2 gene.

The objectives of this study were to identify single nucleotide polymorphisms (SNPs) and resulting haplotypes in the bovine CXCR2 gene. A 311-bp segment of the bovine CXCR2 gene was amplified and sequenced. Five SNPs at positions 612, 684, 777, 858, and 861 were expressed in both Holstein and Jersey dairy cattle. Four SNPs resulted in synonymous substitutions, while a non-synonymous switch at position 777 (G-->C) resulted in a glutamine to histidine substitution at amino acid residue 245. Strong linkage disequilibrium was exhibited for both breeds among all five loci (P<0.001). Both allele and genotype frequencies differed significantly with respect to breed at four of the five loci (P<0.001). The five polymorphisms generated ten distinct haplotypes. Six haplotypes were common between the two breeds, while Holsteins and Jerseys each uniquely expressed two haplotypes. Of the six common haplotypes, two represented 83% of the Jersey population; whereas four of these haplotypes represented 95% of the Holstein population.

Animals↗
PubMed2000

Primate DAX1, SRY, and SOX9: evolutionary stratification of sex-determination pathway.

The molecular evolution of DAX1, SRY, and SOX9, genes involved in mammalian sex determination, was examined in six primate species. DAX1 and SRY have been added to the X and Y chromosomes, respectively, during mammalian evolution, whereas SOX9 remains autosomal. We determined the genomic sequences of DAX1, SRY, and SOX9 in all six species, and calculated K(a), the number of nonsynonymous substitutions per nonsynonymous site, and compared this with the K(s), the number of synonymous substitutions per synonymous site. Phylogenetic trees were constructed by means of the DAX1, SRY, and SOX9 coding sequences, and phylogenetic analysis was performed using maximum likelihood. Overall measures of gene and protein similarity were closer for DAX1 and SOX9, but DAX1 exhibited nonsynonymous amino acid substitutions at an accelerated frequency relative to synonymous changes, similar to SRY and significantly higher than SOX9. We conclude that, at the protein level, DAX1 and SRY are under less selective pressure to remain conserved than SOX9, and, therefore, diverge more across species than does SOX9. These results are consistent with evolutionary stratification of the mammalian sex determination pathway, analogous to that for sex chromosomes.

Amino Acid Sequence↗
PubMed1995

A method for estimating the numbers of synonymous and nonsynonymous substitutions per site.

A method for estimating the numbers of synonymous (Ks) and nonsynonymous (Ka) substitutions per site is proposed. The method is based on the Li's (J. Mol. Evol. 36:96-99, 1993) and Pamilo and Bianchi's (Mol. Biol. Evol. 10:271-281, 1993) method, but a putative source of bias is solved. It is proposed that the number of synonymous substitutions that are actually transitions or transversions should be computed by separating the twofold degenerate sites into two types of sites, 2S-fold and 2V-fold, where only transitional and transversional substitutions are synonymous, respectively. Kimura's (J. Mol. Evol. 16:111-120, 1980) two-parameter correcting method for multiple substitutions at a site is then applied using the overall observed synonymous transversion frequency to estimate both the numbers of synonymous transversional (Bs) and transitional (As) substitutions per site. This approach, therefore, also minimizes stochastic errors. Computer simulations indicate that the method presented gives more accurate Ks and Ka estimates than the aforementioned methods. Furthermore, the obtention of confidence intervals for divergence estimates by computer simulation is proposed.

Animals↗
PubMed2002

Search for genes positively selected during primate evolution by 5'-end-sequence screening of cynomolgus monkey cDNAs.

It is possible to assess positive selection by using the ratio of K(a) (nonsynonymous substitutions per plausible nonsynonymous sites) to K(s) (synonymous substitutions per plausible synonymous sites). We have searched candidate genes positively selected during primate evolution by using 5'-end sequences of 21,302 clones derived from cynomolgus monkey (Macaca fascicularis) brain cDNA libraries. Among these candidates, 10 genes that had not been shown by previous studies to undergo positive selection exhibited a K(a)/K(s) ratio > 1. Of the 10 candidate genes we found, 5 were included in the mitochondrial respiratory enzyme complexes, suggesting that these nuclear-encoded genes coevolved with mitochondrial-encoded genes, which have high mutation rates. The products of other candidate genes consisted of a cell-surface protein, a member of the lipocalin family, a nuclear transcription factor, and hypothetical proteins.

Animals↗
PubMed2006

Evaluation of six methods for estimating synonymous and nonsynonymous substitution rates.

Methods for estimating synonymous and nonsynonymous substitution rates among protein-coding sequences adopt different mutation (substitution) models with subtle yet significant differences, which lead to different estimates of evolutionary information. Little attention has been devoted to the comparison of methods for obtaining reliable estimates since the amount of sequence variations within targeted datasets is always unpredictable. To our knowledge, there is little information available in literature about evaluation of these different methods. In this study, we compared six widely used methods and provided with evaluation results using simulated sequences. The results indicate that incorporating sequence features (such as transition/transversion bias and nucleotide/codon frequency bias) into methods could yield better performance. We recommend that conclusions related to or derived from Ka and Ks analyses should not be readily drawn only according to results from one method.

Codon↗
PubMed2007

A gene family of putative immune recognition molecules in the hydroid Hydractinia.

Animal taxa display a wide array of immune-type receptors that differ in their specificities, diversity, and mode of evolution. These molecules ensure effective recognition of potential pathogens for subsequent neutralization and clearance. We have characterized a family of putative immune recognition molecules in the colonial hydroid Hydractinia symbiolongicarpus. A complementary DNA fragment with high similarity to the sea urchin L: -rhamnose-binding lectin was isolated and used to screen 9.5 genome equivalents of a H. symbiolongicarpus bacterial artificial chromosome library. One of the resulting 19 positive clones was sequenced and revealed the presence of a 5,111-bp gene organized in 13 exons and 12 introns. The gene was predicted to encode a 726-amino acid secreted modular protein composed of a signal peptide, an anonymous serine-rich domain, eight thrombospondin type 1 repeats, and a L: -rhamnose-binding lectin domain. The molecule was thus termed Rhamnospondin (Rsp). Southern hybridization and sequence analyses indicated the presence of a second Rsp gene. The cDNA from both Rsp genes was sequenced in 18 individuals, revealing high levels of genetic polymorphism. Nucleotide substitutions were distributed throughout the molecule and showed a significantly higher number of synonymous substitutions per synonymous sites than its nonsynonymous counterparts. Whole-mount in situ hybridization and semi-quantitative reverse transcription polymerase chain reaction of microorganism-challenged colonies indicated that Rsp molecules were specifically and constitutively expressed in the hypostome of gastrozooids' mouth. Thus, the combination of (1) comparative analysis on domain composition and function, (2) polymorphism, and (3) expression patterns, suggest that Rsp genes encode a family of putative immune recognition receptors, which may act by binding microorganisms invading the colony through the polyp's mouth.

Amino Acid Sequence↗
PubMed2003

Invertebrate species with nonpelagic larvae have elevated levels of nonsynonymous substitutions and reduced nucleotide diversities.

Under a nearly neutral model in which most amino acid substitutions are slightly deleterious, variation in demography, population structure, and other ecological factors among closely related species can potentially modify the effective population size or the selective regime, leading to differences in the rate of nonsynonymous substitution. Ratios of nonsynonymous to synonymous substitutions (d(N)/d(S)) between species were analyzed in a sea star genus (Patiriella) and a molluscan genus (Littorina), each with diverse modes of reproduction, including multiple lineages with pelagic and nonpelagic larvae. In both genera, lineages with nonpelagic larvae had significantly higher d(N)/d(S) ratios than lineages with pelagic larvae. The hypothesis that the elevated d(N)/d(S) ratios in species with nonpelagic larvae was due to reduced effective population size was tested by comparing nucleotide diversities in three genera of gastropod mollusks (Littorina, Crepidula, and Hydrobia), each with several modes of reproduction. Overall, there was a significant (p < 0.05) reduction in nucleotide diversity in species with nonpelagic larvae compared to species with pelagic larvae.

Animals↗
PubMed2004

Mitochondrial DNA polymorphisms as risk factors for Parkinson's disease and Parkinson's disease dementia.

The activity of complex I of the mitochondrial respiratory chain has been found to be decreased in patients with Parkinson's disease (PD), but no mutations have been identified in genes encoding complex I subunits. Recent studies have suggested that polymorphisms in mitochondrial DNA (mtDNA)-encoded complex I genes (MTND) modify susceptibility to PD. We hypothesize that the risk of PD is conveyed by the total number of nonsynonymous substitutions in the MTND genes in various mtDNA lineages rather than by single mutations. To test this possibility, we determined the number of nonsynonymous substitutions of the seven MTND genes from 183 Finns. The differences in the total number of nonsynonymous substitutions and the nonsynonymous to synonymous substitution rate ratio ( K(a)/ K(s)) of MTND genes between the European mtDNA haplogroup clusters (HV, JT, KU, IWX) were analysed by using a statistical approach. Patients with PD ( n=238) underwent clinical examination together with mtDNA haplogroup analysis and the clinical features between patient groups defined by the number of nonsynonymous substitutions were compared. Our analysis revealed that the haplogroup clusters HV and KU had a lower average number of amino acid replacements and a lower K(a)/ K(s) ratio in the MTND genes than clusters JT and IWX. Supercluster JTIWX with the highest number of amino acid replacements was more frequent among PD patients and even more frequent among patients with PD who developed dementia. Our results suggest that a relative excess of nonsynonymous mutations in MTND genes in supercluster JTWIX is associated with an increased risk of PD and the disease progression to dementia.

Aged↗
PubMed2001

Contributions of genetic drift and negative selection on the evolution of three strains of wheat streak mosaic tritimovirus.

Genome sequences of three Wheat streak mosaic virus (WSMV) strains were compared. The Type and Sidney 81 strains of WSMV from the American Great Plains were closely related, with sequence identities of 97.6% (nucleotide) and 98.7% (amino acid). In contrast, the El Batán 3 strain from central Mexico was divergent, and shared only 79.2-79.3% (nucleotide) and 90.3-90.5% (amino acid) sequence identity with Type and Sidney 81. All three WSMV strains were serologically related, however the El Batán 3 capsid protein (CP) had 15 fewer amino acid residues. Phylogenetic analysis of the CP cistron indicated that Type, Sidney 81, and nine other American isolates of WSMV were closely related and distinct from the El Batán 3 sequence. Nucleotide substitutions among the WSMV strains were not randomly distributed across the genome with more variation within P1, HC-Pro, and CP, and less within P3. One 400-nucleotide region of the genome, corresponding to the 3'-end of P3, was strikingly deficient in silent substitutions. Nonetheless, the ratio of synonymous to non-synonymous substitutions throughout the genome was essentially the same for all three WSMV strains. Collectively, our data indicate that both genetic drift and negative selection have contributed to the evolution of WSMV strains.

Amino Acid Substitution↗
PubMed2004

Common pattern of evolution of gene expression level and protein sequence in Drosophila.

Sequence divergence scaled by variation within species has been used to infer the action of selection upon individual genes. Applying this approach to expression, we compared whole-genome whole-body RNA levels in 10 heterozygous Drosophila simulans genotypes and a pooled sample of 10 D. melanogaster lines using Affymetrix Genechip. For 972 genes expressed in D. melanogaster, the transcript level was below detection threshold in D. simulans, which may be explained either by sequence divergence between the primers on the chip and the mRNA transcripts or by down-regulation of these genes. Out of 6,707 genes that were expressed in both species, transcript level was significantly different between species for 534 genes (at P < 0.001). Genes whose expression is under stabilizing selection should exhibit reduced genetic variation within species and reduced divergence between species. Expression of genes under directional selection in D. simulans should be highly divergent from D. melanogaster, while showing low genetic variation in D. simulans. Finally, the genes with large variation within species but modest divergence between species are candidates for balancing selection. Rapidly diverging, low-polymorphism genes included those involved in reproduction (e.g., Mst 3Ba, 98Cb; Acps 26Aa, 63F; and sperm-specific dynein). Genes with high variation in transcript abundance within species included metallothionein and hairless, both hypothesized to be segregating in nature because of gene-by-environment interactions. Further, we compared expression divergence and DNA substitution rate in 195 genes. Synonymous substitution rate and expression divergences were uncorrelated, whereas there was a significant positive correlation between nonsynonymous substitution rate and expression divergence. We hypothesize that as a substantial fraction of nonsynonymous divergence has been shown to be adaptive, much of the observed expression divergence is likewise adaptive.

Amino Acid Sequence↗
PubMed1999

Molecular evolution of the COX7A gene family in primates.

COX VIIa is one of 10 nuclear-encoded subunits of the COX holoenzyme, and one of three that have isoforms with tissue-specific differences in expression. Analysis of nucleotide substitution rates revealed an accelerated rate of nonsynonymous substitutions relative to that of synonymous substitutions for the heart isoform gene (COX7AH) in six primate lineages. Rate accelerations have been noted for four other COX-related genes in this time period, suggesting that the COX holoenzyme has experienced an episode of adaptive evolution. A third member of the gene family, COX7AR, has recently been described. Although its function is currently unknown, low nonsynonymous substitution/synonymous substitution (N/S) ratios in mammalian evolution suggest that COX7AR is of functional importance. When the COX7A isoforms were divided into domains, examination of nucleotide substitution rates suggested that mitochondrial targeting residues experienced an accelerated nonsynonymous substitution rate in the period following gene duplication. In contrast, paralogous comparisons of the targeting residues of each isoform show they have been relatively conserved in mammalian evolution. This pattern is consistent with the evolution of tissue-specific function.

Amino Acid Sequence↗
PubMed2005

A novel maternal lineage revealed in sheep (Ovis aries).

It is generally believed that domestic sheep have two maternal lineages (haplotypes A and B), based on mitochondrial DNA analysis. In the present study, we provide evidence that a novel maternal lineage (haplotype C) is exhibited in Chinese native sheep. To verify this finding, 231 samples were collected from six Chinese local breeds, which cover the vast geographical region of sheep inhabitation in China. For comparison, 50 samples were collected from two Western breeds collected in China. Mitochondrial DNA was screened by PCR single-strand conformational polymorphism (SSCP), leading to the identification of novel band patterns in ND2 and ND4 genes in the Chinese breeds. Interestingly, mutations at the two loci were in strong linkage disequilibrium. Direct sequencing of the DNA fragments revealed a non-synonymous substitution in ND2. Furthermore, two synonymous mutations were identified by comparisons of the novel type (haplotype C) and the established types (haplotypes A and B). The entire mitochondrial control region for 55 samples was then sequenced to construct a phylogenetic tree and median joining network. Both the tree and network demonstrated a topology of three groups, which is in consistent with the SSCP analysis. Unlike Western breeds, Chinese breeds are composed mainly of haplotypes A and B, but with a small fraction of haplotype C. According to Fu's test and mismatch distribution, haplotype C has not been subject to a recent population expansion. Based on these results, we propose a novel origin for Chinese sheep.

Animals↗
PubMed2006

Comment on "Large-scale sequence analysis of avian influenza isolates".

Obenauer et al. (Research Articles, 17 March 2006, p. 1576) reported that the influenza A virus PB1-F2 gene is evolving under strong positive selection, as documented by an extremely high ratio of the number of nonsynonymous nucleotide substitutions to the number of synonymous substitutions (dN/dS). However, we show that this observation is likely to be an artifact related to the location of PB1-F2 in the +1 reading frame of the PB1 gene.

Animals↗