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PubMed2006

Long intervals of stasis punctuated by bursts of positive selection in the seasonal evolution of influenza A virus.

BACKGROUND: The interpandemic evolution of the influenza A virus hemagglutinin (HA) protein is commonly considered a paragon of rapid evolutionary change under positive selection in which amino acid replacements are fixed by virtue of their effect on antigenicity, enabling the virus to evade immune surveillance. RESULTS: We performed phylogenetic analyses of the recently obtained large and relatively unbiased samples of the HA sequences from 1995-2005 isolates of the H3N2 and H1N1 subtypes of influenza A virus. Unexpectedly, it was found that the evolution of H3N2 HA includes long intervals of generally neutral sequence evolution without apparent substantial antigenic change ("stasis" periods) that are characterized by an excess of synonymous over nonsynonymous substitutions per site, lack of association of amino acid replacements with epitope regions, and slow extinction of coexisting virus lineages. These long periods of stasis are punctuated by shorter intervals of rapid evolution under positive selection during which new dominant lineages quickly displace previously coexisting ones. The preponderance of positive selection during intervals of rapid evolution is supported by the dramatic excess of amino acid replacements in the epitope regions of HA compared to replacements in the rest of the HA molecule. In contrast, the stasis intervals showed a much more uniform distribution of replacements over the HA molecule, with a statistically significant difference in the rate of synonymous over nonsynonymous substitution in the epitope regions between the two modes of evolution. A number of parallel amino acid replacements - the same amino acid substitution occurring independently in different lineages - were also detected in H3N2 HA. These parallel mutations were, largely, associated with periods of rapid fitness change, indicating that there are major limitations on evolutionary pathways during antigenic change. The finding that stasis is the prevailing modality of H3N2 evolution suggests that antigenic changes that lead to an increase in fitness typically result from epistatic interactions between several amino acid substitutions in the HA and, perhaps, other viral proteins. The strains that become dominant due to increased fitness emerge from low frequency strains thanks to the last amino acid replacement that completes the set of replacements required to produce a significant antigenic change; no subset of substitutions results in a biologically significant antigenic change and corresponding fitness increase. In contrast to H3N2, no clear intervals of evolution under positive selection were detected for the H1N1 HA during the same time span. Thus, the ascendancy of H1N1 in some seasons is, most likely, caused by the drop in the relative fitness of the previously prevailing H3N2 lineages as the fraction of susceptible hosts decreases during the stasis intervals. CONCLUSION: We show that the common view of the evolution of influenza virus as a rapid, positive selection-driven process is, at best, incomplete. Rather, the interpandemic evolution of influenza appears to consist of extended intervals of stasis, which are characterized by neutral sequence evolution, punctuated by shorter intervals of rapid fitness increase when evolutionary change is driven by positive selection. These observations have implications for influenza surveillance and vaccine formulation; in particular, the possibility exists that parallel amino acid replacements could serve as a predictor of new dominant strains. REVIEWERS: Ron Fouchier (nominated by Andrey Rzhetsky), David Krakauer, Christopher Lee.

Journal Article↗
PubMed2005

[Molecular genetic analysis for the A3 alleles].

To study four A(3) subgroup samples identified by serologic tests, among which two belong to a family, three were A(3) subgroup, one was A(3)B subgroup. All four samples were genotyped by PCR-SSP method, and the nucleotide sequences of Exon 6, Exon 7 and part introns at the ABO locus for these samples were detected by ABI Prism 3100 DNA sequencer. Comparison with the consensus of A101 was performed. The results showed that haplotypes of two A(3) subgroups were common A102 allele and O1-2 allele, and haplotypes of one A(3) subgroup were common A102 allele and rare O(1v)-4 allele. Unexpectedly, a synonymous substitution 838C-->T had been found in A allele of the A(3)B subgroup sample, which predict a Leu280Phe alteration. The results suggested that molecular genetic background of the A(3) phenotypes is polymorphic. Possibly, the missense mutation 838C-->T is the molecular genetic basis of A(3)B subgroup that lead to low activity of the glycosyltransferases.

ABO Blood-Group System↗
PubMed2005

Population structure within lineages of Wheat streak mosaic virus derived from a common founding event exhibits stochastic variation inconsistent with the deterministic quasi-species model.

Structure of Wheat streak mosaic virus (WSMV) populations derived from a common founding event and subjected to serial passage at high multiplicity of infection (MOI) was evaluated. The founding population was generated by limiting dilution inoculation. Lineages of known pedigree were sampled at passage 9 (two populations) and at passage 15, with (three populations) or without mixing (four populations) of lineages at passage 10. Polymorphism within each population was assessed by sequencing 17-21 clones containing a 1371 nt region (WSMV-Sidney 81 nts 8001-9371) encompassing the entire coat protein cistron and flanking regions. Mutation frequency averaged approximately 5.0 x 10(-4)/nt across all populations and ranged from 2.4 to 11.6 x 10(-4)/nt within populations, but did not consistently increase or decrease with the number of passages removed from the founding population. Shared substitutions (19 nonsynonymous, 10 synonymous, and 3 noncoding) occurred at 32 sites among 44 haplotypes. Only four substitutions became fixed (frequency = 100%) within a population and nearly one third (10/32) never achieved a frequency of 10% or greater in any sampled population. Shared substitutions were randomly distributed with respect to genome position, with transitions outnumbering transversions 5.4:1 and a clear bias for A to G and U to C substitutions. Haplotype composition of each population was unique with complexity of each population varying unpredictably, in that the number and frequency of haplotypes within a lineage were not correlated with number of passages removed from the founding population or whether the population was derived from a single or mixed lineage. The simplest explanation is that plant virus lineages, even those propagated at high MOI, are subject to frequent, narrow genetic bottlenecks during systemic movement that result in low effective population size and stochastic changes in population structure upon serial passage.

Base Sequence↗
PubMed2001

Elevated rates of nonsynonymous substitution in island birds.

Slightly deleterious mutations are expected to fix at relatively higher rates in small populations than in large populations. Support for this prediction of the nearly-neutral theory of molecular evolution comes from many cases in which lineages inferred to differ in long-term average population size have different rates of nonsynonymous substitution. However, in most of these cases, the lineages differ in many other ways as well, leaving open the possibility that some factor other than population size might have caused the difference in substitution rates. We compared synonymous and nonsynonymous substitutions in the mitochondrial cyt b and ND2 genes of nine closely related island and mainland lineages of ducks and doves. We assumed that island taxa had smaller average population sizes than those of their mainland sister taxa for most of the time since they were established. In all nine cases, more nonsynonymous substitutions occurred on the island branch, but synonymous substitutions showed no significant bias. As in previous comparisons of this kind, the lineages with smaller populations might differ in other respects that tend to increase rates of nonsynonymous substitution, but here such differences are expected to be slight owing to the relatively recent origins of the island taxa. An examination of changes to apparently "preferred" and "unpreferred" synonymous codons revealed no consistent difference between island and mainland lineages.

Amino Acid Sequence↗
PubMed1999

Codon bias and mutability in HIV sequences.

A survey of the patterns of synonymous codon preference in the HIV env gene reveals a correlation between the codon bias and the mutability requirements of different regions of the protein. At hypervariable regions in gp120 one finds a greater proportion of codons that tend to mutate nonsynonymously, but to a target that is similar in hydrophobicity and volume. We argue that this strategy results from a compromise between the selective pressure placed on the virus by the induced immune response, which favors amino acid substitutions in the complementarity determining regions, and the negative selection against missense mutations that violate structural constraints of the env protein.

Codon↗
PubMed2006

The single nucleotide polymorphisms of I(Ks) potassium channel genes and their association with atrial fibrillation in a Chinese population.

Recent studies suggest that genetic mutation of the slow delayed rectifier potassium channel (I(Ks)) may underlie atrial fibrillation (AF). We investigated the association between AF and the single nucleotide polymorphisms (SNPs) of genes KCNQ1, KCNE1 and KCNE4 associated with this channel. Common non-synonymous SNPs in KCNQ1 and KCNE1 known to be frequent in Asian people were selected and direct sequencing of KCNE4 was performed to identify possible SNPs. The AF group consisted of 142 hospitalized patients with AF, the community control group consisted of 120 subjects, and a ward control group consisted of 118 hospitalized patients without AF. Restriction fragment length polymorphism analysis was performed to determine the genotypes. The minor allele frequencies of P448R, R519H, G643S for KCNQ1 and G38S and D85N for KCNE1 in the AF group, the community control group and the ward control group were 9.9, 7.9, 9.3%; 0, 0, -; 4.3, 4.2, 1.7%; 28.4, 31.7, 29.7%; 0.7, 0.4%, -, respectively. There was no significant association between these SNPs and AF phenotype. There were eight SNPs in the whole length of KCNE4 plus 1,000 bases upstream of this gene including the non-synonymous SNP E145D. Logistical regression analysis revealed a difference in the distribution of KCNE4 E145D in the AF and the community control group (minor allele frequency was 34.0 versus 27.1% respectively, OR = 1.66, p = 0.044). We provided the frequencies of non-synonymous SNPs of KCNQ1 and KCNE1 in Chinese population; none of these SNPs was associated with AF. But KCNE4 E145D may be associated with the AF phenotype.

Aged↗
PubMed2001

Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia.

Disturbances in glutamate function have been implicated in the pathophysiology of schizophrenia. We searched for mutations in the exons of the metabotropic glutamate receptor mGluR4 (GRM4) gene on human chromosome 6p21.3 and evaluated associations between these polymorphisms with schizophrenia in Japanese patients. Nine nuclear variants of 450G > T, 1455T > C, 2202A > G, 2389G > A (Val797 > Ile797), 2890A > G, 3601C > T, 3639C > T, IVS4-36G > A, and IVS5 + 29(CCGGG)1-2, were found. The Val797Ile variant, although found in both the patient and control groups, was rare and the only variant that causes a non-synonymous amino acid change. There was no statistically significant association between any mGluR4 gene polymorphism and schizophrenia. Thus, this study did not provide evidence for the contribution of the mGluR4 gene to schizophrenia in the Japanese.

Adult↗
PubMed2003

Mutation screening of the Homer gene family and association analysis in schizophrenia.

Homer proteins are a group of proteins that regulate group 1 metabotropic glutamate receptor function. As altered glutamate function has been implicated in many neuro psychiatric disorders, particularly schizophrenia, we have screened all three known Homer genes for sequence variation for use under the candidate gene association paradigm. We found seven SNPs, including three in exons. Of these, none was non-synonymous. Allele frequencies of all the detected SNPs were estimated in DNA pools of 368 schizophrenics and 368 controls. Only one (Homer 1 IVS4 + 18A > G) was associated with schizophrenia in this sample, a finding confirmed by individual genotyping (P = 0.01). However, in our extended sample of 680 cases and 671 controls, the evidence for association diminished (P = 0.05). Our results suggest it is unlikely that sequence variants in the Homer genes contribute to the aetiology of schizophrenia, but the variants we identified are plausible candidates for other neuropsychiatric phenotypes.

Adult↗
PubMed1980

A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences.

Some simple formulae were obtained which enable us to estimate evolutionary distances in terms of the number of nucleotide substitutions (and, also, the evolutionary rates when the divergence times are known). In comparing a pair of nucleotide sequences, we distinguish two types of differences; if homologous sites are occupied by different nucleotide bases but both are purines or both pyrimidines, the difference is called type I (or "transition" type), while, if one of the two is a purine and the other is a pyrimidine, the difference is called type II (or "transversion" type). Letting P and Q be respectively the fractions of nucleotide sites showing type I and type II differences between two sequences compared, then the evolutionary distance per site is K = -(1/2) ln [(1-2P-Q) square root of 1-2Q]. The evolutionary rate per year is then given by k = K/(2T), where T is the time since the divergence of the two sequences. If only the third codon positions are compared, the synonymous component of the evolutionary base substitutions per site is estimated by K'S = -(1/2) ln (1-2P-Q). Also, formulae for standard errors were obtained. Some examples were worked out using reported globin sequences to show that synonymous substitutions occur at much higher rates than amino acid-altering substitutions in evolution.

Animals↗
PubMed1994

Molecular evolution in the gnd locus of Salmonella enterica.

The gnd gene, the structural gene for 6-phosphogluconate dehydrogenase, was sequenced and analyzed in 34 isolates from different serovars of the seven subspecies of Salmonella enterica to provide comparative information on the evolution in this gene, which has been studied extensively in Escherichia coli. The gene tree obtained by the neighbor-joining method in general gave separate branches for each subspecies, with the few exceptions readily explained by recombination. There is evidence of recombination involving transfer of long (more than 400 bp) and short (30-150 bp) segments of DNA. Four of the six long-segment transfers detected are at the 5' end of the gene, and in all four cases a variant of the chi sequence is located close to the recombination junction and appears to have mediated the recombination events. We suggest that in these four cases and in a fifth case with intersubspecies transfer of the whole gnd gene, the adjacent rfb (O antigen) locus may have been transferred in the same event. The estimates of the number of synonymous substitutions per synonymous site, KS, and the number of nonsynonymous substitutions per nonsynonymous site, KA, within the E. coli and S. enterica gnd genes, and also between the two species show an interesting distribution, with KS being lower toward the ends of the gene and KA in particular being lower in the first than in the second domain. In S. enterica, synonymous sites also seem to be subjected to negative selection. The ratio of KA to KS was higher within S. enterica and E. coli than between them, which may indicate that intraspecies variation is essentially between clones and that mildly deleterious mutations can be fixed within clones, which would thus raise KA within species.

Amino Acid Sequence↗
PubMed1989

Chromosomal location and evolutionary rate variation in enterobacterial genes.

The basal rate of DNA sequence evolution in enterobacteria, as seen in the extent of divergence between Escherichia coli and Salmonella typhimurium, varies greatly among genes, even when only "silent" sites are considered. The degree of divergence is clearly related to the level of gene expression, reflecting constraints on synonymous codon choice. However, where this constraint is weak, among genes not expressed at high levels, divergence is also related to the chromosomal location of the gene; it appears that genes furthest away from oriC, the origin of replication, have a mutation rate approximately two times that of genes near oriC.

Bias↗
PubMed2004

Positive selection scanning of parasite DNA sequences.

Parasites successfully exist within the host as a result of highly specific genetic adaptations. Therefore, detecting genes that contain relevant adaptive mutations can provide a guide to biological processes that are potentially essential to the parasite. Random genetic mutations that confer selective advantage can act to alter amino acids so as to confer gain of function that has positive impact on the survival of the parasite. Directional selection of advantageous mutations results from an elevated rate of nonsynonymous substitutions in rapidly evolving genes. Genes on which this positive selection operates are considered to have an evolutionary characteristic such that the normalized number of nonsynonymous (dn) substitutions is greater than that of synonymous (ds) substitutions. By searching in a statistically robust way for genes that contain this characteristic, it is possible to apply a stringent method to identify genes that may be under positive selection and thus to identify biological processes involving those genes that are essential to the survival of the parasite. Genes detected typically class into those under host immune surveillance and those intrinsic to pathways essential to survival of the parasite within the host. Depending on their function and location of protein expression, such genes have the potential to provide exceptional vaccine and drug candidates.

Amino Acid Sequence↗
PubMed2004

Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans.

A prominent trend in the evolution of humans is the progressive enlargement of the cerebral cortex. The ASPM (Abnormal spindle-like microcephaly associated) gene has the potential to play a role in this evolutionary process, because mutations in this gene cause severe reductions in the cerebral cortical size of affected humans. Here, we show that the evolution of ASPM is significantly accelerated in great apes, especially along the ape lineages leading to humans. Additionally, the lineage from the last human/chimpanzee ancestor to humans shows an excess of non-synonymous over synonymous substitutions, which is a signature of positive Darwinian selection. A comparison of polymorphism and divergence using the McDonald-Kreitman test confirms that ASPM has indeed experienced intense positive selection during recent human evolution. This test also reveals that, on average, ASPM fixed one advantageous amino acid change in every 300,000-400,000 years since the human lineage diverged from chimpanzees some 5-6 million years ago. We therefore conclude that ASPM underwent strong adaptive evolution in the descent of Homo sapiens, which is consistent with its putative role in the evolutionary enlargement of the human brain.

Adaptation, Biological↗
PubMed1998

Contribution of Taq polymerase-induced errors to the estimation of RNA virus diversity.

The genetic diversity of a vesicular stomatitis virus population was analysed by RT-PCR, cloning and sequencing of two approximately 500 nucleotide regions of the virus genome. PCR amplifications were performed in parallel experiments with both Taq and Pfu DNA polymerases, and important differences were observed. Between 10 and 22 mutations were detected when virus populations were analysed by Taq amplification (20 clones from each region), whereas amplification of the same samples with Pfu revealed between 0 and 5 mutations. PCR fidelity assays, performed under the same PCR conditions as those used in the population analysis, showed that the Taq error-rate estimate of 0.27 x 10(-4) misincorporations per bp per cycle was within the range estimated elsewhere from PCR amplification of recombinant plasmids (0.27-0.85 x 10(-4) errors per bp per cycle) or from functional assays (0.2-2 x 10(-4) errors per bp per cycle). The error rate of Taq was found to be 9.3 times higher than the error rate of Pfu with DNA as a template, and about 10 times higher with cDNAs obtained by reverse transcription of viral RNA templates from natural populations. In the present study, we discuss (i) the implications of Taq errors on the analysis of genetic variability, based on both the frequency and nature (replacement vs synonymous) of the observed substitutions and (ii) the sample size required to assess the genetic variability in a virus population generated by a single infection.

Animals↗
PubMed1990

Genetic code 1990. Outlook.

The genetic code is evolving as shown by 9 departures from the universal code: 6 of them are in mitochondria and 3 are in nuclear codes. We propose that these changes are preceded by disappearance of a codon from coding sequences in mRNA of an organism or organelle. The function of the codon that disappears is taken by other, synonymous codons, so that there is no change in amino acid sequences of proteins. The deleted codon then reappears with a new function. Wobble pairing between anticodons and codons has evolved, starting with a single UNN anticodon pairing with 4 codons. Directional mutation pressure affects codon usage and may produce codon reassignments, especially of stop codons. Selenocysteine is coded by UGA, which is also a stop codon, and this anomaly is discussed. The outlook for discovery of more changes in the code is favorable, and open reading frames should be compared with actual sequential analyses of protein molecules in this search.

Anaerobiosis↗
PubMed2003

Codon usage bias amongst plant viruses.

An internet database (DPVweb) was established containing details of all sequences of viruses, viroids and satellites of plants that are complete or that contain at least one complete gene (n>4600). The start and end positions of each feature (genes, non-translated regions etc) were recorded and checked for accuracy. Client software was written to enable easy selection of sequences and features of a chosen virus and to analyse codon usage bias. Codon usage was analysed for each gene of one example of each fully-sequenced plant virus. There were large differences in codon preferences, related to the nucleotide composition of the genome, particularly the GC content of the third codon position. There was no effect of gene size on codon bias. Genes from the same genome usually had similar coding strategies except where constrained by the overlap of reading frames. Although some synonymous codons were consistently used with low frequency by both plants and viruses, viruses were not generally adapted to use (or avoid) those codons most frequently used by their host plants and there was no obvious association with the type of transmission. Mutational bias, rather than translational selection appears to account for the majority of the variation detected. The software is available at http://www.dpvweb.net/analysis/codons.php.

Codon↗
PubMed1985

Evidence for higher rates of nucleotide substitution in rodents than in man.

When the coding regions of 11 genes from rodents (mouse or rat) and man are compared with those from another mammalian species (usually bovine), it is found that rodents evolve significantly faster than man. The ratio of the number of nucleotide substitutions in the rodent lineage to that in the human lineage since their divergence is 2.0 for synonymous substitutions and 1.3 for nonsynonymous substitutions. Rodents also evolve faster in the 5' and 3' untranslated regions of five different mRNAs; the ratios are 2.6 and 3.1, respectively. The numbers of nucleotide substitutions between members of the beta-globin gene family that were duplicated before the man-mouse split are also higher in mouse than in man. The difference is, again, greater for synonymous substitutions than for nonsynonymous substitutions. This tendency is more consistent with the neutralist view of molecular evolution than with the selectionist view. A simple explanation for the higher rates in rodents is that rodents have shorter generation times and, thus, higher mutation rates. The implication of our findings for the study of molecular phylogeny is discussed.

Animals↗
PubMed2005

A dissection of volatility in yeast.

It has been suggested that volatility, the proportion of mutations which change an amino acid, can be used to infer the level of natural selection acting upon a gene. This conjecture is supported by a correlation between volatility and the rate of nonsynonymous substitution (dN), or the ratio of nonsynonymous and synonymous substitution rates, in a variety of organisms. These organisms include yeast, in which the correlations are quite strong. Here we show that these correlations are a by-product of a correlation between synonymous codon bias toward translationally optimal codons and dN. Although this analysis suggests that volatility is not a good measure of the selection, we suggest that it might be possible to infer something about the level of natural selection, from a single genome sequence, using translational codon bias.

Base Sequence↗