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PubMed2006

Influenza A H5N1 hemagglutinin cleavable signal sequence substitutions.

Eleven influenza A H5N1 hemagglutinin N-terminal cleavable signal sequences, coded by single nucleotide substitutions relative to reference A/Viet Nam/1203/2004, were identified by BLASTN search of GenBank and were characterized by molecular modeling. The signal sequences statistically segregated into two classes of states. Members of one class were uncharged and conformationally compact while members of the second class each carried a 2+ electric charge and were conformationally extended. Virtual signal sequences, not found on GenBank and based upon hypothetical transversions in the third codon, had molecular characteristics intermediate to those of the two classes of actual signal sequences. The high incidence of non-synonymous substitutions (63.6%), the high transition/transversion ratio (10/1) and the results of molecular modeling all suggest that the N-terminal cleavable signal sequence is mutationally evolving more rapidly than proteins which must assume specific conformational states in the mature influenza virion.

Evolution, Molecular↗
PubMed2007

HMDB: the Human Metabolome Database.

The Human Metabolome Database (HMDB) is currently the most complete and comprehensive curated collection of human metabolite and human metabolism data in the world. It contains records for more than 2180 endogenous metabolites with information gathered from thousands of books, journal articles and electronic databases. In addition to its comprehensive literature-derived data, the HMDB also contains an extensive collection of experimental metabolite concentration data compiled from hundreds of mass spectra (MS) and Nuclear Magnetic resonance (NMR) metabolomic analyses performed on urine, blood and cerebrospinal fluid samples. This is further supplemented with thousands of NMR and MS spectra collected on purified, reference metabolites. Each metabolite entry in the HMDB contains an average of 90 separate data fields including a comprehensive compound description, names and synonyms, structural information, physico-chemical data, reference NMR and MS spectra, biofluid concentrations, disease associations, pathway information, enzyme data, gene sequence data, SNP and mutation data as well as extensive links to images, references and other public databases. Extensive searching, relational querying and data browsing tools are also provided. The HMDB is designed to address the broad needs of biochemists, clinical chemists, physicians, medical geneticists, nutritionists and members of the metabolomics community. The HMDB is available at: www.hmdb.ca.

Databases, Factual↗
PubMed2004

Comparison of the chicken and turkey genomes reveals a higher rate of nucleotide divergence on microchromosomes than macrochromosomes.

A distinctive feature of the avian genome is the large heterogeneity in the size of chromosomes, which are usually classified into a small number of macrochromosomes and numerous microchromosomes. These chromosome classes show characteristic differences in a number of interrelated features that could potentially affect the rate of sequence evolution, such as GC content, gene density, and recombination rate. We studied the effects of these factors by analyzing patterns of nucleotide substitution in two sets of chicken-turkey sequence alignments. First, in a set of 67 orthologous introns, divergence was significantly higher in microchromosomes (chromosomes 11-38; 11.7% divergence) than in both macrochromosomes (chromosomes 1-5; 9.9% divergence; P = 0.016) and intermediate-sized chromosomes (chromosomes 6-10; 9.5% divergence; P = 0.026). At least part of this difference was due to the higher incidence of CpG sites on microchromosomes. Second, using 155 orthologous coding sequences we noted a similar pattern, in which synonymous substitution rates on microchromosomes (13.1%) were significantly higher than were rates on macrochromosomes (10.3%; P = 0.024). Broadly assuming neutrality of introns and synonymous sites, or constraints on such sequences do not differ between chromosomal classes, these observations imply that microchromosomal genes are exposed to more germ line mutations than those on other chromosomes. We also find that dN/dS ratios for genes located on microchromosomes (average, 0.094) are significantly lower than those of macrochromosomes (average, 0.185; P = 0.025), suggesting that the proteins of genes on microchromosomes are under greater evolutionary constraint.

Animals↗
PubMed2006

Association of a melanocortin 4 receptor (MC4R) polymorphism with performance traits in Lithuanian White pigs.

The melanocortin 4 receptor is expressed in virtually all brain regions of mammals and plays an important role in energy homeostasis. Polymorphisms in this gene may thus be related to growth and obesity. In pigs, a non-synonymous polymorphic site was described (Asp298Asn) and demonstrated to affect cAMP production and to alter adenylyl cyclase signalling. Association studies revealed significant linkage of this mutation with production trait in pigs. In this study, 207 Lithuanian White pigs were genotyped at the MC4R locus and analysed on relationships between genotype and breeding values for several performance traits. The observed allele and genotype frequencies did not deviate significantly from Hardy-Weinberg equilibrium (wildtype allele 0.59; mutant allele 0.41) and are comparable with those described in other Large White populations. The mutant Asn298 allele of the MC4R gene was significantly associated with increased test daily gain, higher lean meat percentage and lower backfat thickness. There was a trend towards an improved feed conversion ratio (p = 0.065) in animals with the mutant allele whereas no significant effect was found on lifetime daily gain. These results indicate that the MC4R polymorphism should be integrated in selection programmes in the Lithuanian White to improve carcass composition.

Adenylyl Cyclases↗
PubMed2001

Identification of novel polymorphisms in the pM5 and MRP1 (ABCC1) genes at locus 16p13.1 and exclusion of both genes as responsible for pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder of connective tissue, characterized by progressive calcification of the elastic fibers in the eye, the skin, and the cardiovascular system. The PXE locus has been mapped to chromosome 16p13.1, and was recently further refined to a 500 kb-region, containing four candidate genes : MRP1 (ABCC1), MRP6 (ABCC6), pM5, and two copies of an unknown gene, the later we subsequently found to be identical to the gene encoding the Nuclear Pore Interacting Protein (NPIP). In a comprehensive mutational screening, we have analysed the entire coding region of the pM5, MRP1, and NPIP genes in 7 patients affected with pseudoxanthoma elasticum, but failed to find evidence of disease-causing defects in any of these three genes. Five synonymous (G232G, P395P, A862A, G912G, D1106D), and five non synonymous (V404I, N458K, D490N, F1141I, G1195R) polymorphisms were found in the pM5 gene, for which we also corrected errors in the published cDNA sequence. Analysis of the MRP1 transcript lead to the discovery of two polymorphisms (T117M, S1512L). No variant was evidenced during our screening of the NPIP gene. Our data exclude the responsibility of the pM5, MRP1 and NPIP genes in PXE, and strongly suggest that mutations in the last remaining candidate gene, MRP6, which encodes a 1503 amino-acid ABC membrane transporter, are the genetic defect responsible for PXE.

ATP-Binding Cassette Transporters↗
PubMed2004

Patterns of evolutionary constraints in intronic and intergenic DNA of Drosophila.

We develop methods to infer levels of evolutionary constraints in the genome by comparing rates of nucleotide substitution in noncoding DNA with rates predicted from rates of synonymous site evolution in adjacent genes or other putatively neutrally evolving sites, while accounting for differences in base composition. We apply the methods to estimate levels of constraint in noncoding DNA of Drosophila. In introns, constraint (the estimated fraction of mutations that are selectively eliminated) is absolute at the 5' and 3' splice junction dinucleotides, and averages 72% in base pairs 3-6 at the 5'-end. Constraint at the 5' base pairs 3-6 is significantly lower in the lineage leading to Drosophila melanogaster than in Drosophila simulans, a finding that agrees with other features of genome evolution in Drosophila and indicates that the effect of selection on intron function has been weaker in the melanogaster lineage. Elsewhere in intron sequences, the rate of nucleotide substitution is significantly higher than at synonymous sites. By using intronic sites outside splice control regions as a putative neutrally evolving standard, constraint in the 500 bp of intergenic DNA upstream and downstream regions of protein-coding genes averages approximately 44%. Although the estimated level of constraint in intergenic regions close to genes is only about one-half of that of amino acid sites, selection against single-nucleotide mutations in intergenic DNA makes a substantial contribution to the mutation load in Drosophila.

Animals↗
PubMed2005

Multiple major increases and decreases in mitochondrial substitution rates in the plant family Geraniaceae.

BACKGROUND: Rates of synonymous nucleotide substitutions are, in general, exceptionally low in plant mitochondrial genomes, several times lower than in chloroplast genomes, 10-20 times lower than in plant nuclear genomes, and 50-100 times lower than in many animal mitochondrial genomes. Several cases of moderate variation in mitochondrial substitution rates have been reported in plants, but these mostly involve correlated changes in chloroplast and/or nuclear substitution rates and are therefore thought to reflect whole-organism forces rather than ones impinging directly on the mitochondrial mutation rate. Only a single case of extensive, mitochondrial-specific rate changes has been described, in the angiosperm genus Plantago. RESULTS: We explored a second potential case of highly accelerated mitochondrial sequence evolution in plants. This case was first suggested by relatively poor hybridization of mitochondrial gene probes to DNA of Pelargonium hortorum (the common geranium). We found that all eight mitochondrial genes sequenced from P. hortorum are exceptionally divergent, whereas chloroplast and nuclear divergence is unexceptional in P. hortorum. Two mitochondrial genes were sequenced from a broad range of taxa of variable relatedness to P. hortorum, and absolute rates of mitochondrial synonymous substitutions were calculated on each branch of a phylogenetic tree of these taxa. We infer one major, approximately 10-fold increase in the mitochondrial synonymous substitution rate at the base of the Pelargonium family Geraniaceae, and a subsequent approximately 10-fold rate increase early in the evolution of Pelargonium. We also infer several moderate to major rate decreases following these initial rate increases, such that the mitochondrial substitution rate has returned to normally low levels in many members of the Geraniaceae. Finally, we find unusually little RNA editing of Geraniaceae mitochondrial genes, suggesting high levels of retroprocessing in their history. CONCLUSION: The existence of major, mitochondrial-specific changes in rates of synonymous substitutions in the Geraniaceae implies major and reversible underlying changes in the mitochondrial mutation rate in this family. Together with the recent report of a similar pattern of rate heterogeneity in Plantago, these findings indicate that the mitochondrial mutation rate is a more plastic character in plants than previously realized. Many molecular factors could be responsible for these dramatic changes in the mitochondrial mutation rate, including nuclear gene mutations affecting the fidelity and efficacy of mitochondrial DNA replication and/or repair and--consistent with the lack of RNA editing--exceptionally high levels of "mutagenic" retroprocessing. That the mitochondrial mutation rate has returned to normally low levels in many Geraniaceae raises the possibility that, akin to the ephemerality of mutator strains in bacteria, selection favors a low mutation rate in plant mitochondria.

Base Sequence↗
PubMed2004

Mutation and selection on the anticodon of tRNA genes in vertebrate mitochondrial genomes.

The H-strand of vertebrate mitochondrial DNA is left single-stranded for hours during the slow DNA replication. This facilitates C-->U mutations on the H-strand (and consequently G-->A mutations on the L-strand) via spontaneous deamination which occurs much more frequently on single-stranded than on double-stranded DNA. For the 12 coding sequences (CDS) collinear with the L-strand, NNY synonymous codon families (where N stands for any of the four nucleotides and Y stands for either C or U) end mostly with C, and NNR and NNN codon families (where R stands for either A or G) end mostly with A. For the lone ND6 gene on the other strand, the codon bias is the opposite, with NNY codon families ending mostly with U and NNR and NNN codon families ending mostly with G. These patterns are consistent with the strand-specific mutation bias. The codon usage biased towards C-ending and A-ending in the 12 CDS sequences affects the codon-anticodon adaptation. The wobble site of the anticodon is always G for NNY codon families dominated by C-ending codons and U for NNR and NNN codon families dominated by A-ending codons. The only, but consistent, exception is the anticodon of tRNA-Met which consistently has a 5'-CAU-3' anticodon base-pairing with the AUG codon (the translation initiation codon) instead of the more frequent AUA. The observed CAU anticodon (matching AUG) would increase the rate of translation initiation but would reduce the rate of peptide elongation because most methionine codons are AUA, whereas the unobserved UAU anticodon (matching AUA) would increase the elongation rate at the cost of translation initiation rate. The consistent CAU anticodon in tRNA-Met suggests the importance of maximizing the rate of translation initiation.

Animals↗
PubMed1994

The cis-effect of a nascent peptide on its translating ribosome: influence of the cat-86 leader pentapeptide on translation termination at leader codon 6.

Inducible cat genes from Gram-positive bacteria are regulated by translation attenuation. The inducer chloramphenicol stalls a ribosome at a specific site in the leader of cat transcripts; this destabilizes a downstream stem-loop structure that normally sequesters the ribosome-binding site for the cat structural gene. The five-amino-acid peptide MVKTD that is synthesized when a ribosome has translated to the leader induction site is an inhibitor of peptidyl transferase in vitro. Thus, the peptide may be the in vivo determinant of the site of ribosome stalling. Here we provide evidence that the leader pentapeptide can exert a cis-effect on its translating ribosome in vivo. Converting leader codon 6 to the ochre codon results in expression of cat-86 in the absence of inducer. We term this autoinduction. Autoinduction is abolished by mutations that change the amino-acid sequence of the leader peptide but have no, or little, effect on the sequence of nucleotides at the leader stall site. In contrast, four nucleotide changes within the leader site occupied by the stalled ribosome that result in synonymous codon replacements do not diminish autoinduction. Our evidence indicates that the cat-86 leader pentapeptide can alter the function of its translating ribosome.

Amino Acid Sequence↗
PubMed2005

Evolutionary relationships between the former species Saccharomyces uvarum and the hybrids Saccharomyces bayanus and Saccharomyces pastorianus; reinstatement of Saccharomyces uvarum (Beijerinck) as a distinct species.

Analysis of the nucleotide sequence of the GDH1 homologues from Saccharomyces bayanus strain CBS 380T and S. pastorianus strains showed that they share an almost identical sequence, SuGDH1*, which is a diverged form of the SuGDH1 from the type strain of the former species S. uvarum, considered as synonym of S. bayanus. SuGDH1* is close to but differs from SuGDH1 by the accumulation of a high number of neutral substitutions designated as Multiple Neutral Mutations Accumulation (MNMA). Further analysis carried out with three other markers, BAP2, HO and MET2 showed that they have also diverged from their S. uvarum counterparts by MNMA. S. bayanus CBS 380T is placed between S. uvarum and S. pastorianus sharing MET2, CDC91 sequences with the former and BAP2, GDH1, HO sequences with the latter. S. bayanus CBS 380T has been proposed to be a S. uvarum/S. cerevisiae hybrid and this proposal is confirmed by the presence in its genome a S. cerevisiae SUC4 gene. Strain S. bayanus CBS 380T, with a composite genome, is genetically isolated from strains of the former S. uvarum species, thus justifying the reinstatement of S. uvarum as a distinct species.

Base Sequence↗
PubMed1993

Contrasting evolutionary rates in the duplicate chaperonin genes of Mycobacterium tuberculosis and M. leprae.

A phylogenetic analysis of chaperonin (heat shock protein 60) sequences from prokaryotes and eukaryotes indicated that a single gene duplication event in the common ancestor of Mycobacterium tuberculosis, M. leprae, and Streptomyces albus gave rise to the duplicate chaperonin genes found in these species (designated HSP65 and GroEL in the mycobacterial species). Comparison of rates of synonymous and nonsynonymous nucleotide substitution in different gene regions suggested that the 5' end of the HSP65 gene was homogenized by an ancient recombination event between M. tuberculosis and M. leprae. In S. albus, the two duplicated chaperonin genes have evolved at essentially the same rate. In both M. tuberculosis and M. leprae, however, the GroEL gene has evolved considerably more rapidly at nonsynonymous nucleotide sites than has the HSP65 gene. Because this difference is not seen at synonymous sites, it must be due to a difference in selective constraint on the proteins encoded by the two genes, rather than to a difference in mutation rate. The difference between GroEL and HSP65 is striking in regions containing epitopes recognized by T cells of the vertebrate host; in certain cross-reactive epitopes conserved across all organisms, nonsynonymous sites in GroEL have evolved twice as fast as those in HSP65. It is suggested that these differences are correlated with differences in the way in which the duplicate chaperonins of M. tuberculosis and M. leprae interact with the host immune system.

Amino Acid Sequence↗
PubMed2001

Phylogenetic reconstruction of intrapatient evolution of human immunodeficiency virus type 1: predominance of drift and purifying selection.

The intra-host evolution of 73 human immunodeficiency virus type 1 quasispecies was analysed by split decomposition analysis. Non-synonymous and synonymous nucleotide substitutions were counted along the shortest path connecting all sequences and compared with the numbers expected under the assumption of a random model of mutation. For the majority of substitutions, drift and negative selection seemed to prevail.

Biological Evolution↗
PubMed2006

Strand bias in complementary single-nucleotide polymorphisms of transcribed human sequences: evidence for functional effects of synonymous polymorphisms.

BACKGROUND: Complementary single-nucleotide polymorphisms (SNPs) may not be distributed equally between two DNA strands if the strands are functionally distinct, such as in transcribed genes. In introns, an excess of A<-->G over the complementary C<-->T substitutions had previously been found and attributed to transcription-coupled repair (TCR), demonstrating the valuable functional clues that can be obtained by studying such asymmetry. Here we studied asymmetry of human synonymous SNPs (sSNPs) in the fourfold degenerate (FFD) sites as compared to intronic SNPs (iSNPs). RESULTS: The identities of the ancestral bases and the direction of mutations were inferred from human-chimpanzee genomic alignment. After correction for background nucleotide composition, excess of A-->G over the complementary T-->C polymorphisms, which was observed previously and can be explained by TCR, was confirmed in FFD SNPs and iSNPs. However, when SNPs were separately examined according to whether they mapped to a CpG dinucleotide or not, an excess of C-->T over G-->A polymorphisms was found in non-CpG site FFD SNPs but was absent from iSNPs and CpG site FFD SNPs. CONCLUSION: The genome-wide discrepancy of human FFD SNPs provides novel evidence for widespread selective pressure due to functional effects of sSNPs. The similar asymmetry pattern of FFD SNPs and iSNPs that map to a CpG can be explained by transcription-coupled mechanisms, including TCR and transcription-coupled mutation. Because of the hypermutability of CpG sites, more CpG site FFD SNPs are relatively younger and have confronted less selection effect than non-CpG FFD SNPs, which can explain the asymmetric discrepancy of CpG site FFD SNPs vs. non-CpG site FFD SNPs.

Algorithms↗
PubMed1998

Rare mutations in a domain crucial for V3-loop structure prevail in replicating HIV from long-term non-progressors.

OBJECTIVE: To evaluate the role of the selective forces exerted by the host on the HIV-1 structures involved in viral entry. DESIGN AND METHODS: The V3 region of the env gene was analysed in cell-free HIV-1 RNA from 17 infected subjects: 11 long-term non-progressors (LTNP) and six symptomless, typical progressor patients. To evaluate the potential biological significance of one of the rare variants detected in the LTNP, it was reproduced by recombinant PCR into a HIV-1 molecular clone. RESULTS: The intrapatient divergence of the V3-loop sequences averaged 8.62% in LTNP and 5.29% in progressors, although LTNP displayed lower divergence from the clade B consensus than progressors (16.65 and 19.76%, respectively). The analysis of non-synonymous and synonymous substitutions indicated that selective pressure was exerted in this region in both LTNP and progressors. Individual peculiarities (unique and rare V3-loop variants) emerged, however, in most sequences from LTNP, and variants bearing mutations in a domain crucial for the V3-loop structure were more prevalent in LTNP (P = 0.0012). The pNL4-3-derived mutant reproducing a V3-loop variant detected in a LTNP was efficiently expressed upon transfection, but the mutant virus was nearly completely unable to infect CD4+ cell lines, activated primary peripheral blood lymphocytes, or monocyte-derived macrophages, suggesting that a defect impaired the entry phase of the replication cycle. CONCLUSIONS: The results indicate that host factors impose selective constraints on the evolution of the HIV-1 structures involved in viral entry. In LTNP, these factors are likely to force the virus into attenuated variants.

Amino Acid Sequence↗
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↗
PubMed2006

Spatial covariation of mutation and nonsynonymous substitution rates in vertebrate mitochondrial genomes.

Mitochondrial genomes encode fundamental subunits of the basic energy producing machinery of eukaryotic cells that are under strong functional constraint. Paradoxically, these genes evolve rapidly in general, and there is substantial variation in evolutionary rates among genes within genomes. In order to investigate spatial variation in selection intensity, we conducted tests of neutrality using ratios of synonymous to nonsynonymous substitutions (dN/dS = omega) on numerous protein gene segments from fishes and mammals. Values of omega were very low for nearly all genomic regions. However, values of both omega and dN varied in a clinal pattern with increasing distance from the light-strand origin of replication. Spatial heterogeneity of nonsynonymous substitution rates exhibits a significantly positive correlation with variation in mutation rates that are related to the mode of mitochondrial DNA replication. The finding that nonsynonymous substitution rates are proportional to mutation rates is expected if a majority of substitutions are selectively neutral or slightly deleterious. Spatial patterns of among-gene variation in nonsynonymous rates were highly similar between fishes and mammals, suggesting that forces governing mitochondrial gene evolution have remained relatively constant over 450 Myr of vertebrate evolution. Conservation of substitution patterns despite major shifts in thermal habit and metabolic demands among taxa implicates a conserved replication mechanism controlling relative mutation rates as a major determinant of mitochondrial protein evolution.

Animals↗
PubMed1997

Analysis of mutation rates in the SMCY/SMCX genes shows that mammalian evolution is male driven.

Mammalian evolution is believed to be male driven because the greater number of germ cell divisions per generation in males increases the opportunity for errors in DNA replication. Since the Y Chromosome (Chr) replicates exclusively in males, its genes should also evolve faster than X or autosomal genes. In addition, estimating the overall male-to-female mutation ratio (alpha m) is of great importance as a large alpha m implies that replication-independent mutagenic events play a relatively small role in evolution. A small alpha m suggests that the impact of these factors may, in fact, be significant. In order to address this problem, we have analyzed the rates of evolution in the homologous X-Y common SMCX/SMCY genes from three different species--mouse, human, and horse. The SMC genes were chosen because the X and Y copies are highly homologous, well conserved in evolution, and in all probability functionally interchangeable. Sequence comparisons and analysis of synonymous substitutions in approximately 1kb of the 5' coding region of the SMC genes reveal that the Y-linked copies are evolving approximately 1.8 times faster than their X homologs. The male-to-female mutation ratio alpha m was estimated to be 3. These data support the hypothesis that mammalian evolution is male driven. However, the ratio value is far smaller than suggested in earlier works, implying significance of replication-independent mutagenic events in evolution.

Amino Acid Sequence↗
PubMed1997

Evolution of codon usage bias in Drosophila.

We first review what is known about patterns of codon usage bias in Drosophila and make the following points: (i) Drosophila genes are as biased or more biased than those in microorganisms. (ii) The level of bias of genes and even the particular pattern of codon bias can remain phylogenetically invariant for very long periods of evolution. (iii) However, some genes, even very tightly linked genes, can change very greatly in codon bias across species. (iv) Generally G and especially C are favored at synonymous sites in biased genes. (v) With the exception of aspartic acid, all amino acids contribute significantly and about equally to the codon usage bias of a gene. (vi) While most individual amino acids that can use G or C at synonymous sites display a preference for C, there are exceptions: valine and leucine, which prefer G. (vii) Finally, smaller genes tend to be more biased than longer genes. We then examine possible causes of these patterns and discount mutation bias on three bases: there is little evidence of regional mutation bias in Drosophila, mutation bias is likely toward A+T (the opposite of codon usage bias), and not all amino acids display the preference for the same nucleotide in the wobble position. Two lines of evidence support a selection hypothesis based on tRNA pools: highly biased genes tend to be highly and/or rapidly expressed, and the preferred codons in highly biased genes optimally bind the most abundant isoaccepting tRNAs. Finally, we examine the effect of bias on DNA evolution and confirm that genes with high codon usage bias have lower rates of synonymous substitution between species than do genes with low codon usage bias. Surprisingly, we find that genes with higher codon usage bias display higher levels of intraspecific synonymous polymorphism. This may be due to opposing effects of recombination.

Animals↗