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At least 523 records · Page 29Linked to original sources
PubMed2005

Codon and amino acid usage in two major human pathogens of genus Bartonella--optimization between replicational-transcriptional selection, translational control and cost minimization.

Intra-genomic variation in synonymous codon and amino acid usage in two human pathogens Bartonella henselae and B. quintana has been carried out through multivariate analysis. Asymmetric mutational bias, coupled with replicational-transcriptional selection, has been identified as the prime selection force behind synonymous codon selection--a characteristic of the genus Bartonella, not exhibited by any other alpha-proteobacterial genome. Distinct codon usage patterns and low synonymous divergence values between orthologous sequences of highly expressed genes from the two Bartonella species indicate that there exists a residual intra-strand synonymous codon bias in the highly expressed genes, possibly operating at the level of translation. In the case of amino acid usage, the mean hydropathy level and aromaticity are the major sources of variation, both having nearly equal impact, while strand-specific mutational pressure and gene expressivity strongly influence the inter-strand variations. In both species under study, the highly expressed gene products tend not to contain heavy and/or aromatic residues, following the cost-minimization hypothesis in spite of their intracellular lifestyle. The codon and amino acid usage in these two human pathogens are, therefore, consequences of a complex balance between replicational-transcriptional selection, translational control, protein hydropathy and cost minimization.

Amino Acids↗
PubMed2004

Systematic screening for mutations in the human N-methyl-D-aspartate receptor 1 gene in schizophrenic patients from the German population.

Evidence for a dysfunction of the N-methyl-D-aspartate (NMDA) type of ionotropic glutamate receptors in schizophrenic patients, comes from neurochemical and clinical pharmacologic data. Therefore, the NMDAR1 gene can be regarded as an interesting candidate gene for schizophrenia. Several groups have tried to identify variants of this gene in schizophrenic patients in different, however not in German, populations. We sought to identify sequence changes of potential functional relevance in genomic DNA from 46 German unrelated schizophrenic patients by means of single-strand conformation analysis. No mutations of likely functional relevance were observed. We identified two synonymous coding Single Nucleotide Polymorphisms (cSNPs) in exons 6 and 7, and two SNPs in exon-flanking intronic sequences. Genotype distribution of these four SNPs was not significantly different between schizophrenic patients and controls. Our results suggest that the NMDAR1 subunit is not frequently involved in the development of schizophrenia in the German population.

DNA↗
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↗
PubMed2006

Rapp-Hodgkin ectodermal dysplasia syndrome: the clinical and molecular overlap with Hay-Wells syndrome.

We report on the clinical and molecular abnormalities in a 7-month-old girl and her mother with an ectodermal dysplasia disorder that most closely resembles Rapp-Hodgkin syndrome (RHS). At birth, the child had bilateral cleft palate, a narrow pinched nose, small chin, and hypoplastic nipples, and suffered from respiratory distress, feeding difficulties, and poor weight gain, although developmental progress was normal. Her mother had a cleft palate, sparse hair, high forehead, dental anomalies, a narrow nose, dysplastic nails, and reduced sweating. Sequencing of the p63 gene in genomic DNA from both individuals revealed a heterozygous frameshift mutation, 1721delC, in exon 14. This mutation has not been described previously and is the seventh report of a pathogenic p63 gene mutation in RHS. The frameshift results in changes to the tail of p63 with the addition of 90 missense amino acids downstream and a delayed termination codon that extends the protein by 21 amino acids. This mutation is predicted to disrupt the normal repressive function of the transactivation inhibitory domain leading to gain-of-function for at least two isoforms of the p63 transcription factor. The expanding p63 mutation database demonstrates that there is considerable overlap between the molecular pathology of RHS and Hay-Wells syndrome, with identical mutations in some cases, and that these two disorders may in fact be synonymous.

Adult↗
PubMed2005

Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters.

Genetic variations in drug metabolizing enzymes and targets are established determinants of adverse drug reactions and interactions, but less is known about the role of genetic polymorphisms in membrane transport proteins. MRP1 (ABCC1) is one of 13 polytopic membrane proteins that comprise the 'C' subfamily of the ATP-binding cassette (ABC) superfamily of transport proteins. MRP1 and related ABCC family members, including MRP2, 3, 4 and 5 (ABCC2, 3, 4 and 5), each have a distinctive pattern of tissue expression and substrate specificity. Together, these five transporters play important roles in the disposition and elimination of drugs and other organic anions, and in maintenance of blood-tissue barriers, as confirmed by enhanced chemosensitivity of respective knockout mice. Moreover, Mrp2 (Abcc2) deficient animals display mild conjugated hyperbilirubinemia, corresponding to a human condition known as Dubin-Johnson syndrome (DJS). Naturally occurring mutations in MRP/ABCC-related drug transporters have been reported, some of which are non-synonymous single nucleotide polymorphisms. The consequences of the resulting amino acid changes can sometimes be predicted from in vitro site-directed mutagenesis studies or from knowledge of mutations of analogous (conserved) residues in ABCC proteins that cause DJS, Pseudoxanthoma elasticum (ABCC6), cystic fibrosis (CFTR/ABCC7) or persistent hyperinsulinemic hypoglycemia of infancy (SUR1/ABCC8). Continual updating of databases of sequence variants and haplotype analysis, together with in vitro biochemical validation assays and pharmacological studies in knockout animals, should make it possible to determine how genetic variation in the MRP-related transporters contributes to the range of responses to drugs and chemicals observed in different human populations.

Adenosine Triphosphate↗
PubMed2001

Accelerated regulatory gene evolution in an adaptive radiation.

The disparity between rates of morphological and molecular evolution remains a key paradox in evolutionary genetics. A proposed resolution to this paradox has been the conjecture that morphological evolution proceeds via diversification in regulatory loci, and that phenotypic evolution may correlate better with regulatory gene divergence. This conjecture can be tested by examining rates of regulatory gene evolution in species that display rapid morphological diversification within adaptive radiations. We have isolated homologues to the Arabidopsis APETALA3 (ASAP3/TM6) and APETALA1 (ASAP1) floral regulatory genes and the CHLOROPHYLL A/B BINDING PROTEIN9 (ASCAB9) photosynthetic structural gene from species in the Hawaiian silversword alliance, a premier example of plant adaptive radiation. We have compared rates of regulatory and structural gene evolution in the Hawaiian species to those in related species of North American tarweeds. Molecular evolutionary analyses indicate significant increases in nonsynonymous relative to synonymous nucleotide substitution rates in the ASAP3/TM6 and ASAP1 regulatory genes in the rapidly evolving Hawaiian species. By contrast, no general increase is evident in neutral mutation rates for these loci in the Hawaiian species. An increase in nonsynonymous relative to synonymous nucleotide substitution rate is also evident in the ASCAB9 structural gene in the Hawaiian species, but not to the extent displayed in the regulatory loci. The significantly accelerated rates of regulatory gene evolution in the Hawaiian species may reflect the influence of allopolyploidy or of selection and adaptive divergence. The analyses suggest that accelerated rates of regulatory gene evolution may accompany rapid morphological diversification in adaptive radiations.

Adaptation, Physiological↗
PubMed1992

Patterns of interallelic divergence at the rabbit b-locus of the immunoglobulin light chain constant region are in agreement with population genetical evidence for overdominant selection.

Population studies at the b-locus of the "constant" regions of the rabbit immunoglobulin kappa 1 light chain (c kappa 1) revealed patterns of gene diversity resembling those that mark the peculiar nature of the major histocompatibility complex, such as large number of alleles, high heterozygosity levels, consistent excess of heterozygous individuals and long allele coalescence times. This paper documents the evolutionary patterns at the b-locus as inferred from DNA sequence comparisons. Among alleles, synonymous substitutions outnumbered expectations for neutral alleles by an order of magnitude. They were distributed randomly throughout the c kappa 1 coding region while interallelic amino acid differences did cluster into segments overlapping with the regions exposed to the solvent. Within these regions, acceptance rates of mutation at amino acid replacement sites were even higher than those at synonymous sites (dr/ds = 1.6-3.0), while in the intervals between these regions the opposite was found (dr/ds approximately 0.3). Under the assumption that allelic variation is adaptive at the molecular surface, the divergence patterns at the b-locus are therefore very similar to those reported for the major histocompatibility complex. An analysis at the quasi silent bas-locus (c kappa 2), which is linked to the b-locus, and comparisons among genes of the "variable" region of the kappa 1 light chains (v kappa 1), revealed patterns of divergence which differed markedly from those observed at the c kappa 1 constant regions. It is suggested that allelic variability at immunoglobulin constant regions can be due to mechanisms similar to those enhancing diversity at histocompatibility loci.

Alleles↗
PubMed1998

Characterization of the mitochondrial genome in childhood multiple sclerosis. I. Optic neuritis and LHON mutations.

The occurrence of optic neuropathy in patients with MS-like disorders who carry one of the pathogenetically significant LHON mutations as well as the higher incidence of maternal transmission in familial cases of MS support the hypothesis that mitochondrial genes may be implicated in susceptibility to MS. We sequenced the entire mtDNA of six children with MS who developed optic neuritis as early and prominent visual involvement. The analysis revealed a high degree of nucleotide variations relative to the standard mtDNA sequence. After excluding various synonymous nucleotide changes and common neutral polymorphisms, eight discrete novel missense mutations within the protein coding, tRNA or rRNA genes were detected. None of the eight polymorphic sites were found in common between the patients with MS. Of particular interest was the observation that five of six children carried a total of nine secondary LHON mutations at nucleotide positions 4216, 4917 or 13708. We conclude that variation in mtDNA is unlikely to contribute to genetic predisposition for MS. However, secondary LHON mutations may be regarded as additional risk factor for developing prominent optic nerve involvement. The association of individual sets of mtDNA variations with phenotypic presentation in certain subgroups of MS patients remains to be clarified.

Child↗
PubMed1998

Deleterious mutations in animal mitochondrial DNA.

A simple neutral model predicts that the ratio of non-synonymous to synonymous fixed differences between species will be the same as the ratio of non-synonymous to synonymous polymorphisms within species. This prediction is tested with existing mitochondrial datasets from 25 animal species. In slightly over half of the studies, the ratio of replacement to silent polymorphisms within species is significantly greater than the ratio of replacement to silent fixed differences between species. These observations are best explained by a substantial number of mildly deleterious amino acid mutations that contribute to heterozygosity but rarely become fixed.

Animals↗
PubMed2003

Genomic basis of mucopolysaccharidosis type IIID (MIM 252940) revealed by sequencing of GNS encoding N-acetylglucosamine-6-sulfatase.

Mucopolysaccharidosis type IIID (MPS IIID; Sanfilippo syndrome type D; MIM 252940) is caused by deficiency of the activity of N-acetylglucosamine-6-sulfatase (GNS), which is normally required for degradation of heparan sulfate. The clinical features of MPS IIID include progressive neurodegeneration, with relatively mild somatic symptoms. Biochemical features include accumulation of heparan sulfate and N-acetylglucosamine-6-sulfate in the brain and viscera. To date, diagnosis required a specific lysosomal enzyme assay for GNS activity. From genomic DNA of a subject with MPS IIID, we amplified and sequenced the promoter and 14 exons of GNS. We found a homozygous nonsense mutation in exon 9 (1063C --> T), which predicted premature termination of translation (R355X). We also identified two common synonymous coding single-nucleotide polymorphisms and genotyped these in samples from four ethnic groups. This first report of a mutation in GNS resulting in MPS IIID indicates the potential utility of molecular diagnosis for this rare condition.

Genome, Human↗
PubMed2003

Evolutionary rate variation in anthocyanin pathway genes.

Over a broad taxonomic range that spans monocots and dicots, upstream enzymes of the anthocyanin pigment pathway have evolved less rapidly than downstream enzymes. In this article we show that this pattern is also evident within the genus Ipomoea. Specifically, the most upstream enzyme, chalcone synthase (CHS-D), evolves more slowly than the two most downstream enzymes, ancyocyanidin synthase (ANS) and UDP glucose flavonoid 3-oxy-glucosyltransferase (UFGT). This pattern appears not to be due to variation in mutation rates, because the CHS-D gene exhibits higher synonymous substitution rates than the genes for the other two enzymes. Codon-based tests for positive selection suggest that it has been negligible or absent in all three genes. In addition, the mean number of indel-creating events is four times as high in the downstream genes as in CHS-D. Unlike the downstream genes, CHS-D also exhibits evidence of codon bias. Together, the evidence suggests that the difference in nonsynonymous substitution rates between upstream and downstream genes is due to relaxed constraint on the downstream genes rather than a greater frequency of positively selected substitutions.

Acyltransferases↗
PubMed2006

Codon usage and selection on proteins.

Selection pressures on proteins are usually measured by comparing homologous nucleotide sequences (Zuckerkandl and Pauling 1965). Recently we introduced a novel method, termed volatility, to estimate selection pressures on proteins on the basis of their synonymous codon usage (Plotkin and Dushoff 2003; Plotkin et al. 2004). Here we provide a theoretical foundation for this approach. Under the Fisher-Wright model, we derive the expected frequencies of synonymous codons as a function of the strength of selection on amino acids, the mutation rate, and the effective population size. We analyze the conditions under which we can expect to draw inferences from biased codon usage, and we estimate the time scales required to establish and maintain such a signal. We find that synonymous codon usage can reliably distinguish between negative selection and neutrality only for organisms, such as some microbes, that experience large effective population sizes or periods of elevated mutation rates. The power of volatility to detect positive selection is also modest--requiring approximately 100 selected sites--but it depends less strongly on population size. We show that phenomena such as transient hyper-mutators can improve the power of volatility to detect selection, even when the neutral site heterozygosity is low. We also discuss several confounding factors, neglected by the Fisher-Wright model, that may limit the applicability of volatility in practice.

Algorithms↗
PubMed2004

Selection on codon usage for error minimization at the protein level.

Given the structure of the genetic code, synonymous codons differ in their capacity to minimize the effects of errors due to mutation or mistranslation. I suggest that this may lead, in protein-coding genes, to a preference for codons that minimize the impact of errors at the protein level. I develop a theoretical measure of error minimization for each codon, based on amino acid similarity. This measure is used to calculate the degree of error minimization for 82 genes of Drosophila melanogaster and 432 rodent genes and to study its relationship with CG content, the degree of codon usage bias, and the rate of nucleotide substitution. I show that (i) Drosophila and rodent genes tend to prefer codons that minimize errors; (ii) this cannot be merely the effect of mutation bias; (iii) the degree of error minimization is correlated with the degree of codon usage bias; (iv) the amino acids that contribute more to codon usage bias are the ones for which synonymous codons differ more in the capacity to minimize errors; and (v) the degree of error minimization is correlated with the rate of nonsynonymous substitution. These results suggest that natural selection for error minimization at the protein level plays a role in the evolution of coding sequences in Drosophila and rodents.

Amino Acids↗
PubMed2001

Sex and U.

Resolution of several unsettled problems in genetics depends on the genomic rate of deleterious mutation, U. Selection against mutations can be a major factor in evolution only if U > or =1. Recently, significant progress has been made in measuring U in multicellular eukaryotes. An indirect estimate, based on a human-chimpanzee pseudogene comparison, produced U>3 for hominoids. By contrast, an estimate for Drosophila based on comparison of synonymous protein-coding sites produced U<0.1. However, the Drosophila figure might be underestimated because of selection at synonymous sites. Perhaps, the best way to measure U is to observe mutations shortly after they appear. So far, this direct approach has been applied only to humans and Caenorhabditis elegans, yielding high estimates of mutation rates.

Animals↗
PubMed1992

Cytotoxic T lymphocytes do not appear to select for mutations in an immunodominant epitope of simian immunodeficiency virus gag.

Studies to date assessing HIV escape from CTL in vivo have yielded conflicting results. Previous studies have demonstrated that simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys expressing the MHC class I allele Mamu-A*01 reproducibly develop a gag-specific CTL response limited to a 9-amino acid epitope of the SIVmac gag protein (residues 182-190 within peptide 11C). To determine whether CTL have a role in selecting for AIDS virus mutants, we examined mutations in SIVmac proviral DNA encoding this gag CTL epitope in PBL of infected rhesus monkeys. Three Mamu-A*01+ rhesus monkeys were infected with SIVmac and assessed for gag- and peptide 11C-specific CTL responses. This specific CTL response was maintained in two monkeys, but lost in the third animal 2 yr after infection. The generation of proviral gag mutations was then determined by sequencing 500-bp proviral fragments amplified from fresh PBL obtained from the monkeys more than 2.5 yr after infection. Although numerous point mutations were characterized in 131 polymerase chain reaction-generated clones of SIVmac gag, only four mutations within the gag CTL epitope-coding region of the genome were identified. Comparison of synonymous and nonsynonymous nucleotide substitutions in the regions encoding peptide 11C (p11C) and the flanking gag protein indicated a lack of selective pressure for viral mutations in the CTL epitope coding region. Interestingly, a predominant gag mutant encoding a single amino acid change in p11C was found in a monkey which lost its CTL activity. However, even in this setting there was no evidence for selection of mutations in the CTL epitope coding region when compared with the flanking region. Furthermore, synthetic peptides corresponding to all naturally occurring variants in the gag epitope-coding region were recognized by cloned and bulk cultured effector cells of the infected monkeys with persistent CTL. These results indicate that SIVmac gag- and p11C-specific CTL do not select for mutations in the immunodominant epitope-coding region and that the naturally occurring mutants do not appear to escape CTL recognition.

Amino Acid Sequence↗
PubMed2002

Further polymorphism of the MICA gene.

The MHC class I chain-related (MIC) gene family constitutes an interesting genetic group that is related to major histocompatibility complex (MHC) class I genes and is located within the MHC. The MIC gene products, MICA and MICB, have similar structures to HLA class I molecules. So far over 50 MICA alleles have been reported, which suggests that this genetic system is highly polymorphic. In order to investigate further the extent of MICA polymorphism we have studied exons 2-5 of the MICA gene in over 200 homozygous and heterozygous cell lines. Altogether we have identified 11 new MICA alleles and report 13 new nucleotide variations, one in exon 2, four in exon 3, four in exon 4, two in intron 1, one in intron 4 and one (a deletion) in exon 4. Eight of the 10 exonic variations are non-synonymous. The deletion in exon 4 leads to a frame-shift mutation and the introduction of a repeat of 12 leucine residues encoded by the microsatellite in exon 5. This study provides further evidence that the MICA gene is highly polymorphic. In contrast to MHC class I molecules, the polymorphic sites in MICA are predominantly within the alpha2 and alpha3 domains. The distribution of synonymous and non-synonymous substitutions suggests that there is selection for the polymorphic positions, which therefore define potential functional sites in the protein. We were also able to determine the association between MICA and HLA-B alleles in a number of homozygous cell lines bearing extended haplotypes.

Alleles↗
PubMed1996

On transition bias in mitochondrial genes of pocket gophers.

The relative contribution of mutation and purifying selection to transition bias has not been quantitatively assessed in mitochondrial protein genes. The observed transition/transversion (s/v) ratio is (micros Ps)/(microv Pv), where micros and microv denote mutation rate of transitions and transversions, respectively, and Ps and Pv denote fixation probabilities of transitions and transversions, respectively. Because selection against synonymous transitions can be assumed to be roughly equal to that against synonymous transversions, Ps/Pv approximately 1 at fourfold degenerate sites, so that the s/v ratio at fourfold degenerate sites is approximately micros/microv, which is a measure of mutational contribution to transition bias. Similarly, the s/v ratio at nondegenerate sites is also an estimate of micros/microv if we assume that selection against nonsynonymous transitions is roughly equal to that against nonsynonymous transversions. In two mitochondrial genes, cytochrome oxidase subunit I (COI) and cytochrome b (cyt-b) in pocket gophers, the s/v ratio is about two at nondegenerate and fourfold degenerate sites for both the COI and the cyt-b genes. This implies that mutation contribution to transition bias is relatively small. In contrast, the s/v ratio is much greater at twofold degenerate sites, being 48 for COI and 40 for cyt-b. Given that the micros/microv ratio is about 2, the Ps/Pv ratio at twofold degenerate sites must be on the order of 20 or greater. This suggests a great effect of purifying selection on transition bias in mitochondrial protein genes because transitions are synonymous and transversions are nonsynonymous at twofold degenerate sites in mammalian mitochondrial genes. We also found that nonsynonymous mutations at twofold degenerate sites are more neutral than nonsynonymous mutations at nondegenerate sites, and that the COI gene is subject to stronger purifying selection than is the cyt-b gene. A model is presented to integrate the effect of purifying selection, codon bias, DNA repair and GC content on s/v ratio of protein-coding genes.

Analysis of Variance↗
PubMed1986

An evolutionary perspective on synonymous codon usage in unicellular organisms.

Observed patterns of synonymous codon usage are explained in terms of the joint effects of mutation, selection, and random drift. Examination of the codon usage in 165 Escherichia coli genes reveals a consistent trend of increasing bias with increasing gene expression level. Selection on codon usage appears to be unidirectional, so that the pattern seen in lowly expressed genes is best explained in terms of an absence of strong selection. A measure of directional synonymous-codon usage bias, the Codon Adaptation Index, has been developed. In enterobacteria, rates of synonymous substitution are seen to vary greatly among genes, and genes with a high codon bias evolve more slowly. A theoretical study shows that the patterns of extreme codon bias observed for some E. coli (and yeast) genes can be generated by rather small selective differences. The relative plausibilities of various theoretical models for explaining nonrandom codon usage are discussed.

Amino Acid Sequence↗