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PubMed1990

Processes of genome evolution reflected by base frequency differences among Serratia marcescens genes.

The G + C content of silent sites in codons varies greatly among Serratia marcescens genes; the value in any one gene seems to reflect a balance between mutation pressure towards high G + C content and natural selection constraining choice among synonymous codons. Interestingly, non-coding sequences have substantially lower G + C content than silent sites thought to be under little selective constraint.

Base Composition↗

PubMed2001

Identification of new endogenous retroviral sequences belonging to the HERV-W family in human cancer cells.

A human endogenous retroviral family (HERV-W) has recently been identified on chromosome 7 that contains a single complete open reading frame putatively encoding an envelope protein. We have identified fifteen HERV-W families on human genomic DNA using a monochromosomal panel in our previous study. In order to identify additional families, we examined genomic DNA derived from cancer cell lines (A549, AZ521, OVCAR3, RT4) using the PCR approach. Five env fragments of a HERV-W family were newly identified and analyzed. They showed a high degree of nucleotide sequence similarity (93-97%) to that of the other HERV-W families. Translation of the env fragments showed no frameshift and termination codon by deletion/insertion or point mutation in clones A549-2, AZ521-3, and OVCAR-3. The ratio of synonymous to nonsynonymous substitutions indicated that negative selective pressure is acting on A549-2, AZ521-3, and OVCAR-3 sequences. These env gene sequences could be associated with an active provirus in human cancer cells (A549, AZ521, OVCAR3).

Amino Acid Sequence↗

PubMed2006

Multidrug-resistant Mycobacterium tuberculosis, Bangui, Central African Republic.

We investigated multidrug-resistant (MDR) Mycobacterium tuberculosis strains in Bangui, Central African Republic. We found 39.6% with the same spoligotype and synonymous single nucleotide polymorphism in the mutT1 gene. However, strains had different rpoB mutations responsible for rifampin resistance. MDR strains in Bangui may emerge preferentially from a single, MDR-prone family.

Antitubercular Agents↗

PubMed1998

Nonneutral evolution and differential mutation rate of gender-associated mitochondrial DNA lineages in the marine mussel Mytilus.

Mussels have two types of mitochondrial DNA (mtDNA). The M type is transmitted paternally, and the F type is transmitted maternally. To test hypotheses of the molecular evolution of both mtDNA genomes, 50 nucleotide sequences were obtained for 396 bp of the COIII gene of European populations of Mytilus edulis and the Atlantic and Mediterranean forms of M. galloprovincialis. Analysis based on the proportion of synonymous and nonsynonymous substitutions indicate that mtDNA is evolving in a non-neutral and complex fashion. Previous studies on American mussels demonstrated that the F genome experiences a higher purifying selection and that the M genome evolves faster. Here we show that these patterns also hold in European populations. However, in contrast to American populations, where an excess of replacement substitution between F and M lineages has been reported, a significant excess of replacement polymorphism within mtDNA lineages is observed in European populations of M. galloprovincialis. European populations also show an excess of replacement polymorphism within the F but not within the M genome with respect to American M. trossulus, as well as a consistent pattern of excess of rare variants in both F and M genomes. These results are consistent with a nearly neutral model of molecular evolution and a recent relaxation of selective constraints on European mtDNA. Levels of diversity are significantly higher for the M than F genome, and the M genome also accumulates synonymous and nonsynonymous substitutions at a higher rate, in contrast with earlier reports where no difference for the synonymous rate was observed. It is suggested that a subtle balance between relaxed selection and a higher mutation rate explains the faster evolutionary rate of the M lineage.

Animals↗

PubMed2005

Candidate gene screening for posterior polymorphous dystrophy.

PURPOSE: To perform candidate gene screening for posterior polymorphous corneal dystrophy (PPCD). The initial 3 genes chosen, ID1, BCL2L1, and VSX1, lie within the region on chromosome 20 to which the PPCD gene has been linked, and mutations in VSX1 have previously been identified in patients with PPCD. METHODS: DNA extraction, PCR amplification, and direct sequencing of the VSX1, BCL2L1, and ID1 genes were performed in 14 affected patients (12 families) as well as in unaffected family members and healthy control subjects. RESULTS: No coding region mutations in the BCL2L1 or ID1 genes were identified in affected patients. In the VSX1 gene, the previously identified Gly160Asp missense change was not present in any of our 12 probands, and the Asp144Glu mutation was identified in 1 affected patient as well as 1 unaffected control individual. Additionally, 2 synonymous substitutions were identified, Ala182Ala (8 affected patients from 8 families) and Gly239Gly (1 affected patient and 1 unaffected patient from the same family). In the ID1 gene, the synonymous substitution Gly216Gly was observed in 2 affected patients (2 families) who also demonstrated a single nucleotide change in both the 5'UTR (2129T>C) and 3'UTR (3267A>G). Another 5'UTR change, 2177T>C, was identified in 1 affected patient and his unaffected parent, both of whom also demonstrated the 2129T>C and 3267A>G changes. CONCLUSIONS: None of the 12 probands with PPCD demonstrated the previously described Gly160Asp mutation within the VSX1 gene. The Asp144Glu missense change, present in an affected patient as well as an unaffected control individual, appears to be a rare polymorphism, not a disease-causing mutation. No coding region changes were identified in the ID1 or BCL2L1 genes. Therefore, although we report a number of novel polymorphisms in the VSX1 and ID1 genes, the failure to identify any sequence variants that sort with the disease phenotype suggests that other genetic factors are involved in PPCD.

Corneal Dystrophies, Hereditary↗

PubMed1998

Silent mutations in the Escherichia coli ompA leader peptide region strongly affect transcription and translation in vivo.

In order to test the effect of silent mutations on the regulation of gene expression, we monitored several steps of transcription and translation of the ompA gene in vivo , in which some or all codons between codons 6 and 14, frequently used in Escherichia coli , had been exchanged for infrequent synonymous codons. Northern blot analysis revealed an up to 4-fold reduction in the half-life of the mutated messengers and a >10-fold reduction in their steady-state amounts. Western blot analysis showed a 10-fold reduction in the amount of OmpA protein. Use of a system expressing a Rho-specific anti-terminator allowed us to detect a strong transcription polarity effect in the silent mutants. These results demonstrate that silent mutations can severely inhibit several steps of gene expression in E. coli and that code degeneracy is efficiently exploited in this species for setting signals for gene control and regulation.

Bacterial Outer Membrane Proteins↗

PubMed2006

Selection intensity on preferred codons correlates with overall codon usage bias in Caenorhabditis remanei.

Adaptive codon usage provides evidence of natural selection in one of its most subtle forms: a fitness benefit of one synonymous codon relative to another. Codon usage bias is evident in the coding sequences of a broad array of taxa, reflecting selection for translational efficiency and/or accuracy as well as mutational biases. Here, we quantify the magnitude of selection acting on alternative codons in genes of the nematode Caenorhabditis remanei, an outcrossing relative of the model organism C. elegans, by fitting the expected mutation-selection-drift equilibrium frequency distribution of preferred and unpreferred codon variants to the empirical distribution. This method estimates the intensity of selection on synonymous codons in genes with high codon bias as N(e)s = 0.17, a value significantly greater than zero. In addition, we demonstrate for the first time that estimates of ongoing selection on codon usage among genes, inferred from nucleotide polymorphism data, correlate strongly with long-term patterns of codon usage bias, as measured by the frequency of optimal codons in a gene. From the pattern of polymorphisms in introns, we also infer that these findings do not result from the operation of biased gene conversion toward G or C nucleotides. We therefore conclude that coincident patterns of current and ancient selection are responsible for shaping biased codon usage in the C. remanei genome.

Animals↗

PubMed1993

Overdispersed molecular evolution in constant environments.

According to recent data analysis of DNA sequences, the dispersion index, defined as the variance-to-mean ratio of the number of base substitutions in a lineage, is often much larger than unity, which is in conflict with simple Poisson processes assumed in the molecular clock hypothesis. In this paper, it will be shown that the dispersion index can be much larger than unity in a model in which the fitness of DNA sequences, mutation rate, and population size are all constant with time, and that moderately deleterious sequences are more abundant than the best fit sequences. Since the fixation probability of novel mutations depends on their fitness relative to the current sequence, the neutral mutation rate is enhanced once a deleterious mutation is fixed. In a simple case with two fitness classes, a large dispersion index can be produced by moderately deleterious mutations (3 < 4Ns < 6), but neither by nearly neutral (4Ns < 2) nor by strongly deleterious (4Ns > 7) mutations. Analysis of the case with 100 fitness classes shows that the dispersion index is insensitive to the population size, but greatly changes with the fitness distribution of DNA sequences. The model can explain why non-synonymous substitutions often have a larger dispersion index than synonymous substitutions.

Animals↗

PubMed2003

BUB1 infrequently mutated in human breast carcinomas.

The BUB1 gene is a key player in the mitotic spindle checkpoint machinery that monitors proper segregation of sister chromatides during mitosis. It has been suggested that mutations in BUB1 may disrupt the spindle checkpoint and thereby cause chromosomal instability, which is a hallmark of solid tumors including those from the breast. From a series of breast carcinomas we selected 20 cases with genomic instability, as scored by Comparative Genome Hybridization (CGH), and without somatic TP53 (p53) mutations, and sequenced the entire coding region of the BUB1 gene. Two different constitutional sequence variants were found; a base substitution in exon 5, c.481G>A (CAG>CAA, a synonymous change encoding Gln144) in two samples, and a base substitution 8 bp upstream of exon 10, c.1007-8T>C in two other samples. No somatic mutations were detected. These results indicate that genomic instability scored as copy number alterations by CGH in TP53 wild type breast carcinomas is not caused by somatic mutations in the BUB1 gene.

Breast Neoplasms↗

PubMed2005

Fast accumulation of nonsynonymous mutations on the female-specific W chromosome in birds.

Following cessation of recombination during sex chromosome evolution, the nonrecombining sex chromosome is affected by a number of degenerative forces, possibly resulting in the fixation of deleterious mutations. This might take place because of weak selection against recessive or partly recessive deleterious mutations due to permanent heterozygosity of nonrecombining chromosomes. Furthermore, population genetic processes, such as selective sweeps, background selection, and Muller's ratchet, result in a reduction in Ne, which increase the likelihood of fixation of deleterious mutations. Theory thus predicts that nonrecombining genes should show increased levels of nonsynonymous (dN) to synonymous substitutions (dS). We tested this in an avian system by estimating the ratio between dN and dS in six gametologous gene pairs located on the Z chromosome and the nonrecombining, female-specific W chromosome. In comparisons, we found a significantly higher dN/dS ratio for the W-linked than the Z-linked copy in three of the investigated genes. In a concatenated alignment of all six genes, the dN/dS ratio was six times higher for W-linked than Z-linked genes. By using human and mouse as outgroup in maximum likelihood analyses, W-linked genes were found to evolve differently compared with their Z-linked gametologues and outgroup sequences. This seems not to be a consequence of functional diversification because d(N)/d(S) ratios between gametologous gene copies were consistently low. We conclude that deleterious mutations are accumulating at a high rate on the avian W chromosome, probably as a result of the lack of recombination in this female-specific chromosome.

Animals↗

PubMed2004

Influence of random genetic drift on human immunodeficiency virus type 1 env evolution during chronic infection.

Human immunodeficiency virus type 1 (HIV-1) has high replication and mutation rates that generate large census populations and high levels of genetic variation. We examined the roles of natural selection, population growth, random genetic drift, and recombination in shaping the variation in 1509 C2-V5 env sequences derived from nine men with chronic HIV-1 infection. These sequences were obtained from clinical visits that reflect the first 6-13.7 years of infection. Pairwise comparisons of nonsynonymous and synonymous distances, Tajima's D test, Fu and Li's D* test, and a test of recurrent mutation revealed evidence for episodes of nonneutral evolution in a total of 22 out of 145 blood samples, representing six of the nine individuals. Using three coalescent-based maximum-likelihood estimators, we found viral effective population sizes in all nine individuals to be approximately 10(3). We also show that a previous estimate of the effective population size of approximately 10(5) based on rare haplotype frequencies decreases to approximately 10(3) upon correcting a biased sampling procedure. We conclude that the genetic variation in these data sets can be explained by a predominance of random genetic drift of neutral mutations with brief episodes of natural selection that were frequently masked by recombination.

Base Sequence↗

PubMed2006

Mutational analysis of PDGFR-RAS/MAPK pathway activation in childhood medulloblastoma.

Aberrant signalling via platelet derived growth factor receptors (PDGFRs) and the RAS/MAPK pathway has been implicated in the development of medulloblastoma, the most common malignant brain tumour in childhood. To determine whether genetic mechanisms play a role in the activation of PDGFR-RAS/MAPK signalling in medulloblastoma, we performed a direct sequence analysis of the established mutational "hotspots" of known targets of activating mutations within the pathway (PDGFRA, NRAS, KRAS, HRAS and BRAF) and PDFRFB, in a cohort of 28 primary tumours. A synonymous sequence variation in PDGFRA (CCG to CCA; PRO 567 PRO) was detected in two cases (approximately 7%), but not in 150 normal chromosomes assessed, suggesting that the PDGFRA locus may be associated with medulloblastoma development in certain cases. No evidence for oncogenic mutations affecting NRAS, KRAS, HRAS, BRAF or PDFRFB was found in any case. These data demonstrate that activating mutations in established mutational hotspots within the PDGFR-RAS/MAPK pathway are rare events in medulloblastoma development, and suggest that alternative mechanisms are responsible for RAS/MAPK pathway activation in this disease.

Adolescent↗

PubMed2003

The ldb1 mutant of Saccharomyces cerevisiae is defective in Pmr1p, the yeast secretory pathway/Golgi Ca(2+)/Mn(2+)-ATPase.

The LDB1 gene of Saccharomyces cerevisiae was identified by complementation of the ldb1 mutant phenotype with a genomic library. We found that the ldb1 defect is complemented by PMR1 which codes for the yeast secretory pathway/Golgi Ca(2+)/Mn(2+)-ATPase. Besides that, the analysis of a null mutation of the PMR1 gene revealed a phenotype identical to that of ldb1 mutant. Thus, LDB1 must be considered a synonym of PMR1.

Calcium↗

PubMed2005

Novel mutations in BCOR in three patients with oculo-facio-cardio-dental syndrome, but none in Lenz microphthalmia syndrome.

Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked dominant condition with male lethality characterized by microphthalmia, congenital cataracts, facial dysmorphic features, congenital heart defects, and dental anomalies. Mutations in BCOR (BCL6 co-repressor) located in Xp11.4 have been described to cause OFCD syndrome. Lenz microphthalmia syndrome is inherited in an X-linked recessive pattern comprising microphthalmia/anophthalmia, mental retardation, malformed ears, digital, skeletal, and urogenital anomalies (synonym: microphthalmia with associated anomalies (MAA)). One locus for MAA has been mapped to Xq27-q28. Nonetheless, linkage and subsequent mutation analysis revealed a single missense mutation (p.P85L) in BCOR in a large family with presumed Lenz microphthalmia syndrome (MAA2). We describe novel mutations in BCOR in three patients with OFCD syndrome, two small deletions (c.2488_2489delAG and c.3286delG) and a submicroscopic deletion of about 60 kb encompassing at least BCOR exons 2-15. No BCOR mutation was detected in eight patients with Lenz microphthalmia syndrome. Our data confirm that BCOR is the causative gene for OFCD syndrome; however, the failure to identify any mutation in patients with Lenz microphthalmia syndrome together with the oligosymptomatic phenotype in the reported MAA2 patients suggest that BCOR is not the major gene for this syndrome.

Abnormalities, Multiple↗

PubMed2005

Missense mutations in exon 4 of the porcine LEPR gene encoding extracellular domain and their association with fatness traits.

Three non-synonymous single nucleotide polymorphisms (T221C, T232A and C233T) were detected in exon 4 of the porcine leptin receptor (LEPR) gene. The T232A substitution could be identified as a (Tsp509I) restriction fragment length polymorphism. The frequency of genotype TT varied in six genetic groups from 0.62 (Duroc) to 0.99 (Polish Large White). Sequencing of exon 4, performed for 30 animals, revealed that only two intragenic haplotypes (TC and AT at nucleotide position 232-233) were present. The phenotypic effect of the Tsp509I polymorphism was tested for the Polish Landrace (n = 241) and a synthetic line 990 (n = 243). There was no statistical evidence for the direct effect of the LEPR polymorphisms on fatness traits. However, in Polish Landrace allele A at position 232 was associated with thicker backfat over shoulder.

Animals↗

PubMed2002

No missense mutation of WKL1 in a subgroup of probands with schizophrenia.

Recently, a Leu309Met mutation in WKL1 (MLC1, KIAA0027), a gene mapped to chromosome 22q13.33, was reported to co-segregate with periodic catatonia, a clinical sub-type of schizophrenia, in seven members of an extended pedigree.(1) WKL1 encodes a putative membrane protein expressed exclusively in the brain, particularly in the amygdala, nucleus caudatus, thalamus, and hippocampus.(1) We screened WKL1 for etiologic mutations in 28 probands from the United States who were given a consensus diagnosis of schizophrenia and met at least one of these criteria: (1) were from multiplex schizophrenia families where at least two schizophrenic subjects were reported to display catatonic behavior at sometime during the course of their illness; or (2) were from multiplex schizophrenia families where, in a genome scan for schizophrenia susceptibility loci, evidence for excess allele sharing among affected family members for markers in the 22q13 region was seen. In addition, 15 affected subjects from 15 German pedigrees were similarly screened for causative mutations. This German cohort exhibited the catatonia phenotype but had ambiguous linkage to 22q13 and included the mutation-positive proband as a positive control. The 43 probands were screened for base changes in WKL1: 15 SNPs in the non-coding regions of the gene, three SNPs in the 3'UTR, four synonymous coding SNPs and two non-synonymous (amino acid changing) SNPs were identified. We were able to rapidly confirm the Leu309Met nucleotide change in the positive control. No missense mutations were detected in any of the other 42 probands studied. These data exclude the role of WKL1 in schizophrenia susceptibility in the subjects studied.

Adolescent↗

PubMed1997

Synonymous substitution rates in Drosophila: mitochondrial versus nuclear genes.

Synonymous substitution rates in mitochondrial and nuclear genes of Drosophila were compared. To make accurate comparisons, we considered the following: (1) relative synonymous rates, which do not require divergence time estimates, should be used; (2) methods estimating divergence should take into account base composition; (3) only very closely related species should be used to avoid effects of saturation; (4) the heterogeneity of rates should be examined. We modified the methods estimating synonymous substitution numbers to account for base composition bias. By using these methods, we found that mitochondrial genes have 1.7-3.4 times higher synonymous substitution rates than the fastest nuclear genes or 4.5-9.0 times higher rates than the average nuclear genes. The average rate of synonymous transversions was 2.7 (estimated from the melanogaster species subgroup) or 2.9 (estimated from the obscura group) times higher in mitochondrial genes than in nuclear genes. Synonymous transversions in mitochondrial genes occurred at an approximately equivalent rate to those in the fastest nuclear genes. This last result is not consistent with the hypothesis that the difference in turnover rates between mitochondrial and nuclear genomes is the major factor determining higher synonymous substitution rates in mtDNA. We conclude that the difference in synonymous substitution rates is due to a combination of two factors: a higher transitional mutation rate in mtDNA and constraints on nuclear genes due to selection for codon usage.

Animals↗

PubMed1999

The evolution of codon preferences in Drosophila: a maximum-likelihood approach to parameter estimation and hypothesis testing.

Synonymous codon usage in related species may differ as a result of variation in mutation biases, differences in the overall strength and efficiency of selection, and shifts in codon preference-the selective hierarchy of codons within and between amino acids. We have developed a maximum-likelihood method to employ explicit population genetic models to analyze the evolution of parameters determining codon usage. The method is applied to twofold degenerate amino acids in 50 orthologous genes from D. melanogaster and D. virilis. We find that D. virilis has significantly reduced selection on codon usage for all amino acids, but the data are incompatible with a simple model in which there is a single difference in the long-term Ne, or overall strength of selection, between the two species, indicating shifts in codon preference. The strength of selection acting on codon usage in D. melanogaster is estimated to be |Nes| approximately 0.4 for most CT-ending twofold degenerate amino acids, but 1.7 times greater for cysteine and 1.4 times greater for AG-ending codons. In D. virilis, the strength of selection acting on codon usage for most amino acids is only half that acting in D. melanogaster but is considerably greater than half for cysteine, perhaps indicating the dual selection pressures of translational efficiency and accuracy. Selection coefficients in orthologues are highly correlated (rho = 0.46), but a number of genes deviate significantly from this relationship.

Amino Acids↗