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PubMed1998

Genetic polymorphism and natural selection in the malaria parasite Plasmodium falciparum.

We have studied the genetic polymorphism at 10 Plasmodium falciparum loci that are considered potential targets for specific antimalarial vaccines. The polymorphism is unevenly distributed among the loci; loci encoding proteins expressed on the surface of the sporozoite or the merozoite (AMA-1, CSP, LSA-1, MSP-1, MSP-2, and MSP-3) are more polymorphic than those expressed during the sexual stages or inside the parasite (EBA-175, Pfs25, PF48/45, and RAP-1). Comparison of synonymous and nonsynonymous substitutions indicates that natural selection may account for the polymorphism observed at seven of the 10 loci studied. This inference depends on the assumption that synonymous substitutions are neutral, which we test by analyzing codon bias and G+C content in a set of 92 gene loci. We find evidence for an overall trend towards increasing A+T richness, but no evidence for mutation bias. Although the neutrality of synonymous substitutions is not definitely established, this trend towards an A+T rich genome cannot explain the accumulation of substitutions at least in the case of four genes (AMA-1, CSP, LSA-1, and PF48/45) because the Gleft and right arrow C transversions are more frequent than expected. Moreover, the Tajima test manifests positive natural selection for the MSP-1 and, less strongly, MSP-3 polymorphisms; the McDonald-Kreitman test manifests natural selection at LSA-1 and PF48/45. We conclude that there is definite evidence for positive natural selection in the genes encoding AMA-1, CSP, LSA-1, MSP-1, and Pfs48/45. For four other loci, EBA-175, MSP-2, MSP-3, and RAP-1, the evidence is limited. No evidence for natural selection is found for Pfs25.

Animals↗
PubMed2005

Somatic mutations of the protein kinase gene family in human lung cancer.

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of approximately 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.

Adenocarcinoma↗
PubMed1999

The causes of synonymous rate variation in the rodent genome. Can substitution rates be used to estimate the sex bias in mutation rate?

Miyata et al. have suggested that the male-to-female mutation rate ratio (alpha) can be estimated by comparing the neutral substitution rates of X-linked (X), Y-linked (Y), and autosomal (A) genes. Rodent silent site X/A comparisons provide very different estimates from X/Y comparisons. We examine three explanations for this discrepancy: (1) statistical biases and artifacts, (2) nonneutral evolution, and (3) differences in mutation rate per germline replication. By estimating errors and using a variety of methodologies, we tentatively reject explanation 1. Our analyses of patterns of codon usage, synonymous rates, and nonsynonymous rates suggest that silent sites in rodents are evolving neutrally, and we can therefore reject explanation 2. We find both base composition and methylation differences between the different sets of chromosomes, a result consistent with explanation 3, but these differences do not appear to explain the observed discrepancies in estimates of alpha. Our finding of significantly low synonymous substitution rates in genomically imprinted genes suggests a link between hemizygous expression and an adaptive reduction in the mutation rate, which is consistent with explanation 3. Therefore our results provide circumstantial evidence in favor of the hypothesis that the discrepancies in estimates of alpha are due to differences in the mutation rate per germline replication between different parts of the genome. This explanation violates a critical assumption of the method of Miyata et al., and hence we suggest that estimates of alpha, obtained using this method, need to be treated with caution.

Animals↗
PubMed2004

Heterozygous TGFBR2 mutations in Marfan syndrome.

Marfan syndrome is an extracellular matrix disorder with cardinal manifestations in the eye, skeleton and cardiovascular systems associated with defects in the gene encoding fibrillin (FBN1) at 15q21.1 (ref. 1). A second type of the disorder (Marfan syndrome type 2; OMIM 154705) is associated with a second locus, MFS2, at 3p25-p24.2 in a large French family (family MS1). Identification of a 3p24.1 chromosomal breakpoint disrupting the gene encoding TGF-beta receptor 2 (TGFBR2) in a Japanese individual with Marfan syndrome led us to consider TGFBR2 as the gene underlying association with Marfan syndrome at the MSF2 locus. The mutation 1524G-->A in TGFBR2 (causing the synonymous amino acid substitution Q508Q) resulted in abnormal splicing and segregated with MFS2 in family MS1. We identified three other missense mutations in four unrelated probands, which led to loss of function of TGF-beta signaling activity on extracellular matrix formation. These results show that heterozygous mutations in TGFBR2, a putative tumor-suppressor gene implicated in several malignancies, are also associated with inherited connective-tissue disorders.

Amino Acid Sequence↗
PubMed1985

Genetic code redundancy and the evolutionary stability of protein secondary structure.

The genetic code has an inherent bias towards some amino acids because of the variable number of synonymous codons per amino acid. The extent to which these biases are expressed in protein secondary structure is described through the analysis of the overall amino acid compositions of the alpha-helix, beta-sheet, beta-turn and random coil segments elucidated by X-ray crystallography. Given the concept of neutral mutation in proteins, the allocation of synonyms in the genetic code appears to protect secondary structures from amino acid changes and discourages the appearance of chemically complex residues. The level of protection is similar for each structural form, despite their clear preferences for certain amino acids. The organization of the code is therefore relevant to the preservation of conformation seen in the evolution of many protein families.

Amino Acids↗
PubMed2006

Strong regional heterogeneity in base composition evolution on the Drosophila X chromosome.

Fluctuations in base composition appear to be prevalent in Drosophila and mammal genome evolution, but their timescale, genomic breadth, and causes remain obscure. Here, we study base composition evolution within the X chromosomes of Drosophila melanogaster and five of its close relatives. Substitutions were inferred on six extant and two ancestral lineages for 14 near-telomeric and 9 nontelomeric genes. GC content evolution is highly variable both within the genome and within the phylogenetic tree. In the lineages leading to D. yakuba and D. orena, GC content at silent sites has increased rapidly near telomeres, but has decreased in more proximal (nontelomeric) regions. D. orena shows a 17-fold excess of GC-increasing vs. AT-increasing synonymous changes within a small (approximately 130-kb) region close to the telomeric end. Base composition changes within introns are consistent with changes in mutation patterns, but stronger GC elevation at synonymous sites suggests contributions of natural selection or biased gene conversion. The Drosophila yakuba lineage shows a less extreme elevation of GC content distributed over a wider genetic region (approximately 1.2 Mb). A lack of change in GC content for most introns within this region suggests a role of natural selection in localized base composition fluctuations.

Animals↗
PubMed2004

On the effects of background selection in small populations on comparisons of molecular variation.

Deleterious mutations affect genetic variation at linked neutral loci. Neutral variation can be reduced due to background selection, but in small population and with tight linkage such variation may increase due to associative overdominance. Here I report the results of computer simulations of diploid genotypes in small populations, where I look at the effect of deleterious mutations and linkage on comparisons of intra- and interspecific variation. Each chromosome consisted of 2000 loci where deleterious and neutral mutations occurred. The ratio of nonsynonymous to synonymous substitution rates (Ka/Ks) either increases with tight linkage or is unaffected, depending on the strength of selection. The ratio of the numbers of segregating mutations to the number of fixed mutations decreases under the conditions leading to background selection but can increase at tight linkage. Numbers of segregating sites (Sn) are less affected than nucleotide site diversity (pi), pi reduces more than Sn at intermediate linkage, but pi increases more than Sn when linkage is tight. Similar effects as found for Sn and pi are observed for heterozygosity and variance in allele size of tandem repeat loci.

Animals↗
PubMed1996

Selection intensity for codon bias and the effective population size of Escherichia coli.

The selection intensity for codon bias and the synonymous diversity have been used in the recent literature to estimate the effective population size of Escherichia coli. The results have varied between (10)5 and (10)8. It is suggested here that most of this disparity can be explained by a model that accounts for the population structure of the species. Thus it is assumed that weakly selected characters, like synonymous substitutions, are selectively fixed within individual lines or colonies but spread throughout the population in an essentially neutral way when colonies replace one another. In this way, the effective population size that enters expressions for the codon bias will be that of an individual colony, which, if hitchhiking effects are considered, can be a very small number. The effective population size that appears together with the mutation rate in expressions for the synonymous diversity, on the other hand, will be related to the total number of colonies that make up the species and can be a very large number.

Codon↗
PubMed1983

Codon substitution in evolution and the "saturation" of synonymous changes.

A mathematical model for codon substitution is presented, taking into account unequal mutation rates among different nucleotides and purifying selection. This model is constructed by using a 61 X 61 transition probability matrix for the 61 nonterminating codons. Under this model, a computer simulation is conducted to study the numbers of silent (synonymous) and amino acid-altering (nonsynonymous) nucleotide substitutions when the underlying mutation rates among the four kinds of nucleotides are not equal. It is assumed that the substitution rates are constant over evolutionary time, the codon frequencies being in equilibrium, and, thus, the numbers of synonymous and nonsynonymous substitutions both increase linearly with evolutionary time. It is shown that, when the mutation rates are not equal, the estimate of synonymous substitutions obtained by F. Perler, A. Efstratiadis, P. Lomedico, W. Gilbert, R. Kolodner and J. Dodgson's "Percent Corrected Divergence" method increases nonlinearly, although the true number of synonymous substitutions increases linearly. It is, therefore, possible that the "saturation" of synonymous substitutions observed by Perler et al. is due to the inefficiency of their method to detect all synonymous substitutions.

Amino Acids↗
PubMed2005

Evolution of relative synonymous codon usage in Human Immunodeficiency Virus type-1.

Mutation in Human Immunodeficiency Virus type-1 (HIV-1) is extremely rapid, a consequence of a low-fidelity viral reverse transcription process. The envelope gene has been shown to accumulate substitutions at a rate of approximately 1% per year and can frequently spend a long time in the host (approximately 10 years). The relative synonymous codon usage (RSCU) in HIV-1 is known to be different from that of the human host. However, by reengineering the protein coding sequences of HIV-1 to reflect the RSCU patterns observed in humans, a large increase in protein expression is observed. It is reasonable to suggest that within a host there may be a selective drive for change in the RSCU of HIV-1 towards human RSCU. To test this hypothesis we analyzed HIV-1 partial envelope sequences from eight patients sampled serially in time. For each sequence, an RSCU table was constructed. Sequences were labelled as "early" or "late" depending on whether they were sampled before or after the mid-point of the study. Using the RSCU values as descriptor variables, a Principal Components Analysis (PCA) was performed. The first three components clearly discriminated between early and late sequences. We also constructed pooled groupwise RSCU tables for early and late sequences. The viral RSCU values of each of the groups were correlated with human RSCU. If there is selection for host-adaptation in RSCU, we expect that "late" viral RSCUs would tend to be more highly correlated with human RSCU than "early" viral RSCUs. In fact, tests of significance suggest that this is the case. However, closer examination of the data revealed that the apparent trend towards human RSCU can be attributed to the homogenization of the codon usage by mutation pressure rather than host adaptation.

Algorithms↗
PubMed2004

Mitochondrial genome mutations in hypertensive individuals.

Human essential hypertension (HTN), a polygenic, multifactorial, and highly heterogeneous disorder of unknown etiology, has been shown to have excess maternal transmission in several studies, suggesting a possible mitochondrial involvement. In an effort to assess the contribution of the mitochondrial genome to HTN we initiated a systematic, extended screening of hypertensive individuals to identify potentially pathogenic mtDNA mutations. We applied our newly developed novel class of tests for the detection of mitochondrial mutation involvement in complex diseases to the hypertension data set from 350 pedigrees of white ethnicity and 98 of African American ethnicity ascertained at HTN clinics associated with Boston Medical Center, and we identified families with a likely mitochondrial involvement. We analyzed the sequence of the entire mitochondrial genome in probands from 20 such pedigrees, consisting of 10 African American and 10 white families. Comparison with the reference "Cambridge" sequence revealed a total of 297 base changes, including 24 in the ribosomal RNA (rRNA) genes, 15 in the transfer RNA (tRNA) genes, and 46 amino acid substitutions, with the remainder involving the noncoding regions or synonymous changes. Among the coding region mutations, 30 are novel, with 13 hypertensive probands carrying at least one novel variant, usually in combination with the previously described common polymorphisms, several of which are associated with cardiovascular and renal pathologies. These data will serve as a starting point for large-scale case-control association studies.

Black People↗
PubMed2005

Comparative analysis of the base composition and codon usages in fourteen mycobacteriophage genomes.

To study the possible codon usage and base composition variation in the bacteriophages, fourteen mycobacteriophages were used as a model system here and both the parameters in all these phages and their plating bacteria, M. smegmatis had been determined and compared. As all the organisms are GC-rich, the GC contents at third codon positions were found in fact higher than the second codon positions as well as the first + second codon positions in all the organisms indicating that directional mutational pressure is strongly operative at the synonymous third codon positions. Nc plot indicates that codon usage variation in all these organisms are governed by the forces other than compositional constraints. Correspondence analysis suggests that: (i) there are codon usage variation among the genes and genomes of the fourteen mycobacteriophages and M. smegmatis, i.e., codon usage patterns in the mycobacteriophages is phage-specific but not the M. smegmatis-specific; (ii) synonymous codon usage patterns of Barnyard, Che8, Che9d, and Omega are more similar than the rest mycobacteriophages and M. smegmatis; (iii) codon usage bias in the mycobacteriophages are mainly determined by mutational pressure; and (iv) the genes of comparatively GC rich genomes are more biased than the GC poor genomes. Translational selection in determining the codon usage variation in highly expressed genes can be invoked from the predominant occurrences of C ending codons in the highly expressed genes. Cluster analysis based on codon usage data also shows that there are two distinct branches for the fourteen mycobacteriophages and there is codon usage variation even among the phages of each branch.

Bacteriophages↗
PubMed2001

Charcot-Marie-Tooth type X: A novel mutation in the Cx32 gene with central conduction slowing.

Charcot-Marie-Tooth disease (CMT) is characterized by distal muscle weakness and wasting, often resulting in foot deformities and gait disturbances, distal sensory impairment and by more or less typical changes in sural nerve biopsy. CMT type 1 is also characterized by reduced nerve conduction velocities. For these demyelinating subtypes, most frequently a 1.5 Mb tandem duplication in chromosome 17p11.2-12 comprising the gene for the peripheral myelin protein 22 (PMP22) is observed (CMT1A), but point mutations in PMP22 have also rarely been reported. X-linked, dominant CMTX1 disease is the second most common type of these hereditary motor and sensory neuropathies (HMSN). Mutations in the X chromosomal gene Connexin32 (Cx32) synonymous gap junction beta-1 (GJB1) are detectable in most X-linked CMT families. We report a novel missense mutation--Tyr65His--in the first extracelullar domain of the Cx32 gene in a Czech CMTX1 family. The mutation was not detectable in 50 healthy controls. The clinical phenotype in both the male proband and his mother was moderate with pronounced peroneal weakness and foot drop. Nerve conduction velocities were intermediately decreased (31-38 m/s) in both patients and slowing of central acoustic conduction (BAEP) was found in both the son and the mother whereas visual central conduction slowing (VEP) was detectable only in the son.

Adolescent↗
PubMed1999

Pneumocystis carinii dihydropteroate synthase but not dihydrofolate reductase gene mutations correlate with prior trimethoprim-sulfamethoxazole or dapsone use.

Recent studies of the human Pneumocystis carinii dihydropteroate synthase (DHPS) gene suggest that P. carinii is developing resistance to sulfamethoxazole (SMX) and dapsone. To explore whether P. carinii is also developing resistance to trimethoprim (TMP), the human P. carinii dihydrofolate reductase (DHFR) gene was cloned, DHFR and DHPS genes in 37 P. carinii isolates from 35 patients were sequenced, and the relationship between TMP-SMX or dapsone use and gene mutations was analyzed. The DHFR gene sequences were identical in all isolates except 1 with a synonymous substitution. In contrast, the DHPS gene sequences showed mutations in 16 of the 37 isolates; prior sulfa/sulfone prophylaxis was associated with the presence of these mutations (P<.001). In addition to suggesting that there is less selective pressure on DHFR than on DHPS, this study reinforces the hypothesis that mutations in the DHPS gene are likely involved in the development of sulfa resistance in P. carinii.

Amino Acid Sequence↗
PubMed2006

Aryl hydrocarbon receptor interacting protein variants in sporadic pituitary adenomas.

CONTEXT: Proximal pathogenesis of pituitary tumors remains largely unclear. Recently, three heterozygous germline mutations were reported in the aryl hydrocarbon receptor interacting protein (AIP) gene in Finnish and Italian families with pituitary tumor predisposition and in Finnish patients harboring sporadic pituitary tumors. OBJECTIVE: The objectives of this study were to examine the frequency of the three AIP germline mutations in U.S. patients harboring sporadic pituitary tumors and to correlate clinical features of pituitary tumors with these mutations, if they exist in these patients. DESIGN: Genomic DNA was extracted from lymphoblastoid cell lines established from patients with sporadic pituitary tumors. Three segments of the AIP gene that contain the reported mutation sites for Q14X, IVS3-1G>A, and R304X were amplified by PCR and sequenced. SETTING: The study was conducted in a private nonprofit academic medical center. PATIENTS: The subjects were 66 consecutive patients (including 52 with acromegaly or prolactinoma) participating in a pituitary tumor database who consented to genetic study. MAIN OUTCOME MEASURE(S): The main outcome measure was the prevalence of these specific germline mutations in affected individuals. RESULTS: AIP mutations were not detected in the 66 patients. A synonymous polymorphism was found in a single patient with acromegaly. CONCLUSIONS: The three specific AIP germline mutations do not play an important role in pathogenesis of sporadic pituitary tumors in U.S. patients.

Adenoma↗
PubMed2003

Gene expression level influences amino acid usage, but not codon usage, in the tsetse fly endosymbiont Wigglesworthia.

Wigglesworthia glossinidia brevipalpis, the obligate bacterial endosymbiont of the tsetse fly Glossina brevipalpis, is characterized by extreme genome reduction and AT nucleotide composition bias. Here, multivariate statistical analyses are used to test the hypothesis that mutational bias and genetic drift shape synonymous codon usage and amino acid usage of Wigglesworthia. The results show that synonymous codon usage patterns vary little across the genome and do not distinguish genes of putative high and low expression levels, thus indicating a lack of translational selection. Extreme AT composition bias across the genome also drives relative amino acid usage, but predicted high-expression genes (ribosomal proteins and chaperonins) use GC-rich amino acids more frequently than do low-expression genes. The levels and configuration of amino acid differences between Wigglesworthia and Escherichia coli were compared to test the hypothesis that the relatively GC-rich amino acid profiles of high-expression genes reflect greater amino acid conservation at these loci. This hypothesis is supported by reduced levels of protein divergence at predicted high-expression Wigglesworthia genes and similar configurations of amino acid changes across expression categories. Combined, the results suggest that codon and amino acid usage in the Wigglesworthia genome reflect a strong AT mutational bias and elevated levels of genetic drift, consistent with expected effects of an endosymbiotic lifestyle and repeated population bottlenecks. However, these impacts of mutation and drift are apparently attenuated by selection on amino acid composition at high-expression genes.

Amino Acids↗
PubMed2004

Diversity of human immunodeficiency virus type 1 subtype A and CRF03_AB protease in Eastern Europe: selection of the V77I variant and its rapid spread in injecting drug user populations.

To characterize polymorphisms of the subtype A protease in the former Soviet Union, proviral DNA samples were obtained, with informed consent, from 119 human immunodeficiency virus type 1 (HIV-1)-positive untreated injecting drug users (IDUs) from 16 regions. All individuals studied have never been treated with antiretroviral drugs. The isolates were defined as IDU-A (n = 115) and CRF03_AB (n = 4) by using gag/env HMA/sequencing. The pro region was analyzed by using sequencing and original HIV-ProteaseChip hybridization technology. The mean of pairwise nucleotide distance between 27 pro sequences (23 IDU-A and 4 CRF03_AB) was low (1.38 +/- 0.79; range, 0.00 to 3.23). All sequences contained no primary resistance mutations. However, 13 of 23 (56.5%) subtype A isolates bore the V77I substitution known as the secondary protease mutation. V77I was associated with two synonymous substitutions in triplets 31 and 78, suggesting that all V77I-bearing viruses evolved from a single source in 1997. Hybridization analysis showed that 55 of 115 (47.8%) HIV-1 isolates contained V77I, but this variant was not found in any of 31 DNA samples taken from regions, where the HIV-1 epidemic among IDUs started earlier 1997, as well as in any of four CRF03_AB isolates. The results of analysis of 12 additional samples derived from epidemiologically linked subjects showed that in all four epidemiological clusters the genotype of the donor and the recipients was the same irrespective of the route of transmission. This finding demonstrates the transmission of the V77I mutant variant, which is spreading rapidly within the circulating viral pool in Russia and Kazakhstan. The continued molecular epidemiological and virological monitoring of HIV-1 worldwide thus remains of great importance.

Adolescent↗
PubMed2001

Phylogeny of Thogoto virus.

Thogoto virus is a tick-borne member of the family Orthomyxoviridae. Previously, based on the similarity in antigenic relationship by cross-neutralization test, all virus strains were concluded to have derived from the same origin. In this study, we obtained partial gene sequences of 4 genes (PB1-like protein, PA-like protein, glycoprotein, and nucleoprotein) of 8 Thogoto virus strains isolated in Africa, Asia, and Europe and studied the genetic variation and phylogeny. Unrooted phylogenetic trees created by both neighbor-joining and maximum likelihood methods based on nucleotide and amino acid sequences for 4 genes were mostly similar and revealed two lineages, Euro-Asian and African. Intra-lineage nucleotide sequence variation was greater in the Euro-Asian lineage than in the African lineage for all 4 genes. Furthermore, for the strains of Euro-Asian lineage, variations for two genes associated with RNA-dependent RNA polymerase activities were greater than those for glycoprotein or nucleoprotein gene, based on both nucleotide and amino acid sequence differences as well as on synonymous and nonsynonymous differences, indicating greater mutation rates for the polymerase activity genes in these strains.

Base Sequence↗