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PubMed2006

Identification of variations in the human phosphoinositide 3-kinase p110delta gene in children with primary B-cell immunodeficiency of unknown aetiology.

Our recent study demonstrated that defects in p110delta result in B-cell immunodeficiency that is very similar to that observed in BTK-deficient mice. We revealed that the p110delta fit the B-cell signal transduction complex and played a non-redundant role in the development and function of B cells. In humans, most children with primary B-cell immunodeficiency have mutations in the BTK, whereas a few have defects in the components of the B-cell signal transduction complex. But little is known about the genetic variation of p110delta in children with defects in B-cell immunodeficiency of unknown aetiology. Sixteen patients from 15 unrelated families and 112 normal controls underwent sequence analysis to identify genetic variations of the p110delta. Allele frequency in each group was also analysed and compared. We identified five single base-pair polymorphic nucleotide exchanges in both patient and control groups with similar allele frequencies, which did not contribute to the immunodeficiency. Three of them are novel (m.953A>G, m.1200C>T and m.1561A>G), and the m.953A>G and m.1561A>G nucleotide exchanges are non-synonymous (N253S and T456A, respectively). The novel m.1561A>G was in complete linkage disequilibrium with the known m.873A>G in our study of Taiwanese group. In addition, one novel single base-pair missense mutation, m.3256G>A (E1021K), was identified in one boy with typical clinical features of primary B-cell immunodeficiency and could not be found in either his family or the normal control population. By atomic structural analysis of the amino acid as well as the alignment comparison between species, it resulted in the replacement of the negative-charged amino acid E with the positive-charged amino acid K at codon 1021, located in the highly conservative and important catalytic functional domain. Our findings could shed light on further understanding the polymorphisms of p110delta in B-cell immunodeficiency and different populations. Moreover, the 3256G>A missense mutation raised the attention and warranted further extensive analysis to elucidate the role of p110delta in human immunodeficiency.

Amino Acid Sequence↗

PubMed2004

Are residues in a protein folding nucleus evolutionarily conserved?

Protein is the working molecule of the cell, and evolution is the hallmark of life. It is important to understand how protein folding and evolution influence each other. Several studies correlating experimental measurement of residue participation in folding nucleus and sequence conservation have reached different conclusions. These studies are based on assessment of sequence conservation at folding nucleus sites using entropy or relative entropy measurement derived from multiple sequence alignment. Here we report analysis of conservation of folding nucleus using an evolutionary model alternative to entropy-based approaches. We employ a continuous time Markov model of codon substitution to distinguish mutation fixed by evolution and mutation fixed by chance. This model takes into account bias in codon frequency, bias-favoring transition over transversion, as well as explicit phylogenetic information. We measure selection pressure using the ratio omega of synonymous versus non-synonymous substitution at individual residue site. The omega-values are estimated using the PAML method, a maximum-likelihood estimator. Our results show that there is little correlation between the extent of kinetic participation in protein folding nucleus as measured by experimental phi-value and selection pressure as measured by omega-value. In addition, two randomization tests failed to show that folding nucleus residues are significantly more conserved than the whole protein, or the median omega value of all residues in the protein. These results suggest that at the level of codon substitution, there is no indication that folding nucleus residues are significantly more conserved than other residues. We further reconstruct candidate ancestral residues of the folding nucleus and suggest possible test tube mutation studies for testing folding behavior of ancient folding nucleus.

Amino Acid Sequence↗

PubMed2005

Is ectopic expression caused by deregulatory mutations or due to gene-regulation leaks with evolutionary potential?

It has long been thought that gene expression is tightly regulated in multicellular eukaryotes, so that expression profiles match functional profiles. This conception emerged from the assumption that gene activity is synonymous with gene function. This paradigm was first challenged by comparative protein electrophoresis studies showing extensive differences in expression patterns among related species. The paradigm is now being challenged by evolutionary transcriptomics using microarray technologies. Most gene expression profiles display features that lack any obvious functional significance. The so-called "ectopic" expression refers to the expression of genes at times and locations where the target gene is not known to have a function. However, ectopic expression might be associated with genuine function even if this function is not essential or has yet to be ascertained. Alternatively, ectopic expression might come about as a superfluous by-product of regulatory systems, which would call for a revision of prevailing ideas about the specificity of gene regulation. We herein review available evidence for ectopic expression and the hypotheses proposed for its origin and evolution. We propose that ectopic expression must be regarded as part of an integrated phenotypic whole. It seems likely that ectopic expression represents a leak in the evolution of regulatory systems, but one that is endowed with considerable evolutionary possibilities.

Animals↗

PubMed1998

Analysis of the insulin receptor gene tyrosine kinase domain in obese patients with hyperandrogenism, insulin resistance and acanthosis nigricans (type C insulin resistance).

OBJECTIVE: To test the hypothesis that the triad of hyperandrogenism, insulin resistance and acanthosis nigricans (HAIR-AN syndrome) in the presence of obesity, also known as type C insulin resistance (type C), is caused by mutations at the tyrosine kinase domain of the insulin receptor gene. DESIGN: A candidate gene approach to study the molecular basis for a syndrome of obesity. SUBJECTS: 15 patients with type C insulin resistance and 25 control individuals. MEASUREMENTS: Analysis of polymerase chain reaction (PCR) products of exons 17 to 21 of the insulin receptor gene, comprising the tyrosine kinase domain, for single strand conformational polymorphisms (SSCP) and sequence analysis of exons with variant SSCP patterns. RESULTS: A synonymous C to T substitution in position 3 of codon 984, which does not alter the amino acid predicted, was found in one patient and in four of 25 control individuals. CONCLUSION: Type C insulin resistance is not commonly caused by mutations in the tyrosine kinase domain of the insulin receptor gene.

Acanthosis Nigricans↗

PubMed1999

Recent selection on synonymous codon usage in Drosophila.

Evidence from a variety of sources indicates that selection has influenced synonymous codon usage in Drosophila. It has generally been difficult, however, to distinguish selection that acted in the distant past from ongoing selection. However, under a neutral model, polymorphisms usually reflect more recent mutations than fixed differences between species and may, therefore, be useful for inferring recent selection. If the ancestral state is preferred, selection should shift the frequency distribution of derived states/site toward lower values; if the ancestral is unpreferred, selection should increase the number of derived states/site. Polymorphisms were classified as ancestrally preferred or unpreferred for several genes of D. simulans and D. melanogaster. A computer simulation of coalescence was employed to derive the expected frequency distributions of derived states/site under various modifications of the Wright-Fisher neutral model, and distributions of test statistics (t and Mann-Whitney U) were derived by appropriate sampling. One-tailed tests were applied to transformed frequency data to assess whether the two frequency distributions deviated from neutral expectations in the direction predicted by selection on codon usage. Several genes from D. simulans appear to be subject to recent selection on synonymous codons, including one gene with low codon bias, esterase-6. Selection may also be acting in D. melanogaster.

Animals↗

PubMed2004

Characterization of the Anaplasma marginale msp2 locus and its synteny with the omp1/p30 loci of Ehrlichia chaffeensis and E. canis.

Major surface protein 2 (MSP2) is an immunodominant and antigenically variant protein in the outer membrane of the rickettsia Anaplasma marginale. MSP2 variation is generated by recombination into a single operon-linked genomic expression site. The complete 5.6-kb msp2 locus was identified by sequencing a 90-kb region of the St. Maries strain of A. marginale. The locus encoded, in a 5' to 3' direction, a transcriptional regulator followed by five outer membrane proteins, OMP1, OpAG3, OpAG2, OpAG1, and MSP2. The sequences of this entire locus were analyzed using six genetically and phenotypically distinct strains of A. marginale. The overall locus structure was highly conserved with 100% identity among strains in the transcriptional regulator. Synonymous and nonsynonymous exchanges were infrequent in omp1 and rare in opag1 and opag2 among the six strains without strong bias for either type of exchange (neutral mutations). In contrast, mutations in opag3 seem to underlie purifying (negative) selection reflecting pressure to retain protein structure, in marked contrast to the highly antigenically variant MSP2. Interestingly, the 5' structure of this A. marginale msp2 locus is conserved in the omp1 gene locus of Ehrlichia chaffeensis and p30 gene locus of E. canis despite marked divergence between genera in the structure of the 3' region of the loci. This supports the hypothesis that the expression sites of these important immunogenic proteins are derived from a common precursor with later divergent evolution along genus lines.

Anaplasma marginale↗

PubMed2005

Single nucleotide polymorphisms in genes for 2'-5'-oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infection.

BACKGROUND: Infection with the flavivirus West Nile virus (WNV) is a growing problem across the United States, where there is a case-fatality rate of 15%-29% in individuals >70 years old and no consistently effective treatment. Susceptibility to WNV disease in inbred strains of mice was mapped to a nonsense mutation in the gene encoding the 1b isoform of 2'-5'-oligoadenylate synthetase (OAS), a member of the OAS/RNase L system of innate viral resistance. Genetic susceptibility to severe WNV disease in humans has not been determined. METHODS: We sequenced each exon within all OAS and RNASEL genes in 33 individuals hospitalized with WNV infection in Houston to assess if there is a defect in this system in patients with severe WNV disease. RESULTS: Sequencing did not reveal any insertions, deletions, or nonsense mutations in any OAS or RNASEL gene. However, comparison of the exonic sequences between case patients and control subjects identified 23 single nucleotide polymorphisms (SNPs), including a synonymous SNP in OASL exon 2 (rs3213545), in which the reference allele occurred at a higher frequency in case patients (P < .004). CONCLUSION: Because the reference allele contains a splice enhancer site, our finding suggests that the RNA transcripts generated from this allele may undergo increased splicing, which results in a dominant-negative OASL isozyme similar to the nonsense/truncation mutant form of Oas1b in mice.

2',5'-Oligoadenylate Synthetase↗

PubMed2001

V3 variation in HIV-seropositive patients receiving a V3- targeted vaccine.

OBJECTIVE: To analyze V3 loop sequences of HIV-1 in three seropositive individuals who exhibited declines in viremia while receiving a V3-targeted vaccine. DESIGN: Retrospective analysis of case series at an HIV Clinic, University of Tel Aviv. PATIENTS: Three HIV-1-seropositive, PPD-DTHR-positive (PPD, Siebert purified protein derivative of tuberculin; DTHR, delayed type hypersensitivity reaction) individuals who had been inoculated with a mixture of PPD-cross-linked V3 peptides from five HIV strains and then exhibited declines in HIV-1 viremia during the course of vaccination in the absence of combination antiretroviral therapy and whose virus levels resurged once vaccine boosting was discontinued. RESULTS: Declines in viremia were observed even when the viral V3 sequences of the patients' HIV differed by at least one or two amino acid residues from those of the five peptides in the vaccine. Although viral mutants with amino acid substitutions within V3 appeared during vaccination, plasma virus loads remained at low levels for several months after these variants appeared. About a year after boosting was discontinued, anti-V3 peptide antibodies in the patients had declined and plasma virus returned to the prevaccination levels or higher. Compared with the isolates that predominated during the course of vaccination, the resurgent viruses contained zero to six amino acid residue differences in the V3 loop but few synonymous substitutions. CONCLUSIONS: Viruses with altered V3 sequences did emerge but did not result in increased viremia during the course of vaccination. In two individuals where V3 mutations were absent in the virus that re-emerged after vaccine boosting ceased, resurgence could not have been a consequence of V3 changes.

AIDS Vaccines↗

PubMed1998

Evolution of envelope sequences from the genital tract and peripheral blood of women infected with clade A human immunodeficiency virus type 1.

The development of viral diversity during the course of human immunodeficiency virus type 1 (HIV-1) infection may significantly influence viral pathogenesis. The paradigm for HIV-1 evolution is based primarily on studies of male cohorts in which individuals were presumably infected with a single virus variant of subtype B HIV-1. In this study, we evaluated virus evolution based on sequence information of the V1, V2, and V3 portions of HIV-1 clade A envelope genes obtained from peripheral blood and cervical secretions of three women with genetically heterogeneous viral populations near seroconversion. At the first sample following seroconversion, the number of nonsynonymous substitutions per potential nonsynonymous site (dn) significantly exceeded substitutions at potential synonymous sites (ds) in plasma viral sequences from all individuals. Generally, values of dn remained higher than values of ds as sequences from blood or mucosa evolved. Mutations affected each of the three variable regions of the envelope gene differently; insertions and deletions dominated changes in V1, substitutions involving charged amino acids occurred in V2, and sequential replacement of amino acids over time at a small subset of positions distinguished V3. The relationship among envelope nucleotide sequences obtained from peripheral blood mononuclear cells, plasma, and cervical secretions was evaluated for each individual by both phylogenetic and phenetic analyses. In all subjects, sequences from within each tissue compartment were more closely related to each other than to sequences from other tissues (phylogenetic tissue compartmentalization). At time points after seroconversion in two individuals, there was also greater genetic identity among sequences from the same tissue compartment than among sequences from different tissue compartments (phenetic tissue compartmentalization). Over time, temporal phylogenetic and phenetic structure was detectable in mucosal and plasma viral samples from all three women, suggesting a continual process of migration of one or a few infected cells into each compartment followed by localized expansion and evolution of that population.

Amino Acid Sequence↗

PubMed1996

Clinical significance of drug resistance in HIV-1 infection.

OVERVIEW: The limited duration of clinical benefit from nucleoside analogue therapy for HIV-1 infection may be explained, in part, by the emergence of virus isolates resistant to the drugs used. Additional reasons may include the presence of syncytium-inducing variants of HIV-1, progressive increase in viral load and progressive immunologic decline despite antiretroviral therapy. DISCUSSION: Antiretroviral therapy may inevitably select for mutational changes in HIV-1 populations. However, recent advances in the understanding of drug resistance in HIV-1 infection suggest that, in certain cases, genotypic and phenotypic changes associated with drug resistance in vitro are not always synonymous with clinical drug failure. We consider the following examples: (1) the benefit of switching therapy may be independent of drug resistance; (2) patients may progress on therapy despite persistence of 'sensitive' virus; (3) drug susceptibility testing may underestimate the significance of drug resistance, and antiviral activity may persist despite resistance; and (4) resistance may be overcome with higher dosing. CONCLUSION: Laboratory evidence for drug resistance does not necessarily imply clinical drug failure. Emergence of (-)-2',3-d-deoxy-3'-thiacytidine (3TC, lamivudine) resistance may potentiate activity of zidovudine in patients treated with 3TC/zidovudine combination therapy. Novel therapeutic strategies that exploit this mutational interaction, or challenge the limits of adaptation of the virus, may lead to more effective long-term suppression of HIV-1.

Anti-HIV Agents↗

PubMed2005

Genomic divergence of Escherichia coli strains: evidence for horizontal transfer and variation in mutation rates.

This report describes the sequencing in the Escherichia coli B genome of 36 randomly chosen regions that are present in most or all of the fully sequenced E. coli genomes. The phylogenetic relationships among E. coli strains were examined, and evidence for the horizontal gene transfer and variation in mutation rates was determined. The overall phylogenetic tree indicated that E. coli B and K-12 are the most closely related strains, with E. coli O157:H7 being more distantly related, Shigella flexneri 2a even more, and E. coli CFT073 the most distant strain. Within the B, K-12, and O157:H7 clusters, several regions supported alternative topologies. While horizontal transfer may explain these phylogenetic incongruities, faster evolution at synonymous sites along the O157:H7 lineage was also identified. Further interpretation of these results is confounded by an association among genes showing more rapid evolution and results supporting horizontal transfer. Using genes supporting the B and K-12 clusters, an estimate of the genomic mutation rate from a long-term experiment with E. coli B, and an estimate of 200 generations per year, it was estimated that B and K-12 diverged several hundred thousand years ago, while O157:H7 split off from their common ancestor about 1.5-2 million years ago.

Codon↗

PubMed2006

Random mutagenesis of wheat streak mosaic virus HC-Pro: non-infectious interfering mutations in a gene dispensable for systemic infection of plants.

Mutations within the HC-Pro coding region of Wheat streak mosaic virus (WSMV) were introduced by misincorporation during PCR and evaluated for phenotype within the context of an infectious clone. Nine synonymous substitutions and 15 of 25 non-synonymous substitutions had no phenotypic effect. Four non-synonymous substitutions, including one that reverted consistently to wild type, resulted in attenuated systemic infection. Six non-synonymous substitutions and one nonsense substitution abolished systemic infectivity. Mutants bearing the GUS reporter gene were evaluated for the ability to establish primary infection foci. All attenuated mutants and two systemic infection-deficient mutants produced localized regions of GUS expression on inoculated leaves 3 days post-inoculation. In vitro assays revealed that mutants able to establish infection foci retained HC-Pro proteinase activity. Among mutants unable to establish infection foci, HC-Pro proteinase activity was retained, reduced or absent. As a complete HC-Pro deletion mutant can infect plants systemically, certain substitutions in this dispensable gene probably prevented infection of WSMV via interference.

Base Sequence↗

PubMed2001

Human immunodeficiency virus type 1 reverse-transcriptase and protease subtypes: classification, amino acid mutation patterns, and prevalence in a northern California clinic-based population.

Phylogenetic analysis of the reverse transcriptase (RT) and protease of 117 published complete human immunodeficiency virus (HIV) type 1 genome sequences demonstrated that these genes cluster into distinct subtypes. There was a slightly higher proportion of informative sites in the RT (40.4%) than in the protease (34.8%; P= .03). Although most variation between subtypes was due to synonymous nucleotide substitutions, several subtype-specific amino acid patterns were observed. In the protease, the subtype-specific variants included 7 positions associated with drug resistance. Variants at positions 10, 20, 36, and 82 were more common in non-B isolates, whereas variants at positions 63, 77, and 93 were more common in subtype B isolates. In the RT, the subtype-specific mutations did not include positions associated with anti-retroviral drug resistance. RT and protease sequences from 2246 HIV-infected persons in northern California were also examined: 99.4% of the sequences clustered with subtype B, whereas 0.6% clustered with subtype A, C, or D.

Amino Acid Sequence↗

PubMed2007

Somatic sequence alterations in twenty-one genes selected by expression profile analysis of breast carcinomas.

INTRODUCTION: Genomic alterations have been observed in breast carcinomas that affect the capacity of cells to regulate proliferation, signaling, and metastasis. Re-sequence studies have investigated candidate genes based on prior genetic observations (changes in copy number or regions of genetic instability) or other laboratory observations and have defined critical somatic mutations in genes such as TP53 and PIK3CA. METHODS: We have extended the paradigm and analyzed 21 genes primarily identified by expression profiling studies, which are useful for breast cancer subtyping and prognosis. This study conducted a bidirectional re-sequence analysis of all exons and 5', 3', and evolutionarily conserved regions (spanning more than 16 megabases) in 91 breast tumor samples. RESULTS: Eighty-seven unique somatic alterations were identified in 16 genes. Seventy-eight were single base pair alterations, of which 23 were missense mutations; 55 were distributed across conserved intronic regions or the 5' and 3' regions. There were nine insertion/deletions. Because there is no a priori way to predict whether any one of the identified synonymous and noncoding somatic alterations disrupt function, analysis unique to each gene will be required to establish whether it is a tumor suppressor gene or whether there is no effect. In five genes, no somatic alterations were observed. CONCLUSION: The study confirms the value of re-sequence analysis in cancer gene discovery and underscores the importance of characterizing somatic alterations across genes that are related not only by function, or functional pathways, but also based upon expression patterns.

Breast Neoplasms↗

PubMed2001

MtDNA mutations in maternally inherited diabetes: presence of the 3397 ND1 mutation previously associated with Alzheimer's and Parkinson's disease.

Mutations in the mitochondrial tRNA(leu) (UUR) gene have been associated with diabetes mellitus and deafness. We screened for the presence of mtDNA mutations in the tRNA(leu) (UUR) gene and adjacent ND1 sequences in 12 diabetes mellitus pedigrees with a possible maternal inheritance of the disease. One patient carried a G to A substitution at nt 3243 (tRNA(leu) (UUR) gene) in heteroplasmic state. In a second pedigree a patient had an A to G substitution at nt 3397 in the ND1 gene. All maternal relatives of the proband had the 3397 substitution in homoplasmic state. This substitution was not present in 246 nonsymptomatic Caucasian controls. The 3397 substitution changes a highly conserved methionine to a valine at aa 31 and has previously been found in Alzheimer's (AD) and Parkinson's (PD) disease patients. Substitutions in the mitochondrial ND1 gene at aa 30 and 31 have associated with a number of different diseases (e.g. AD/PD, MELAS, cardiomyopathy and diabetes mellitus, LHON, Wolfram-syndrome and maternal inherited diabetes) suggesting that changes at these two codons may be associated with very diverse pathogenic processes. In a further attempt to search for mtDNA mutations outside the tRNAleu gene associated with diabetes, the whole mtDNA genome sequence was determined for two patients with maternally inherited diabetes and deafness. Except for substitutions previously reported as polymorphisms, none of the two patients showed any non-synonymous substitutions either in homoplasmic or heteroplasmic state. These results imply that the maternal inherited diabetes and deafness in these patients must result from alterations of nuclear genes and/or environmental factors.

Alzheimer Disease↗

PubMed1983

The significance of redundancy in the genetic code.

The genetic code has an inherent bias towards some amino acids because of the variable number of synonymous codons per amino acid. In proteins generally, this bias is expressed in the relative proportions of the twenty amino acids. It is suggested that even though neutral mutation may be responsible for the expression of this bias, the latter could be providing a positive advantage by directing mutation to introduce chemically simpler and more immutable amino acids where selective criteria have become relaxed.

Amino Acid Sequence↗

PubMed2005

High divergence among Drosophila simulans mitochondrial haplogroups arose in midst of long term purifying selection.

We characterize the type of selection acting within and among mitochondrial lineages in five closely related Drosophila species. We focus on D. simulans, where three genetically distinct mitochondrial haplogroups show high interhaplogroup divergence and low intrahaplogroup polymorphism. Using maximum likelihood models we find that the branches leading to these three distinct mitochondrial groups show a significantly reduced rate of nonsynonymous relative to synonymous substitution. This interhaplogroup rate is significantly reduced compared to the intrahaplogroup rate, and closely resembles the rate observed between distinct species. The data suggest that slightly deleterious mutations segregating within D. simulans haplogroups are removed by selection prior to their fixation among haplogroups. We explore several hypotheses to explain how lineages within a single species can be compatible with this model of slightly deleterious mutation. The most likely hypothesis is that D. simulans haplogroups have persisted in isolation, perhaps due to association with the bacterial symbiont Wolbachia and/or demographic history, introducing a bias against the fixation of slightly deleterious mutations.

Animals↗

PubMed2000

Diphtheria toxin NAD affinity and ADP ribosyltransferase activity are reduced at tryptophan 153 substitutions for alanine or phenylalanine.

Previous studies on chemical modifications of diphtheria toxin (DT) fragment A have suggested that the Trp153 amino acid residue is essential for the ADP ribosylation of elongation factor 2. We verified this experimentally after replacing Trp153 by Phe or Ala residues through in vitro mutagenesis of a cloned toxin gene fragment. Each of the mutant fragment A forms were found to reveal a reduced ADP ribosyl transferase (ADPRT) activity as well as lower affinity for NAD. Both ADPRT activity and NAD affinity of DT fragment A were only partially destroyed by nearly synonymous Trp153 ==> Phe153 substitution, but dramatically destroyed by Ala153 substitution. At the same time, each of the mutant fragment A forms appeared to be thermostable, suggesting that the mutations do not dramatically destroy the structure of the protein. These results clearly demonstrate that Trp153 is not highly specific for DT fragment A structure maintenance, but is highly specific for the key toxin functions such as ADP ribosylation of elongation factor 2 and NAD binding. We suggest that the Trp153 role in DT functioning may be that of binding the ribose moiety of NAD, which is crucial for DT catalytic activity and hence for toxicity.

Adenosine Diphosphate Ribose↗