Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Allele replacement”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 631 records · Page 35Linked to original sources
PubMed1977

Frequency of the gene for cystic fibrosis with a view of replacement and recognition effects and reproduction by homozygotes.

The apparent frequency of the recessive autosomal allele for cystic fibrosis (cf) is too high to be satisfactorily explained by mutation equilibrium. However, higher reproductive fitness by heterozygotes (expressed by t greater than 0) or higher gametic viability of the cf allele (expressed by a greater than 0.5) can provide reasonable explanations of the present frequency. Furthermore, birth replacement in families with CF children (RPE) can account for the estimated historical values of t. Today, however, t is probably at or approaching zero as a result of discontinuation of RPE. In the future we can look for an imperceptibly slow decrease in the incidence of CF. Reproduction by CF females will not cause an increase in incidence; it will only slightly slow the rate of decrease.

Cystic Fibrosis↗
PubMed1989

Sequence and gene transfer analyses of HLA-CwBL18 (HLA-C blank) and HLA-Cw5 genes. Implications for the control of expression and immunogenicity of HLA-C antigens.

Our previous studies suggested that a serologically undetectable HLA-C blank allele (HLA-CwBL18) is either a variant Cw5 allele or a novel HLA-C Ag. To examine these possibilities, the CwBL18 and Cw5 genes from the TCC (HLA-A1, -A2, -B52, -B18, -Cw-, -Cw-) and QBL (HLA-A26, -B18, -Cw5) EBV-transformed B lymphoblastoid cell lines (LCL) were cloned, sequenced, and transferred into HLA-A, -B, -C null LCL mutant .221 cells. The CwBL18 Ag was detected on the cell surface of CwBL18 transferents by flow cytometry with the anti-class I mAb W6/32 but not by complement-mediated cytotoxicity with currently available HLA-C specific antisera. Sequence analysis of the Cw-BL18 gene indicated that the CwBL18 Ag is "C"-like because it contains all C-locus-specific residues and amino acid replacements commonly found in HLA-C alleles. However, the amino acid sequence of the CwBL18 Ag is unusual; CwBL18 lacks unique allele-specific residues when compared with the sequences of other HLA-C alleles. Moreover, apart from the C-locus-specific differences, the sequence of CwBL18 is identical to the HLA class I consensus sequence. This striking homology of CwBL18 to other HLA class I alleles suggests that CwBL18 may be a weak Ag. Taken together, these data demonstrate that CwBL18 is not a variant Cw5 Ag but is a newly described HLA-C Ag. In contrast to CwBL18, the Cw5 Ag is serologically detectable on the cell surface of Cw5 transferents with HLA-specific allo-antisera. Rather unexpectedly, Cw5 was usually expressed at a lower level than CwBL18 on the surface of .221 transferents as evaluated by W6/32 mAb binding analyses. The sequence of Cw5 revealed several unique amino acid replacements. Two of these substitutions, at residue 35 of the alpha 1 domain and residue 275 of the transmembrane domain, may be responsible for the reduced cell surface expression of Cw5. Additional unique replacements at residues 138 and 177 of the alpha 2 domain suggest that these amino acids may be important in the formation of an epitope recognized by a Cw5-specific antibody.

Amino Acid Sequence↗
PubMed1999

let-756, a C. elegans fgf essential for worm development.

In vertebrates, Fibroblast Growth Factors (FGFs) and their receptors are involved in various developmental and pathological processes, including neoplasia. The number of FGFs and their large range of activities have made the understanding of their precise functions difficult. Investigating their biology in other species might be enlightening. A sequence encoding a putative protein presenting 30-40% identity with the conserved core of vertebrate FGFs has been identified by the C. elegans sequencing consortium. We show here that this gene is transcribed and encodes a putative protein of 425 amino acids (aa). The gene is expressed at all stages of development beyond late embryogenesis, peaking at the larval stages. Loss-of-function mutants of the let-756 gene are rescued by the wild type fgf gene in germline transformation experiments. Two partial loss-of-function alleles, s2613 and s2809, have a mutation that replaces aa 317 by a stop. The truncated protein retains the FGF core but lacks a C-termins portion. These worms are small and develop slowly into clear and scrawny, yet viable and fertile adults. A third allele, s2887, is inactivated by an inversion that disrupts the first exon. It causes a developmental arrest early in the larval stages. Thus, in contrast to the other nematode fgf gene egl-17, let-756/fgf is essential for worm development.

Amino Acid Sequence↗
PubMed1997

Changes in locus-specific V(D)J recombinase activity induced by immunoglobulin gene products during B cell development.

The process of V(D)J recombination is crucial for regulating the development of B cells and for determining their eventual antigen specificity. Here we assess the developmental regulation of the V(D)J recombinase directly, by monitoring the double-stranded DNA breaks produced in the process of V(D)J recombination. This analysis provides a measure of recombinase activity at immunoglobulin heavy and light chain loci across defined developmental stages spanning the process of B cell development. We find that expression of a complete immunoglobulin heavy chain protein is accompanied by a drastic change in the targeting of V(D)J recombinase activity, from being predominantly active at the heavy chain locus in pro-B cells to being exclusively restricted to the light chain loci in pre-B cells. This switch in locus-specific recombinase activity results in allelic exclusion at the immunoglobulin heavy chain locus. Allelic exclusion is maintained by a different mechanism at the light chain locus. We find that immature, but not mature, B cells that already express a functional light chain protein can undergo continued light chain gene rearrangement, by replacement of the original rearrangement on the same allele. Finally, we find that the developmentally regulated targeting of V(D)J recombination is unaffected by enforced rapid transit through the cell cycle induced by an E mu-myc transgene.

Animals↗
PubMed2005

Identification of three novel HLA class I alleles: HLA-A*0261, HLA-B*1585 and HLA-B*1587.

Three novel human leucocyte antigen (HLA) class I alleles have been characterized by means of direct DNA sequencing analysis. HLA-A* 0261 showed sequence variation at conserved codon. It differs from HLA-A* 020601 by a single-nucleotide substitution at codon 57 (CCG-->GCG) resulting in an amino acid change from Pro to Ala. The sequences of HLA-B*1585 are similar to those of HLA-B*15010101, but differed five nucleotides on exon 3 resulting in three amino acid changes at residues 94 (Thr-->Ile), 95 (Leu-->Ile) and 103 (Val-->Leu). Likewise, HLA-B*1587 is identical to HLA-B*15010101 except at codons 80-83 (Asn-Leu-Arg-Gly-->Ile-Ala-Leu-Arg) which has been replaced by HLA-Bw4 motif. These alleles seemed to be generated by either a point mutation or a gene conversion-like event from alleles existing in the population with high frequencies.

Adult↗
PubMed1999

The mutA mistranslator tRNA-induced mutator phenotype requires recA and recB genes, but not the derepression of lexA-regulated functions.

The mapping of mutA and mutC mutator alleles to the glyV and glyW glycine tRNA genes, respectively, and the subsequent discovery that the mutA phenotype is abolished in a DeltarecA strain raise the possibility that asp --> gly misinsertion may induce a novel mutagenic pathway. The recA requirement suggests three possibilities: (i) the SOS mutagenesis pathway is activated in mutA cells; (ii) loss of recA function interferes with mutA-promoted asp --> gly misinsertion; or (iii) a hitherto unrecognized recA-dependent mutagenic pathway is activated by translational stress. By assaying the expression levels of a reporter plasmid bearing a umuC :lacZ fusion, we show that the SOS regulon is not in a derepressed state in mutA cells. Neither overexpression of the lexA gene through a multicopy plasmid nor replacement of the wild-type lexA allele with the lexA1[Ind-] allele interferes with the expression of the mutA phenotype. The mutA phenotype is unaffected in cells defective for dinB, as shown here, and is unaffected in cells defective for umuD and umuC genes, as shown previously. We show that mutA-promoted asp --> gly misinsertion occurs in recA- cells and, therefore, the requirement for recA is 'downstream' of mistranslation. Finally, we show that the mutA phenotype is abolished in cells deficient for recB, suggesting that cellular recombination functions may be required for the expression of the mutator phenotype. We propose that translational stress induces a previously unrecognized mutagenic pathway in Escherichia coli.

Alleles↗
PubMed1986

An inversion that disrupts the Antennapedia gene causes abnormal structure and localization of RNAs.

Mutations in Drosophila homeotic genes lead to the developmental replacement of one normal body part by another. We have examined the mechanism by which a dominant allele of the Antennapedia (Antp) gene causes the antennae to be replaced by legs. Normal Antp gene activity is required for thoracic but not for head development. We demonstrate that the Antp73b inversion mutation results in Antp transcription in the head. Antp transcripts found in this abnormal location are of two types: normal-sized Antp RNAs and fusion RNAs joining Antp exons (including the protein-coding region) to 5' exons from another gene. This foreign gene is normally expressed in the head, suggesting the cause for abnormal activation of Antp. The result is a change of cell identity from head to thorax.

Animals↗
PubMed1995

Biological characterization of nef in long-term survivors of human immunodeficiency virus type 1 infection.

We have previously shown that there were no gross deletions or obvious sequence abnormalities within nef of human immunodeficiency virus type 1 (HIV-1) in the 10 long-term survivors studied (Y. Huang, L. Zhang, and D. D. Ho, J. Virol. 69:93-100, 1995). Here we extend our study to examine these nef alleles in a functional context. Using a new technique, termed site-directed gene replacement, we have precisely replaced the nef of an infectious molecular clone, HIV-1HXB2, with nef alleles derived from 10 long-term survivors as well as from a patient with AIDS. The replication properties of these chimeric viruses demonstrated that the nef alleles derived from long-term survivors neither significantly increased nor decreased viral replication, compared with the nef allele of Nef+ HIV-1HXB2 and that derived from a patient with AIDS. However, Nef+ viruses always replicated faster than virus lacking nef. Moreover, single-cell infection analysis by the MAGI assay showed that these chimeric viruses, as well as Nef+ HIV-1HXB2, were more infectious than Nef- HIV-1HXB2 was. Therefore, we conclude that the genotypic and phenotypic features of nef are not likely to account for the nonprogression of HIV-1 infection in the 10 cases studied, unless the function of the nef gene in vivo is not accurately reflected by the in vitro assays we used.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Construction and analysis of a Streptococcus parasanguis recA mutant: homologous recombination is not required for adhesion in an in vitro tooth surface model.

PCR was used to amplify an internal region of the recA gene from Streptococcus parasanguis FW213. The PCR fragment was used as a probe to recover the entire streptococcal recA gene from an S. parasanguis genomic library, and the sequence of the gene was determined. The deduced product of the S. parasanguis recA gene showed a high degree of amino acid identity with other prokaryotic RecA proteins. The cloned recA sequence was disrupted in vitro by insertional mutagenesis, and the mutated allele was then introduced into the S. parasanguis chromosome by homologous recombination. Results of Southern hybridizations confirmed the replacement of the wild-type recA gene with the mutated allele. The recA mutant strain was considerably more sensitive to UV light than the parental strain, and this phenotype was consistent with a mutation in recA. The S. parasanguis recA mutant showed no reduction in its ability to adhere in the in vitro tooth surface model, saliva-coated hydroxylapatite (SHA), or in its ability to express the fimbria-associated adhesin Fap1. These results demonstrate that in vitro attachment of S. parasanguis FW213 to SHA and expression of Fap1 are recA independent.

Adhesins, Bacterial↗
PubMed1999

Ornithine decarboxylase gene deletion mutants of Leishmania donovani.

A knockout strain of Leishmania donovani lacking both ornithine decarboxylase (ODC) alleles has been created by targeted gene replacement. Growth of Deltaodc cells in polyamine-deficient medium resulted in a rapid and profound depletion of cellular putrescine pools, although levels of spermidine were relatively unaffected. Concentrations of trypanothione, a spermidine conjugate, were also reduced, whereas glutathione concentrations were augmented. The Deltaodc L. donovani exhibited an auxotrophy for polyamines that could be circumvented by the addition of the naturally occurring polyamines, putrescine or spermidine, to the culture medium. Whereas putrescine supplementation restored intracellular pools of both putrescine and spermidine, exogenous spermidine was not converted back to putrescine, indicating that spermidine alone is sufficient to meet the polyamine requirement, and that L. donovani does not express the enzymatic machinery for polyamine degradation. The lack of a polyamine catabolic pathway in intact parasites was confirmed radiometrically. In addition, the Deltaodc strain could grow in medium supplemented with either 1,3-diaminopropane or 1, 5-diaminopentane (cadaverine), but polyamine auxotrophy could not be overcome by other aliphatic diamines or spermine. These data establish genetically that ODC is an essential gene in L. donovani, define the polyamine requirements of the parasite, and reveal the absence of a polyamine-degradative pathway.

Alleles↗
PubMed1996

Mucopolysaccharidosis IVA: submicroscopic deletion of 16q24.3 and a novel R386C mutation of N-acetylgalactosamine-6-sulfate sulfatase gene in a classical Morquio disease.

The N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene, which is responsible for autosomal recessive mucopolysaccharidosis IVA (MPSIVA), has been assigned to the long arm of chromosome 16, subregion 24.3, an area where the adenine phosophoribosyltransferase (APRT) gene and renal dipeptidase (DPEP I) gene are also localized. Molecular genetic studies on a severely affected patient with MPSIVA (Morquio disease), without karyotypic abnormality, revealed a partial submicroscopic deletion of 16q24.3 and a single point mutation on the other allele, with no functional GALNS activity. The patient, his mother, and siblings were hemizygous for GALNS and APRT loci, evidenced by informative RFLP and gene dosage analyses combined with a fluorescence in situ hybridization, utilizing a partial genomic clone of GALNS, but heterozygosity was retained at the DPEP I locus and proximal D16S7. Haplotyping of the family members revealed recombinational events between DPEP I locus and three other polymorphic loci on the paternal chromosome, localizing GALNS gene on the proximal side to DPEP I gene. As estimated from the genetic distance between two flanking markers of proximal D16S7 and distal DPEP I locus, size of the deletion was less than 3Mb. Mother of the boy and two older siblings were asymptomatic, despite this interstitial deletion of the Giemsa-light G band. The remaining paternal allele had no gene rearrangement but GALNS activity was not encoded as Arginine at 386 was replaced with Cysteine (R386C), suggesting this alteration accounts for the severe phenotype. Allelic loss of APRT is frequently observed in cancer tissues, thereby suggesting that the tumor suppressor gene locates near the APRT locus. No family member has evidence of any malignant disease. This study is apparently the first documentation of interstitial deletion of 16q24.3, involving GALNS and APRT genes.

Adenine Phosphoribosyltransferase↗
PubMed1995

CYP52 (cytochrome P450alk) multigene family in Candida maltosa: identification and characterization of eight members.

Previously, we characterized three genes and presented evidence for an n-alkane-inducible cytochrome P450 (P450alk) multigene family in an n-alkane-assimilating and diploid-type yeast, Candida maltosa. In the present report, we isolated and characterized additional members of this gene family, including a total of thirteen P450alk-related sequences (eight genes and five of their alleles). Two sets, each consisting of two genes, were tandemly arranged in the genome. A gene replacement experiment showed that at least one gene had only a single allele in the genome. The determined nucleotide and the deduced amino acid sequences indicated that all had a characteristic constituent for P450s and exhibited amino acid identities from 94% to 37% to each other. Six genes showed relatively higher similarities to each other than to the other two genes and were thus classified into a subfamily. All the members of this subfamily were assigned to the same single chromosome, showing a good correlation between sequence similarity and chromosomal linkage. Although all the genes except for one were induced by n-alkane, their inducibilities by some other aliphatic carbon sources showed variabilities.

Alleles↗
PubMed1995

Sequence diversity and unusual variability at the het-c locus involved in vegetative incompatibility in the fungus Podospora anserina.

The het-c locus of the filamentous fungus Podospora anserina controls heterokaryon formation through genetic interaction with alleles of the unlinked loci het-e and het-d. We have isolated four wild-type and two mutant alleles of the het-c locus. A comparison of the predicted proteins encoded by the different wild-type alleles revealed an unusual high level of amino-acid replacements compared to silent polymorphisms but only one amino-acid difference is sufficient to modify the specificity of het-c alleles. Chimeric genes constructed in vitro may exhibit a new specificity different from that of any known wild-type allele.

Alleles↗
PubMed1991

Mutations at rfc or pmi attenuate Salmonella typhimurium virulence for mice.

Insertion mutations were constructed in cloned pmi and rfc genes of Salmonella typhimurium, and these mutations were recombined (singly) into the chromosome of mouse-virulent S. typhimurium C5, displacing the wild-type alleles. Phage sensitivity profiles, lipopolysaccharide analysis, and DNA blotting all confirmed that the replacement events had occurred. The mutations were complemented by plasmid-borne wild-type alleles, as judged by the restoration of wild-type phage plaquing profiles and lipopolysaccharide production (both mutants) and the restoration of pmi-encoded enzyme production (pmi mutant). The virulence, persistence, and immunizing capacities of the mutants fed to mice were compared with those of the wild-type strain and complemented mutants. Both mutants were much reduced in virulence, with the rfc mutant being avirulent even at 10(9) bacteria per mouse. This mutant was also avirulent at up to 10(6) bacteria per mouse when administered intraperitoneally. Both the rfc and pmi mutant strains persisted in the Peyer's patches of the gut after feeding and were capable of colonizing the deeper tissues of the mice from such initial infective foci. Both mutant strains were effective as live oral vaccines (10(7) bacteria or more) against oral S. typhimurium challenge (10(4) 50% lethal doses; 6 x 10(8) bacteria) in mice.

Animals↗
PubMed2006

Impact of small fitness costs on pest adaptation to crop varieties with multiple toxins: a heuristic model.

A deterministic two-locus model was used to examine how small fitness costs to individuals carrying resistance alleles could impact the risk of panmictic insect pest populations adapting to crop varieties that produced two distinct toxins. Parameters examined were (1) level of toxicity of each toxin, (2) initial frequencies of alleles for adaptation to the toxins, (3) percentage of population feeding on nontoxic plants, and (4) level of fitness cost associated with adaptation to each of the two toxins. Resistance to each toxin was assumed to be biochemically independent, controlled by a resistance coding allele at a single locus, and inherited as a partially recessive trait in the field. When plants are extremely toxic to the pest, effective refuge size is 10%, and there is a fitness cost to resistance alleles only when in homozygous form (5%), the pest population is never predicted to adapt to either toxin as long as the initial frequencies of the resistance alleles are below 0.05. Even if the initial frequency of the allele for adapting to one toxin is 0.95 when a two-toxin cultivar completely replaces a one-toxin cultivar, the model predicts that a low equilibrium allelic frequency will develop for both resistance alleles, as long as the frequency of the allele for adapting to the second toxin is initially 0.001 or less. If cultivars with one and two toxins are planted, the model predicts that resistance will develop. Nonrandom mating and stochastic variation within subpopulations also could lead to evolution of resistance.

Adaptation, Physiological↗
PubMed1976

The mucopolysaccharidoses (a review).

The mucopolysaccharidoses are a group of genetic diseases characterized by storage of incompletely degraded glycosaminoglycans. Such storage causes marked distortion of many tissues with consequent severe somatic changes and mental retardation. Storage of glycosaminoglycans results from markedly diminished activity of specific hydrolases requisite for the normal degradation of glycosaminoglycans. The specific enzymic defects have been identified in nine different diseases. In some cases evidence has been obtained indicating the existence of additional allelic diseases based on the same enzyme. The knowledge obtained from these studies has made prenatal diagnosis possible and has led to the possibility that therapy may be undertaken utilizing enzyme replacement.

Acetylglucosaminidase↗
PubMed2005

On the worldwide spread of an insecticide resistance gene: a role for local selection.

Adaptation occurs by gene replacement (or transient balanced polymorphism). Replacement may be caused by selection (local or global) and/or genetic drift among alleles. In addition, historical events may blur the respective effects of selection and drift during the course of replacement. We address the relative importance of these processes in the evolution of insecticide resistance genes in the mosquito Culex pipiens. The resistance allele, Ester2, has a broad geographic distribution compared to the other resistance alleles. To distinguish between the different processes explaining this distribution, we reviewed the literature and analysed updated data from the Montpellier area of southern France. Overall, our data indicate that Ester2 prevails over other Ester resistance alleles in moderately treated areas. Such conditions are common and favour the hypothesis of selection acting at a local level. This places an emphasis on the importance of ecological conditions during the evolution of resistance. Finally, we highlight that historical events have contributed to its spread in some areas.

Adaptation, Physiological↗
PubMed1990

Cloning of genes involved in erythromycin biosynthesis from Saccharopolyspora erythraea using a novel actinomycete-Escherichia coli cosmid.

Two plasmids were constructed that replicate in Saccharopolyspora (Sac.) erythraea, Escherichia coli and Streptomyces (S.) lividans, and used for the cloning of a locus involved in the synthesis of the macrolide antibiotic erythromycin (Er). Plasmid pAL7002 contains the thiostrepton-resistance gene (tsr), a replicon-containing fragment from pJVI and pUC9. Plasmid pNJI contains the lambda cos site but is otherwise similar to pAL7002. A library of total DNA from Sac. erythraea was constructed in pNJI and probed in colony hybridizations with a DNA fragment containing ermE, the Sac. erythraea ErR-encoding gene. Plasmids obtained were subsequently introduced into EryA mutants of Sac. erythraea blocked in synthesis of Er (Ery-) and transformants were screened for restoration of Er production (Ery+). Several plasmids were found to convert two mutants to Ery+, but a third EryA strain could not be restored to Ery+ by any of the plasmids employed. A 5-kb segment, designated eryAI, responsible for restoring the Ery+ phenotype in the EryA strains, was identified and mapped in the segment 12 to 17 kb downstream from ermE. Gene disruption experiments indicated that the 5-kb length of eryAI is fully internal to an eryAI-containing transcript. In Southern blots it was shown that one of the EryA strains carried a small deletion in eryAI and that, in at least some of the transformants restored to Ery+, the deletion had been replaced by the wild-type eryAI allele.(ABSTRACT TRUNCATED AT 250 WORDS)

Actinomycetaceae↗