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PubMedDate not supplied

Effect of selection, mutation, and linkage on the equilibrium structure of selfing systems.

One-, two- and three-locus models of selection and mutation in completely self-fertilizing populations are examined. Equilibrium frequencies can be determined for these systems. Numerical analyses indicate that random genetic drift attributable to selfing plays a major role in determining equilibrium frequencies, even when strong directional selection is operating. Linkage has no effect on marginal gene frequencies or single-locus heterozygosity at equilibrium. The only model of those examined which leads to linkage disequilibrium is disruptive selection. In that model, selection reinforced the effect of selfing in favoring the homozygous genotypes.

Alleles↗

PubMed1990

Cloning of wild-type Pseudomonas solanacearum phcA, a gene that when mutated alters expression of multiple traits that contribute to virulence.

Pseudomonas solanacearum undergoes a spontaneous mutation that pleiotropically reduces extracellular polysaccharide (EPS) production, endoglucanase activity, and virulence and increases motility. We refer to the process that coordinately affects these traits as phenotype conversion (PC) and the resulting mutants as PC types. Previous research with the wild-type strain AW1 suggested that inactivation of a single locus could mimic phenotype conversion (T. P. Denny, F. W. Makini, and S. M. Brumbley, Mol. Plant-Microbe Interact. 1:215-223, 1988). Additional Tn5 mutagenesis of AW1 generated three more mutants (AW1-81, AW1-82, and AW1-84) that were indistinguishable from the PC type and one slightly leaky mutant (AW1-87); all four had single insertions in the same 4.0-kilobase (kb) EcoRI fragment that were responsible for the PC-like phenotype. Another insertion mutant, AW1-83, which lacks an insertion in this 4.0-kb fragment, resembled the PC type except that it was reversibly induced to produce wild-type levels of EPS when cultured adjacent to AW1. The wild-type region containing the gene that controls traits affected by phenotype conversion in AW1, designated phcA, was cloned on a 2.2-kb DNA fragment that restored all the phcA::Tn5 mutants and 11 independent spontaneous PC-type derivatives of AW1 to wild-type status. Homology with the phcA region was found in diverse wild-type strains of P. solanacearum, although restriction fragment length polymorphisms were seen. No major DNA alterations were observed in the phcA homologous region of PC types from strain AW1 or 82N. PC types from 7 of 11 conjugal strains of P. solanacearum were restored to EPS+ by phcA from AW1; however, only some PC types of strain K60 were restored, whereas others were not. We believe that a functional phcA gene is required to maintain the wild-type phenotype in P. solanacearum, and for most strains phenotype conversion results from a loss of phcA gene expression or the function of its gene product.

Cell Movement↗

PubMed1994

[Gene amplification and chromosomal rearrangements during acquisition of cellular resistance to the antimetabolite coformycin].

We studied the early stages of gene amplification in a Chinese hamster cell line and we show that two distinct mechanisms can operate at a single locus. Both of them rely on an unequal segregation of gene copies at mitosis. We conclude that cycles of chromatid breakage, followed by fusion of sister chromatids devoid of a telomere that lead to further breaks in mitosis, have a key role in the coupling of gene amplification and genome remodeling. Rearrangements are first limited to a single chromosome but can then potentially spread to any additional chromosome. Occasionally, a sequence containing the selected gene can be looped out, generating a "double minute" and thus initiating an independent process of extrachromosomal amplification.

Animals↗

PubMed1985

A symmetric two-locus fertility model.

A model in which selection is mediated by differential fertilities among the genotypes at two diallelic loci is proposed. Fertility depends only on the number of heterozygous loci participating in the mating. Classes analogous to symmetric equilibria in symmetric viability models are determined explicitly and shown to exhibit stability behavior very different from the viability results. Linkage equilibrium is shown to occur in a relatively asymmetric fashion and to overlap in stability with linkage disequilibrium. In many cases single-locus or two-locus polymorphism is shown to be stable simultaneously with chromosome fixation even under very tight linkage. It is suggested that historical effects may be of great significance in the evolution of systems in which fertility is the primary agent of natural selection.

Alleles↗

PubMed1998

Paracentromeric sequences on tomato chromosome 6 show homology to human satellite III and to the mammalian CENP-B binding box.

In order to isolate centromeric sequences from tomato (Lycopersicon esculentum) chromosome 6, a large-scale RAPD screen was performed. Among 1500 polymorphic RAPD markers tested, 100 were identified as chromosome 6-specific, using a L. esculentum substitution line carrying chromosome 6 from L. pennellii. Fifty-seven of these markers proved to originate from L. pennellii, and of these, 13 were genetically mapped between the morphological markers yellow virescent (yv) and thiaminless (tl), which flank the centromere. These markers could be assigned to three genetic loci, with 11 of the markers mapping to a single locus. Further resolution of this cluster was achieved using radiation-induced deletions that removed yv or tl but not the centromere. Seven markers were shown to be located outside all of the deletions. These seven markers and three of the other markers of the cluster were cloned and sequenced. Five of the clones are present as single-copy or low-copy-number sequences and five represent middle repetitive sequences. Three sequences show homology to the mammalian CENP-B binding box; clone AG12 contains two of these boxes and also shows homology to human satellite III.

Autoantigens↗

PubMed1990

Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12-q14. The French Spinal Muscular Atrophy Investigators.

Linkage analysis in twenty-five families with acute (type I) spinal muscular atrophy (SMA) showed that the mutant gene responsible for the disorder is tightly linked to the D5S39 locus. The mutation(s) causing the intermediate (type II) and juvenile chronic (type III) forms of SMA were also mapped to DNA marker D5S39 on chromosome 5 (5q12-q14). Thus, the three forms, which have been differentiated clinically on the basis of age of onset and clinical course, are most probably due to different mutations at a single locus on chromosome 5. Prenatal diagnosis of SMA type I will now be possible.

Acute Disease↗

PubMed1987

Apolipoproteins, quantitative lipoprotein traits and multifactorial hyperlipidaemia.

Genetic polymorphism and rare mutants of apolipoproteins occur in humans. The polymorphism of apolipoprotein E (apoE) is controlled by three common alleles, epsilon 2, epsilon 3, and epsilon 4, which code for proteins that differ in lipoprotein receptor binding activity, or in their catabolism in vivo, or both. This may explain the observed significant effects of the apoE alleles on the phenotypic variance of plasma lipoprotein concentrations in different ethnic groups and, moreover, the involvement of apoE alleles in the pathogenesis of multifactorial forms of hyperlipidaemia, for example, hypertriglyceridaemia, familial type III hyperlipidaemia (apoE-2 Arg-158----Cys) and polygenic hypercholesterolaemia (apoE-4 Cys-112----Arg). A further polymorphic gene locus controls the concentrations of the Lp(a) lipoprotein complex in plasma, which may vary from less than 1 mg/dl to greater than 200 mg/dl between different individuals. This lipoprotein contains two different polypeptides, apoB-100 and the Lp(a) glycoprotein. The Lp(a) glycoprotein exhibits genetic polymorphism which is controlled by a series of autosomal alleles at a single locus and which is associated with lipoprotein concentrations in plasma. This suggests that the same gene locus is involved in determining Lp(a) glycoprotein phenotypes and Lp(a) lipoprotein concentrations in plasma. Thus, there is evidence that variability in apolipoprotein genes relates to the normal variance of lipoprotein concentrations in the population and that this variability is a major genetic factor in multifactorial forms of hyperlipidaemia.

Alleles↗

PubMed1997

Rapid fixation of deleterious alleles can be caused by Muller's ratchet.

Theoretical arguments are presented which suggest that each advance of Muller's ratchet in a haploid asexual population causes the fixation of a deleterious mutation at a single locus. A similar process operates in a diploid, fully asexual population under a wide range of parameter values, with respect to fixation within one of the two haploid genomes. Fixations of deleterious mutations in asexual species can thus be greatly accelerated in comparison with a freely recombining genome, if the ratchet is operating. In a diploid with segregation of a single chromosome, but no crossing over within the chromosome, the advance of the ratchet can be decoupled from fixation if mutations are sufficiently close to recessivity. A new analytical approximation for the rate of advance of the ratchet is proposed. Simulation results are presented that validate the assertions about fixation. The simulations show that none of the analytical approximations for the rate of advance of the ratchet are satisfactory when population size is large. The relevance of these results for evolutionary processes such as Y chromosome degeneration is discussed.

Alleles↗

PubMed2000

Segregation distortion of T-DNA markers linked to the self-incompatibility (S) locus in Petunia hybrida.

In plants with a gametophytic self-incompatibility system the specificity of the pollen is determined by the haploid genotype at the self-incompatibility (S) locus. In certain crosses this can lead to the exclusion of half the gametes from the male parent carrying a particular S-allele. This leads to pronounced segregation distortion for any genetic markers that are linked to the S-locus. We have used this approach to identify T-DNA insertions carrying a maize transposable element that are linked to the S-locus of Petunia hybrida. A total of 83 T-DNA insertions were tested for segregation distortion of the selectable marker used during transformation with Agrobacterium. Segregation distortion was observed for 12 T-DNA insertions and at least 8 of these were shown to be in the same linkage group by intercrossing. This indicates that differential transmission of a single locus (S) is probably responsible for all of these examples of T-DNA segregation distortion. The identification of selectable markers in coupling with a functional S-allele will allow the preselection of recombination events around the S-locus in petunia. Our approach provides a general method for identifying transgenes that are linked to gametophytic self-incompatibility loci and provides an opportunity for transposon tagging of the petunia S-locus.

Crosses, Genetic↗

PubMed2000

The mismatch repair gene hMSH2 is mutated in the prostate cancer cell line LNCaP.

PURPOSE: Mismatch repair genes are responsible for the coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating and inherited mutations in the prototypic mismatch repair gene hMSH2 have been described in a cancer predisposition syndrome known as hereditary nonpolyposis colon cancer. Patients with hereditary nonpolyposis colon cancer are at increased risk for colon cancer and extracolonic cancers such as upper tract transitional cell carcinoma but not prostate cancer. We investigated expression of hMSH2 in prostate cancer cell lines using genetic and molecular analysis. MATERIALS AND METHODS: We used the 3 well described prostate cancer cell lines, DU145, LNCaP and PC3. Western blot analysis with monoclonal antibody to hMSH2 was used to assess expression. Southern blot and polymerase chain reaction of genomic DNA were used to identify genetic alterations in the hMSH2 gene. Single cell cloning, dinucleotide repeats and BAT-26 were used to assess the cell lines for microsatellite instability. RESULTS: The prostate cancer cell line LNCaP did not express hMSH2 and was found to have a homozygous deletion of hMSH2 exons 9 to 16, resulting in truncation of the protein. While microsatellite analysis did not reveal alterations at the BAT-26 locus, single cell cloning produced several LNCaP subclones with alteration at 1 dinucleotide repeat. CONCLUSIONS: The well described prostate cancer cell line LNCaP has a mutation in the hMSH2 gene, resulting in loss of expression and possible evidence of microsatellite instability. To our knowledge our finding is the first demonstration of a genetic alteration in hMSH2 in a prostate cancer cell line.

Base Pair Mismatch↗

PubMed1999

Spatial autocorrelation analysis of individual multiallele and multilocus genetic structure.

Population genetic theory predicts that plant populations will exhibit internal spatial autocorrelation when propagule flow is restricted, but as an empirical reality, spatial structure is rarely consistent across loci or sites, and is generally weak. A lack of sensitivity in the statistical procedures may explain the discrepancy. Most work to date, based on allozymes, has involved pattern analysis for individual alleles, but new PCR-based genetic markers are coming into vogue, with vastly increased numbers of alleles. The field is badly in need of an explicitly multivariate approach to autocorrelation analysis, and our purpose here is to introduce a new approach that is applicable to multiallelic codominant, multilocus arrays. The procedure treats the genetic data set as a whole, strengthening the spatial signal and reducing the stochastic (allele-to-allele, and locus-to-locus) noise. We (i) develop a very general multivariate method, based on genetic distance methods, (ii) illustrate it for multiallelic codominant loci, and (iii) provide nonparametric permutational testing procedures for the full correlogram. We illustrate the new method with an example data set from the orchid Caladenia tentaculata, for which we show (iv) how the multivariate treatment compares with the single-allele treatment, (v) that intermediate frequency alleles from highly polymorphic loci perform well and rare alleles poorly, (vi) that a multilocus treatment provides clearer answers than separate single-locus treatments, and (vii) that weighting alleles differentially improves our resolution minimally. The results, though specific to Caladenia, offer encouragement for wider application.

Alleles↗

PubMed1978

Genetic variation in the activity of the histidine catabolic enzymes between inbred strains of mice: a structural locus for a cytosol histidine aminotransferase isozyme (Hat-1).

Variation in activity of the main histidine catabolic enzymes (histidase, urocanase, and aminotransferase) has been surveyed using inbred strains of mice (C57BL, DBA, Peru, SM, and SWR). Some variation was found in the activity of all enzymes, but only in the case of cytosolic histidine aminotransferase was it greater than twofold (SM 3.3-fold greater than C57BL). The divergent strains for the activity of this enzyme were crossed and the F1's were backcrossed; the segregation analysis indicated a single locus with additively acting alleles (designated Hat-1: a allele SM, b allele C57BL). Cytosolic histidine aminotransferase differed in heat stability between SM and C57BL, indicating that Hat-1 is a structural locus. The conflict in the biochemical literature (Morris et al., 1973; Noguchi et al., 1976a,b) over the number and subcellular distribution of the histidine aminotransferase isozymes is partly resolved by the acquisition of a variant at the Hat-1 locus. Hat-1 affects the cytosolic form but not the mitochondrial form of the enzyme. Purification and analysis of the isozymes of histidine aminotransferase from livers of C57BL and SM mice will further clarify the situation.

Animals↗

PubMed1996

Common subtypes of idiopathic generalized epilepsies: lack of linkage to D20S19 close to candidate loci (EBN1, EEGV1) on chromosome 20.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). A trait locus (EBN1) for a rare subtype of IGEs, the benign neonatal familial convulsions, and a susceptibility gene (EEGV1) for the common human low-voltage electroencephalogram have been mapped close together with D20S19 to the chromosomal region 20q13.2. Both loci are potential candidates for the susceptibility to IGE spectra with age-related onset beyond the neonatal period. The present study tested the hypothesis that a putative susceptibility locus linked to D20S19 predisposes to spectra of IGEs with age-related onset from childhood to adolescence. Linkage analyses were conducted in 60 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy. Our results provide evidence against linkage of a putative susceptibility gene for four hierarchically broadened IGE spectra with D20S19 assuming tentative single-locus genetic models. The extent of an "exclusion region" (lod scores below-2) varied from 0.5 cM up to 22 cM on either side of D20S19 depending on the trait assumed. These results are contrary to the expectation that a susceptibility gene in vicinity to D20S19 confers a common major gene effect to the expression of IGE spectra with age-related onset from childhood to adolescence.

Chromosome Mapping↗

PubMed1999

Further evidence for the increased power of LOD scores compared with nonparametric methods.

In genetic analysis of diseases in which the underlying model is unknown, "model free" methods-such as affected sib pair (ASP) tests-are often preferred over LOD-score methods, although LOD-score methods under the correct or even approximately correct model are more powerful than ASP tests. However, there might be circumstances in which nonparametric methods will outperform LOD-score methods. Recently, Dizier et al. reported that, in some complex two-locus (2L) models, LOD-score methods with segregation analysis-derived parameters had less power to detect linkage than ASP tests. We investigated whether these particular models, in fact, represent a situation that ASP tests are more powerful than LOD scores. We simulated data according to the parameters specified by Dizier et al. and analyzed the data by using a (a) single locus (SL) LOD-score analysis performed twice, under a simple dominant and a recessive mode of inheritance (MOI), (b) ASP methods, and (c) nonparametric linkage (NPL) analysis. We show that SL analysis performed twice and corrected for the type I-error increase due to multiple testing yields almost as much linkage information as does an analysis under the correct 2L model and is more powerful than either the ASP method or the NPL method. We demonstrate that, even for complex genetic models, the most important condition for linkage analysis is that the assumed MOI at the disease locus being tested is approximately correct, not that the inheritance of the disease per se is correctly specified. In the analysis by Dizier et al., segregation analysis led to estimates of dominance parameters that were grossly misspecified for the locus tested in those models in which ASP tests appeared to be more powerful than LOD-score analyses.

Genes, Dominant↗

PubMed2004

Linkage disequilibrium mapping via cladistic analysis of single-nucleotide polymorphism haplotypes.

We present a novel approach to disease-gene mapping via cladistic analysis of single-nucleotide polymorphism (SNP) haplotypes obtained from large-scale, population-based association studies, applicable to whole-genome screens, candidate-gene studies, or fine-scale mapping. Clades of haplotypes are tested for association with disease, exploiting the expected similarity of chromosomes with recent shared ancestry in the region flanking the disease gene. The method is developed in a logistic-regression framework and can easily incorporate covariates such as environmental risk factors or additional unlinked loci to allow for population structure. To evaluate the power of this approach to detect disease-marker association, we have developed a simulation algorithm to generate high-density SNP data with short-range linkage disequilibrium based on empirical patterns of haplotype diversity. The results of the simulation study highlight substantial gains in power over single-locus tests for a wide range of disease models, despite overcorrection for multiple testing.

Chromosome Mapping↗

PubMed2006

Tryptophan hydroxylase-1 gene variants associate with a group of suicidal borderline women.

Alterations in the serotonin (5-HT) system have been related to impulsive aggression and suicidal behavior, common features of the borderline personality disorder (BPD). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. Two isoforms are known, TPH-1 and TPH-2. TPH-1 has been correlated to various psychiatric and behavioral disorders by gene polymorphism association studies. We aimed to determine whether specific TPH-1 haplotypes associate with BPD. A case-control design was employed. The control group included 98 women without psychiatric history. In all, 95 patients were included, all Caucasian women with a BPD diagnosis who had attempted suicide at least twice during their lifetime. Exclusion criteria were: (i) substance dependence; (ii) dementia or other irreversible organic brain syndromes; (iii) psychotic disorders or major depressive illness with melancholic features; (iv) life-threatening eating disorders. Six single-nucleotide polymorphisms (SNPs) were found at significant linkage disequilibrium across 23 kb of the TPH-1 gene in both patients and controls, suggesting a haplotype block structure. While no individual SNP showed association, several haplotypes associated with the BPD group. In particular, one six-SNP haplotype was absent from the control group while representing about one-quarter of all haplotypes in the BPD group (corrected P<<10(-5)). A 'sliding window' analysis attributed the strongest disease association to haplotype configurations located between the gene promoter and intron 3. We conclude that TPH-1 associates with BPD in suicidal women. Our data support the expectation that haplotype analysis is superior to single locus analysis in gene-disease, case-control association studies.

Adult↗

PubMedDate not supplied

Linkage associations in hybridized Salvelinus genomes. The duplicate loci encoding pepidase-D and glucosephosphate isomerase and the unduplicated sorbitol dehydrogenase locus.

Electrophoresis was performed on parents and progeny of 21 families of tetraploid derivative Salvelinus species. Variable phenotypes were shown for the duplicate loci encoding the enzyme peptidase D in lake (S. namaycush) and brook trout (S. fontinalis) and in the fertile hybrid (splake) between them. Pairwise examinations of joint segregation between the duplicated PepD loci and 23 other biochemical loci were performed. Nonrandom assortment was found among progeny of parents doubly heterozygous for the PepD-1 and PepD-2 loci, the duplicate loci encoding glucosephosphate isomerase (Gpi-1 and Gpi-2) and the single locus encoding sorbitol dehydrogenase (Sdh). Two classical linkage groups were found among the uniquely marked loci; PepD-1 with Gpi-1 and PepD-2 with Gpi-2 with Sdh. Pseudolinkage among loci in the two different groups was found in males. The results are shown to fit a chromosomal model involving preferential tetravalent pairing of homoeologous chromosomes. The linkage of PepD and Gpi loci is consistent with that reported in a variety of vertebrate species and indicates the conservation of this linkage group over taxa separated by at least 300 million years of evolution.

Animals↗

PubMed1991

Frequency-domain fluorescence spectroscopy resolves the location of maleimide-directed spectroscopic probes within the tertiary structure of the Ca-ATPase of sarcoplasmic reticulum.

We have used fluorescence spectroscopy to characterize three covalently bound spectroscopic maleimide derivatives with respect to their location within the tertiary structure of the Ca-ATPase of sarcoplasmic reticulum (SR). These derivatives include (1) 2-(4'-maleimidoanilino)naphthalene-6-sulfonic acid, (2) 4-(dimethylamino)azobenzene-4'-maleimide, and (3) fluorescein 5'-maleimide. Biochemical assays demonstrate that modification with any of these three derivatives results in the same functional effects, observed following derivatization of cysteines 344 and 364 by N-ethylmaleimide [Saito-Nakatsuka et al. (1987) J. Biochem. (Tokyo) 101, 365-376]. These residues bracket the ATPase's phosphorylation site (Asp 351) and thus may provide spectroscopic probes of the protein's conformation in this essential region. In agreement with sequencing results, SDS-polyacrylamide gels show that maleimide-modified SR exhibits fluorescence exclusively on the A1 tryptic fragment of the Ca-ATPase. Extensive tryptic digestion followed by centrifugation demonstrates essentially all of the fluorescence was associated with the soluble rather than insoluble (membrane-associated) peptides, confirming the predicted extramembranous location of these residues. Utilizing frequency-domain fluorescence spectroscopy, we were able to recover the transient effects associated with a distribution of donor-acceptor distances. We find from these fluorescence resonance energy transfer measurements that covalently bound maleimide probes are 36 A apart, independent of whether a discrete distance is assumed or a distance distribution model is utilized, in which the conformational variability of the protein is taken into account. While a unimodal distance distribution is adequate to describe the intensity decay associated with maleimide-directed donor-acceptor pairs, a bimodal distribution of distances is necessary to describe the frequency response associated with the energy transfer between maleimide-directed chromophores and other covalently bound probes on the Ca-ATPase, consistent with the large spatial separation observed between maleimides. We recover mean distances of 42 and 77 A between maleimide sites and bound FITC (Lys 515) and mean distances of 28 and 37 A between the maleimide- and the iodoacetamide-directed probes (Cys 670 and 674, whose close proximity approximates a single locus). The measured distances are presented in a model and have permitted us to describe a unique arrangement of these covalently bound probes within both the secondary and tertiary structure of the Ca-ATPase. The resolution inherent in the frequency-domain fluorescence technique to multiple donor-acceptor distances should be generally applicable to a wide range of biological systems in which specific labeling of single unique donor-acceptor sites is not feasible.

Amino Acid Sequence↗