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PubMed2002

Mating-type locus of Cryptococcus neoformans: a step in the evolution of sex chromosomes.

The sexual development and virulence of the fungal pathogen Cryptococcus neoformans is controlled by a bipolar mating system determined by a single locus that exists in two alleles, alpha and a. The alpha and a mating-type alleles from two divergent varieties were cloned and sequenced. The C. neoformans mating-type locus is unique, spans >100 kb, and contains more than 20 genes. MAT-encoded products include homologs of regulators of sexual development in other fungi, pheromone and pheromone receptors, divergent components of a MAP kinase cascade, and other proteins with no obvious function in mating. The alpha and a alleles of the mating-type locus have extensively rearranged during evolution and strain divergence but are stable during genetic crosses and in the population. The C. neoformans mating-type locus is strikingly different from the other known fungal mating-type loci, sharing features with the self-incompatibility systems and sex chromosomes of algae, plants, and animals. Our study establishes a new paradigm for mating-type loci in fungi with implications for the evolution of cell identity and self/nonself recognition.

Alleles↗

PubMed1996

Recipient cells expressing single donor MHC locus products can substitute for donor-specific transfusion in the induction of transplantation tolerance when pretreatment is combined with anti-Cd4 monoclonal antibody. Evidence for a vital role of Cd4+ T cells in the induction of tolerance to class I molecules.

Syngeneic cells expressing single donor MHC locus products have been shown to induce specific immunological hyporesponsiveness, but not tolerance, to an allograft. In this study we have attempted to potentiate the beneficial effect of pretreatment with single donor MHC locus products by the addition of anti-Cd4(2) monoclonal antibody to the pretreatment protocol. We show that pretreatment with recipient L cells expressing the products of a single donor locus (K, D, or IA) can induce tolerance to a C57BL/10 (H2b) cardiac allograft in C3H/He (H2k) mice, when given in combination with the depleting anti-Cd4 monoclonal antibody YTA 3.1.2. Both the induction and maintenance phases of tolerance were found to be antigen-specific. Cells expressing donor class II antigens, IA(b) were found to be most effective. Interestingly, donor class I molecules were also found to be capable of inducing specific unresponsiveness in combination with anti-Cd4, provided an optimal antigenic load was delivered at the time of pretreatment. Pretreatment with cells expressing donor class I and anti-Cd8 monoclonal antibody had no beneficial effect on graft survival. These data show that single donor MHC locus products can induce immunologic tolerance to fully MHC and minor histocompatibility antigen-mismatched heart grafts when given under the cover of anti-Cd4 mAb. They also show that Cd4+ T cells play an important role in the induction of specific unresponsiveness to class I alloantigen in vivo and suggest that the blockade of T cells capable of recognizing class I alloantigen presented indirectly is important in the induction of tolerance.

Animals↗

PubMed1993

A single B1 subunit mapped to mouse chromosome 7 may be a common component of Na channel isoforms from brain, skeletal muscle and heart.

A beta 1 subunit associated with one or more isoforms of brain voltage-sensitive Na channels has previously been cloned, sequenced and expressed. Northern and Western blot analyses have suggested that homologues to this protein are expressed in skeletal muscle and heart. Here, reverse transcriptase-polymerase chain reaction (RT-PCR)/cloning reveals that transcripts encoding identical beta 1 subunit ORFs are expressed in adult rat brain, skeletal muscle and heart. Heterologous co-expression of beta 1 with brain (RIIA) and skeletal muscle (mu 1) alpha subunits caused a stabilization of normal, rapidly inactivating (mode 1) gating relative to anomalous, non-inactivating (mode 2) states and a negative shift in steady state inactivation. Chromosome mapping of the beta 1 subunit showed a single locus (Scn1b) in mouse chromosome 7 1.8 cM (+/- 1.2 cM) distal to D19F11S1h and 0.9 cM (+/- 0.9 cM) proximal to Pkca. This locus is in the region of the mouse mutant "quivering," characterized by a variety of neurological disorders and muscle paralysis. A mutation in a single beta 1 subunit forming functional complexes with multiple Na channel isoforms could underlie these deficits.

Animals↗

PubMed2005

Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing.

Half of the cases with congenital impaired hearing are hereditary (HIH). HIH may occur as part of a multisystem disease (syndromic HIH) or as disorder restricted to the ear and vestibular system (nonsyndromic HIH). Since nonsyndromic HIH is almost exclusively caused by cochlear defects, affected patients suffer from sensorineural hearing loss. One percent of the total human genes, i.e. 300-500, are estimated to cause syndromic and nonsyndromic HIH. Of these, approximately 120 genes have been cloned thus far, approximately 80 for syndromic HIH and 42 for nonsyndromic HIH. In the majority of the cases, HIH manifests before (prelingual), and rarely after (postlingual) development of speech. Prelingual, nonsyndromic HIH follows an autosomal recessive trait (75-80%), an autosomal dominant trait (10-20%), an X-chromosomal, recessive trait (1-5%), or is maternally inherited (0-20%). Postlingual nonsyndromic HIH usually follows an autosomal dominant trait. Of the 41 mutated genes that cause nonsyndromic HIH, 15 cause autosomal dominant HIH, 15 autosomal recessive HIH, 6 both autosomal dominant and recessive HIH, 2 X-linked HIH, and 3 maternally inherited HIH. Mutations in a single gene may not only cause autosomal dominant, nonsyndromic HIH, but also autosomal recessive, nonsyndromic HIH (GJB2, GJB6, MYO6, MYO7A, TECTA, TMC1), and even syndromic HIH (CDH23, COL11A2, DPP1, DSPP, GJB2, GJB3, GJB6, MYO7A, MYH9, PCDH15, POU3F4, SLC26A4, USH1C, WFS1). Different mutations in the same gene may cause variable phenotypes within a family and between families. Most cases of recessive HIH result from mutations in a single locus, but an increasing number of disorders is recognized, in which mutations in two different genes (GJB2/GJB6, TECTA/KCNQ4), or two different mutations in a single allele (GJB2) are involved. This overview focuses on recent advances in the genetic background of nonsyndromic HIH.

Connexin 26↗

PubMed2005

Outbreak of methicillin-resistant Staphylococcus aureus in two nursing homes in Central Norway.

Until recently, infections with methicillin-resistant Staphylococcus aureus (MRSA) have mainly been associated with hospital outbreaks in Norway. However, increasingly cases are contracted outside hospitals. This paper reports the first two outbreaks of MRSA in two nursing homes in central Norway, affecting 23 residents and five staff members. Pulsed-field gel electrophoresis analysis showed that all strains from nursing home A were identical and that the strains from nursing home B were genotypically similar with one or two band differences. Multi-locus sequence typing (MLST) showed that the strains from the two nursing homes belong to clonal complex 45, with each strain being a single-locus variant of sequence type 45 (ST 45), a well-known European epidemic strain. No evident source of the two outbreaks was found, and there was no obvious connection between the two outbreaks. The latter is also supported by the minor differences observed by MLST, suggesting a connection at some time in the past. The outbreaks led to a heavier workload and economic strain on both nursing homes. The outbreak in nursing home A was brought to an end, whereas two residents remained colonized in nursing home B despite several eradication attempts. These outbreaks show the potential for MRSA spread in a nursing home. If the prevalence of MRSA in Norway continues to increase, nursing home staff and residents may have to be included in the groups to be screened for MRSA upon hospital admission.

Aged↗

PubMed2001

Statistical power when testing for genetic differentiation.

A variety of statistical procedures are commonly employed when testing for genetic differentiation. In a typical situation two or more samples of individuals have been genotyped at several gene loci by molecular or biochemical means, and in a first step a statistical test for allele frequency homogeneity is performed at each locus separately, using, e.g. the contingency chi-square test, Fisher's exact test, or some modification thereof. In a second step the results from the separate tests are combined for evaluation of the joint null hypothesis that there is no allele frequency difference at any locus, corresponding to the important case where the samples would be regarded as drawn from the same statistical and, hence, biological population. Presently, there are two conceptually different strategies in use for testing the joint null hypothesis of no difference at any locus. One approach is based on the summation of chi-square statistics over loci. Another method is employed by investigators applying the Bonferroni technique (adjusting the P-value required for rejection to account for the elevated alpha errors when performing multiple tests simultaneously) to test if the heterogeneity observed at any particular locus can be regarded significant when considered separately. Under this approach the joint null hypothesis is rejected if one or more of the component single locus tests is considered significant under the Bonferroni criterion. We used computer simulations to evaluate the statistical power and realized alpha errors of these strategies when evaluating the joint hypothesis after scoring multiple loci. We find that the 'extended' Bonferroni approach generally is associated with low statistical power and should not be applied in the current setting. Further, and contrary to what might be expected, we find that 'exact' tests typically behave poorly when combined in existing procedures for joint hypothesis testing. Thus, while exact tests are generally to be preferred over approximate ones when testing each particular locus, approximate tests such as the traditional chi-square seem preferable when addressing the joint hypothesis.

Animals↗

PubMed2006

LRTae: improving statistical power for genetic association with case/control data when phenotype and/or genotype misclassification errors are present.

BACKGROUND: In the field of statistical genetics, phenotype and genotype misclassification errors can substantially reduce power to detect association with genetic case/control studies. Misclassification also can bias population frequency parameters such as genotype, haplotype, or multi-locus genotype frequencies. These problems are of particular concern in case/control designs because, short of repeated sampling, there is no way to detect misclassification errors. We developed a double-sampling procedure for case/control genetic association using a likelihood ratio test framework. Different approaches have been proposed to deal with misclassification errors. We have chosen the likelihood framework because of the ease with which misclassification probabilities may be incorporated into in the statistical framework and hypothesis testing. The statistic is called the Likelihood Ratio Test allowing for errors (LRTae) and is freely available via software download. RESULTS: We applied our procedure to 10,000 replicates of simulated case/control data in which we introduced phenotype misclassification errors. The phenotype considered is Ankylosing Spondylitis (AS). The LRTae method power was always greater than LRTstd power for the significance levels considered (5%, 1%, 0.1%, 0.01%). Power gains for the LRTae method over the LRTstd method increased as the significance level became more stringent. Multi-locus genotype frequency estimates using LRTae method were more accurate than estimates using LRTstd method. CONCLUSION: The LRTae method can be applied to single-locus genotypes, multi-locus genotypes, or multi-locus haplotypes in a case/control framework and can be more powerful to detect association in case/control studies when both genotype and/or phenotype errors are present. Furthermore, the LRTae method provides asymptotically unbiased estimates of case and control genotype frequencies, as well as estimates of phenotype and/or genotype misclassification rates.

Case-Control Studies↗

PubMed1997

Association between microsatellites within the human MHC and nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) has been known to be associated with specific HLA haplotypes, in particular HLA A2, B46 and A33, B58 haplotypes. A linkage study based on this observation suggested that HLA antigens are not the cause of NPC but that there exists a gene that lies close to if not within the major histocompatibility complex locus and confers a greatly increased relative risk of NPC. Since then, no further work has elucidated the presence of this gene. One of the difficulties faced by researchers has been the size of the region of chromosome implicated. The MHC locus alone is almost 4 Mb in length, and the number of genes encoded within it is numerous. The purpose of our study was thus to reduce the region of DNA in which the NPC susceptibility gene is likely to be. We report that the NPC susceptibility gene may be within the centromeric end of the class-1 and the telomeric end of the class-III regions of the MHC, near the D6S1624 microsatellite locus, where the presence of allele 4 of the microsatellite conferred a 3 1/2-fold increase in the risk of NPC, the highest reported for a single locus, and the presence of allele 1 of the same microsatellite conferred a highly significant protective effect against NPC.

Centromere↗

PubMed1994

Homozygosity mapping of the Werner syndrome locus (WRN).

Werner syndrome (WS) is an autosomal recessive disorder characterized by the early onset of several age-related diseases. The locus for this disease was recently mapped to 8p12. We studied 27 WS kindreds of mixed ethnic origins, 26 of which were consanguineous. In 24 of these families, the affected subject was given the diagnosis of "definite" WS and affected subjects in the remaining 3 pedigrees were given the diagnosis of "probable" WS. Affected subjects from each kindred were genotyped for 13 short tandem repeat polymorphic sites. Two-point linkage analysis yielded significant evidence for linkage to D8S137, D8S339, D8S87, PLAT, D8S165, and D8S166. The locus yielding a maximum lod score at the smallest recombination fraction was D8S339, suggesting that this marker is the closest to the WS gene (WRN locus) of those tested. D8S339 gave significant lod scores (Zmax > or = 3.0) for both Japanese and non-Japanese (mostly Caucasian) families, demonstrating that a single locus is responsible for WS in both groups. Multipoint analysis of these markers yielded a maximum lod score of 17.05 at a distance of approximately 0.6 cM from D8S339. The combined evidence from 2-point analysis, multipoint analysis, and analysis of regions of homozygosity in subjects from inbred pedigrees indicates that the WRN locus is between D8S131 and D8S87, in an 8.3-cM interval containing D8S339.

Alleles↗

PubMed1999

The evolutionary ecology of dominance-recessivity.

An "adaptive dynamics" modelling approach to the evolution of dominance-recessivity is presented. In this approach, fitness derives from an explicit ecological scenario, and both evolutionary attractivity and invasibility of resident populations are examined. The ecology consists of a within-individual part representing a locus with regulated activity and a between-individual part that is a two-patch soft selection model. Evolutionary freedom is allowed at a single locus. The evolutionary analysis considers directed random walks on trait space, generated by repeated invasions of mutants. The phenotype of an individual is determined by allelic parameters. Mutations can have two effects: they either affect the affinity of the promoter sequence for transcription factors, or they affect the gene product. The dominance interaction between alleles derives from their promoter affinities. Additive genetics is evolutionarily unstable when selection and evolution maintain two alleles in the population. In such a situation, dominance interactions can become stationary and close to additive genetics or they continue to evolve at a very slow pace towards dominance-recessivity. The probability that a specific dominance interaction will evolve depends on the relative mutation rate of promoter compared to gene product and the distribution of mutational effect sizes. Either allele in the dimorphism can become dominant, and dominance-recessivity is always most likely to evolve. Evolution then approaches a population state where every phenotype has maximum viability in one of the two patches. When the within-individual part is replaced by a housekeeping locus that codes for a metabolic enzyme, evolution favours a population of two alleles under the same conditions as for a regulated locus. In the case of a housekeeping gene, however, the evolutionary dynamical system approaches a population state where the heterozygote and only one homozygote phenotype are equivalent to the optimum phenotypes in the two patches.

Alleles↗

PubMed1993

The mat- allele of Podospora anserina contains three regulatory genes required for the development of fertilized female organs.

In the filamentous fungus Podospora anserina, mating type is specified by a single locus with two alternate alleles, termed mat- and mat+. A previous study has shown that the mat+ sequence consists of 3.7 kb and contains a single gene relevant to the sexual cycle. This gene, called FPR1, encodes a protein with a HMG DNA-binding domain and is required for fertilization and for the development of the fertilized fruiting body. The mat- sequence, which is 4.7 kb in length, displays a more complex structure. We present here the characterization of two genes, called SMR1 and SMR2, which are present in the mat- allele along with the FMR1 gene. FMR1, whose role in the sexual cycle has been already partially described, encodes a protein with an alpha 1-domain and was shown to control fertilization. We demonstrate that these three genes are required for the developmental events that occur in the female organ after fertilization. The additional role of FMR1 requires a region of unknown function that is distinct from the alpha 1-domain. SMR1 encodes a protein with a putative acidic/hydrophobic alpha-helix, which has been proposed to be a feature common to transcriptional activators. The protein sequence deduced from SMR2 contains an HMG motif suggesting that it is a transcription factor.

Alleles↗

PubMed2001

Paternity testing using Y-STR haplotypes: assigning a probability for paternity in cases of mutations.

In parentage testing with male children, Y-chromosomal STR evidence is gaining more and more importance. In some cases, multilocus haplotypes of related persons can differ at a single locus due to a mutation. In this work, a likelihood approach is presented for the calculation of a probability for paternity under consideration of a single mutation event on the Y-chromosome. The new methodology is applied to two case examples.

Child↗

PubMed1994

Multiple parallel access in visual attention.

It is widely accepted that there exists a region or locus of maximal resource allocation in visual perception--sometimes referred to as the spotlight of attention. We have argued that even if there is a single locus of processing, there must be multiple loci of parallel access--several places in the visual field must be indexed at once and these indexes can be used to determine where attention is allocated. We have carried out a variety of studies to support these ideas, including experiments showing that subjects can track multiple independent moving targets in a field of identical distractors, that the enhanced ability to detect changes occurring on these targets does not accrue to nontargets nor to items lying inside the convex polygon that they form (so that a zoom-lens of attention does not fit the data). We have used a visual search paradigm to show that (serial or parallel) search can be confined to a subset of indexed items and the layout of these items is of little importance. We have also studied the phenomenon known as subitizing and have shown that subitizing occurs only when items can be preattentively individuated and in those cases location precuing has little effect, compared with when counting occurs, which suggests that subitizing may be carried out by counting active indexes rather than items in the visual field. And finally we have run studies showing that a certain motion effect that is sensitive to attention can occur at multiple precued loci. We believe that this evidence suggests that there is an early preattentive stage in vision where a small number of salient items in the visual field are indexed and thereby made readily accessible for a variety of visual tasks.

Attention↗

PubMed1989

Co-localization to chromosome bands 99E1-3 of the Drosophila melanogaster myosin light chain-2 gene and a haplo-insufficient locus that affects flight behavior.

Using overlapping synthetic deficiencies, we find that a haplo-insufficient locus affecting flight behavior and the myosin light chain-2 gene co-map to the Drosophila melanogaster polytene chromosome interval 99D9-E1 to 99E2-3. From screening over 9000 EMS-treated chromosomes, we obtained alleles of two complementation groups that map to this same interval. One of these complementation groups lfm(3)99Eb, exhibits dominant flightless behavior; thus, flightless behavior of the deficiency is in all likelihood due to hemizygosity of this single locus. Rescue of flightless behavior by a duplication indicates that the single allele, E38, of the Ifm(3)99Eb complementation group is a hypomorph. Based upon its map position and a reduction in concentration of myosin light chain-2 mRNA in heterozygotes, we propose that Ifm(3)Eb(E38) is a mutant allele of the myosin light chain-2 gene. Our genetic analysis also resulted in the identification of four dominant flightless alleles of an unlinked locus, l(3)nc99Eb, that exhibits dominant lethal synergism with Ifm(3)99Eb.

Alleles↗

PubMed2004

Role of transposable elements in the propagation of minisatellites in the rice genome.

A survey of minisatellites (MSs) in 5.3 Mb of randomly selected rice DNA sequences from public databases was carried out to clarify the role of transposable elements (TEs) in the dispersal of MSs in the rice genome. The estimated frequency of MSs in this sample was one per 23.4 kb, and this frequency is approximately equivalent to that of Class I microsatellites in the rice genome. Of the MSs in the 5.3-Mb sequence sample, 82% were found to be present in multiple copies in the rice genome, and all of these were a part of TE sequences. In this study at least 61 TE groups were identified as MS carriers. It was also shown that the GC-rich MS pOs6.2H, which was previously reported to be one of the interspersed MSs in the rice genome, is a component of an En/Spm-like element. These results indicate that the majority of MSs in the rice genome are maintained in TEs, and amplified and dispersed as components of the TEs. The G+C content of the multi-locus MS sequences reflected that of the TE sequences containing those MSs, but no obvious bias towards the high G+C content of DNA was observed. Single locus MSs also did not show any obvious bias towards the high G+C content of DNA in the rice genome. In this respect, the MSs in the rice genome are quite different from those in the human genome: in the latter, the majority of MSs show an obvious bias towards the high G+C content of DNA.

Base Composition↗

PubMed1991

The CEPH consortium linkage map of human chromosome 1.

This paper describes the Centre d'Etude du Polymorphisme Humain (CEPH) consortium linkage map of human chromosome 1. The map contains 101 loci defined by genotypes generated from CEPH family DNAs with 146 different contributions from 11 laboratories. A total of 58 loci are uniquely placed on the map with likelihood support of at least 1000:1. The map extends from loci in the terminal bands of both chromosome arms (locus D1Z2 in 1p36.3 and D1S68 in 1q44) and is anchored at the centromere by the D1Z5 alpha-satellite polymorphism. With the exception of a single locus, the remaining loci are arrayed on the fixed map in short intervals and their possible locations are indicated. Multipoint linkage analyses provided estimates that the male, female, and sex-averaged maps extend for 308, 478, and 390 cM, respectively. The sex-averaged map contains only four intervals greater than 15 cM, and the mean genetic distance between the 58 uniquely placed loci is 6.7 cM.

Chromosome Mapping↗

PubMed1999

Allelic diversity at the Mhc-DQA locus in cotton rats (Sigmodon hispidus) and a comparison of DQA sequences within the family muridae (Mammalia: Rodentia).

The cotton rat (Sigmodon hispidus) is a common murid rodent of the southern United States, Mexico, and Central America. Using single-stranded conformation polymorphism analysis and DNA sequencing techniques, 11 DQA exon 2 alleles were detected among 180 S. hispidus from Caddo County, Oklahoma, USA. The alleles represent a single locus exhibiting a high level of polymorphism. Nucleotide and amino acid distance values among DQA alleles of S. hispidus were higher than those within Mus musculus and species of Rattus. Although the distribution of polymorphic amino acid residues among alleles of S. hispidus was similiar to that of Mus and Rattus, some residues of the alpha-helix region were more variable in S. hispidus. Comparisons of nonsynonymous and synonymous substitutions indicated a trend toward higher numbers of nonsynonymous substitutions; however, this difference was not significant statistically among S. hispidus alleles. To examine evolution of DQA alleles within Muridae, we performed a phylogenetic analysis that included DQA alleles from S. hispidus, Peromyscus leucopus, M. musculus, R. norvegicus, and six Australian species of Rattus. Results depicted monophyly for each genus, and this concordance between species and gene trees represents a lack of evidence for trans-species persistence of alleles among these genera.

Alleles↗

PubMed2006

Locus-specific mutational events in a multilocus variable-number tandem repeat analysis of Escherichia coli O157:H7.

Multilocus variable-number tandem repeat analysis (MLVA) is a validated molecular subtyping method for detecting and evaluating Escherichia coli O157:H7 outbreaks. In a previous study, five outbreaks with a total of 21 isolates were examined by MLVA. Nearly 20% of the epidemiologically linked strains were single-locus variants (SLV) of their respective predominant outbreak clone. This result prompted an investigation into the mutation rates of the seven MLVA loci (TR1 to TR7). With an outbreak strain that was an SLV at the TR1 locus of the predominant clone, parallel and serial batch culture experiments were performed. In a parallel experiment, none (0/384) of the strains analyzed had mutations at the seven MLVA loci. In contrast, in the two 5-day serial experiments, 4.3% (41/960) of the strains analyzed had a significant variation in at least one of these loci (P < 0.001). The TR2 locus accounted for 85.3% (35/41) of the mutations, with an average mutation rate of 3.5 x 10(-3); the mutations rates for TR1 and TR5 were 10-fold lower. Single additions accounted for 77.1% (27/35) of the mutation events in TR2 and all (6/6) of the additions in TR1 and TR5. The remaining four loci had no slippage events detected. The mutation rates were locus specific and may impact the interpretation of MLVA data for epidemiologic investigations.

DNA, Bacterial↗