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PubMed1979

Regulation of Leishmania populations within the host. III. Mapping of the locus controlling susceptibility to visceral leishmaniasis in the mouse.

Acute susceptibility of the mouse to Leishmania donovani is largely determined by a single locus designated Lsh. Linkage between the Lsh locus and the Chromosome 1 marker Id-1 was detected using several sets of recombinant inbred strains. Chromosome 1 linkage was confirmed in backcross generations using isoenzymes and a cytogenetic marker. The data indicate that the gene order is centromere-Lsh-Id-1-ln-Dip-1. The estimated recombination frequency between Lsh and Id-1 is 0.12 +/- 0.04. This mapping is away from the known histocompatibility loci.

Alleles↗

PubMedDate not supplied

Cloning of the initiation region of a mammalian chromosomal replicon.

In eukaryotic cells, each chromosome is divided into several thousand tandemly arranged replicons, each synthesized at a characteristic time during the S period. Although as yet no eukaryotic DNA sequence known for certain to be a eukaryotic chromosomal replication origin has been isolated, electron microscopic and biochemical evidence suggests that eukaryotic DNA synthesis is initiated at specific sites. We have attempted to establish a system in which functional chromosomal origins could be identified in vivo before their isolation by molecular cloning. For this purpose, we have developed a methotrexate-resistant Chinese hamster ovary cell line (CHOC 400) that contains 1,000 copies of a 135-kilobase (kb) early-replicating sequence, and which includes the gene for dihydrofolate reductase (DHFR). We have shown that initiation of DNA synthesis within each repeated unit (amplicon) is restricted to a small subset of restriction fragments at the beginning of the S period, suggesting that these fragments contain or flank origins of DNA synthesis. Here we report molecular cloning and restriction mapping experiments showing that all of these early-labelled fragments (ELFs) are derived from a single locus within each repeated unit. This result implies that synthesis of each amplicon initiates from a single origin of replication at the onset of S, and that an amplicon is formally equivalent to a replicon.

Animals↗

PubMed2001

Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes.

Previous analyses indicate major gene control of susceptibility to leprosy per se and the HLA class II region has been implicated in determining susceptibility and control of clinical phenotype. Segregation analysis using data from 76 Brazilian leprosy multi-case pedigrees (1166 individuals) supported a two locus model as the best fit: a recessive major gene and a recessive modifier gene(s) (single locus vs two locus model, P = 0.0007). Combined segregation and linkage analysis to the major locus, showed strong linkage to HLA class II (HLA-DQB1 P = 0.000002, HLA-DQA1 P = 0.000002, HLA-DRB1 P = 0.0000003) and tumour necrosis factor genes (TNF P = 0.00002, LTA P = 0.003). Extended transmission disequilibrium testing, using multiple affected family members, demonstrated that the common allele TNF*1 of the -308 promoter region polymorphism showed linkage and/or association with disease per se, at a high level of significance (P < 0.0001). Two locus transmission disequilibrium testing suggested susceptibility (TNF*1/LTA*2) and protective (TNF*2/LTA*2) haplotypes in the class iii region. Taken together the segregation and HLA analyses suggest the possibility of more than one susceptibility locus in the MHC.

Brazil↗

PubMed1996

Human immunodeficiency virus fitness in vivo: calculations based on a single zidovudine resistance mutation at codon 215 of reverse transcriptase.

We monitored a subject newly infected with a zidovudine-resistant human immunodeficiency virus type 1 strain and found that in the absence of drug, the viral population with the resistance-conferring tyrosine (TAC) codon 215 of reverse transcriptase was gradually replaced. By using standard formulas to model the effects of selection at a single locus in an asexual haploid population, the relative fitness gain of the viral population with a single mutation at codon 215 creating a serine (TCC) was calculated. We concluded that a viral population with a serine at reverse transcriptase codon 215 conferring zidovudine sensitivity was between 0.4 and 2.3% more fit.

HIV Infections↗

PubMed2005

Detecting deletions in families affected by a dominant disease by use of marker data.

A method of testing for whether inherited deletions are a cause of a single-locus dominant disease was derived, involving analysis of the marker segregation within the pedigree of a single family that segregates for the disease. It is shown that markers can be used to test deductively for the presence of an inherited deletion. The probabilities of confirming or rejecting the presence of a deletion in an arbitrary pedigree without inbreeding are then derived. The power of the test is shown to be limited in single trios but to increase rapidly as the size of the pedigree increases. For larger pedigrees, the probabilities of confirming or rejecting a deletion are higher than 0.9 for SNPs having a minor allele frequency greater than 0.4. The probabilities are higher using multiallelic markers such as microsatellites, reaching levels as high as 0.9 in even rather small pedigrees. In certain cases the test outcome is not deductive, a deletion being neither confirmed nor rejected. It is shown to still be possible then to employ a statistical test for the presence of a deletion by use of an a priori probability for a deletion.

Family↗

PubMed1995

The Triplo-lethal locus of Drosophila: reexamination of mutants and discovery of a second-site suppressor.

In the genome of Drosophila melanogaster there is a single locus, Triplo-lethal (Tpl), that causes lethality when present in either one or three copies in an otherwise diploid animal. Previous attempts to mutagenize Tpl produced alleles that were viable over a chromosome bearing a duplication of Tpl, but were not lethal in combination with a wild-type chromosome, as deficiencies for Tpl are. These mutations were interpreted as hypomorphic alleles of Tpl. In this work, we show that these alleles are not mutations at Tpl; rather, they are dominant mutations in a tightly linked, but cytologically distant, locus that we have named Suppressor-of-Tpl (Sul(Tpl)). Su(Tpl) mutations suppress the lethality associated with three copies of the Triplo-lethal locus and are recessive lethal. We have mapped Su(Tpl) to the approximate map position 3-46.5, within the cytological region 76B-76D.

Animals↗

PubMed2005

Hepatocyte nuclear factor-3alpha binding at P sequences of the human growth hormone locus is associated with pituitary repressor function.

The human GH family consists of five genes, including the placental chorionic somatomammotropins (CS), within a single locus on chromosome 17. Based on nuclease sensitivity, the entire GH/CS locus is accessible in pituitary chromatin, yet only GH-N is expressed. Previously, we reported a P sequence element (263P) capable of repressing placental CS-A promoter activity in transfected pituitary (GC) cells, and our data indicated a possible role for nuclear factor-1 (NF-1) and regulatory factor X1 in this repression. In this study we show the formation of two independent pituitary complexes in vitro: a repressor complex containing NF-1 and a nonfunctional complex containing regulatory factor X1. In vitro repressor function is stabilized by the presence of P sequence element C (PSE-C), downstream of the previously characterized PSE-A and PSE-B. Repressor function is also dependent on an intact Pit-1 binding site in the CS-A promoter. EMSAs with PSE-C reveal binding of the hepatocyte nuclear factor-3/forkhead (HNF-3/fkh) family of transcription factors in rat pituitary GC cells. This observation is extended to human pituitary tissue, where HNF-3alpha's association with P sequences is confirmed by chromatin immunoprecipitation. Furthermore, protein-protein interactions between HNF-3alpha and NF-1 family members are demonstrated. These results identify HNF-3alpha as an additional member of the pituitary P sequence regulatory complex, implicating it in tissue-specific expression of the human GH/CS family.

Animals↗

PubMed1997

Bulked segregant analysis using microsatellites: mapping of the dominant white locus in the chicken.

In order to perform a linkage study, the genotypes of a large number of individuals from a segregating population need to be determined. In case the phenotype to be mapped is influenced by a single locus or a major gene, sampling of the DNA from individual animals with the same phenotype into a single pool (bulked segregant) can reduce the number of typings. In this study we used bulked segregant analysis in order to map the Dominant White locus in the chicken. In a pilot experiment, we showed that allele frequencies can be accurately estimated from pooled samples using fluorescently labeled microsatellite markers. A segregating population for the Dominant White locus was obtained by performing a cross between a white male chicken (Genotype li for Dominant White) and a black female chicken (ii). The resulting progeny of 21 white and 18 black chickens were divided in two pools. Genotypes for both the parents and the pools were determined using 168 fluorescently labeled microsatellite markers, of which 68 were informative. The relative allele frequencies between the pools were estimated for these 68 informative markers. One marker (MCW188) was found to segregate with the Dominant White locus. Subsequent typing of all individuals from this cross and an additional 148 animals from five different families showed only two recombinants between the marker and the Dominant White locus, resulting in a LODlinkage score (log10 of odds) of 36. Using the pooled DNA approach, the Dominant White locus was successfully mapped on linkage group 22 of the East Lansing reference family at a distance of 2 cM from MCW188.

Animals↗

PubMed1980

The albino locus produces abnormal responses to opiates in the mouse.

Pedigreed inbred lines of pigmented mice were compared with albino lines differing at either a single locus or by a chromosomal segment of interest, for their responses to morphine. In either of two tests, behavioral activation or reduction in core temperature, albino mice were aberrant in their responses, demonstrating reliably less sensitivity to morphine than closely related pigmented lines. These findings suggest the need for caution in the use of albino lines in opiate research.

Animals↗

PubMed2004

Variation in the urokinase-plasminogen activator gene does not explain the chromosome 10 linkage signal for late onset AD.

Linkage studies indicate that the same region of chromosome 10 contains a risk locus for late onset Alzheimer disease (LOAD) and a QTL for plasma Abeta42 levels suggesting that a single locus may influence risk for AD by elevating plasma Abeta42 [Ertekin-Taner et al., 2000; Myers et al., 2000]. A strong positional and biological candidate is the urokinase-plasminogen activator (PLAU) gene. Eight polymorphisms spanning the entire gene were examined using case control (CC) and family-based association methods. No association was observed by any method making it unlikely that variation in PLAU explains our linkage data.

Aged↗

PubMed2003

A new approach to extending the wheat marker pool by anchored PCR amplification of compound SSRs.

A study was undertaken to determine the utility in bread wheat of anchored PCR for the development of single locus SSR markers targeted at compound repeat motifs. In anchored PCR, microsatellite amplification is achieved using a single primer complementary to the flanking sequence, and one which anchors to the repeat junction of the compound SSR. The recovery rate of useable markers was found to be similar (43%) to that reported for conventionally generated SSRs. Thus, anchored PCR can be used to reduce the costs of marker development, since it requires that only half the number of primers be synthesised. Where fluorescence-based platforms are used, marker deployment costs are lower, since only the anchoring primers need to be labelled. In addition, anchored PCR improves the recovery of useful markers, as it allows assays to be generated from microsatellite clones with repeat sequences located close to their ends, a situation where conventional PCR amplification fails as two flanking primers cannot be designed. Strategies to permit the large-scale development of compound SSR markers amplified by anchored PCR are discussed.

Alleles↗

PubMed2000

Fine scale association mapping of disease loci using simplex families.

We present a new method for the fine scale mapping of disease loci based on samples of simplex families, each containing an affected child. The method is based on a generalisation of a single locus allele transmission model to multiple marker loci. The model is developed under the assumption of a single ancestral mutation and allows for the calculation of posterior probabilities that each allele at a particular marker was present on the founder chromosome. We illustrate the method using simulated family data for cystic fibrosis and Huntingtons disease, for which the locations of mutations in the disease genes are now known. For both diseases, our new method provides good estimates of the location of the mutations.

Alleles↗

PubMed1999

A single nuclear transcript encoding mitochondrial RPS14 and SDHB of rice is processed by alternative splicing: common use of the same mitochondrial targeting signal for different proteins.

The rice mitochondrial genome has a sequence homologous to the gene for ribosomal protein S14 (rps14), but the coding sequence is interrupted by internal stop codons. A functional rps14 gene was isolated from the rice nuclear genome, suggesting a gene-transfer event from the mitochondrion to the nucleus. The nuclear rps14 gene encodes a long N-terminal extension showing significant similarity to a part of mitochondrial succinate dehydrogenase subunit B (SDHB) protein from human and a malarial parasite (Plasmodium falciparum). Isolation of a functional rice sdhB cDNA and subsequent sequence comparison to the nuclear rps14 indicate that the 5' portions of the two cDNAs are identical. The sdhB genomic sequence shows that the SDHB-coding region is divided into two exons. Surprisingly, the RPS14-coding region is located between the two exons. DNA gel blot analysis indicates that both sdhB and rps14 are present at a single locus in the rice nucleus. These findings strongly suggest that the two gene transcripts result from a single mRNA precursor by alternative splicing. Protein blot analysis shows that the size of the mature RPS14 is 16.5 kDa, suggesting removal of the N-terminal 22.6-kDa peptide region. Considering that the rice mitochondrial genome lacks the sdhB gene but contains the rps14-related sequence, transfer of the sdhB gene seems to have occurred before the transfer of the rps14 gene. The migration of the mitochondrial rps14 sequence into the already existing sdhB gene could bestow the capacity for nuclear expression and mitochondrial targeting.

Alternative Splicing↗

PubMed1998

Epigenetic allelic states of a maize transcriptional regulatory locus exhibit overdominant gene action.

Using alleles of the maize purple plant locus (pl), which encodes a transcriptional regulator of anthocyanin pigment synthesis, we describe a case of single-locus heterosis, or overdominance, where the heterozygote displays a phenotype that is greater than either homozygote. The Pl-Rhoades (Pl-Rh) allele is subject to epigenetic changes in gene expression, resulting in quantitatively distinct expression states. Allelic states with low-expression levels, designated Pl'-mahogany (Pl'-mah), are dominant to the high-expression state of Pl-Rh. Pl'-mah states retain low-expression levels in subsequent generations when homozygous or heterozygous with Pl-Rh. However, Pl'-mah alleles frequently exhibit higher expression levels when heterozygous with other pl alleles; illustrating an overdominant allelic relationship. Higher expression levels are also observed when Pl'-mah is hemizygous. These results suggest that persistent allelic interactions between Pl'-mah and Pl-Rh are required to maintain the low-expression state and that other pl alleles are missing sequences required for this interaction. The Pl-Rh state can be sexually transmitted from Pl'-mah/pl heterozygotes, but not from Pl'-mah hemizygotes, suggesting that fixation of the high-expression state may involve synapsis. The existence of such allele-dependent regulatory mechanisms implicates a novel importance of allele polymorphisms in the genesis and maintenance of genetic variation.

Alleles↗

PubMed2003

[Genetic co-adaptability among structural genes under the condition of genetic disequilibrium].

With the technology of PAGE,the genetic polymorphism of blood protein and enzyme was investigated,and genetic co-adaptability among structural genes was studied in three goat populations(147 goats) including Chaidamu goat(CS), Chaidamu Cashmere goat(CRS) and Liaoning Cashmere goat(LRS) in Qinghai Province, China. The results were showed that the genetic disequilibrium of 10 locus combinations was found among 45 locus combinations in the three goat populations,and these genetic disequilibria were caused only by the difference of genetic co-adaptability among genes,because there didn't exist the linkage disequilibrium among non-allelic genes. The genetic disequilibrium including the difference of genetic co-adaptability between non-allelic genes was only found at Tf-P(A-3) locus combinations in LRS population,the other ones were all caused by the genetic disequilibrium at a single locus. The difference of genetic co-adaptability of LAP-EsD locus combinations could be messaged among different populations.

English Abstract↗

PubMed1996

Affected-sib-pair analyses reveal support of prior evidence for a susceptibility locus for bipolar disorder, on 21q.

In 22 multiplex pedigrees screened for linkage to bipolar disorder, by use of 18 markers on chromosome 21q, single-locus affected-sib-pair (ASP) analysis detected a high proportion (57%-62%) of alleles shared identical by descent (IBD), with P values of .049-.0008 on nine marker loci. Multilocus ASP analyses revealed locus trios in the distal region between D21S270 and D21S171, with excess allele sharing (nominal P values <.01) under two affection-status models, ASM I (bipolars and schizoaffectives) and ASM II (ASM I plus recurrent unipolars). In addition, under ASM I, the proximal interval spanned by D21S1436 and D21S65 showed locus trios with excess allele sharing (nominal P values of .03-.0003). These findings support prior evidence that a susceptibility locus for bipolar disorder is on 21q.

Bipolar Disorder↗

PubMed1980

Control of natural resistance to Salmonella typhimurium and Leishmania donovani in mice by closely linked but distinct genetic loci.

Inbred strains of mice vary in their sensitivity to infection with both Salmonella typhimurium and Leishmania donovani. In both cases, this differential susceptibility is genetically controlled. Resistance to the intracellular parasite L. donovani is determined by a single locus on chromosome 1, designated Lsh (ref. 4). The primary regulator of resistance to S. typhimurium is a single, dominant autosomal gene, named Ity (for immunity to typhimurium), and it has also been recently mapped to chromosome 1 (ref. 6). In addition, two other genetic loci regulate resistance to S. typhimurium in mice. These genes, Lpsd and xid, are mutant alleles that render C3H/HeJ and CBA/N mice, respectively, salmonella susceptible. Both Bradley and his colleagues, and Plant and Glynn, noted similar patterns of resistance or susceptibility of inbred strains of mice to L. donovani and S. typhimurium, and therefore suggested that Lsh and Ity might be the same gene. Mapping of both genes to the same region of chromosome 1 supported this hypothesis but no linkage studies have been used to test it. Since recombinant inbred (RI) mouse strains are, in effect, permanent segregant populations, they are ideal for determing linkage between resistance genes to two different pathogens. Therefore, we determined the S. typhimurium susceptibility of five sets of RI mouse strains that had been previously typed for Lsh and conclude that Lsh and Ity are closely linked but distinct genetic loci.

Animals↗

PubMed1983

The genetics of the sixth and seventh components of complement in the dog: polymorphism, linkage, locus duplication, and silent alleles.

The complement components C6 and C7 exhibit genetic polymorphism in the domestic dog. In the case of C6, there is a single locus with a null allele and two structural alleles; in the case of C7, there are two linked loci, each with three structural alleles. There is a null allele or locus deletion at one of these loci. In all cases, inheritance is autosomal and codominant. The C7 loci are closely linked to each other and to C6. This complex is not close to the dog major histocompatibility complex (MHC) locus.

Alleles↗