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PubMed1991

[The affected sib-set method: revision based on the mixed model using a conditional probability approach].

One of the implicit assumptions of the single locus model, having been used so far in the analysis of linkage between the genetic marker locus and the disease predisposition locus, is the requirement of independent--from the rest of genotype--action of genotypes of the disease predisposition locus considered. In this communication, it is emphasized that the lack of this requirement makes problematical the theoretical substantiation of the affected sib-pair method in the linkage analysis. To remove this obstacle, explicit pointing out of independence of the action of the single locus genotypes on the rest of the genotype is necessary in formulating of the single locus model which, with due regard for this assumption, represents a special, perhaps, unique case of the gene action characterized by incomplete differential penetrances of the genotypes under conditions, when the genes of the rest of genotype involved to the disease, are fixed. In this connection, the mixed model of inheritance with the "major gene", proposed by Morton and MacLean (1974), is considered, on the basis of which the theoretical expectations of the proportions of the affected sib pairs, sharing the x = 2, 1, 0 haplotypes, identical by descent (IBD) in phenotypic matings with the h = 2, 1, 0 affected parents are derived. Based on the combinatorial analysis of IBD relationships in sib pairs and of the distribution of sibships of any size s greater than or equal to 2 by the numbers L = 2, 3, 4 haplotypes, inherited by s siblings, the empirical assessment of data on sibships of any size with r greater than or equal to 2 affected siblings is considered, which makes it possible to reduce the data observed on distribution of the numbers L in sibships, to that of the IBD relationships in the affected sib pairs. It is also pointed out that conditional probability approach, proposed by the author earlier, allows at the same time to obtain the empirical estimates of the recurrence risks, conditional both on phenotypes of siblings (r affected; s-r normal siblings), and on the number of L haplotypes inherited by sibships.

Chromosome Mapping↗

PubMed2005

Association analysis of estrogen receptor alpha gene polymorphisms with cross-sectional geometry of the femoral neck in Caucasian nuclear families.

Bone geometry is a key factor in bone strength, which is the ultimate intrinsic determinant of fracture risk. Though the heritability of bone geometry is high, little effort has been spent on searching for the underlying genes. In this study, employing a sample of 1,873 subjects from 405 Caucasian nuclear families, we studied seven single nucleotide polymorphisms (SNPs) and their haplotypes of the ER-alpha gene for association with six hip geometric variables, namely, cross-sectional area (CSA), cortical thickness (CT), endocortical diameter (ED), subperiosteal width (W), sectional modulus (Z) and buckling ratio (BR). The major method used was the quantitative transmission disequilibrium test (QTDT). Our major findings were summarized below. The within-family association between SNP4 (rs1801132) in exon 4 with endocortical diameter and subperiosteal width was detected in single locus analyses (P=0.008 and 0.021, respectively) and verified in haplotype analyses (P=0.034 and 0.058, respectively). The total association of SNP4 with these two diameters was also observed in both single locus and haplotype analyses (P=0.005 and 0.031 for ED, plus P=0.003 and 0.070 for W). In addition, the total association between SNP5 (rs932477) in intron 4 with cortical thickness and buckling ratio was detected (single locus analyses: P=0.035 and 0.041, respectively). Haplotype analyses further supported the above association (P=0.010 and 0.004, respectively). Similar patterns of associations with the studied SNPs and their haplotypes were present in subsamples stratified by sex, too. However, after permutation tests, the empirical significance level was set as P<0.011, which renders most associations insignificant. Therefore, we concluded that polymorphisms in the ER-alpha gene were nominally associated with femoral neck (FN) geometry variables estimated from DXA. Such genetic effects on hip geometry were not sex specific.

Adult↗

PubMed1984

Platelet monoamine oxidase (MAO) activity: evidence for a single major locus.

Monoamine oxidase (MAO), a mitochondrial enzyme involved in the degradation of biogenic amines, has been associated with psychiatric morbidity. Although twin and family studies have indicated that MAO activity is familial, the exact mode of transmission is unclear. We performed segregation analysis on 154 nuclear families containing 419 individuals using the mixed model, which allows for a single major locus with a polygenic background. We were able to reject a dominant and additive locus with or without a heritable background and a recessive locus without background. The acceptable models were: (1) a codominant model without background where the mean of the heterozygote distribution was 30% of the distance from the low to the high homozygote distributions, and (2) a recessive locus with heritable background. In both cases, the gene frequency for the high-MAO allele is approximately .25--at odds with suggestions that low-MAO represents a genetic marker for a disorder such as schizophrenia with a lifetime risk of only 0.85%. To ensure that results were not artifacts from a familial, skewed distribution, the data were also analyzed after power transformation. In addition, hypotheses were tested using both the joint and conditional likelihoods to examine for possible misspecification of the model with respect to intergenerational differences. Finally, we allowed for non-Mendelian transmission probabilities to provide another class of alternatives against which to test the hypothesis of a major locus. All these approaches provided additional confirmation for the presence of a major locus segregating within these families.

Alleles↗

PubMed2002

Identification of quantitative trait loci and epistatic interactions for plant height and heading date in rice.

Appropriate heading date and plant height are prerequisites for attaining the desired yield level in rice breeding programs. In this study, we analyzed the genetic bases of heading date and plant height at both single- locus and two-locus levels, using a population of 240 F(2:3) families derived from a cross between two elite rice lines. Measurements for the traits were obtained over 2 years in replicated field trials. A linkage map was constructed with 151 polymorphic marker loci, based on which interval mapping was performed using Mapmaker/QTL. The analyses detected six QTLs for plant height and six QTLs for heading date; collectively the QTLs for heading date accounted for a much greater amount of phenotypic variation than did the QTLs for plant height. Two-way analyses of variance, with all possible two-locus combinations, detected large numbers (from 101 to 257) of significant digenic interactions in the 2 years for both traits involving markers distributed in the entire genome; 22 and 39 were simultaneously detected in both years for plant height and heading date, respectively. Each of the interactions individually accounted for only a very small portion of the phenotypic variation. The majority of the significant interactions involved marker loci that did not detect significant effects by single-locus analyses, and many of the QTLs detected by single-locus analyses were involved in epistatic interactions. The results clearly demonstrated the importance of epistatic interactions in the genetic bases of heading date and plant height.

Journal Article↗

PubMed2000

Identification of the major Spanish clones of penicillin-resistant pneumococci via the Internet using multilocus sequence typing.

Multilocus sequence typing was used to characterize isolates of the major Spanish clones of penicillin-resistant and multiple-antibiotic-resistant Streptococcus pneumoniae. Isolates of the multidrug-resistant Spanish serotype 23F clone and serotype variants of this clone either had identical allelic profiles or their allelic profiles differed from this typical allelic profile at only one of the seven housekeeping loci. Similarly, isolates of the Spanish serotype 6B and 14 clones and the penicillin-resistant serotype 9V clone (and serotype variants of this clone) each had the same allelic profiles or profiles that differed at a single locus. Multilocus sequence typing therefore allows resistant pneumococci to be assigned to the Spanish clones if they have the typical allelic profile of the clone or if their profiles differ from that profile at a single locus. A few resistant isolates that had allelic profiles typical of that of a Spanish clone or whose profiles differed from that of the typical profile at only a single locus possessed penicillin-binding protein pbp1a, pbp2b, or pbp2x genes that differed from those that are characteristic of the clone. In most cases these isolates could be assigned as variant members of the clone. Since almost all serotype 9V isolates have very similar genotypes, independently emerging penicillin-resistant clones of this serotype will inevitably appear to be similar by molecular typing procedures. Analysis of the pbp genes, in addition to multilocus sequence typing (or any other molecular typing procedure), is therefore required to assign isolates unambiguously to the penicillin-resistant Spanish serotype 9V clone.

Alleles↗

PubMed2000

Equivalence of single- and multilocus markers: power to detect linkage with composite markers derived from biallelic loci.

The reintroduction of biallelic markers, now in the form of single-nucleotide polymorphisms (SNPs), has again raised concerns about the practicality of the use of markers with low heterozygosity for genomic screening for complex traits, even if thousands of such markers are available. Like the early blood-group markers (e.g., Rh and MNS), tightly linked biallelic SNPs can be combined into composite markers with heterozygosity similar to that of short-tandem-repeat polymorphisms. The assumptions that underlie the equivalence between single-locus multiallelic and composite markers are presented. We used computer simulation to determine the power of the Haseman-Elston test for linkage with composite markers when not all of these assumptions hold. The Genometric Analysis Simulation Program was used to simulate continuous and discrete traits, one single-locus four-allele marker, and six biallelic markers. We studied composite markers created from pairs, trios, and quartets of biallelic markers in nuclear families and in independent sib pairs. The power to detect linkage with a two-point approach for composite markers and with a multipoint approach that incorporated all six biallelic markers was compared with that for a single-locus, four-allele reference marker. Although the power to detect linkage with a single biallelic marker was considerably less than that of the reference marker, the power to detect linkage with two- and three-locus composite markers was quite similar to that of the reference marker. The power to detect linkage with four-locus composite markers was similar to that of a multipoint approach.

Alleles↗

PubMed1981

Immunologic control of the ascites form of murine adenocarcinoma 755. III. Efficacy of serum therapy is controlled by a single genetic locus.

We have previously described a passive serum therapy system in which potent protection against challenge of syngeneic mice with large doses (10(4) X LD100) of AD755a tumor cells can be accomplished by administration of as little as 2 to 5 microliters/mouse of hyperimmune anti-tumor cell serum. The present results demonstrate that the efficacy of the serum protection effect is strain-dependent and is under the control of a single genetic locus, denoted ADP-1. Through a series of crosses between highly protected C57BL/6J and nonprotected BALB/cJ mice, the ADP-locus has been mapped to chromosome 2 [linkage group V], approximately 23 centimorgans toward te centromere from the locus controlling agouti coat color. Thus, the protection locus is not linked to either the H-2 region or to previously described loci regulating the replication and disease induction of type-C viruses closely related to the virus associated with the AD775a tumor. The possible functions of the ADP-1 locus are discussed and further aspects of this experimental model are described in the accompanying papers.

Animals↗

PubMed1983

Morphine tolerance and dependence in the locus coeruleus: single cell studies in brain slices.

Extracellular single unit recordings in vitro from the locus coeruleus in rat brainstem slices revealed the presence of spontaneously active neurons. These cells fired between 0.1 and 3.0 spikes/s and were inhibited by nM concentrations of morphine and clonidine. Locus coeruleus neurons in slices from animals treated chronically, but not subacutely, with morphine exhibited a significant decrease in sensitivity to morphine. This tolerance appeared to be specific for opiates since no decrease in sensitivity was seen for the alpha 2-adrenoceptor agonist clonidine. However, in contrast to what has been reported in vivo, no signs of dependence (withdrawal activation) were evident in slices from morphine tolerant animals.

Animals↗

PubMed1998

Segregation analysis reveals a major gene effect controlling systolic blood pressure and BMI in an Israeli population.

It has been suggested that genetic factors control blood pressure level at all ages. However, the evidence is limited because of the composite nature of blood pressure and the heterogeneity of the studied samples. The purpose of the present study is to test for genetic influences on systolic blood pressure (SBP) level in a community-based Israeli family study. Segregation analysis was performed on 622 adults from 208 pedigrees. Age, sex, and body mass index (BMI) were significant covariates of SBP. Segregation analysis rejected the environmental transmission model but not the mixed Mendelian transmission model. The best-fitting genetic model was the mixed codominant model, with a heritability of 0.32 and an allele frequency of 0.18 for high SBP level. We further tested whether SBP and BMI shared a common major gene effect. Using bivariate segregation analysis involving two traits and a single locus, we found evidence for a single-locus pleiotropic effect on SBP and BMI. The allele frequency of this major locus was 0.24. The residual genetic correlation resulting from additive polygenes and the environmental correlation between these two traits were not different from zero after taking into account the shared major gene effect. The proportion of phenotypic variation attributable to this major gene effect increased with age for SBP but decreased with age for BMI.

Adult↗

PubMed2003

PCR-multiplexes for a genome-wide framework of simple sequence repeat marker loci in cultivated sunflower.

Simple sequence repeat (SSR) and other DNA sequence-tagged site markers can be genotyped more rapidly and cost efficiently by simultaneously amplifying multiple loci (multiplex PCR). The development of PCR-multiplexes for a nearly genome-wide framework of 78 SSR marker loci in cultivated sunflower ( Helianthus annuus L.) is described herein. The most outstanding single-locus SSR markers in the public collection (300 out of 1,089) were identified and screened for polymorphisms among 24 elite inbred lines, preparatory to selecting SSR markers for testing in multiplex PCRs. The selected SSR markers produced robust PCR products, amplified a single locus each, were polymorphic among elite inbred lines (minimum, mean and maximum heterozygosities were 0.08, 0.53 and 0.85, respectively), and supply a dense genome-wide framework of predominantly or completely codominant, single-locus DNA markers for molecular breeding and genomics research in sunflower. Thirteen six-locus multiplex PCRs were developed for 78 SSR marker loci strategically positioned throughout the sunflower genome (three to five per linkage group) by identifying compatible SSR primer combinations and optimizing multiplex PCR protocols. The multiplexed SSR markers, when coupled with 17 complementary SSR marker loci, create a 'standard genotyping' set ideal for first-pass scans of the genome, as are often needed when screening bulked-segregant DNA samples or mapping phenotypic trait loci. The minimum, mean and maximum heterozygosities of the multiplexed SSR markers were 0.38, 0.62 and 0.83, respectively. The PCR-multiplexes increase genotyping throughput, reduce reagent costs, and are ideal for repetitive genotyping applications where common sets of SSR marker loci are required or advantageous.

Chromosome Mapping↗

PubMed1988

Two different mRNAs are transcribed from a single genomic locus encoding the chicken erythrocyte anion transport proteins (band 3).

The chicken erythrocyte anion transport protein (band 3 of the erythrocyte cytoskeleton) is a central component taking part in two widely divergent functions of erythroid cells; it is a primary determinant of cytoskeletal architecture and responsible for electroneutral Cl-/HCO3- exchange across the plasma membrane. To analyze interesting aspects of the developmental regulation of this gene, we have cloned the cDNA and genomic counterparts of the erythroid-specific anion transport protein. We show that a single genetic locus for band 3 encodes two different erythroid cell-specific mRNAs, with different translational initiation sites, which predict polypeptides of sizes very close to those observed in vivo. In vitro translation and immune precipitation of synthetic mRNA derived from one putative fully encoding cDNA clone demonstrate that this clone gives rise to a protein which is identical in size and antigenicity to bona fide chicken erythroid band 3.

Amino Acid Sequence↗

PubMed2006

Association study with 33 single-nucleotide polymorphisms in 11 candidate genes for hypertension in Chinese.

Essential hypertension is considered to be a typical complex disease with multifactorial etiology, which leads to inconsistent findings in genetic studies. One possibility of failure to replicate some single-locus results is that the underlying genetics of hypertension are not only based on multiple genes with minor effects but also on gene-gene interactions. To test this hypothesis, a case-control study was constructed in Chinese subjects, detecting both single locus and multilocus effects. Eleven candidate genes were selected from biochemical pathways that have been implicated in the development and progression of hypertension, and 33 polymorphisms were evaluated in 503 hypertension patients and 490 age- and gender-matched controls. Single-locus associations, using traditional logistic regression analyses, and multilocus associations, using classification and regression trees and multivariate adaptive regression splines, were both explored in this study. Final models were selected using either Bonferroni correction or cross-validation. Three polymorphisms, TH*rs2070762, ADRB2*Q27E, and GRK4*A486V, were found to be independently associated with essential hypertension in Chinese subjects. In addition to these individual predictors, a potential interaction of CYP11B2-AGTR1 is also involved in the etiology of hypertension. These findings support the multigenic nature of the etiology of essential hypertension and propose a potential gene-gene interactive model for future studies.

Alanine↗

PubMed2003

Natural resistance to Clover yellow vein virus in beans controlled by a single recessive locus.

We characterized the resistance of the common bean cv. Jolanda to Clover yellow vein virus no. 30 (ClYVV). After inoculation, the virus was detected in neither inoculated nor upper leaves, suggesting that the resistance operates at either the viral replication or cell-to-cell movement level. To analyze the mechanism of resistance, we developed a green fluorescent protein (GFP)-tagged ClYVV, and monitored GFP fluorescence at sites of infection on ClYVV-inoculated leaves. No GFP fluorescence was detected in Jolanda, whereas its expression in single cells and spread on inoculated leaves were observed clearly in susceptible cultivars. ClYVV-introduced Jolanda cells were found to be still viable; therefore, it is unlikely that the restriction of multiplication was due to rapid cell death. Genetic analysis indicated that a single recessive locus controlled the resistant phenotype of Jolanda. We designated this locus desc (determinant of susceptibility to ClYVV). Meanwhile, a spontaneous mutant virus that overcomes the resistance (ClYVV-Br) was isolated. Inoculation assays using chimeric viruses suggested that a viral genome-linked protein (VPg) might be the avirulence determinant. The resistance mechanism may be associated with the role of VPg in the viral infection cycle.

Amino Acid Sequence↗

PubMed2004

Role of two angiotensinogen polymorphisms in blood pressure variation.

Genetic analysis of hypertension has yielded inconsistent results, making it difficult to draw clear conclusions regarding the impact of specific variants on blood pressure regulation. Among the most studied of the candidate genes for blood pressure regulation is angiotensinogen (AGT), but as with other candidate loci associations with blood pressure have been inconsistent. We examined the contributions of two AGT polymorphisms (T174M and M235T) to detect the effects of each on blood pressure variation, using single-site and two-site analyses. We analysed data from a study of 177 subjects from Accra, Ghana. We observed significant single-locus associations of the T174M polymorphism with average systolic (SBP) and diastolic blood pressure (DBP) when age was used as a covariate (P<0.001 and P=0.010, respectively). Also, we observed a significant association of the M235T polymorphism with SBPs and DBPs (P<0.001 and P=0.014, respectively). Finally, we observed a simultaneous significant association of the two polymorphisms with SBP and DBP (P<0.001 and P=0.026, respectively), although the two-loci model is not significantly better than either single-locus model. However, for SBP the two-loci model is marginally better (P=0.08 in comparison to both single-locus models). These results suggest that variants at these two AGT sites together, in conjunction with age, may be significantly associated with elevated SBP, whereas the single-site models are as good models of DBP. It is possible that earlier inconsistent results with these AGT polymorphisms with hypertension in African-derived populations may have resulted from an 'incomplete' model in the different study populations. Given the inconclusive nature of our two-loci results, this possibility requires further investigation.

Aging↗

PubMed2003

The genetics of deafness.

Deafness is an etiologically heterogeneous trait with many known genetic and environmental causes. Genetic factors account for at least half of all cases of profound congenital deafness, and can be classified by the mode of inheritance and the presence or absence of characteristic clinical features that may permit the diagnosis of a specific form of syndromic deafness. The identification of more than 120 independent genes for deafness has provided profound new insights into the pathophysiology of hearing, as well as many unexpected surprises. Although a large number of genes can clearly cause deafness, recessive mutations at a single locus, GJB2 or Connexin 26, account for more than half of all genetic cases in some, but not all populations. The high frequency may well be related to the greatly improved social, educational, and economic circumstances of the deaf that began with the introduction of sign language 300-400 years ago, along with a high frequency of marriages among the deaf in many countries. Similar mechanisms may account for the rapid fixation of genes for speech after the first mutations appeared 50,000-100,000 years ago. Molecular studies have shown that mutations involving several different loci may be the cause for the same form of syndromic deafness. Even within a single locus, different mutations can have profoundly different effects, leading to a different pattern of inheritance in some cases, or isolated hearing loss without the characteristic syndromic features in others. Most cases of genetic deafness result from mutations at a single locus, but an increasing number of examples are being recognized in which recessive mutations at two loci are involved. For example, digenic interactions are now known to be an important cause of deafness in individuals who carry a single mutation at the Connexin 26 locus along with a deletion involving the functionally related Connexin 30 locus. This mechanism complicates genetic evaluation and counseling, but provides a satisfying explanation for Connexin 26 heterozygotes who, for previously unknown reasons, are deaf. A specific genetic diagnosis can sometimes be of great clinical importance, as in the case of the mitochondrial A1555G mutation which causes gene carriers to be exquisitely sensitive to the ototoxic effects of aminoglycosides. This potentially preventable genetic-environmental interaction was the most common cause of genetic deafness in countries where these antibiotics were used indiscriminately in the past. Advances in genetic knowledge along with the use of cochlear implants have posed unique ethical dilemmas for society as well as the deaf community. Since most deaf children are born to hearing parents, it seems likely that deaf culture, and intermarriages among those born with deafness will recede during this century. Will future critics view this as one of the medical triumphs of the 21(st) Century, or as an egregious example of cultural genocide? On the other hand, genetics can provide empowering knowledge to the deaf community that for the first time can allow many deaf couples to know whether their children will be hearing or deaf even before they are conceived.

Biotinidase Deficiency↗

PubMed1993

Two distinct defects in intracellular growth complemented by a single genetic locus in Legionella pneumophila.

Legionella pneumophila mutants specifically defective for intracellular replication were isolated using an intracellular thymineless death enrichment strategy. Mutants belonging to two distinct phenotypic classes were unable to grow in macrophage-like cultured cells. One class of mutants was defective for both inhibition of phagosome-lysosome fusion and association of host cell organelles with bacteria-containing phagosomes ('recruitment'). Another class of mutants was defective only for organelle recruitment, suggesting that recruitment may be necessary for intracellular growth. Recombinant clones were identified that complemented the intracellular growth defects of these mutants. A single genetic locus, designated dot (for defect in organelle trafficking), restored wild-type phenotypes for intracellular growth, organelle recruitment, and inhibition of phagosome-lysosome fusion to mutants belonging to both phenotypic classes.

DNA Transposable Elements↗

PubMedDate not supplied

A single genetic locus encoded by Yersinia pseudotuberculosis permits invasion of cultured animal cells by Escherichia coli K-12.

For many species of pathogenic bacteria, invasion and survival within animal cells is central to establishing a successful host-parasite relationship. Localization within host cells protects the microorganism from host defences, or permits it to cross epithelial barriers and subsequently become systemically distributed. The precise mechanisms that permit entry of bacteria into host tissues are unclear, therefore we have been studying the invasion of epithelial cells by Yersinia pseudotuberculosis. As a first step towards identifying the factors required for this process, we report here the identification of a single genetic locus from this organism that is sufficient to convert the innocuous Escherichia coli K-12 strain into an organism capable of invading cultured animal cells.

Carcinoma, Squamous Cell↗

PubMed1977

B-lymphocyte Fc receptor-associated non-H-2 antigens are determined by a single polymorphic locus which is linked to the Mls locus.

Certain non-H-2 alloantigens are associated with murine B-lymphocyte Fc receptors in that pretreatment of spleen cells with alloantibodies against these antigens inhibited binding of Ig complexes to B-cell Fc receptors. This inhibition was specific in that: (a) as has been shown previously, the Fc portion of the alloantibody was not required to produce inhibition; and (b) antibodies against some non-H-2 antigens but not antibodies against others (including some that were expressed on B cells) caused such inhibition. Backcross experiments revealed that the B-cell Fc receptor-associated non-H-2 antigens were determined by the gene(s) of a single background locus in each of the three strains tested (A/J, B10, and CBA/J). This locus was poly-morphic in that at least four different B-cell Fc receptor:associated non-H-2 antigens were identified (one each in the A/J, B10, and CBAJJ and one antigen shared or crossreactive between the B10 and CBA/J). These antigens were primarily but not exclusively expressed on B lymphocytes as determined by immunofluorescence studies, and on the basis of capping experiments they did not appear to be identical to B-cell Fc receptors. Linkage studies revealed that the locus which determined these antigens was not linked to the albino locus nor the heavy chain allotype locus and expression was neither sex-limited nor an X-linked recessive trait. However, this locus was closely linked but not identical to the Mls locus (apparent recombination frequency 6.8 percent). Thus, two closely linked non-H-2 loci both determine the expression of antigens which have characteristics similar to Ia antigens. One locus is polymorphic and determines the expression of antigens which are primarily expressed on B cells and are specifically associated with the Fc receptors of these cells. The other (Mls locus) determines antigens which are stimulatory in mixed lymphocyte cultures. These observations suggest that there may be a second gene complex which is the analogue of the I region of the H-2 complex.

Animals↗