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Results for “quantitative trait locus”

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PubMed2006

Deletion of nicotinamide nucleotide transhydrogenase: a new quantitive trait locus accounting for glucose intolerance in C57BL/6J mice.

The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion. The genetic locus underlying this phenotype was mapped to nicotinamide nucleotide transhydrogenase (Nnt) on mouse chromosome 13, a nuclear-encoded mitochondrial protein involved in beta-cell mitochondrial metabolism. C57BL/6J mice have a naturally occurring in-frame five-exon deletion in Nnt that removes exons 7-11. This results in a complete absence of Nnt protein in these mice. We show that transgenic expression of the entire Nnt gene in C57BL/6J mice rescues their impaired insulin secretion and glucose-intolerant phenotype. This study provides direct evidence that Nnt deficiency results in defective insulin secretion and inappropriate glucose homeostasis in male C57BL/6J mice.

Animals↗

PubMed2002

Simultaneous mining of linkage and linkage disequilibrium to fine map quantitative trait loci in outbred half-sib pedigrees: revisiting the location of a quantitative trait locus with major effect on milk production on bovine chromosome 14.

A maximum-likelihood QTL mapping method that simultaneously exploits linkage and linkage disequilibrium and that is applicable in outbred half-sib pedigrees is described. The method is applied to fine map a QTL with major effect on milk fat content in a 3-cM marker interval on proximal BTA14. This proximal location is confirmed by applying a haplotype-based association method referred to as recombinant ancestral haplotype analysis. The origin of the discrepancy between the QTL position derived in this work and that of a previous analysis is examined and shown to be due to the existence of distinct marker haplotypes associated with QTL alleles having large substitution effects.

Animals↗

PubMed2002

A quantitative trait locus analysis of the dopamine transporter gene in adults with ADHD.

Numerous lines of evidence have shown that attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, whether it is considered as a category or a dimension. We tested for an association between the dopamine transporter gene (DAT1) and ADHD considering the disorder as categorical as well as a continuous trait. Genotypes for the DAT1 variable number of tandem repeat (VNTR) alleles, along with Brown Attention Deficit Disorder Scale (BADDS) and Wender Utah Rating Scale (WURS) scores were available for 152 adult ADHD patients. In 72 of these patients DNAs from at least one parent were accessible to perform a family-based analysis (FBAT). The mean quantitative trait values of the whole sample of singleton patients were compared among the specific genotype groups using ANOVA. The family-based analysis did not reveal any association between DAT1 alleles and ADHD either when it was considered as a dichotomous trait (Z = 0.16, p =.86) or as a continuous trait (Wender Scale Z = -1.67, p =.09; Brown ADD Scale Z = 0.28, p =.77). No significant differences were detected in the mean symptom scores among the specific genotype groups. The results from our study do not support a major role for the DAT1 VNTR alleles in our sample of adult ADHD. In view of several positive reports in child ADHD, more work is required to elucidate the potential role of the DAT1 VNTR as a risk factor in ADHD.

Adult↗

PubMed2003

Cuttine edge: diabetes-associated quantitative trait locus, Idd4, is responsible for the IL-12p40 overexpression defect in nonobese diabetic (NOD) mice.

APCs of the nonobese diabetic (NOD) mouse have a genetically programmed capacity to overexpress IL-12p40, a cytokine critical for development of pathogenic autoreactive Th1 cells. To determine whether a diabetes-associated NOD chromosomal locus (i.e., Idd) was responsible for this defect, LPS-stimulated macrophages from several recombinant congenic inbred mice with Idd loci on a C57BL/6 background or with different combinations of NOD and CBA genomic segments were screened for IL-12p40 production. Only macrophages from the congenic strains containing the Idd4 locus showed IL-12p40 overproduction/expression. Moreover, analysis of IL-12p40 sequence polymorphisms demonstrated that the Idd4 intervals in these strains contained the IL-12p40 allele of the NOD, although further analysis is required to determine whether the IL-12p40 allele itself is responsible for its overexpression. Thus, the non-MHC-associated Idd4 locus appears responsible for IL-12p40 overexpression, which may be a predisposing factor for type 1 diabetes in NOD mice.

Alleles↗

PubMed2003

Congenic rats reveal three independent Copenhagen alleles within the Mcs1 quantitative trait locus that confer resistance to mammary cancer.

It has previously been shown that the Copenhagen (COP) rat contains several genetic loci that contribute to its mammary tumor-resistant phenotype after 7,12-dimethylbenz(a)anthracene (DMBA) administration. One of these loci, mammary carcinoma susceptibility 1 (Mcs1), is located on the centromeric end of chromosome 2 and appears to act in a semidominant fashion. To confirm the existence and independent action of this locus and also aid in the identification of the physical location of the Mcs1 gene, congenic lines were generated by transferring the Mcs1 COP allele onto a Wistar Furth (WF) genetic background. Male carriers were genotyped using microsatellite markers spanning 20-30 cM of the Mcs1 locus. One of the congenic lines minimally retained the COP allele at D2Mit29 on the centromeric end of chromosome 2 and extended distally to D2Rat201. Heterozygous Mcs1 carrier rats were interbred, and the female offspring were treated with DMBA. The female rats from the Mcs1 congenic line that carried one or two COP alleles of the Mcs1 region had a significantly reduced (65 and 85%, respectively) tumor development (P < 0.001) compared with rats carrying zero COP alleles at this locus. A WF.COP-D2Mit29/D2Rat201 homozygous congenic strain derived at the N10 generation was treated with DMBA, and the COP homozygous rats developed 1.5 +/- 0.3 carcinomas/rat versus 6.3 +/- 0.5 in WF control rats (P < 0.0001). Fine mapping of this congenic interval using several recombinant lines identified three genetic loci within the Mcs1 congenic region that independently supported a tumor resistance phenotype. These genetic loci have been termed Mcs1a, Mcs1b, and Mcs1c. In rats for which each locus was homozygous for the COP allele, tumor development was reduced by approximately 60% compared with littermate controls. The identification of these independent loci within the Mcs1 COP allele provide a model of the genetic complexity of cancer.

Alleles↗

PubMed2003

Generation and analysis of an artificial gene dosage series in tomato to study the mechanisms by which the cloned quantitative trait locus fw2.2 controls fruit size.

It has been proposed that fw2.2 encodes a negative fruit-growth regulator that underlies natural fruit-size variation in tomato (Lycopersicon spp.) via heterochronic allelic variation of fw2.2 expression, rather than by variation in the structural protein itself. To further test the negative regulator and the transcriptional control hypotheses, a gene dosage series was constructed, which produced a wider range of fw2.2 transcript accumulation than can be found in natural tomato populations. Fruit developmental analyses revealed that fw2.2 transcript levels were highly correlated (negatively) with fruit mass, supporting the negative regulator and transcriptional regulation hypotheses. Further, the effect of fw2.2 on fruit mass was mediated by repressing three- and two-dimensional cell division in placental and pericarp tissues, respectively. Finally, fw2.2 had little effect on fertility and seed size/number, indicating that fruit size effects of fw2.2 are due largely to expression in the maternal tissues of developing fruit and not mediated through fertility or seed-setting-related processes.

Alleles↗

PubMed2001

Quantitative trait locus mapping in laboratory mice derived from a replicated selection experiment for open-field activity.

Bidirectional selection in rodents has been used to derive animal models of human behavior. An important question is whether selection for behavior operates on a limited number of QTL or whether the number and individual contribution of QTL varies between selection experiments. To address this question, we mapped QTL in two large F2 intercrosses (N = 815 and 821) from the four lines derived from a replicated selection experiment for open-field activity, an animal model for susceptibility to anxiety. Our analyses indicate that selection operated on the same relatively small number of loci in both crosses. Haplotype information and the direction of effect of each QTL allele were used to confirm that the QTL mapped in the two crosses lie in the same chromosomal regions, although we were unable to determine whether QTL in the two crosses represent the same genes. We conclude that the genetic architecture of the selected strains is similar and relatively simple.

Animals↗

PubMed2006

A quantitative trait locus on chromosome 18q for physical activity and dietary intake in Hispanic children.

OBJECTIVE: Genetic components of energy homeostasis contributing to childhood obesity are poorly understood. Genome scans were performed to identify chromosomal regions contributing to physical activity and dietary intake traits in Hispanic children participating in the VIVA LA FAMILIA Study. RESEARCH METHODS AND PROCEDURES: We report linkage findings on chromosome 18 for physical activity and dietary intake in 1030 siblings from 319 Hispanic families. Measurements entailed physical activity by accelerometry, dietary intake by two 24-hour recalls, and genetic linkage analyses using SOLAR software. RESULTS: Significant heritabilities were seen for physical activity and dietary intake, ranging from 0.46 to 0.69, except for vigorous activity (h2 = 0.18). Percentage time in sedentary activity mapped to markers D18S1102-D18S64 on chromosome 18 [logarithm of the odds (LOD) score = 4.07], where melanocortin 4 receptor gene (MC4R) resides. Quantitative trait loci (QTLs) for total activity counts, percentage time in light or in moderate activity, and carbohydrate intake and percentage of energy intake from carbohydrates were detected in the same region (LOD = 2.28, 2.79, 2.2, 1.84, and 1.51, respectively). A novel loss of function mutation in MC4R (G55V) was detected in six obese relatives, but not in the rest of the cohort. Removal of these MC4R-deficient subjects from the analysis reduced the LOD score for sedentary activity to 3.94. DISCUSSION: Given its role in the regulation of food intake and energy expenditure, MC4R is a strong positional candidate gene for the QTL on chromosome 18 detected for physical activity and dietary intake in Hispanic children.

Adolescent↗

PubMed2003

Molecular dissection of a quantitative trait locus: a phenylalanine-to-tyrosine substitution in the transmembrane domain of the bovine growth hormone receptor is associated with a major effect on milk yield and composition.

We herein report on our efforts to improve the mapping resolution of a QTL with major effect on milk yield and composition that was previously mapped to bovine chromosome 20. By using a denser chromosome 20 marker map and by exploiting linkage disequilibrium using two distinct approaches, we provide strong evidence that a chromosome segment including the gene coding for the growth hormone receptor accounts for at least part of the chromosome 20 QTL effect. By sequencing individuals with known QTL genotype, we identify an F to Y substitution in the transmembrane domain of the growth hormone receptor gene that is associated with a strong effect on milk yield and composition in the general population.

Amino Acid Substitution↗

PubMed2003

Diet-dependent obesity and hypercholesterolemia in the New Zealand obese mouse: identification of a quantitative trait locus for elevated serum cholesterol on the distal mouse chromosome 5.

AIMS: New Zealand obese (NZO) mice exhibit a polygenic syndrome of obesity, insulin resistance, and hypercholesterolemia that resembles the human metabolic syndrome. This study was performed in order to locate genes responsible for elevated serum cholesterol and to compare their effects under a standard and high fat diet. METHODS: A backcross population of NZO with SJL mice (NZO x F1(SJL x NZO)) was generated. Mice were raised on a normal or high fat diet and were monitored for 22 weeks (body weight, serum cholesterol, and blood glucose). A genome-wide scan was performed by genotyping of approximately 200 polymorphic microsatellite markers by PCR and linkage analysis was performed with the MAPMAKER program. RESULTS: In the genome-wide scan, a single susceptibility locus for hypercholesterolemia (Chol1/NZO, maximum LOD score 14.5 in a combined population of 523 backcross mice) was identified on chromosome 5. Cholesterol levels were significantly elevated in both male and female homozygous carriers of the Chol1/NZO allele. The locus maps 40cM distal of the previously described obesity locus Nob1 in the vicinity of the marker D5Mit244 and in the vicinity of hypercholesterolemia QTL previously identified in the NZB, CAST, and C57BL/6J strains. Chol1/NZO was not associated with elevated body weight, serum insulin, or hyperglycemia. The high fat diet significantly increased serum cholesterol levels, but the fat content of the diet did not alter the absolute effect of Chol1/NZO. CONCLUSIONS: Chol1/NZO is a major susceptibility locus on the distal mouse chromosome 5, which produces gender-independent hypercholesterolemia in NZO mice. The effect of Chol1/NZO was independent of the dietary fat content and was not associated with the other traits of the metabolic syndrome. Thus, it is suggested that the responsible gene might be involved in cholesterol metabolism.

Animals↗

PubMed2003

Two-loci interaction confirms arthritis-regulating quantitative trait locus on rat chromosome 6.

A form of genetic interaction, or epistasis, occurs when one gene interferes with the phenotypic effect of another nonallelic gene. In pristane-induced arthritis (PIA) in rats we have previously identified Pia3, on chromosome 6, to be a locus that regulates onset of disease. In a single congenic strain containing Pia3 on the arthritis-susceptible DA background, DA.Pia3, no difference in onset of disease or early disease severity could be detected. After a two-loci interaction analysis of (E3 x DA)F2 intercross data, Pia3 was found to interact with Pia4 (chromosome 12). Subsequently, the DA.Pia3 congenic strain was combined with the DA.Pia4 congenic strain so that an effect of Pia3 could be observed. The effect of heterozygosity in Pia4 results in lower severity and thus in combination with Pia3 made it possible to observe that Pia3 alleles from the arthritis-resistant E3 strain rendered more severe arthritis into the otherwise 100% susceptible DA strain. As the introduction of Pia4 heterozygosity results in a lower level of arthritis severity we regard this as an additive interaction with a severity threshold-lowering effect.

Animals↗

PubMed2005

The non-MHC quantitative trait locus Cia5 contains three major arthritis genes that differentially regulate disease severity, pannus formation, and joint damage in collagen- and pristane-induced arthritis.

Cia5 is a locus on rat chromosome 10 which regulates the severity of collagen- and pristane-induced arthritis (CIA and PIA). To refine the region toward positional identification, Cia5 subcongenic strains were generated and studied in PIA and CIA. The protective effect of the telomeric locus Cia5a was confirmed in both models. A second arthritis severity locus (Cia5d) was identified within the most centromeric portion of Cia5. DA.F344(Cia5d) rats had a significantly lower median arthritis severity index in PIA, but not in CIA, compared with DA. On histologic analyses DA.F344(Cia5a) and DA.F344(Cia5d) congenics with PIA preserved a nearly normal joint architecture compared with DA, including significant reduction in synovial hyperplasia, pannus, angiogenesis, inflammatory infiltration, bone and cartilage erosions. Cia5 and Cia5a synovial levels of IL-1beta mRNA were reduced. Although both DA.F344(Cia5) and DA.F344(Cia5a) rats were protected in CIA, the arthritis scores of DA.F344(Cia5) were significantly higher than those of DA.F344(Cia5a), suggesting the existence of a third locus where F344-derived alleles centromeric from Cia5a contribute to increased arthritis severity. The existence of the third locus was further supported by higher levels of autoantibodies against rat type II collagen in DA.F344(Cia5) congenics compared with DA.F344(Cia5a). Our results determined that Cia5 contains three major arthritis severity regulatory loci regulating central events in the pathogenesis of arthritis, and differentially influencing CIA and PIA. These loci are syntenic to regions on human chromosomes 17q and 5q implicated in the susceptibility to rheumatoid arthritis, suggesting that the identification of these genes will be relevant to human disease.

Animals↗

PubMed2002

Analysis of quantitative trait locus effects on the size and shape of mandibular molars in mice.

While >50 genes have been found to influence the development of teeth in mice, we still know very little about the genetic basis for the adaptive characteristics of teeth, such as size and shape. We applied interval mapping procedures to Procrustes size and shape data obtained from 10 morphological landmarks on the mandibular molar row of the F(2) progeny from a cross between the LG/J and SM/J strains of mice. This revealed many more QTL for molar shape (18) than for molar centroid size (3), although levels of dominance effects were comparable among QTL for size and shape. Comparisons of patterns of Procrustes additive and dominance shape effects and ordination of QTL effects by principal components analysis suggested that the effects of the shape QTL were dispersed among the three molars and thus that none of these molars represents a genetically distinct developmental structure. The results of an analysis of co-occurrence of QTL for molar shape, mandible shape, and cranial dimensions in these mice suggested that many of the QTL for molar shape may be the same as those affecting these other sets of characters, although in some cases this could be due to effects of closely linked genes.

Animals↗

PubMed2006

High-resolution quantitative trait locus analysis reveals multiple diabetes susceptibility loci mapped to intervals<800 kb in the species-conserved Niddm1i of the GK rat.

Niddm1i, a 16-Mb locus within the major diabetes QTL in the diabetic GK rat, causes impaired glucose tolerance in the congenic NIDDM1I strain. Niddm1i is homologous to both human and mouse regions linked with type 2 diabetes susceptibility. We employed multiple QTL analyses of congenic F2 progeny selected for one recombination event within Niddm1i combined with characterization of subcongenic strains. Fine mapping located one hyperglycemia locus within 700 kb (Niddm1i4, P=5x10(-6)). Two adjacent loci were also detected, and the GK allele at Niddm1i2 (500 kb) showed a glucose-raising effect, whereas it had a glucose-lowering effect at Niddm1i3 (400 kb). Most proximally, Niddm1i1 (800 kb) affecting body weight was identified. Experimental data from subcongenics supported the four loci. Sorcs1, one of the two known diabetes susceptibility genes in the region, resides within Niddm1i3, while Tcf7l2 maps outside all four loci. Multiple-marker QTL analysis incorporating the effect of cosegregating QTL as cofactors together with genetically selected progeny can remarkably enhance resolution of QTL. The data demonstrate that the species-conserved Niddm1i is a composite of at least four QTL affecting type 2 diabetes susceptibility and that two adjacent QTL (Niddm1i2GK and Niddm1i3GK) act in opposite directions.

Alleles↗

PubMed2004

A major quantitative trait locus for CD4-CD8 ratio is located on chromosome 11.

CD4-CD8 ratio is an important diagnostic measure of immune system functioning. In particular, CD4-CD8 ratio predicts the time taken for progression of HIV infection to acquired immune deficiency syndrome (AIDS) and the long-term survival of AIDS patients. To map genes that regulate differences between healthy individuals in CD4-CD8 ratio, we typed 757 highly polymorphic microsatellite markers at an average spacing of approximately 5 cM across the genome in 405 pairs of dizygotic twins at ages 12, 14 and 16. We used multipoint variance components linkage analysis to test for linkage between marker loci and CD4-CD8 ratio at each age. We found suggestive evidence of linkage on chromosome 11p in 12-year-old twins (LOD=2.55, P=0.00031) and even stronger evidence of linkage in the same region at age 14 (LOD=3.51, P=0.00003). Possible candidate genes include CD5 and CD6, which encode cell membrane proteins involved in the positive selection of thymocytes. We also found suggestive evidence of linkage at other areas of the genome including regions on chromosomes 1, 3, 4, 5, 6, 12, 13, 15, 17 and 22.

Adolescent↗

PubMed2005

Genome-wide scan of IQ finds significant linkage to a quantitative trait locus on 2q.

A genome-wide linkage scan of 795 microsatellite markers (761 autosomal, 34 X chromosome) was performed on Multidimensional Aptitude Battery subtests and verbal, performance and full scale scores, the WAIS-R Digit Symbol subtest, and two word-recognition tests (Schonell Graded Word Reading Test, Cambridge Contextual Reading Test) highly predictive of IQ. The sample included 361 families comprising 2-5 siblings who ranged in age from 15.7 to 22.2 years; genotype, but not phenotype, data were available for 81% of parents. A variance components analysis which controlled for age and sex effects showed significant linkage for the Cambridge reading test and performance IQ to the same region on chromosome 2, with respective LOD scores of 4.15 and 3.68. Suggestive linkage (LOD score>2.2) for various measures was further supported on chromosomes 6, 7, 11, 14, 21 and 22. Where location of linkage peaks converged for IQ subtests within the same scale, the overall scale score provided increased evidence for linkage to that region over any individual subtest. Association studies of candidate genes, particularly those involved in neural transmission and development, will be directed to genes located under the linkage peaks identified in this study.

Chromosome Mapping↗

PubMed2005

Quantitative trait locus study design from an information perspective.

We examine the efficiency of different genotyping and phenotyping strategies in inbred line crosses from an information perspective. This provides a mathematical framework for the statistical aspects of QTL experimental design, while guiding our intuition. Our central result is a simple formula that quantifies the fraction of missing information of any genotyping strategy in a backcross. It includes the special case of selectively genotyping only the phenotypic extreme individuals. The formula is a function of the square of the phenotype and the uncertainty in our knowledge of the genotypes at a locus. This result is used to answer a variety of questions. First, we examine the cost-information trade-off varying the density of markers and the proportion of extreme phenotypic individuals genotyped. Then we evaluate the information content of selective phenotyping designs and the impact of measurement error in phenotyping. A simple formula quantifies the information content of any combined phenotyping and genotyping design. We extend our results to cover multigenotype crosses, such as the F(2) intercross, and multiple QTL models. We find that when the QTL effect is small, any contrast in a multigenotype cross benefits from selective genotyping in the same manner as in a backcross. The benefit remains in the presence of a second unlinked QTL with small effect (explaining <20% of the variance), but diminishes if the second QTL has a large effect. Software for performing power calculations for backcross and F(2) intercross incorporating selective genotyping and marker spacing is available from http://www.biostat.ucsf.edu/sen.

Animals↗

PubMed2005

Evolution of salamander life cycles: a major-effect quantitative trait locus contributes to discrete and continuous variation for metamorphic timing.

The evolution of alternate modes of development may occur through genetic changes in metamorphic timing. This hypothesis was examined by crossing salamanders that express alternate developmental modes: metamorphosis vs. paedomorphosis. Three strains were used in the crossing design: Ambystoma tigrinum tigrinum (Att; metamorph), wild-caught A. mexicanum (Am; paedomorph), and laboratory Am (paedomorph). Att/Am hybrids were created for each Am strain and then backcrossed to their respective Am line. Previous studies have shown that a dominant allele from Att (met(Att)) and a recessive allele from lab Am (met(lab)) results in metamorphosis in Att/Am hybrids, and met(Att)/met(lab) and met(lab)/met(lab) backcross genotypes are strongly associated with metamorphosis and paedomorphosis, respectively. We typed a molecular marker (contig325) linked to met and found that met(Att)/met(lab) and met(Att)/met(wild) were associated with metamorphosis in 99% of the cases examined. However, the frequency of paedomorphosis was 4.5 times higher for met(lab)/met(lab) than for met(wild)/met(wild). We also found that met(Att)/met(wild) and met(wild)/met(wild) genotypes discriminated distributions of early and late metamorphosing individuals. Two forms of phenotypic variation are contributed by met: continuous variation of metamorphic age and expression of discrete, alternate morphs. We suggest that the evolution of paedomorphosis is associated with genetic changes that delay metamorphic timing in biphasic life cycles.

Age Factors↗