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Results for “quantitative trait locus”

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PubMed2004

Pleiotropic effects of a chromosome 3 locus on speech-sound disorder and reading.

Speech-sound disorder (SSD) is a complex behavioral disorder characterized by speech-sound production errors associated with deficits in articulation, phonological processes, and cognitive linguistic processes. SSD is prevalent in childhood and is comorbid with disorders of language, spelling, and reading disability, or dyslexia. Previous research suggests that developmental problems in domains associated with speech and language acquisition place a child at risk for dyslexia. Recent genetic studies have identified several candidate regions for dyslexia, including one on chromosome 3 segregating in a large Finnish pedigree. To explore common genetic influences on SSD and reading, we examined linkage for several quantitative traits to markers in the pericentrometric region of chromosome 3 in 77 families ascertained through a child with SSD. The quantitative scores measured several processes underlying speech-sound production, including phonological memory, phonological representation, articulation, receptive and expressive vocabulary, and reading decoding and comprehension skills. Model-free linkage analysis was followed by identification of sib pairs with linkage and construction of core shared haplotypes. In our multipoint analyses, measures of phonological memory demonstrated the strongest linkage (marker D3S2465, P=5.6 x 10(-5), and marker D3S3716, P=6.8 x 10(-4)). Tests for single-word decoding also demonstrated linkage (real word reading: marker D3S2465, P=.004; nonsense word reading: marker D3S1595, P=.005). The minimum shared haplotype in sib pairs with similar trait values spans 4.9 cM and is bounded by markers D3S3049 and D3S3045. Our results suggest that domains common to SSD and dyslexia are pleiotropically influenced by a putative quantitative trait locus on chromosome 3.

Articulation Disorders↗
PubMed1998

Genetic dissection of testicular weight in the mouse with the BXD recombinant inbred strains.

Testicular weights were studied in the mouse BXD recombinant inbred (RI) strains. These strains were derived from DBA/2J and C57BL/6J progenitors that differ significantly in their testicular weights (0.224 g +/- 0.015 vs. 0.161 g +/- 0.03, P < 0.0001). The heritability of testicular weights was calculated to be 0.53, and the minimum number of responsible effective factors was estimated to be 5.7. The total genome scanning of the BXD RI strains with over 1000 markers revealed a quantitative trait locus (QTL) on mouse Chromosome (Chr) 13 near the D13Mit3 marker (LOD score 6.9). This QTL region was designated Twq1 and associated with over 75% of genetic variability.

Animals↗
PubMed2004

INS VNTR is a QTL for the insulin response to oral glucose in obese children.

We performed a genotype-phenotype association study to examine whether the insulin VNTR (INS VNTR) polymorphism located in the insulin gene promoter was associated with changes in insulin response to oral glucose. Two classes of INS VNTR alleles are observed in Caucasians, the "short" class I and the "long" class III. Plasma insulin and glucose concentrations and indices of insulin secretion (IGI) and sensitivity (ISI) were measured using an oral glucose tolerance test (OGTT) in 387 obese children aged 12 +/- 0.1 yr with a mean body mass index (BMI) of 30.6 kg/m(2) (161% of the normal mean). During OGTT, plasma insulin and IGI were 20-30% higher in I/I obese children vs. III carriers (P < 0.01). A general linear model adjusting for age, sex, and puberty was also used to evaluate the influence of the VNTR genotype on the BMI-IGI (P = 0.07) and the BMI-ISI (P < 0.006) relationships. The INS VNTR can therefore be considered a quantitative trait locus influencing glucose-stimulated insulin physiology in obese juveniles.

Administration, Oral↗
PubMed1998

Identifying candidate genes for blood pressure quantitative trait loci using differential gene expression and a panel of congenic strains.

The most difficult step in dissecting the molecular basis of a quantitative trait is proceeding from chromosomal locations associated with this trait (i.e., quantitative trait locus, QTL) to determining what gene(s) in the QTL region is causative. Using standard positional cloning methodology to identify candidate genes for a particular QTL has three drawbacks: 1) it is labor intensive; 2) defining variants in genes causing quantitative variation from sequence information alone is difficult or impossible; and 3) many (or most) genes in a particular chromosomal interval will not be relevant for a specific disease/trait because they are not expressed in critical candidate organs. Instead of positional cloning, we propose using a panel of congenic strains, where each carries an allele for a different QTL on a similar genetic background, in conjunction with identification of differentially-expressed genes in target organs of inbred strains of contrasting phenotype. This will identify genes having altered expression in organs critical to regulating blood pressure and the development of hypertension. Radiation hybrid mapping of such genes will result in a transcription map of differentially-expressed genes in a target organ of a rat model of genetic hypertension. This approach could rapidly identify genes mapping to genomic regions near QTL, which will be strong candidates to explain, in part, the observed strain differences in blood pressure. This novel approach, which uses a panel of congenic strains to facilitate the mapping and subsequent identification of differentially-expressed and QTL-associated genes, should be applicable to any genetic model for identifying candidate genes located near QTL, given the availability of a panel of congenic strains.

Animals↗
PubMed2000

A cholesterol-lowering gene maps to chromosome 13q.

A cholesterol-lowering gene has been postulated from familial hypercholesterolemia (FH) families having heterozygous persons with normal LDL levels and homozygous individuals with LDL levels similar to those in persons with heterozygous FH. We studied such a family with FH that also had members without FH and with lower-than-normal LDL levels. We performed linkage analyses and identified a locus at 13q, defined by markers D13S156 and D13S158. FASTLINK and GENEHUNTER yielded LOD scores >5 and >4, respectively, whereas an affected-sib-pair analysis gave a peak multipoint LOD score of 4.8, corresponding to a P value of 1.26x10-6. A multipoint quantitative-trait-locus (QTL) linkage analysis with maximum-likelihood binomial QTL verified this locus as a QTL for LDL levels. To test the relevance of this QTL in an independent normal population, we studied MZ and DZ twin subjects. An MZ-DZ comparison confirmed genetic variance with regard to lipid concentrations. We then performed an identity-by-descent linkage analysis on the DZ twins, with markers at the 13q locus. We found strong evidence for linkage at this locus with LDL (P<.0002), HDL (P<.004), total cholesterol (P<.0002), and body-mass index (P<.0001). These data provide support for the existence of a new gene influencing lipid concentrations in humans.

Adult↗
PubMed1999

Genome-wide linkage analysis of chronic relapsing experimental autoimmune encephalomyelitis in the rat identifies a major susceptibility locus on chromosome 9.

The immunization of inbred Dark Agouti (DA) rats with an emulsion containing homogenized spinal cord and CFA induces chronic relapsing experimental autoimmune encephalomyelitis (EAE), a disease with many similarities to multiple sclerosis. We report here the first genome-wide search for quantitative trait loci regulating EAE in the rat using this model. We identified one quantitative trait locus on chromosome 9, Eae4, in a [DA(RT1av1) x BN(RT1n)]F2 intercross showing linkage to disease susceptibility and expression of mRNA for the proinflammatory cytokine IFN-gamma in the spinal cord. Eae4 had a larger influence on disease incidence among rats that were homozygous for the RT1av1 MHC haplotype (RT1av1 rats) compared with RT1n/av1 rats, suggesting an interaction between Eae4 and the MHC. Homozygosity for the DA allele at markers in Eae4 and in the MHC was sufficient for EAE. Thus, Eae4 is a major genetic factor determining susceptibility to EAE in this cross of DA rats. In addition, there was support for linkage to phenotypes of EAE on chromosomes 1, 2, 5, 7, 8, 12, and 15. The chromosome 12 region has been shown previously to predispose DA rats to arthritis, and the chromosome 2 region is syntenic to Eae3 in mice. We conclude that Eae4 and probably the other identified genome regions harbor genes regulating susceptibility to neuroinflammatory disease. The identification and functional characterization of these genes may disclose critical events in the pathogenesis of multiple sclerosis; understanding these events could be essential for the development of new therapies against the disease.

Animals↗
PubMed2002

Linkage of the A locus for the presence of anthocyanin and fs10.1, a major fruit-shape QTL in pepper.

The purple color of the foliage, flower and immature fruit of pepper ( Capsicum spp.) is a result of the accumulation of anthocyanin pigments in these tissues. The expression of anthocyanins is controlled by the incompletely dominant gene A. We have mapped A to pepper chromosome 10 in a Capsicum annuum (5226) x Capsicum chinense (PI 159234) F(2) population to a genomic region that also controls anthocyanin expression in two other Solanaceous species, tomato and potato, suggesting that variation for tissue-specific expression of anthocyanin pigments in these plants is controlled by an orthologous gene(s). We mapped an additional locus, Fc, for the purple anther filament in an F(2) population from a cross of IL 579, a C. chinense introgression line and its recurrent parent 100/63, to the same position as A, suggesting that the two loci are allelic. The two anthocyanin loci were linked to a major quantitative trait locus, fs10.1, for fruit-shape index (ratio of fruit length to fruit width), that also segregated in the F(2) populations. This finding verified the observation of Peterson in 1959 of linkage between fruit color and fruit-shape genes in a cross between round and elongated-fruited parents. The linkage relationship in pepper resembles similar linkage in potato, in which anthocyanin and tuber-shape genes were found linked to each other in a cross of round and elongated-tuber parents. It is therefore possible that the shape pattern of distinct organs such as fruit and tuber in pepper and potato is controlled by a similar gene(s).

Anthocyanins↗
PubMed2004

Genomics tools for QTL analysis and gene discovery.

In recent years, several new genomics resources and tools have become available that will greatly assist quantitative trait locus (QTL) mapping and cloning of the corresponding genes. Genome sequences, tens of thousands of molecular markers, microarrays, and knock-out collections are being applied to QTL mapping, facilitating the use of natural accessions for gene discovery.

Genes, Plant↗
PubMed2000

Progenitor cell mobilization by granulocyte colony-stimulating factor controlled by loci on chromosomes 2 and 11.

Granulocyte colony-stimulating factor (G-CSF) can effectively mobilize hematopoietic stem and progenitor cells from bone marrow into blood, thereby allowing peripheral blood stem cells (PBSCs) to be used for transplantation. The efficiency of PBSC mobilization response to G-CSF is a multigene trait. DBA/2 (high-responder) and C57BL/6 (low-responder) mice were used for a genetic analysis of G-CSF-induced progenitor release. Significant linkages were found on chromosome 2 by analyzing segregation distortion among the high responders of 500 backcross mice and on chromosome 11 by using the quantitative trait locus analysis of 26 strains of BXD recombinant inbred mice. (Blood. 2000;95:1872-1874)

Animals↗
PubMed2003

Precise mapping of a locus affecting grain protein content in durum wheat.

Grain protein content (GPC) is an important factor in pasta and breadmaking quality, and in human nutrition. It is also an important trait for wheat growers because premium prices are frequently paid for wheat with high GPC. A promising source for alleles to increase GPC was detected on chromosome 6B of Triticum turgidum var. dicoccoides accession FA-15-3 (DIC). Two previous quantitative trait locus (QTL) studies found that the positive effect of DIC-6B was associated to a single locus located between the centromere and the Nor-B2 locus on the short arm of chromosome 6B. Microsatellite markers Xgwm508 and Xgwm193 flanking the QTL region were used in this study to develop 20 new homozygous recombinant substitution lines (RSLs) with crossovers between these markers. These 20 RSLs, plus nine RSLs developed in previous studies were characterized with four new RFLP markers located within this chromosome segment. Grain protein content was determined in three field experiments organized as randomized complete block designs with ten replications each. The QTL peaks for protein content were located in the central region of a 2.7-cM interval between RFLP markers Xcdo365 and Xucw67 in the three experiments. Statistical analyses showed that almost all lines could be classified unequivocally within low- and high- protein groups, facilitating the mapping of this trait as a single Mendelian locus designated Gpc-6B1. The Gpc-6B1 locus was mapped 1.5-cM proximal to Xcdo365 and 1.2-cM distal to Xucw67. These new markers can be used to reduce the size of the DIC chromosome segment selected in marker-assisted selection programs. Markers Nor-B2 and Xucw66 flanking the previous two markers can be used to select against the DIC segment and reduce the linkage drag during the transfer of Gpc-6B1 into commercial bread and pasta wheat varieties. The precise mapping of the high GPC gene, the high frequency of recombinants recovered in the targeted region, and the recent development of a tetraploid BAC library including the Gpc-6B1 DIC allele are the first steps towards the map-based cloning of this gene.

Alleles↗
PubMed2004

Confirmation of a dyslexia susceptibility locus on chromosome 1p34-p36 in a set of 100 Canadian families.

Dyslexia is a common and genetically complex trait that manifests primarily as a reading disability independent of general intelligence and educational opportunity. Strong evidence for a dyslexia susceptibility locus on chromosome 1p34-p36 (near marker D1S199) was recently reported, and an earlier study found suggestive evidence for linkage to the same region. We tested for the presence of a dyslexia gene in this region in a sample of 100 Canadian families using both qualitative and quantitative definitions of the phenotype. Using a qualitative definition of dyslexia (affected, unaffected, or uncertain), the largest multipoint Genehunter Maximum LOD-Score (MLS) in 100 core nuclear families was 3.65 at D1S507, distal to D1S199. Quantitative trait locus (QTL) linkage analysis was performed for four measures of dyslexia (phonological awareness, phonological coding, spelling, and rapid automatized naming speed) employing the variance components approach implemented in Genehunter. Using a model with QTL additive and dominance variance and polygenic additive variance, the multipoint LOD scores maximized proximal to D1S199 (between D1S552 and D1S1622), with peaks of 4.01 for spelling and 1.65 for phonological coding (corresponding LOD scores under 1 degree of freedom were 3.30 and 1.13, respectively). In conclusion, our study confirms and strengthens recent findings of a dyslexia susceptibility gene on chromosome 1p34-p36 (now designated DYX8).

Canada↗
PubMed2006

Heterosis: revisiting the magic.

Heterosis results in the phenotypic superiority of a hybrid over its parents with respect to traits such as growth rate, reproductive success and yield. This hybrid vigor is determined by non-mutually exclusive mechanisms, including dominance complementation, overdominance and epistasis. Heterotic genes responsible for elevating crop yields are now being sought using genomics, particularly transcriptomics, but with contradictory results. Because heterosis is an environmentally modified quantitative phenotype, genomic analyses alone will not suffice. Future research should focus on integrating genomic tools in a framework of comprehensive quantitative trait locus (QTL)-based phenotyping, followed by map-based cloning. This 'phenomics' approach should identify loci controlling heterotic phenotypes, and improve understanding of the role of heterosis in evolution and the domestication of crop plants.

Animals↗
PubMed2003

Simple sequence repeat (SSR) markers linked to E1, E3, E4, and E7 maturity genes in soybean.

Soybean near isogenic lines (NILs), contrasting for maturity and photoperiod sensitivity loci, were genotyped with approximately 430 mapped simple sequence repeats (SSRs), also known as microsatellite markers. By analysis of allele distributions across the NILs, it was possible to confirm the map location of the Dt1 indeterminate growth locus, to refine the SSR mapping of the T tawny pubescence locus, to map E1 and E3 maturity loci with molecular markers, and to map the E4 and E7 maturity loci for the first time. Molecular markers flanking these loci are now available for marker-assisted breeding for these traits. Analysis of map locations identified a putative homologous relationship among four chromosomal regions; one in the middle of linkage group (LG) C2 carrying E1 and E7, one on LG I carrying E4, one at the top of LG C2, at which there is a reproductive period quantitative trait locus (QTL), and the fourth on LG B1. Other evidence suggests that homology also exists between the E1 + E7 region on LG C2 and a region on LG L linked to a pod maturity QTL. Homology relationships predict possible locations in the soybean genome of additional maturity loci, as well as which maturity loci may share a common evolutionary origin and similar mechanism(s) of action.

Chromosome Mapping↗
PubMed1999

Identification of a novel inflammation-protective locus in the Fischer rat.

Inbred LEW/N rats are relatively susceptible, while histocompatible inbred F344/N rats are relatively resistant to development of a wide variety of inflammatory diseases in response to a range of pro-inflammatory stimuli. In a LEW/N vs. F344/N F2 intercross, we identified a quantitative trait locus (QTL) on Chr 10 that protects in a dominant fashion against the exudate volume component of innate inflammation in the F344/N rat, as well as a suggestive QTL on Chr 2 near the Fibrinogen cluster region. The exudate volume linkage region on Chr 10 may be similar to one of the multiple regions found to link to inflammatory arthritis phenotypes in other crosses. The suggestive linkage on Chr 2 has not been previously reported and does not seem to contribute to this phenotype in the same manner as the QTL on Chr 10. These findings are consistent with the hypothesis that the innate exudate volume trait is a sub-phenotype of more complex inflammatory phenotypes, such as arthritis, and genes within the Chr 10 linkage region could account for differences in this non-specific acute phase component of the inflammatory response. Since the rat Chr 10 exudate volume linkage region we have identified is syntenic with a region of human Chr 17 that has been shown to link to a variety of autoimmune/inflammatory diseases, including insulin-dependent diabetes mellitus, multiple sclerosis, and psoriasis, identification of genes within this linkage region will shed light on genes relevant to the earliest inflammatory component and to susceptibility and resistance to such human autoimmune/inflammatory diseases.

Animals↗
PubMed2006

Genetic control of X chromosome inactivation in mice: definition of the Xce candidate interval.

In early mammalian development, one of the two X chromosomes is silenced in each female cell as a result of X chromosome inactivation, the mammalian dosage compensation mechanism. In the mouse epiblast, the choice of which chromosome is inactivated is essentially random, but can be biased by alleles at the X-linked X controlling element (Xce). Although this locus was first described nearly four decades ago, the identity and precise genomic localization of Xce remains elusive. Within the X inactivation center region of the X chromosome, previous linkage disequilibrium studies comparing strains of known Xce genotypes have suggested that Xce is physically distinct from Xist, although this has not yet been established by genetic mapping or progeny testing. In this report, we used quantitative trait locus (QTL) mapping strategies to define the minimal Xce candidate interval. Subsequent analysis of recombinant chromosomes allowed for the establishment of a maximum 1.85-Mb candidate region for the Xce locus. Finally, we use QTL approaches in an effort to identify additional modifiers of the X chromosome choice, as we have previously demonstrated that choice in Xce heterozygous females is significantly influenced by genetic variation present on autosomes (Chadwick and Willard 2005). We did not identify any autosomal loci with significant associations and thus show conclusively that Xce is the only major locus to influence X inactivation patterns in the crosses analyzed. This study provides a foundation for future analyses into the genetic control of X chromosome inactivation and defines a 1.85-Mb interval encompassing all the major elements of the Xce locus.

Alleles↗
PubMed1997

Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels.

Nitric oxide (NO) has an important physiological role in regulating vascular tone and is also relevant to many pathological processes including hypertension and atherosclerosis. Endothelial constitutive nitric oxide synthase (ecNOS) is the key enzyme in determining basal vascular wall NO production. We used a combination of maximum-likelihood-based statistical genetic methods to explore the contributions of the ecNOS gene and other unmeasured genes to basal NO production measured by its metabolites (NOx: nitrite and nitrate) in 428 members of 108 nuclear families. Our initial quantitative genetic analysis estimated that approximately 30% of the variance in fasting NOx levels is due to genes (chi 2(1) = 16.04, P = .000062). Complex segregation analysis detected the effects of both a single locus and residual polygenes on NOx levels, and measured genotype analysis showed that plasma NOx levels in those homozygous for the rare allele (64.9 +/- 7.8 mumol/L) were significantly higher (P = .000242) than those homozygous for the common allele (30.2 +/- 3.1 mumol/L). The results of the variance component linkage analysis were consistent with linkage of a quantitative trait locus in or near the ecNOS gene to variation in plasma NOx levels (P = .0066). While many environmental factors have been shown to alter transiently plasma NOx levels, our study is the first to identify a substantial effect of the ecNOS locus on the variance of plasma NOx, i.e. basal NO production. This finding may be relevant to atherogenesis and NO-related disorders.

Adolescent↗
PubMed2001

Genetic control of neuroadapted sindbis virus replication in female mice maps to chromosome 2 and associates with paralysis and mortality.

Neuroadapted Sindbis virus (NSV) infection of mice causes hindlimb paralysis and 100% mortality in the C57BL/6 mouse strain, while adults of the BALB/cBy mouse strain are resistant to fatal encephalomyelitis. Levels of viral RNA are higher in the brains of infected C57BL/6 mice than in BALB/cBy mice (D. C. Thach et al., J. Virol. 74:6156-6161, 2000). These phenotypic differences between the two strains allowed us to map genetic loci involved in mouse susceptibility to NSV and to find relationships between mortality, paralysis, and viral RNA levels. Analysis of percent mortality in H2-congenic and F(1) mice suggested that the H2 locus, sex linkage, and imprinting were not involved in determining susceptibility and that resistance was partially dominant over susceptibility. Segregation analysis using CXB recombinant inbred (RI) mice indicated that the percent mortality was multigenic. Interval mapping detected a suggestive quantitative trait locus (QTL) on chromosome 2 near marker D2Mit447. Analysis of paralysis in the RI mice detected the same suggestive QTL. Viral RNA level in F(1) mice was intermediate. Interval mapping using viral RNA levels in RI mice detected a significant QTL near marker D2Mit447 that explained 69% of the genetic variance. This QTL was confirmed in F2 mice and was designated as Nsv1. Viral RNA level, percent paralyzed, and percent mortality were linearly correlated (r = 0.8 to 0.9). These results indicate that mortality, paralysis, and viral RNA levels are related complex traits and that Nsv1 controls early viral load and determines the likelihood of paralysis and death.

Adaptation, Physiological↗
PubMed1997

A pharmacogenetic approach to blood pressure in Lyon hypertensive rats. A chromosome 2 locus influences the response to a calcium antagonist.

In a backcross population (n = 281) derived from a cross of the Lyon hypertensive rat with Lyon normotensive rat, we investigated whether genetic factors influence the acute cardiovascular responses to pharmacological modulation of the renin-angiotensin system, the sympathetic nervous system, and the voltage-sensitive L-type calcium channels. Using microsatellite markers, a quantitative trait locus was identified and mapped on rat chromosome 2 that specifically influences the systolic (peak LOD score 4.4) and diastolic (peak LOD score 4.1) blood pressure responses to administration of a dihydropyridine calcium antagonist, PY108-068. The locus accounted for 10.3 and 10.4% of the total variances in the systolic and diastolic responses to PY108-068, respectively. In marked contrast, the locus had no effect on either basal blood pressure or on the responses to acute administration of a ganglionic blocking agent, trimetaphan, or of an angiotensin II subtype 1 receptor antagonist, losartan. These findings provide strong direct support for the paradigm that genetic factors may influence the response to antihypertensive drugs and suggest that the heterogeneity seen in the responses to different antihypertensive agents in human essential hypertension may have a significant genetic determination.

Animals↗