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Both regression and correlation estimates of genetical variance and heritability for a quantitative trait influenced by a major gene can be obtained from the error variance-covariance matrix of MANOVA using relative-relative phenotype pairs as factors. The method is illustrated with parent-offspring data on red cell acid phosphatase phenotypes and serum acid phosphatase activity.
Genome-wide linkage scans were carried out using a multipoint variance components method in white and black families of the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study to identify quantitative trait loci (QTLs) for pancreatic beta-cell function and insulin sensitivity estimated through the newly released nonlinear computer version of homeostasis model assessment 2. Participants fasting <8 h, with diagnosed type 2 diabetes, or taking blood glucose or blood lipid-lowering medications were excluded. Both phenotypes were adjusted separately by race and sex for the effects of age, BMI, and field center before linkage scans using 370 microsatellite markers were performed. A total of 685 white families (1,180 sibpairs) and 773 black families (775 sibpairs) were evaluated as well as subsets including 267 obese white families (757 sibpairs) and 427 obese black families (599 sibpairs) identified through tree-linkage analyses using interacting covariates of age, sex, and BMI. For beta-cell function in the obese white families, significant (logarithm of odds [LOD] score >3.6) evidence supporting linkages was detected on chromosome 8q24 at D8S1179 (135 cM, LOD score 4.2, empirical P = 0.002) and at D8S1128 (140 cM, LOD score 3.7, empirical P = 0.003). In addition, two regions supported linkage for insulin sensitivity index in the obese black families on chromosome 7q11 at D7S3046 (79 cM, LOD score 3.0, empirical P = 0.018) and on chromosome 6q26 at D6S1277 (173 cM, LOD score 3.0, empirical P = 0.018). Reducing clinical heterogeneity using obesity data and improved estimates of beta-cell function and insulin sensitivity may have permitted identification of a QTL on chromosome 8q24 for beta-cell function in the presence of estimated insulin resistance and a QTL on chromosome 7q11 for insulin sensitivity. These regions replicate previous reports for type 2 diabetes-associated traits.
Drought is a major constraint to rice (Oryza sativa) yield and its stability in rainfed and poorly irrigated environments. Identifying genomic regions influencing the response of yield and its components to water deficits will aid in our understanding of the genetics of drought tolerance and development of more drought tolerant cultivars. Quantitative trait loci (QTL) for grain yield and its components and other agronomic traits were identified using a subset of 154 doubled haploid lines derived from a cross between two rice cultivars, CT9993-510 to 1-M and IR62266-42 to 6-2. Drought stress treatments were managed by use of a line source sprinkler irrigation system, which provided a linearly decreasing level of irrigation coinciding with the sensitive reproductive growth stages. The research was conducted at the Ubon Rice Research Center, Ubon, Thailand. A total of 77 QTL were identified for grain yield and its components under varying levels of water stress. Out of the total of 77 QTL, the number of QTL per trait were: 7-grain yield (GY); 8-biological yield (BY); 6-harvest index (HI); 5-d to flowering after initiation of irrigation gradient (DFAIG); 10-total spikelet number (TSN); 7-percent spikelet sterility (PSS); 23-panicle number (PN); and 11-plant height (PH). The phenotypic variation explained by individual QTL ranged from 7.5% to 55.7%. Under well-watered conditions, we observed a high genetic association for BY, HI, DFAIG, PSS, TSN, PH, and GY. However, only BY and HI were found to be significantly associated with GY under drought treatments. QTL flanked by markers RG104 to RM231, EMP2_2 to RM127, and G2132 to RZ598 on chromosomes 3, 4, and 8 were associated with GY, HI, DFAIG, BY, PSS, and PN under drought treatments. The aggregate effects of these QTL on chromosomes 3, 4, and 8 resulted in higher grain yield. These QTL will be useful for rainfed rice improvement, and will also contribute to our understanding of the genetic control of GY under drought conditions at the sensitive reproductive stage. Close linkage or pleiotropy may be responsible for the coincidence of QTL detected in this experiment. Digenic interactions between QTL main effects for GY, BY, HI, and PSS were observed under irrigation treatments. Most (but not all) DH lines have the same response in measure of productivity when the intensity of water deficit was increased, but no QTL by irrigation treatment interaction was detected. The identification of genomic regions associated with GY and its components under drought stress will be useful for marker-based approaches to improve GY and its stability for farmers in drought-prone rice environments.
Evidence from a variety of data suggests that regulatory mechanisms in multicellular eukaryotes have evolved in such a manner that the stoichiometric relationship of the components of regulatory complexes affects target gene expression. This type of mechanism sets the level of gene expression and, as a consequence, the phenotypic characteristics. Because many types of regulatory processes exhibit dosage-dependent behavior, they would impact quantitative traits and contribute to their multigenic control in a semidominant fashion. Many dosage-dependent effects would also account for the extensive modulation of gene expression throughout the genome that occurs when chromosomes are added to or subtracted from the karyotype (aneuploidy). Moreover, because the majority of dosage-dependent regulators act negatively, this property can account for the up-regulation of genes in monosomics and hemizygous sex chromosomes to achieve dosage compensation.
'Boar taint' is a strong perspiration-like, urine-like unpleasant odour given off upon heating or cooking of meat from some intact (uncastrated) male pigs. Data from the F(2) generation of a Large White (LW) x Meishan (MS) crossbred population were analysed to detect quantitative trait loci (QTL) for traits associated with boar taint. Fat samples from 178 intact male pigs slaughtered at 85 +/- 5 kg were analysed for the major contributors to boar taint (androstenone, indole and skatole). Fat and lean samples from cooked meat were scored for boar, abnormal and pork flavour and odour by a trained sensory panel (SP). A scan with 117 markers covering the whole genome was performed in the F(2) individuals, together with their F(1) parents and purebred grandparents. At the 5% chromosomal significance threshold (approximately equal to the genome-wide suggestive significance threshold), QTL were detected for the laboratory estimate of androstenone on chromosomes 2, 4, 6, 7 and 9. However, only on chromosome 6 were there QTL for boar flavour (BF) traits in the same or adjacent marker intervals as a QTL for the laboratory estimate of androstenone. On chromosome 14, QTL were detected for the laboratory estimates of indole and skatole, the SP score for skatole and the scores for BF in lean and BF in fat. In all five cases, the MS allele generally increased the estimate or score, compared with the LW allele, but it appeared that desirable and undesirable alleles were present in both breeds. This locus on chromosome 14 has considerable potential for use to reduce the incidence of boar taint, especially if further research can identify the causative polymorphism or strongly associated markers.
BACKGROUND: Among adolescents, externalizing problem behavior and substance use disorders are often comorbid. Familial influences, including shared genetic risk factors, may account for part of this comorbidity. Previously we reported 2 chromosomal regions (3q24-3q25 and 9q34) likely to contain genes that influence substance dependence vulnerability (DV) in adolescence. OBJECTIVES: To identify quantitative trait loci (QTLs) that influence externalizing problem behavior in adolescence and to determine whether any identified QTL overlap chromosomal regions that influence DV. DESIGN: Regression-based QTL mapping procedures designed for selected sibling pair samples. SETTING: Patient probands were drawn from consecutive admissions to residential and outpatient (milieu-type) treatment facilities for substance abuse and delinquency operated by the University of Colorado; most of these patients were referred for treatment by juvenile justice or social service agencies. PATIENTS: A total of 249 proband-sibling pairs from 191 families were selected for the study. Patient probands were 13 to 19 years of age; siblings of the probands ranged in age from 12 to 25 years. MAIN OUTCOME MEASURES: A community-based sample of 4493 adolescents and young adults was used to define clinically significant, heritable, age- and sex-normed indexes of DV, conduct disorder symptoms (CDS), and a composite index of antisocial substance dependence (DV + CDS). Siblings and parents were genotyped for 374 microsatellite markers distributed across the 22 autosomes (mean intermarker distance, 9.2 centimorgans). RESULTS: For both DV and CDS, there was evidence of linkage to the same region on chromosome 9q34, as well as to 3q24-3q25 for DV, and a novel region on chromosome 17q12 for CDS. Our composite index (DV + CDS) yielded the strongest evidence for linkage (logarithm of odds = 2.65) to the chromosome 9q34 region. CONCLUSION: These results provide the first evidence of a potential molecular genetic basis for the comorbidity between DV and antisocial behavior.
Plant resistance to nematodes is related to the ability of the host to reduce the development of nematode juveniles into females. Resistance to the potato cyst nematode (PCN) Globodera pallida, originating from the wild species Solanum sparsipilum, was dissected by a quantitative trait loci (QTL) approach. Two QTL explained 89% of the phenotypic variation. The QTL GpaV(s)spl on chromosome V displayed the major effect on the cyst number (coefficient of determination [R2] = 76.6%). It restricted G. pallida development to 16.2% of juveniles, 81.5% of males, and 2.3% of females. The QTL GpaXI(s)spl on chromosome XI displayed a lower effect on the cyst number (R2 = 12.7%). It restricted G. pallida development to 13.8% of juveniles, 35.4% of males, and 50.8% of females. Clones carrying both QTL restricted the nematode development to 58.1% juveniles, 41.1% of males, and 0.8% of females. We demonstrated that potato clones carrying both QTL showed a strong necrotic reaction in roots infected by nematodes, while no such reaction was observed in clones carrying a single QTL. This result underlines the importance to introgress together GpaV(s)spl and GpaXI(s)spl into potato cultivars, in order to reduce the density of this quarantine pest in soil and to decrease the risk of selecting overcoming G. pallida subpopulations.
The development of a variety of powerful tools for genome analysis has facilitated the ability to genetically map loci which contribute to the variation of a quantitative trait. However, the fact that these traits are often determined as a result of complex genetic interactions has made their analysis considerably more difficult then the molecular characterization of qualitative traits that are monogenic in origin. We have described the use of a novel method of chromosomal exclusion to map the recessive mutation juvenile cystic kidney (jck) to mouse chromosome 11 using an intercross between (C57BL/6J x DBA/2J) F1 jck/+ mice. The severity of polycystic kidney disease (PKD) in the intercross progeny, which could be quantitated as a function of kidney size, was significantly more variable than that found in the parental C57BL/6J strain, suggesting that a modifier locus or loci introduced from DBA/2J affects expression of jck. Two regions (one from DBA/2J on chromosome 10 and a second from C57BL/6J on chromosome 1) were found to be associated with inheritance of a more severe PKD phenotype. The finding of a highly significant association of inheritance of a C57BL/6J-related locus with disease severity was unexpected since the PKD phenotype in this inbred background is mild. This result suggests that inheritance in the affected F2 mice of loci from the two different parental backgrounds results in the more severe phenotype, presumably as a consequence of a direct or indirect interaction between their protein products. This type of effect, which is an example of genetic epistasis, will make the molecular characterization of loci that contribute to complex traits markedly more difficult than the analysis of monogenic disorders.
Evidence of a large sex-linked effect accounting for 25% of the divergence between mouse lines selected for body weight has been described previously. A marker-based study was undertaken to determine the number and map positions of the putative X-linked quantitative trait loci (QTLs). An F2 population was generated from a reciprocal F1 between an inbred low line derived from the low selection line and the high selection line. To enable inference of marker-associated QTL effects on the X chromosome, an analytical technique was developed based on the multiple regression method of Haley and Knott. The analysis of data on 10 week weight indicated a single QTL of large effect situated at about 23 cM from the proximal end of the chromosome, with a peak LOD score of 24.4. The likelihood curve showed a single well-defined peak, and gave a 95% confidence interval for the QTL location of 8 cM. The estimates for the additive genotypic effects in males and females (half the differences between hemizygous males and between homozygous females) were 2.6 g in both cases, or 17% and 20% of the 10 week body weight in males and females respectively. Dominance effects in the females were found to be non-significant. No significant X-linked effect on carcass fat percentage was detected, but a single X-linked QTL appears to explain almost the entire X-linked body weight effect.
Augmentation of marker genotypes for ungenotyped individuals is implemented in a Bayesian approach via the use of Markov chain Monte Carlo techniques. Marker data on relatives and phenotypes are combined to compute conditional posterior probabilities for marker genotypes of ungenotyped individuals. The presented procedure allows the analysis of complex pedigrees with ungenotyped individuals to detect segregating quantitative trait loci (QTL). Allelic effects at the QTL were assumed to follow a normal distribution with a covariance matrix based on known QTL position and identity by descent probabilities derived from flanking markers. The Bayesian approach estimates variance due to the single QTL, together with polygenic and residual variance. The method was empirically tested through analyzing simulated data from a complex granddaughter design. Ungenotyped dams were related to one or more sons or grandsires in the design. Heterozygosity of the marker loci and size of QTL were varied. Simulation results indicated a significant increase in power when ungenotyped dams were included in the analysis.
Susceptibility to Theiler's murine encephalomyelitis virus-induced demyelination (TMEVD), a mouse model for multiple sclerosis (MS), is genetically controlled. Through a mouse-human comparative mapping approach, identification of candidate susceptibility loci for MS based on the location of TMEVD susceptibility loci may be possible. Composite interval mapping (CIM) identified quantitative trait loci (QTL) controlling TMEVD severity in male and female backcross populations derived from susceptible DBA/2J and resistant BALBc/ByJ mice. We report QTL on chromosomes 1, 5, 15, and 16 affecting male mice. In addition, we identified two QTL in female mice located on chromosome 1. Our results support the existence of three linked sex-specific QTL on chromosome 1 with opposing effects on the severity of the clinical signs of TMEV-induced disease in male and female mice.
Sexual isolating mechanisms that act before fertilization are often considered the most important genetic barriers leading to speciation in animals. While recent progress has been made toward understanding the genetic basis of the postzygotic isolating mechanisms of hybrid sterility and inviability, little is known about the genetic basis of prezygotic sexual isolation. Here, we map quantitative trait loci (QTL) contributing to prezygotic reproductive isolation between the sibling species Drosophila simulans and D. mauritiana. We mapped at least seven QTL affecting discrimination of D. mauritiana females against D. simulans males, three QTL affecting D. simulans male traits against which D. mauritiana females discriminate, and six QTL affecting D. mauritiana male traits against which D. simulans females discriminate. QTL affecting sexual isolation act additively, are largely different in males and females, and are not disproportionately concentrated on the X chromosome: The QTL of greatest effect are located on chromosome 3. Unlike the genetic components of postzygotic isolation, the loci for prezygotic isolation do not interact epistatically. The observation of a few QTL with moderate to large effects will facilitate positional cloning of genes underlying sexual isolation.
Osteoporosis is an important health problem, particularly in the elderly women. Bone mineral density (BMD) is a major determinant of osteoporosis. For a sample of 53 pedigrees that contain 1249 sibling pairs, 1098 grandparent-grandchildren pairs, and 2589 first cousin pairs, we performed a whole- genome linkage scan using 380 microsatellite markers to identify genomic regions that may contain quantitative trait loci (QTL) of BMD. Each pedigree was ascertained through a proband with BMD values belonging to the bottom 10% of the population. We conducted two-point and multipoint linkage analyses. Several potentially important genomic regions were suggested. For example, the genomic region near the marker D10S1651 may contain a QTL for hip BMD variation (with two-point analysis LOD score of 1.97 and multipoint analysis LOD score of 2.29). The genomic regions near the markers D4S413 and D12S1723 may contain QTLs for spine BMD variation (with two-point analysis LOD score of 2.12 and 2.17 and multipoint analysis LOD score of 3.08 and 2.96, respectively). The genomic regions identified in this and some earlier reports are compared for exploration in extension studies with larger samples and/or denser markers for confirmation and fine mapping to eventually identify major functional genes involved in osteoporosis.
UNLABELLED: QTL analyses identified several chromosomal regions influencing skeletal phenotypes of the femur and tibia in BXD F2 and BXD RI populations of mice. QTLs for skeletal traits co-located with each other and with correlated traits such as body weight and length, adipose mass, and serum alkaline phosphatase. INTRODUCTION: Past research has shown substantial genetic influence on bone quality, and the impact of reduced bone mass on our aging population has heightened the interest in skeletal genetic research. MATERIALS AND METHODS: Quantitative trait loci (QTL) analyses were performed on morphologic measures and structural and material properties of the femur and tibia in 200-day-old C57BL/6J x DBA/2 (BXD) F2 (second filial generation; n = 400) and BXD recombinant inbred (RI; n = 23 strains) populations of mice. Body weight, body length, adipose mass, and serum alkaline phosphatase were correlated phenotypes included in the analyses. RESULTS: Skeletal QTLs for morphologic bone measures such as length, width, cortical thickness, and cross-sectional area mapped to nearly every chromosome. QTLs for both structural properties (ultimate load, yield load, or stiffness) and material properties (stress and straincharacteristics and elastic modulus) mapped to chromosomes 4, 6, 9, 12, 13, 15, and 18. QTLs that were specific to structural properties were identified on chromosomes 1, 2, 3, 7, 8, and 17, and QTLs that were specific to skeletal material properties were identified on chromosomes 5, 11, 16, and 19. QTLs for body size (body weight, body length, and adipose mass) often mapped to the same chromosomal regions as those identified for skeletal traits, suggesting that several QTLs identified as influencing bone could be mediated through body size. CONCLUSION: New QTLs, not previously reported in the literature, were identified for structural and material properties and morphological measures of the mouse femur and tibia. Body weight and length, adipose mass, and serum alkaline phosphatase were correlated phenotypes that mapped in close proximity of skeletal chromosomal loci. The more specific measures of bone quality included in this investigation enhance our understanding of the functional significance of previously identified QTLs.
Barbiturate dependence is associated with the development of physiological dependence (withdrawal), tolerance, or a maladaptive pattern of drug use. Analysis of strain and individual differences with animal models for physiological dependence liability are useful means to identify potential genetic determinants of liability in humans. Behavioral and quantitative trait locus (QTL) mapping analyses were conducted with mice that are resistant versus sensitive to pentobarbital withdrawal. With a multistage genetic mapping strategy, a pentobarbital withdrawal QTL (Pbw1) was mapped to the distal region of mouse Chromosome (Chr) 1 and may be identical to an alcohol withdrawal QTL mapped to this chromosomal region. Two suggestive QTLs for pentobarbital withdrawal, both in proximity to QTLs definitely mapped for alcohol withdrawal, were also tentatively identified. These were on Chr 11 in proximity to a gene cluster including several members of the GABAA receptor gene family, and on Chr 4 near a locus associated with beta-carboline-induced seizure severity. These data represent the first detection and mapping of loci influencing risk for physiological dependence on barbiturates, and suggest the involvement of common genes in physiological dependence on pentobarbital and alcohol.
We constructed a pig F2 resource population by crossing a Meishan sow and a Duroc boar to locate economically important trait loci. The F2 generation was composed of 865 animals (450 males and 415 females) from four F1 males and 24 F1 females and was genotyped for 180 informative microsatellite markers spanning 2,263.6 cM of the whole pig genome. Results of the genome scan showed evidence for significant quantitative trait loci (<1% genomewise error rate) affecting weight at 30 d and average daily gain on Sus scrofa chromosome (SSC) 6, carcass yield on SSC 7, backfat thickness on SSC 7 and SSC X, vertebra number on SSC 1 and SSC 7, loin muscle area on SSC 1 and SSC 7, moisture on SSC 13, intramuscular fat content on SSC 7, and testicular weight on SSC 3 and SSC X. Moreover, 5% genomewise significant QTL were found for birth weight on SSC 7, average daily gain on SSC 4, carcass length on SSC 6, SSC 7, and SSC X and lightness (L value) on SSC 3. We identified 38 QTL for 28 traits at the 5% genomewise level. Of the 38 QTL, 24 QTL for 17 traits were significant at the 1% genomewise level. Analysis of marker genotypes supported the breed of origin results and provided further evidence that a suggestive QTL for circumference of cannon bone also was segregating within the Meishan parent. We identified genomic regions related with growth and meat quality traits. Fine mapping will be required for their application in introgression programs and gene cloning.
Hypercalciuria is the most common risk factor for kidney stones and has a substantial genetic component. The genetic hypercalciuric stone-forming (GHS) rat model displays complex changes in physiology involving intestine, bone, and kidney and overexpression of the vitamin D receptor, thereby reproducing the human phenotype of idiopathic hypercalciuria. Through quantitative trait locus (QTL) mapping of rats that were bred from GHS female rats and normocalciuric Wistar Kyoto (WKY) male rats, loci that are linked to hypercalciuria and account for a 6 to eight-fold phenotypic difference between the GHS and WKY progenitors were mapped. GHS x WKY rats were backcrossed to breed for congenic rats with the chromosome 1 QTL HC1 on a normocalciuric WKY background. Ten generations of backcrosses produced N10F1 rats, which were intercrossed to produce rats that were homozygous for GHS loci in the HC1 region between markers D1Mit2 and D1Mit32. On a high-calcium diet (1.2% calcium), significantly different levels of calcium excretion were found between male congenic (1.67 +/- 0.71 mg/24 h) and male WKY control rats (0.78 +/- 0.19 mg/24 h) and between female congenic (3.11 +/- 0.90 mg/24 h) and female WKY controls (2.11 +/- 0.50 mg/24 h); the congenics preserve the calcium excretion phenotype of the GHS parent strain. Microarray expression analyses of the congenic rats, compared with WKY rats, showed that of the top 100 most changed genes, twice as many as were statistically expected mapped to chromosome 1. Of these, there is a clear bias in gene expression change for genes in the region of the HC1. Of >1100 gene groups analyzed, one third of the 50 most differentially expressed gene groups have direct or secondary action on calcium metabolism or transport. This is the first QTL for hypercalciuria to be isolated in a congenic animal.
AIMS/HYPOTHESIS: While there are sex-related differences in both the prevalence of type 2 diabetes mellitus and disease risk factors, there is only limited research on sex-specific influences on type 2 diabetes aetiology within the same study population. Thus, we assessed genotype-by-sex interaction using a liability threshold model in an attempt to localise sex-specific type 2 diabetes quantitative trait loci (QTLs). SUBJECTS, MATERIALS AND METHODS: Hypertensive siblings and their offspring and/or parents in the Hypertension Genetic Epidemiology Network of the Family Blood Pressure Program were recruited from five field centres. The diabetic phenotype was adjusted for race, study centre, age and non-linear age effects. In total, 567 diabetic individuals were identified in 385 families. Variance component linkage analyses in the combined sample and stratified by sex and race were performed (SOLAR program) using race-specific marker allele frequencies derived from a random sample of participants at each centre. RESULTS: We observed a QTL-specific genotype-by-sex interaction (p=0.009) on chromosome 17 at 31 cM, with females displaying a robust adjusted logarithm of odds (LOD) of 3.0 compared with 0.2 in males and 1.3 in the combined sample. Three additional regions demonstrating suggestive evidence for linkage were detected: chromosomes 2 and 5 in the female sample and chromosome 22 (adjusted LOD=1.9) in the combined sample. CONCLUSIONS/INTERPRETATION: These findings suggest that multiple genes may regulate susceptibility to type 2 diabetes, demonstrating the importance of considering the interaction of genes and environment in the aetiology of common complex traits.