Detection of quantitative trait loci affecting caffeine metabolism by interval mapping in a genome-wide scan of C3H/HeJ x APN F(2) mice.
(73/2205)
Caffeine metabolite ratios have been widely used to measure cytochrome P-450 1A2 activity in humans. Serum paraxanthine/caffeine ratio is one such index of this activity. We had previously demonstrated genetic variation of this trait among inbred mouse strains. In the present study, we have undertaken a genome-wide scan for quantitative trait loci affecting this trait with an interval mapping approach on an F(2) intercross population of acetaminophen nonsusceptible and C3H/HeJ inbred mice. A statistically significant association (log-likelihood ratio = 25.0) between a locus on chromosome 9, which colocalized with the murine Cyp1a2 locus, and the plasma paraxanthine/caffeine ratio was identified. This result suggested the presence of an expression polymorphism affecting this gene. A second locus was identified on chromosome 1 (log-likelihood ratio = 9.7) for which no obvious candidate gene has been identified. The influence of this locus on the paraxanthine/caffeine index was more significant among males (log-likelihood ratio = 6.3) than females (log-likelihood ratio = 3.6). A third locus was identified on chromosome 4 with a less statistically robust association (log-likelihood ratio = 3.4) to the paraxanthine/caffeine phenotype. Collectively, these three loci accounted for 63.2% of the variation observed in the F(2) population for this phenotype. These results demonstrate the potential for genetic variation arising from factors other than CYP1A2 activity to influence the plasma paraxanthine/caffeine ratio in mice. This study demonstrates the utility of quantitative genetics in the analysis of polygenic drug metabolism. (+info)
Pathophysiological and genetic characterization of the major diabetes locus in GK rats.
(74/2205)
Genetic studies of the type 2 diabetes-like GK rat have revealed several susceptibility loci for the compound diabetes phenotype. Congenic strains were established for Niddm1, the major quantitative trait locus (QTL) for postprandial glucose levels, by transfer of GK alleles onto the genome of the normoglycemic F344 rat. Despite the polygenic nature of diabetes in GK, the locus-specific diabetes phenotype was retained in the congenic strain Niddmla, containing a GK-derived genomic fragment of 52 cM from the Niddm1 locus. Furthermore, Niddm1 was divided into two non-overlapping loci, physically separated in the two congenic strains Niddmlb and Niddm1i with distinct metabolic phenotypes. Both strains displayed postprandial hyperglycemia and reduced insulin action in isolated adipose cells. Furthermore, Niddm1i already exhibits a pronounced in vivo insulin secretion defect at 65 days, while Niddm1b develops a relative insulin secretory defect at 95 days. This suggests that Niddm1i impairs mechanisms common to insulin secretion in pancreatic B-cells and insulin action in adipocytes. Niddm1b rats show signs of increasing insulin resistance with age associated with obesity, hyperinsulinemia, and dyslipidemia. Moreover, the data indicated nonallelic interaction (epistasis) between Niddm1b and Niddm1i on the postprandial glucose levels. These data emphasize the pathophysiological complexity of diabetes, even within an apparently single QTL, and demonstrate the potential of the GK model in transforming the multifactorial diabetes phenotype into single traits, suitable for positional cloning. (+info)
A quantitative genetic analysis of male sexual traits distinguishing the sibling species Drosophila simulans and D. sechellia.
(75/2205)
A quantitative trait locus (QTL) genetic analysis of morphological and reproductive traits distinguishing the sibling species Drosophila simulans and D. sechellia was carried out in a backcross design, using 38 markers with an average spacing of 8.4 cM. The direction of QTL effects for the size of the posterior lobe was consistent across the identified QTL, indicating directional selection for this trait. Directional selection also appears to have acted on testis length, indicating that sexual selection may have influenced many reproductive traits, although other forms of directional selection cannot be ruled out. Sex comb tooth number exhibited high levels of variation both within and among isofemale lines and showed no evidence for directional selection and, therefore, may not have been involved in the early speciation process. A database search for genes associated with significant QTL revealed a set of candidate loci for posterior lobe shape and size, sex comb tooth number, testis length, tibia length, and hybrid male fertility. In particular, decapentaplegic (dpp), a gene known to influence the genital arch, was found to be associated with the largest LOD peak for posterior lobe shape and size. (+info)
Fluxes and metabolic pools as model traits for quantitative genetics. I. The L-shaped distribution of gene effects.
(76/2205)
The fluxes through metabolic pathways can be considered as model quantitative traits, whose QTL are the polymorphic loci controlling the activity or quantity of the enzymes. Relying on metabolic control theory, we investigated the relationships between the variations of enzyme activity along metabolic pathways and the variations of the flux in a population with biallelic QTL. Two kinds of variations were taken into account, the variation of the average enzyme activity across the loci, and the variation of the activity of each enzyme of the pathway among the individuals of the population. We proposed analytical approximations for the flux mean and variance in the population as well as for the additive and dominance variances of the individual QTL. Monte Carlo simulations based on these approximations showed that an L-shaped distribution of the contributions of individual QTL to the flux variance (R(2)) is consistently expected in an F(2) progeny. This result could partly account for the classically observed L-shaped distribution of QTL effects for quantitative traits. The high correlation we found between R(2) value and flux control coefficients variance suggests that such a distribution is an intrinsic property of metabolic pathways due to the summation property of control coefficients. (+info)
Method to detect genotype-environment interactions for quantitative trait loci in association studies.
(77/2205)
Khoury et al. (Am J Hum Genet 1988;42:89-95 and Am J Epidemiol 1993;137:1241-50) presented an epidemiologic approach to examine genotype-environment interaction in situations where the disease is either present or absent. In this article, the author extends the approach of Khoury et al. to quantitative outcome variables. This extension is relevant for diseases that are extremes on a continuum or when continuous risk factors are studied. To account for a possible admixture of subgroups in the sample, tests for genotype-environment interaction are discussed for designs with parents as controls as well as without parents as controls. Assuming two environmental conditions, the author demonstrates how the power of these tests can be calculated and used to estimate the sample sizes needed to detect genotype-environment interaction in a variety of conditions. In addition, he analyzes simulated data to demonstrate the detection of different mechanisms of genotype-environment interaction and to study the effectiveness of this approach to identify the correct mechanism. Finally, extensions to multiple environmental conditions and designs with multiple subjects per family are discussed. (+info)
A QTL for the degree of spotting in cattle shows synteny with the KIT locus on chromosome 6.
(78/2205)
The proportion of unpigmented coat on the trunk was determined from photographs of 38 German Simmental and 627 German Holstein bulls distributed over three generations. All 665 animals were members of 18 Holstein and 3 Simmental half-sib families. A Bayesian estimation of heritability yielded a posterior mean of 0.88 and a standard error of 0.08. A quantitative trait loci (QTL) scan over all chromosomes covered by 229 microsatellite marker loci (2926 cM) was performed by fitting a multiple marker regression model to 625 observations from the youngest generation in 18 families. On chromosome 6 a QTL for the proportion of white coat with large effects (experiment-wise error probability < .0001) was found and a less important one on chromosome 3 (chromosome-wise error probability < .009). Chromosome 6 is known to harbor the KIT locus (receptor tyrosinase kinase), which is associated with various depigmentation phenotypes in mice, humans, and pigs. Similarity of phenotypic KIT effects in other species and synteny with the reported QTL suggest that KIT is a serious candidate gene for the degree of spotting in cattle. The results are also discussed with respect to resistance to solar radiation, heat stress, and photosensitization. (+info)
QTL for live weight traits in Pere David's x red deer interspecies hybrids.
(79/2205)
Interspecies hybrids between Pere David's deer (Elaphurus davidianus) and red deer (Cervus elaphus) have proved to be a powerful resource in the search for quantitative trait loci (QTL) in deer. Several regions of the genome with significant effects on live weight and growth rates in backcross hybrids were detected. These include putative QTL for 6-month live weight (LOD 3.90) on linkage group 12, for 14-month live weight (LOD 3.19) on linkage group 1, three putative QTL for growth rate from 3 to 6 months (LOD 4.19 on linkage group 12, LOD 3.92 on linkage group 12, and LOD 3.34 on linkage group 5). In addition, linkage groups 20 and 1 appear to be associated with live weight traits between 9 and 16 months. The variance in traits explained by these QTL ranged between 5.3% and 11.2%. Allele substitution with Pere David's alleles at different loci had both positive and negative effects on live weights and growth rates. (+info)
Quantitative trait locus mapping of airway responsiveness to chromosomes 6 and 7 in inbred mice.
(80/2205)
Quantitative trait locus (QTL) mapping was used to identify chromosomal regions contributing to airway hyperresponsiveness in mice. Airway responsiveness to methacholine was measured in A/J and C3H/HeJ parental strains as well as in progeny derived from crosses between these strains. QTL mapping of backcross [(A/J x C3H/HeJ) x C3H/HeJ] progeny (n = 137-227 informative mice for markers tested) revealed two significant linkages to loci on chromosomes 6 and 7. The QTL on chromosome 6 confirms the previous report by others of a linkage in this region in the same genetic backgrounds; the second QTL, on chromosome 7, represents a novel locus. In addition, we obtained suggestive evidence for linkage (logarithm of odds ratio = 1.7) on chromosome 17, which lies in the same region previously identified in a cross between A/J and C57BL/6J mice. Airway responsiveness in a cross between A/J and C3H/HeJ mice is under the control of at least two major genetic loci, with evidence for a third locus that has been previously implicated in an A/J and C57BL/6J cross; this indicates that multiple genetic factors control the expression of this phenotype. (+info)