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At least 1,261 records · Page 70Linked to original sources
PubMed2005

Genetic analysis of the hypothalamic corticotropin-releasing factor system.

The goal of this study was to use BxD recombinant inbred mice to search for genes that control the hypothalamic corticotrophin-releasing factor (CRF) system. The specific phenotype that was measured was abundance of transcripts that encode CRF, CRF receptor (Crf-R1), CRF binding protein, and arginine vasopressin (AVP) in total hypothalamic RNA. The strain distribution patterns for the transcript abundances for each target were continuously distributed, consistent with these being quantitative traits. Marker regression and interval mapping revealed associations with quantitative trait loci (QTL) for CRF transcript abundance on chromosome 1 (at 89.2 cM), chromosome 12 (between 54-58 cM), and chromosome 13 (between 26-30 cM); for Crf-R1 transcript abundance on chromosome 7 (at 1.5 cM), chromosome 12 (at 37 cM), and chromosome X (at 30 cM); for CRF binding protein transcript abundance on chromosome 7 (at 48.5 cM), chromosome 8 (at 65 cM), and chromosome 12 (at 19 cM); and for AVP transcript abundance on chromosome 7 (at 1 cM), chromosome 12 (at 13 cM), and chromosome 13 (at 45 cM). The transcript abundance QTL were not linked to their respective structural genes. Interval mapping on chromosome 7 reveals substantial overlap between QTL that control AVP and Crf-R1 transcript abundance and on chromosome 12 for QTL that control CRF and Crf-R1, which may indicate loci that coordinate regulation of the CRF system. There are QTL for all four targets on chromosome 12. There are a number of neurodevelopmental genes in very close proximity to the transcript abundance QTL that are potential candidate genes.

Animals↗
PubMed1997

MCMC segregation and linkage analysis.

Our objective was to infer the genetic model for the quantitative traits using a variety of methods developed in our group. Only a single data set was analyzed in any one analysis, although some comparison between data sets was made. In addition, the simulated model was not known during the course of the analysis. Basic modeling and segregation analyses for the five quantitative traits was followed by several simple genome scans to indicate areas of interest. A Markov chain Monte Carlo (MCMC) multipoint quantitative trait locus (QTL) mapping approach was then used to estimate the posterior probabilities of linkage of QTL to each chromosome simultaneously with trait model parameters, and to further localize the genes. Comparisons between the nuclear family and pedigree data sets indicated a greater power for QTL detection and mapping with the pedigree data sets. Even with the pedigree data, however, precise localization of the QTL did not appear to be possible using single replicate data sets. Two of the three genes with effects on trait Q1 were detected by the MCMC method.

Chromosome Mapping↗
PubMed1994

Genetic mapping of two new blood pressure quantitative trait loci in the rat by genotyping endothelin system genes.

The endothelin system, consisting of a series of potent vasoconstrictor peptides and their receptors, is potentially important in the control of blood pressure. We found that the gene coding for endothelin-2 (ET2), also known as vasoctive intestine peptide, cosegregated strongly with systolic blood pressure in a F2 population [F2(S x LEW)] derived from a cross of the Dahl salt-sensitive (S) rat and the Lewis (LEW/NCrlBR) (LEW) rat. The ET2 locus was assigned to rat chromosome 5. The testis-specific histone (HITH) locus also strongly cosegregated with blood pressure in the F2(S x LEW) population and was assigned to rat chromosome 17. Genetic maps of the regions containing the quantitative trait loci (QTL) for blood pressure on chromosomes 5 and 17 were constructed and the QTL were localized using the MAPMAKER/QTL program. The rat genes for endothelin-1, endothelin-3, and endothelin receptor A did not cosegregate with blood pressure in several F2 populations tested and were assigned to rat chromosomes 17, 3, and 19, respectively. Endothelin receptor B cosegregated weakly with blood pressure and was provisionally assigned to rat chromosome 15. We conclude that, in the rat, one new blood pressure QTL is located on chromosome 5 marked by the ET2 locus and another new QTL is located on chromosome 17 near the HITH locus.

Animals↗
PubMed2003

Robust indices of Hardy-Weinberg disequilibrium for QTL fine mapping.

Hardy-Weinberg disequilibrium (HWD) measures have been proposed using dense markers to fine map a quantitative trait locus (QTL) to regions < approximately 1 cM. Earlier HWD measures may introduce bias in the fine mapping because they are dependent on marker allele frequencies across loci. Hence, HWD indices that do not depend on marker allele frequencies are desired for fine mapping. Based on our earlier work, here we present four new HWD indices that do not depend on marker allele frequencies. Two are for use when marker allele frequencies in a study population are known, and two are for use when marker allele frequencies in a study population are not known and are only known in the extreme samples. The new measures are a function of the genetic distance between the marker locus and a QTL. Through simulations, we investigated and compared the fine mapping performance of the new HWD measures with that of the earlier ones. Our results show that when marker allele frequencies vary across loci, the new measures presented here are more robust and powerful.

Chromosome Mapping↗
PubMed2006

A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep.

Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, we performed a whole-genome scan in a Romanov x Texel F2 population. We mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene. We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation.

Animals↗
PubMedDate not supplied

A simple and rapid method for calculating identity-by-descent matrices using multiple markers.

A fast, partly recursive deterministic method for calculating Identity-by-Descent (IBD) probabilities was developed with the objective of using IBD in Quantitative Trait Locus (QTL) mapping. The method combined a recursive method for a single marker locus with a method to estimate IBD between sibs using multiple markers. Simulated data was used to compare the deterministic method developed in the present paper with a stochastic method (LOKI) for precision in estimating IBD probabilities and performance in the task of QTL detection with the variance component approach. This comparison was made in a variety of situations by varying family size and degree of polymorphism among marker loci. The following were observed for the deterministic method relative to MCMC: (i) it was an order of magnitude faster; (ii) its estimates of IBD probabilities were found to agree closely, even though it does not extract information when haplotypes are not known with certainty; (iii) the shape of the profile for the QTL test statistic as a function of location was similar, although the magnitude of the test statistic was slightly smaller; and (iv) the estimates of QTL variance was similar. It was concluded that the method proposed provided a rapid means of calculating the IBD matrix with only a small loss in precision, making it an attractive alternative to the use of stochastic MCMC methods. Furthermore, developments in marker technology providing denser maps would enhance the relative advantage of this method.

Animals↗
PubMed2006

An empirical Bayes method for updating inferences in analysis of quantitative trait loci using information from related genome scans.

Individual genome scans for quantitative trait loci (QTL) mapping often suffer from low statistical power and imprecise estimates of QTL location and effect. This lack of precision yields large confidence intervals for QTL location, which are problematic for subsequent fine mapping and positional cloning. In prioritizing areas for follow-up after an initial genome scan and in evaluating the credibility of apparent linkage signals, investigators typically examine the results of other genome scans of the same phenotype and informally update their beliefs about which linkage signals in their scan most merit confidence and follow-up via a subjective-intuitive integration approach. A method that acknowledges the wisdom of this general paradigm but formally borrows information from other scans to increase confidence in objectivity would be a benefit. We developed an empirical Bayes analytic method to integrate information from multiple genome scans. The linkage statistic obtained from a single genome scan study is updated by incorporating statistics from other genome scans as prior information. This technique does not require that all studies have an identical marker map or a common estimated QTL effect. The updated linkage statistic can then be used for the estimation of QTL location and effect. We evaluate the performance of our method by using extensive simulations based on actual marker spacing and allele frequencies from available data. Results indicate that the empirical Bayes method can account for between-study heterogeneity, estimate the QTL location and effect more precisely, and provide narrower confidence intervals than results from any single individual study. We also compared the empirical Bayes method with a method originally developed for meta-analysis (a closely related but distinct purpose). In the face of marked heterogeneity among studies, the empirical Bayes method outperforms the comparator.

Chromosome Mapping↗
PubMed2005

Association of the protease inhibitor gene with production traits in Holstein dairy cattle.

Positional, comparative candidate gene analysis and previous quantitative trait loci linkage mapping results were used to search for candidate genes affecting milk production and reproduction traits in dairy cattle. The protease inhibitor (PI) gene was chosen for examination, and 5 single nucleotide polymorphisms were detected in coding regions of the gene by direct sequencing of reverse transcription-polymerase chain reaction products from a wide range of cattle tissues. A total of 6 different intragenic haplotypes were identified in North American Holstein population, and these were examined for associations with milk production traits in 24 half-sib families comprising 1007 sons utilizing a granddaughter design. One common haplotype was associated with increased milk and fat yields, increased productive life, and decreased somatic cell score. Another common haplotype was associated with decreased productive life and increased somatic cell score. One rare haplotype was associated with decreased milk, fat, and protein yields and increased milk protein percentage; another rare haplotype was associated with decreased milk yield, increased protein percentage, and decreased productive life. The observation that the PI gene is associated with analogous traits in humans demonstrates the effectiveness of the positional comparative candidate gene analysis that utilizes information about genes present in chromosomal regions with conserved synteny in other species.

Animals↗
PubMed2004

Phenotypic characterization and genealogical tracing in an Afrikaner schizophrenia database.

Founder populations hold tremendous promise for mapping genes for complex traits, as they offer less genetic and environmental heterogeneity and greater potential for genealogical research. Not all founder populations are equally valuable, however. The Afrikaner population meets several criteria that make it an ideal population for mapping complex traits, including founding by a small number of initial founders that likely allowed for a relatively restricted set of mutations and a large current population size that allows identification of a sufficient number of cases. Here, we examine the potential to conduct genealogical research in this population and present initial results indicating that accurate genealogical tracing for up to 17 generations is feasible. We also examine the clinical similarities of schizophrenia cases diagnosed in South Africa and those diagnosed in other, heterogeneous populations, specifically the US. We find that, with regard to basic sample descriptors and cardinal symptoms of disease, the two populations are equivalent. It is, therefore, likely that results from our genetic study of schizophrenia will be applicable to other populations. Based on the results presented here, the history and current size of the population, as well as our previous analysis addressing the extent of background linkage disequilibrium (LD) in the Afrikaners, we conclude that the Afrikaner population is likely an appropriate founder population to map genes for schizophrenia using both linkage and LD approaches.

Adult↗
PubMed2003

Identification of quantitative trait loci influencing wood property traits in loblolly pine (Pinus taeda L.). III. QTL Verification and candidate gene mapping.

A long-term series of experiments to map QTL influencing wood property traits in loblolly pine has been completed. These experiments were designed to identify and subsequently verify QTL in multiple genetic backgrounds, environments, and growing seasons. Verification of QTL is necessary to substantiate a biological basis for observed marker-trait associations, to provide precise estimates of the magnitude of QTL effects, and to predict QTL expression at a given age or in a particular environment. Verification was based on the repeated detection of QTL among populations, as well as among multiple growing seasons for each population. Temporal stability of QTL was moderate, with approximately half being detected in multiple seasons. Fewer QTL were common to different populations, but the results are nonetheless encouraging for restricted applications of marker-assisted selection. QTL from larger populations accounted for less phenotypic variation than QTL detected in smaller populations, emphasizing the need for experiments employing much larger families. Additionally, 18 candidate genes related to lignin biosynthesis and cell wall structure were mapped genetically. Several candidate genes colocated with wood property QTL; however, these relationships must be verified in future experiments.

Chromosome Mapping↗
PubMed2001

Quantitative trait loci influencing morphine antinociception in four mapping populations.

Analgesia (pain reduction, or antinociception) is a classical and clinically important effect of morphine administration, and in rodent models sensitivity to morphine has been shown to be strongly influenced by genotype. For example, several studies have reported marked differences in morphine antinociception between the insensitive C57BL/6 (B6) and sensitive DBA/2 (D2) inbred mouse strains on the hot-plate assay. This prompted the present genome-wide search for quantitative trait loci (QTLs) that are chromosomal sites influencing the magnitude of antinociception, by using four mapping populations derived from the B6 and D2 progenitor inbred strains. These four were the BXD recombinant inbred (RI) strain set, an F2 (B6D2F2) population, short-term selective breeding for antinociception from a B6D2F2 founding population, and incipient or completed congenic strains. In the BXD RI set and in the B6D2F2, a genome-wide search identified 10-12 provisional QTLs at a nominal p <.05. The other populations were subsequently used as confirmation steps to test each of the provisional QTL regions. Based on all available mapping populations, four QTLs emerged as significant (p <.00005) on proximal Chromosome (Chr) 1 (females only), proximal Chr 9 (females only), mid Chr 9, and proximal Chr 10. The Chr 10 QTL comaps to the same region as the micro-opioid receptor gene (Oprm); this receptor is a known mediator of morphine's antinociceptive effects. The Chr 1 QTL was evident only in females and comapped with the kappa-opioid receptor gene, Oprk.

Analgesia↗
PubMed2003

Molecular mapping of capsaicinoid biosynthesis genes and quantitative trait loci analysis for capsaicinoid content in Capsicum.

Quantitative variation in the accumulation of two major capsaicinoids responsible for pungency in the fruit of chile peppers, capsaicin and dihydrocapsaicin, was analyzed in a cross between the non-pungent Capsicum annuum parent cv. Maor and a pungent Capsicum frutescens parent, accession BG 2816. In order to identify quantitative trait loci (QTLs) for capsaicinoid content, we employed the bulked segregant analysis method and screened bulked DNA from F2 individuals at the extremes of the distribution of capsaicinoid content with RAPD primers. Screening with 400 primers allowed the identification of three loci that were polymorphic between the bulks. These RAPD markers were converted to SCARs and subsequently mapped with additional RFLP markers to chromosome 7 of pepper. QTL interval analysis for individual and total capsaicinoid content identified a major QTL, termed cap, which explained 34-38% of the phenotypic variation for this trait in two growing environments. For all measurements, the allele of the pungent parent BG 2816 at cap contributed to the increased level of pungency. To determine whether known structural genes in the pathway could define a candidate for this QTL, 12 clones obtained from differentially expressed transcripts from placental tissue in pungent peppers were also mapped. None of them had a significant effect on this trait, nor did the allelic state at the locus C, the on/off switch for pungency in pepper, located on chromosome 2. The identity of cap and its effect on capsaicin content in other backgrounds will be addressed in future studies.

Alleles↗
PubMed1996

General score tests for associations of genetic markers with disease using cases and their parents.

Association studies of genetic markers with disease play a critical role in the dissection of genetically complex traits because they are relatively easy to conduct and are useful for fine-scale mapping of genetic traits. The advantage of family-based controls has recently received much attention because spurious associations caused by population structure can be controlled for, and marker genotype information on diseased cases and their parents can be used to test the compound hypothesis of both linkage and linkage disequilibrium. However, debate still exists regarding the statistical methods of analysis. Herein are presented statistical methods to test for linkage (in the presence of linkage disequilibrium) between multiallelic genetic markers and disease when diseased subjects (cases) and their parents are sampled. Theoretical considerations for the development of general statistical tests are presented as well as asymptotic formulas to compute their power when planning a study. Furthermore, simulation results for nine specific statistics are used to contrast the power of these methods under different genetic mechanisms leading to disease (dominant vs. recessive, one vs. two high-risk alleles). These results demonstrate substantial gains in power for specific statistical tests designed to detect specified genetic mechanisms. However, without a priori knowledge of the likely genetic mechanism, it is desirable to rely on a fairly robust statistical method, robust so that power is not drastically lost when either dominant or recessive mechanisms are acting, and when either one or more than one marker alleles are associated with disease. Based on both theoretical and simulation results, a general score statistic, which generalizes the transmission/disequilibrium test, tends to offer sufficient power for a variety of genetic mechanisms, so that it is worth considering for broad use in studies which use genetic marker information from both diseased cases and their parents.

Adult↗
PubMed2003

Mapping multiple genetic loci associated with Ceratomyxa shasta resistance in Oncorhynchus mykiss.

Ceratomyxa shasta is enzootic to some rivers of the Pacific Northwest and California, and has caused extensive mortalities of salmonids, the only known host of the actinosporean stage of the pathogen. Mortalities from C. shasta are induced by severe inflammation and necrosis of the intestinal tract, and no therapeutants have been discovered for the treatment of ceratomyxosis. Inheritance studies by previous investigators suggested that C. shasta resistance is genetically controlled, but none have revealed the number and locations of gene regions associated with resistance. Here, we characterized differences in resistance among clonal lines, and used line crosses between clonal lines with resistance differences for a genetic analysis of C. shasta resistance in Oncorhynchus mykiss, following a short term in situ exposure to the pathogen. We found that Oregon State University (OSU) x Arlee (ARL) clonal hybrids were highly susceptible, while OSU x Clearwater (CW) hybrids were highly resistant to C. shasta. Doubled haploids, produced by androgenesis from an F1 hybrid between the OSU and CW lines, were evaluated for the co-segregation of molecular markers and resistance phenotype. Amplified fragment length polymorphic (AFLP) markers, used to construct a genetic linkage map in this cross, were tested for associations with resistance expressed as absolute survival (binary trait) and days to death (survival analysis). Segregation of the resistance phenotype suggested that the resistance was inherited as a single Mendelian locus, but the binary trait failed to map to a single genomic location. Markers identified in single-marker analyses were used in multiple-regression model selection, within both the linear regression and Cox proportional-hazards survival analysis frameworks, to determine the number and potential location of loci simultaneously contributing to variation in the survival phenotypes of doubled-haploid progeny. We found multiple genomic loci associated with C. shasta resistance through these models, confirming studies by previous investigators that suggested C. shasta resistance is polygenic.

Animals↗
PubMed2006

Substitution mapping in dahl rats identifies two distinct blood pressure quantitative trait loci within 1.12- and 1.25-mb intervals on chromosome 3.

Substitution mapping was used to refine the localization of blood pressure (BP) quantitative trait loci (QTL) within the congenic region of S.R-Edn3 rats located at the q terminus of rat chromosome 3 (RNO3). An F2(SxS.R-Edn3) population (n=173) was screened to identify rats having crossovers within the congenic region of RNO3 and six congenic substrains were developed that carry shorter segments of R-rat-derived RNO3. Five of the six congenic substrains had significantly lower BP compared to the parental S rat. The lack of BP lowering effect demonstrated by the S.R(ET3x5) substrain and the BP lowering effect retained by the S.R(ET3x2) substrain together define the RNO3 BP QTL-containing region as approximately 4.64 Mb. Two nonoverlapping substrains, S.R(ET3x1) and S.R(ET3x6), had significantly lower BP compared to the S strain, indicating the presence of two distinct BP QTL in the RNO3 q terminus. The RNO3 q terminus was fine mapped with newly developed polymorphic markers to characterize the extent of the congenic regions. The two RNO3 BP QTL regions were thus defined as within intervals of 0.05-1.12 and 0.72-1.25 Mb, respectively. Also important was our difficulty in fine mapping and marker placement in this portion of the rat genome (and thus candidate gene identification) using the available genomic data, including the rat genome sequence.

Animals↗
PubMed2003

[Testing linkage hypothesis in hybrid analysis of alternatively distributed behavioral traits with incomplete penetrance].

The use of polymorphic microsatellite markers for mapping alternatively distributed behavioral traits with incomplete penetrance was studied with special reference to inheritance of predisposition to catalepsy in mice. Using only backcrosses as a segregating population, the major gene for catalepsy was with high likelihood mapped to region 30-75 cM of murine chromosome 13. It was also established that this gene determines 20% of the trait penetrance whereas the remaining 31% of the observed penetrance are accounted for by numerous polygenes.

Animals↗
PubMed1995

Screening a 2 cM genetic map for allelic association: a simulated oligogenic trait.

In this paper, we explore the use of a variety of familial transmission tests (and case-control analyses) to screen for allelic associations in simulated marker data of a quality (2 cM map) that will feasibly arise from genomic scans within the next 5-10 years. We demonstrate a form of the transmission-disequilibrium test extended to multiallele systems. The methods used were log-linear and related models implemented largely using standard statistical packages.

Alleles↗
PubMed2002

A quantitative trait locus that accounts for glucose intolerance maps to chromosome 8 in hereditary obese KK-A(y) mice.

KK and KK-A(y) mice serve as animal models of non-insulin-dependent diabetes mellitus with moderate obesity. Quantitative trait locus (QTL) analysis was performed to identify gene loci that account for fasting hyperglycemia, glucose intolerance and plasma insulin in 91 F(2) females of a C57BL/6JxKK-A(y) intercross. For glucose intolerance, a significant QTL was identified on chromosome 8, with a maximum lod score of 5.6. This locus had strong influence on the late phase of the intraperitoneal glucose tolerance test (IPGTT), suggesting that the locus may have role in glucose clearance rather than in mere hyperglycemia. In addition, three suggestive QTLs were identified on chromosomes 1 (fasting glucose), 3 (fasting insulin) and 4, (blood glucose at 120 min during IPGTT, and glucose intolerance).

Animals↗