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Results for “expression quantitative trait loci”

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PubMed2004

Chromosomes 6 and 13 harbor genes that regulate pubertal timing in mouse chromosome substitution strains.

Variation in the onset of puberty among inbred strains of mice suggests that quantitative trait loci (QTLs) affect neurological and hormonal aspects of sexual maturation. Taking a novel approach toward identifying factors that regulate the hypothalamic-pituitary-gonadal (HPG) axis, we evaluated pubertal timing [as assessed by vaginal opening (VO)] in two inbred strains of mice, A/J and C57BL/6J (B6), and in a panel of chromosome substitution strains (CSSs) generated from A/J and B6 mice. In each CSS, a single chromosome from A/J has been substituted in a homozygous fashion for the corresponding chromosome in B6, partitioning the A/J genome into 22 strains with a common host (B6) background. VO occurred significantly earlier in A/J compared with B6 mice. Although the majority of the CSSs assessed had a timing of VO that was similar to the progenitor B6 strain, CSSs for chromosomes 6 and 13 each displayed significantly earlier time of VO than B6 mice. F1 (B6 x CSS) mice for chromosomes 6 and 13 displayed phenotypes that were intermediate between the CSS and B6 strains, suggesting that the trait was inherited in a codominant manner. These findings demonstrate that chromosomes 6 and 13 harbor QTLs that control the timing of VO. Identification of the responsible genes may reveal factors that regulate the maturation of the HPG axis and determine the timing of puberty.

Animals↗
PubMed2004

High-resolution comparative mapping of pig Chromosome 4, emphasizing the FAT1 region.

The first quantitative trait locus (QTL) in pigs, FAT1, was found on Chromosome 4 (SSC4) using a Wild Boar intercross. Further mapping has refined the FAT1 QTL to a region with conserved synteny to both human Chromosomes 1 and 8. To both improve the comparative map of the entire SSC4 and to define the specific human chromosome region with conserved synteny to FAT1, we have now mapped 103 loci to pig Chromosome 4 using a combination of radiation hybrid and linkage mapping. The physical data and linkage analysis results are in very good agreement. Comparative analysis revealed that gene order is very well conserved across SSC4 compared to both HSA1 and HSA8. The breakpoint in conserved synteny was refined to an area of about 23 cR on the q arm of SSC4 corresponding to a genetic distance of less than 0.5 cM. Localizations of the centromeres do not seem to have been conserved between the two species. No remnants of the HSA1 centromere were detected on the corresponding region on SSC4 and traces from the centromeric region of SSC4 cannot clearly be revealed on the homologous region on HSA8. This refined SSC4 map and the comparative analysis will be a great aid in the search for the genes underlying the FAT1 locus.

Animals↗
PubMed2004

TraitMap: an XML-based genetic-map database combining multigenic loci and biomolecular networks.

MOTIVATION: Most ordinary traits are well described by multiple measurable parameters. Thus, in the course of elucidating the genes responsible for a given trait, it is necessary to conduct and integrate the genetic mapping of each parameter. However, the integration of multiple mapping results from different publications is prevented by the fact that they are conventionally published and accumulated in printed forms or graphics which are difficult for computers to reuse for further analyses. RESULTS: We have defined an XML-based schema as a container of genetic mapping results, and created a database named TraitMap containing curator-checked data records based on published papers of mapping results in Homosapiens, Mus musculus, and Arabidopsis thaliana. TraitMap is the first database of mapping charts in genetics, and is integrated in a web-based retrieval framework: termed Genome <--> Phenome Superhighway (GPS) system, where it is possible to combine and visualize multiple mapping records in a two-dimensional display. Since most traits are regulated by multiple genes, the system associates every combination of genetic loci to biomolecular networks, and thus helps us to estimate molecular-level candidate networks responsible for a given trait. It is demonstrated that a combined analysis of two diabetes-related traits (susceptibility to insulin resistance and non-HDL cholesterol level) suggests that molecular-level relationships such as the interaction among leptin receptor (Lepr), peroxisome proliferators-activated receptor-gamma (Pparg) and insulin receptor substrate 1 (Irs1), are candidate causal networks affecting the traits in a multigenic manner. AVAILABILITY: TraitMap database and GPS are accessible at http://omicspace.riken.jp/gps/

Chromosome Mapping↗
PubMed2004

Genetic analysis of genome-wide variation in human gene expression.

Natural variation in gene expression is extensive in humans and other organisms, and variation in the baseline expression level of many genes has a heritable component. To localize the genetic determinants of these quantitative traits (expression phenotypes) in humans, we used microarrays to measure gene expression levels and performed genome-wide linkage analysis for expression levels of 3,554 genes in 14 large families. For approximately 1,000 expression phenotypes, there was significant evidence of linkage to specific chromosomal regions. Both cis- and trans-acting loci regulate variation in the expression levels of genes, although most act in trans. Many gene expression phenotypes are influenced by several genetic determinants. Furthermore, we found hotspots of transcriptional regulation where significant evidence of linkage for several expression phenotypes (up to 31) coincides, and expression levels of many genes that share the same regulatory region are significantly correlated. The combination of microarray techniques for phenotyping and linkage analysis for quantitative traits allows the genetic mapping of determinants that contribute to variation in human gene expression.

Alleles↗
PubMed2006

Gene-associated single nucleotide polymorphism discovery in perennial ryegrass (Lolium perenne L.).

Molecular genetic marker development in perennial ryegrass has largely been dependent on anonymous sequence variation. The availability of a large-scale EST resource permits the development of functionally-associated genetic markers based on SNP variation in candidate genes. Genic SNP loci and associated haplotypes are suitable for implementation in molecular breeding of outbreeding forage species. Strategies for in vitro SNP discovery through amplicon cloning and sequencing have been designed and implemented. Putative SNPs were identified within and between the parents of the F(1)(NA(6) x AU(6)) genetic mapping family and were validated among progeny individuals. Proof-of-concept for the process was obtained using the drought tolerance-associated LpASRa2 gene. SNP haplotype structures were determined and correlated with predicted amino acid changes. Gene-length LD was evaluated across diverse germplasm collections. A survey of SNP variation across 100 candidate genes revealed a high frequency of SNP incidence (c. 1 per 54 bp), with similar proportions in exons and introns. A proportion (c. 50%) of the validated genic SNPs were assigned to the F(1)(NA(6) x AU(6)) genetic map, showing high levels of coincidence with previously mapped RFLP loci. The perennial ryegrass SNP resource will enable genetic map integration, detailed LD studies and selection of superior allele content during varietal development.

Breeding↗
PubMed1994

Evidence of linkage between high-glycine-tyrosine keratin gene loci and wool fibre diameter in a Merino half-sib family.

Candidate genes for quantitative trait loci have been studied in a Medium Peppin Merino flock. Obvious candidates for effects on wool production traits are genes for the major proteins expressed in the wool fibre, the keratin and keratin-associated protein genes. Two keratin-associated protein loci, KRTAP6 and KRTAP8, have previously been shown to be linked. The results of analyses between these two loci and production traits gave significant evidence of linkage with wool fibre diameter in one out of eight half-sib groups tested. High-glycine-tyrosine proteins (KRTAP6, 7 and 8) are known to vary considerably in abundance in wool fibres and it is possible that a gene for major effect on fibre diameter is located within the same chromosomal region as KRTAP6 and KRTAP8.

Alleles↗
PubMed2006

Mapping genetic modulators of amyloid plaque deposition in TgCRND8 transgenic mice.

Alzheimer's disease (AD) is a complex disorder for which various in vivo models exist. The TgCRND8 mouse, transgenic for the human amyloid precursor protein, is an aggressive early onset model of brain amyloid deposition. Preliminary studies revealed that when the transgene is expressed on an A/J genetic background, these mice not only survive longer but also deposit less parenchymal amyloid-beta (Abeta) peptides as compared to those on a C57BL/6 background. We performed a genome-wide study of an F2 intercross between TgCRND8 on an A/J background and C57BL/6 mice, to identify genetic modulators of amyloid accumulation and deposition. We identified four highly significant QTLs that together account for 55% of the phenotypic variance in the number of plaques (Thioflavin S). QTLs were found on the distal part of chromosome 4 with an LOD score of 8.1 at D4Mit251, on chromosome 11 with an LOD score of 5.5 at D11Mit242, on chromosome 9 with an LOD score of 5.0 at D9Mit336 and on the proximal part of chromosome 8 with an LOD score of 4.5 at D8Mit223. A/J alleles at these loci are protective and all decreased the amount of Abeta deposition. Interestingly, the QTL on chromosome 11 is also significantly linked to the levels of brain Abeta(42) and Abeta(40). Although these QTLs do not control the levels of plasmatic Abeta, other regions on chromosomes 1 and 6 show significant linkage. Further characterization of these QTL regions may lead to the identification of genes involved in the pathogenesis of AD.

Amyloid beta-Peptides↗
PubMed2006

Linkage mapping of gene-associated SNPs to pig chromosome 11.

Single nucleotide polymorphisms (SNPs) were discovered in porcine expressed sequence tags (ESTs) orthologous to genes from human chromosome 13 (HSA13) and predicted to be located on pig chromosome 11 (SSC11). The SNPs were identified as sequence variants in clusters of EST sequences from pig cDNA libraries constructed in the Sino-Danish pig genome project. In total, 312 human gene sequences from HSA13 were used for similarity searches in our pig EST database. Pig ESTs showing significant similarity with HSA13 genes were clustered and candidate SNPs were identified. Allele frequencies for 26 SNPs were estimated in a group of 80 unrelated pigs from Danish commercial pig breeds: Duroc, Hampshire, Landrace and Large White. Eighteen of the 26 SNPs genotyped in the PiGMaP Reference Families were mapped by linkage analysis to SSC11. The EST-based SNPs published here are new genetic markers useful for linkage and association studies in commercial and experimental pig populations. This study represents the first gene-associated SNP linkage map of pig chromosome 11 and adds new comparative mapping information between SSC11 and HSA13. Furthermore, our data facilitate future studies aimed at the identification of interesting regions on pig chromosome 11, positional cloning and fine mapping of quantitative trait loci in pig.

Animals↗
PubMed2026

Genetic regulation of CPEB3-mediated alternative polyadenylation associated with survival of patients with hepatocellular carcinoma.

BACKGROUND: Alternative polyadenylation (APA) is a key post-transcriptional mechanism that regulates gene expression by modulating 3'UTR length, its dysregulation has been implicated in carcinogenesis. How genetic variants influence APA to affect hepatocellular carcinoma (HCC) prognosis remains unclear. METHODS: Prognosis-APA quantitative trait loci (apaQTL) were performed using genotype and APA profiling from TCGA data. A two-stage survival analysis in 848 Chinese and 369 TCGA LIHC patients and functional validation were used to identify prognostic apaQTL in HCC progression. RESULTS: A total of 2,025 and 817 significant APA events were identified in Chinese and TCGA cohort, respectively. Besides, 859 events were associated with poor prognosis in HCC and enriched in RNA splicing / metabolism pathways. We detected 32,034 significant apaQTLs, predominantly enriched in 3'UTRs and RBP-binding regions. CPEB3 was prioritized as a key APA regulator RBP; its low expression correlated with poor patient survival and promoted proliferation, migration, and invasion in HCC cells. Notably, a functional apaQTL variant rs2037547, located in GSK3B and mediated by CPEB3, demonstrated a poor survival of HCC patients in both cohort (pooled HR=1.29, p=0.016). Mechanistically, rs2037547 promoted aberrant APA at proximal poly(A) sites of GSK3B through CPEB3, leading to increased expression of short 3'UTR isoform. This regulatory alteration enhanced HCC cell proliferation, invasion, and migration, and contributed to HCC progression. CONCLUSION: These findings elucidated the distinct role of apaQTL-mediated APA dysregulation in HCC prognosis, providing insights for prognostic stratification and potential targets for personalized therapy in HCC.

RNA-binding proteins↗
PubMed2006

Natural variation and genetic covariance in adult hippocampal neurogenesis.

Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB/BXA, n = 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1/CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis-acting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.

Animals↗
PubMed2003

New quantitative trait loci that contribute to cholesterol gallstone formation detected in an intercross of CAST/Ei and 129S1/SvImJ inbred mice.

Cholesterol gallstone formation is a response to interactions between multiple genes and environmental stimuli. To determine the subset of cholesterol gallstone susceptibility (Lith) genes possessed by strains CAST/Ei (susceptible) and 129S1/SvImJ (resistant), we conducted quantitative trait locus (QTL) analyses of an intercross between these strains. Parental strains and F(1) mice of both genders were evaluated for gallstone formation after consumption of a lithogenic diet for 8 wk. Gallstone susceptibility of strain CAST was predominantly due to cholesterol hypersecretion. Male intercross offspring were genotyped and phenotyped for cholesterol gallstone formation after consumption of the lithogenic diet for 10 wk. Linkage analysis was performed using PSEUDOMARKER software. One significant, new QTL was detected and named Lith13 [chromosome (Chr) 5, 30 cM]. Statistical analyses and QTL fine mapping suggest this QTL may comprise two closely linked loci. We confirmed the presence of Lith6 (Chr 6). Suggestive QTL were detected on Chrs 1, 2, 5, 14, and 16. The QTL on Chrs 2 and 16 confirmed previously identified, suggestive QTL. Therefore, they were named Lith12 (101 cM) and Lith14 (42 cM), respectively. We identified candidate genes based on known function and location and performed mRNA expression analyses using both parental strains and intercross progeny for preliminary evaluation of their contributions to gallstone formation. Cebpb (Lith12), Pparg (Lith6), and Slc21a1 (Lith6) displayed expression differences. Our work continues to demonstrate the genetic complexity and to elucidate the pathophysiology of cholesterol gallstone formation. It should facilitate the development of new approaches for treating this common human disorder.

Alleles↗
PubMed2005

Genetic disposition to addictive disorders--current knowledge and future perspectives.

It is well established that addictive disorders have a strong genetic background. Multiple, and in part interacting, genes are likely to be responsible for the disease phenotype, making the search for underlying alleles a challenging and complicated task. Linkage analyses and association studies have failed to unequivocally identify underlying genes. Conversely, genome sequencing and the systematic search for polymorphic marker loci have yielded dense chromosome maps so that, along with automated genotyping, the identification of individual genes will soon become possible. Initial results provide hints that regulators of gene expression might play an important role in addiction.

Animals↗
PubMed2003

What's new in neurogenetics? Focus on "primary microcephaly".

Primary microcephaly is a specific form of microcephaly that is inherited in an autosomal recessive manner. Six loci have been mapped for this condition and the genes at two of these loci have recently been identified. These include the Microcephalin gene at the MCPH1 locus and the ASPM gene at the MCPH5 locus.

Cell Cycle Proteins↗
PubMed2005

Quantitative trait loci for yield and related traits in the wheat population Ning7840 x Clark.

Grain yield and associated agronomic traits are important factors in wheat (Triticum aestivum L.) improvement. Knowledge regarding the number, genomic location, and effect of quantitative trait loci (QTL) would facilitate marker-assisted selection and the development of cultivars with desirable characteristics. Our objectives were to identify QTLs directly and indirectly affecting grain yield expression. A population of 132 F12 recombinant inbred lines (RILs) was derived by single-seed descent from a cross between the Chinese facultative wheat Ning7840 and the US soft red winter wheat Clark. Phenotypic data were collected for 15 yield and other agronomic traits in the RILs and parental lines from three locations in Oklahoma from 2001 to 2003. Twenty-nine linkage groups, consisting of 363 AFLP and 47 SSR markers, were identified. Using composite interval mapping (CIM) analysis, 10, 16, 30, and 14 QTLs were detected for yield, yield components, plant adaptation (shattering and lodging resistance, heading date, and plant height), and spike morphology traits, respectively. The QTL effects ranged from 7 to 23%. Marker alleles from Clark were associated with a positive effect for the majority of QTLs for yield and yield components, but gene dispersion was the rule rather than the exception for this RIL population. Often, QTLs were detected in proximal positions for different traits. Consistent, co-localized QTLs were identified in linkage groups 1AL, 1B, 4B, 5A, 6A, and 7A, and less consistent but unique QTLs were identified on 2BL, 2BS, 2DL, and 6B. Results of this study provide a benchmark for future efforts on QTL identification for yield traits.

Chromosome Mapping↗
PubMed2005

Genetic lesions in thymic T cell clonal deletion and thresholds for autoimmunity.

The cause of common polygenic autoimmune diseases is poorly understood because of genetic and cellular complexity in humans and animals. We have investigated the mechanisms of two genetic causes of organ-specific autoimmunity by tracking the fate of high avidity organ-specific CD4 T cells using a transgenic mouse model. Firstly, we have found that an Idd-associated duster of loci from the NOD strain causes a T cell intrinsic failure to delete during in vivo encounter with high-avidity autoantigen, a trait distinguished by the failure to induce the pro-apoptotic gene Bim. Secondly, we have found that inactivation of the autoimmune regulator (Aire) gene reduces the level of thymic expression of organ-specific genes, in a gene-dose dependent manner. In this paper we describe a model relating efficiency of thymic deletion and susceptibility to autoimmunity. Using this model, subtle quantitative trait loci can have an additive effect on each of the parameters of thymic deletion, and the result of interaction between subtle modifications in the multiple parameters can result in large changes in the susceptibility to autoimmunity.

Animals↗
PubMed2002

Identification of quantitative trait loci for cold-tolerance of photosynthesis in maize (Zea mays L.).

The effects of low growth temperature (15 degrees C) on the photosynthetic apparatus of maize were investigated in a set of 233 recombinant inbred lines by means of chlorophyll fluorescence, gas exchange measurements and analysis of photosynthetic pigments. A quantitative trait loci (QTL) analysis of five traits related to the functioning of the photosynthetic apparatus revealed a total of eight genomic regions that were significantly involved in the expression of the target traits. Four of these QTLs, located on chromosomes 1 (around 146 cM), 2 (around 138 cM), 3 (around 70 cM), and 9 (around 62 cM), were identified across several traits and the phenotypic correlation observed among those traits confirmed at the genetic level. The two QTLs on chromosomes 1 and 9 were also expressed in leaves developed at near-optimal temperature (25 degrees C) whilst the two QTLs on chromosomes 2 and 3 were specific to leaves developed at sub-optimal temperature. A QTL analysis conducted on traits related to the pigment composition of the leaves developed at 15 degrees C detected the QTL on chromosome 3 around 70 cM in 7 of the 11 traits analysed. This QTL accounted for up to 28% of the phenotypic variance of the quantum yield of electron transport at PSII in the fourth leaf after about 3 weeks at a sub-optimal temperature. The results presented here suggest that key gene(s) involved in the development of functional chloroplasts of maize at low temperature should be located on chromosome 3, close to the centromere.

Adaptation, Physiological↗
PubMed2004

Quantitative trait locus dissection in congenic strains of the Goto-Kakizaki rat identifies a region conserved with diabetes loci in human chromosome 1q.

Genetic studies in human populations and rodent models have identified regions of human chromosome 1q21-25 and rat chromosome 2 showing evidence of significant and replicated linkage to diabetes-related phenotypes. To investigate the relationship between the human and rat diabetes loci, we fine mapped the rat locus Nidd/gk2 linked to hyperinsulinemia in an F2 cross derived from the diabetic (type 2) Goto-Kakizaki (GK) rat and the Brown Norway (BN) control rat, and carried out its genetic and pathophysiological characterization in BN.GK congenic strains. Evidence of glucose intolerance and enhanced insulin secretion in a congenic strain allowed us to localize the underlying diabetes gene(s) in a rat chromosomal interval of approximately 3-6 cM conserved with an 11-Mb region of human 1q21-23. Positional diabetes candidate genes were tested for transcriptional changes between congenics and controls and sequence variations in a panel of inbred rat strains. Congenic strains of the GK rats represent powerful novel models for accurately defining the pathophysiological impact of diabetes gene(s) at the locus Nidd/gk2 and improving functional annotations of diabetes candidates in human 1q21-23.

Animals↗