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Results for “Expression quantitative trait locus analysis”

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PubMed2005

Role of resistant Drh1 locus in chemical carcinogen-induced hepatocarcinogenesis in rats: analysis with a speed congenic strain.

The DRH is an inbred rat strain established by selective mating of the 3'-Me-DAB resistant progeny of closed colony Donryu rats over 20 generations. Genetic analysis shows that two semidominant QTLs, Drh1 and Drh2, are responsible for strong resistance to chemical-induced hepatocarcinogenesis in DRH strain rats. To evaluate the effect of the single Drh1 locus on various stages of liver carcinogenesis, we constructed a speed congenic strain DRH.F344-Drh1 by transferring a susceptible Drh1 allele of F344 to DRH rats by marker-assisted backcrossing. The DRH.F344-Drh1 rats had a approximately 43 cM segment of chromosome 1 bearing Drh1 but the Drh2 was of the DRH allele. After oral administration of 3'-Me-DAB for 8 weeks, DRH.F344-Drh1 had as many enzyme altered foci as F344, whereas the quantitative parameters of fibrosis, enzyme altered foci, GST-P expression and proliferation of liver cells in DRH.F344-Drh1 rats were intermediate between F344 and DRH. In the liver of carcinogen-fed DRH rats, there was intensive apoptosis as detected by TUNEL stain, but not in the liver of F344 and DRH.F344-Drh1 rats. Injection of lead nitrate (100 micromol/kgB.W) induced a wave of liver cell proliferation, as seen by BrdU uptake within a few days in F344 and DRH.F344-Drh1 rats, but not in DRH rats. Instead, there were numerous TUNEL-positive nuclei in the DRH liver after lead nitrate injection. Apparently, the hepatocytes were removed by apoptosis during transition from G0 to G1. The major role of Drh1 is effective removal of the hepatocytes newly recruited to proliferate after chemical injury. Resistance to preneoplastic lesions in DRH rats may well be based on similar mechanism.

Administration, Oral↗
PubMed2006

Ultrafine mapping of Dyscalc1 to an 80-kb chromosomal segment on chromosome 7 in mice susceptible for dystrophic calcification.

In mice, dystrophic cardiovascular calcification (DCC) is controlled by a major locus on proximal mouse chromosome 7 named Dyscalc1. Here we present a strategy that combines in silico analysis, expression analysis, and extensive sequencing for ultrafine mapping of the Dyscalc1 locus. We subjected 15 laboratory mouse strains to freeze-thaw injury of the heart, and association with respective genotypes allowed condensation of the Dyscalc1 locus to 1 Mb. Within this region, 51 known and predicted genes were studied in DCC-susceptible C3H/He and DCC-resistant C57BL/6 mice with respect to mRNA expression in response to injury. Five genes displayed differential expression. Genotyping of seven novel single nucleotide polymorphisms (SNPs) within these genes revealed an 80-Kb region in NZB mice that were found positive for calcification though carrying otherwise alleles from DCC-resistant mice. This microheterogeneity in NZB mice was evolutionary conserved in all DCC-susceptible mouse strains and contains the genes EMP-3, BC013491, and Abcc6 (partially). The flanking SNPs are rs3703247 and NT_039420.5_2757991. mRNA levels of EMP-3 were found to be upregulated in response to injury in both C57BL/6 and C3H/He mice. Sequencing of EMP-3 revealed an SNP leading to an amino acid substitution (p.T153I) that was found in all mouse strains susceptible for DCC but not in resistant strains such as C57BL/6 mice. Thus, the p.T153I changes might affect the biological function of EMP-3 gene product after injury. Using this combined approach, we ultrafine-mapped the Dyscalc1 locus to an 80-Kb region and identified EMP-3 as a new candidate gene for DCC.

Animals↗
PubMed2005

FRIGIDA-independent variation in flowering time of natural Arabidopsis thaliana accessions.

FRIGIDA (FRI) and FLOWERING LOCUS C (FLC) are two genes that, unless plants are vernalized, greatly delay flowering time in Arabidopsis thaliana. Natural loss-of-function mutations in FRI cause the early flowering growth habits of many A. thaliana accessions. To quantify the variation among wild accessions due to FRI, and to identify additional genetic loci in wild accessions that influence flowering time, we surveyed the flowering times of 145 accessions in long-day photoperiods, with and without a 30-day vernalization treatment, and genotyped them for two common natural lesions in FRI. FRI is disrupted in at least 84 of the accessions, accounting for only approximately 40% of the flowering-time variation in long days. During efforts to dissect the causes for variation that are independent of known dysfunctional FRI alleles, we found new loss-of-function alleles in FLC, as well as late-flowering alleles that do not map to FRI or FLC. An FLC nonsense mutation was found in the early flowering Van-0 accession, which has otherwise functional FRI. In contrast, Lz-0 flowers late because of high levels of FLC expression, even though it has a deletion in FRI. Finally, eXtreme array mapping identified genomic regions linked to the vernalization-independent, late-flowering habit of Bur-0, which has an alternatively spliced FLC allele that behaves as a null allele.

Alternative Splicing↗
PubMed2026

Integration of Genome-Wide Association Studies With Single-Cell and Bulk Expression Quantitative Trait Locus to Identify Stroke Susceptibility Genes.

BACKGROUND: Previous studies have integrated genome-wide association studies with expression quantitative trait locus (eQTL) data from bulk tissues to identify stroke susceptibility genes. However, eQTL data exhibit high cell-type specificity, and genetic variants may have distinct effects across stroke subtypes. METHODS: We applied the summary-data-based Mendelian randomization (MR) method to integrate eQTL data from 7 brain cell types with genome-wide association studies data for 5 stroke phenotypes (stroke, ischemic stroke, cardioembolic stroke, large artery stroke, and small vessel stroke). Results were compared with summary-data-based MR using eQTL data from 49 tissues in the Genotype-Tissue Expression project. Robustness of significant single-cell summary-data-based MR associations was assessed via MR and colocalization analyses. Further evaluations included single-cell RNA-seq differential expression, protein-protein interaction, druggability, and phenome-wide association studies. RESULTS: Single-cell summary-data-based MR identified many novel significant genes not detected using bulk tissue eQTL data. Validated associations revealed 2 stroke risk genes (LRCH1, ICA1L), 3 stroke protective genes (AHI1, LYRM9, CENPQ), 2 large artery stroke risk genes (LIPA, ELL), and 1 ischemic stroke protective gene (CENPQ). Single-cell RNA-seq showed significantly increased LIPA expression in mouse stroke samples compared with controls. Protein-protein interaction and druggability analyses, along with phenome-wide association studies, prioritized LIPA and LRCH1 as potential therapeutic targets for stroke while indicating possible adverse effects. CONCLUSIONS: Integrating single-cell eQTL with stroke-subtype genome-wide association studies uncovers novel cell-type-specific causal genes and highlights promising therapeutic targets, advancing understanding of stroke pathogenesis.

Genome-Wide Association Study↗
PubMed2006

Haplotype-based association analysis of 56 functional candidate genes in the IBD6 locus on chromosome 19.

Evidence from four independent linkage studies and two meta-analyses of genome-wide data support the existence of a locus conferring susceptibility to inflammatory bowel diseases (IBD) in chromosomal region 19p. Identification of a susceptibility allele in this approximately 28.5 Mb region with over 600 genes is a formidable task. To tackle this problem, we undertook two approaches: (1) haplotype-based candidate-gene screen, and (2) evaluation of previously reported associations. For the former, we selected genes with potential implication in IBD pathogenesis based on published functional and expression data, typed SNPs, constructed haplotypes, screened for association in 180 IBD trios, and followed up preliminary associations in 343 IBD patients and 207 control individuals. Overall, we analyzed 465 SNPs, and 260 haplotypes distributed across 56 candidate genes. We found suggestive evidence of association (nominal P<0.01) with four genes (C3, FCER2, IL12RB1, and CRLF1) in a screening stage, but were unable to confirm these preliminary observations at follow-up. In the second approach, we typed four nonsynonymous polymorphisms in genes C3 (R102G and L314P) and ICAM1 (G241R and K469E) in four independent cohorts totaling 2178 IBD cases. We evaluated these data together with previously published reports for three of these variants (C3-Gly102, ICAM1-Arg241, and ICAM1-Glu469), in a meta-analysis. Our pooled meta-analysis provides compelling evidence against association of these variants with disease. Overall, we performed the most comprehensive candidate-gene association study for IBD to date. The information hereby generated constitutes a valuable resource to investigate other common genetic immune diseases, such as celiac disease.

Alleles↗
PubMed2005

[Analysis of heading time genotype for a rice photoperiod and thermo--sensitive male sterile line PeiAi64S].

PeiAi64S, a photoperiod and thermo-sensitive genic male sterile, has been wildly applied to hybrid rice seed production in China, but its photoperiod-sensitivity gene for heading date in this sterile line was still unknown. This definitely limited the further use of this sterile line in breeding practice and re-production of hybrid seeds. To solve this problem, using heading time nearly isogenic lines EGO - EG7, ER - LR, T65 - T65m and six heading date QTL-isogenic lines, NIL (Hd1) - NIL (Hd6) with the genes of Nipponbare but Hd1 - Hd6 genes from Kasalath respectively, we performed a genetic analysis of PeiAi64S with special reference to photoperiod-sensitivity loci, in natural long days at Nanjing (32 degrees N) where the average day-length is about 14 h and in natural short days at Linshui county, Hainan province(18 degrees 29'N), where the average day-length is about 11.6 h during the course of rice growing respectively. The F1 and F2 generations from the crosses 'PeiAi64S x heading time nearly isogenic lines' were subjected to genetic analyses. Experimental results showed that PeiAi64S carries photoperiod-sensitivity allele gene E1 and E3 and dominant earliness gene Ef-1 in E1 and E3 and Ef-1 loci, respectively, and a photoperiod insensitivity allele Se-1 degrees in Se-1 locus. Meanwhile, the photoperiod-sensitivity gene E1 and photoperiod-insensitivity gene Se-1e in PeiAi64S were also identified by crossing with the NIL(Hd1) and NIL(Hd4). In addition, a recessive inhibitor for photoperiod-sensitive gene E1 or Se-1(n) and other modified photoperiod-sensitive genes: i-Se-1, E3, Hd3 (En-Se-1), Hd5 and Hd6, were identified in PeiAi64S by crossing with QTL nearly isogenic lines: NIL(Hd2), NIL (Hd3), NIL (Hd5) and NIL( Hd6), The results indicated that the genotype of PeiAi64S's heading date was: E1E1e2e2E3E3Se-1(e)Se-1(e)Ef-1 Ef-1 i-Se-1 i-Se-1.

Breeding↗
PubMed2002

Developmental traits affecting low-temperature tolerance response in near-isogenic lines for the Vernalization locus Vrn-A1 in wheat (Triticum aestivum L. em Thell).

Investigation of low-temperature (LT) tolerance in cereals has commonly led to the region of the vyn-A1 vernalization gene or its homologue in related genomes. Two cultivars, one a non-hardy spring wheat and one a very cold-hardy winter wheat, whose growth habits are determined by the Vrn-A1 (spring habit) and vrn-A1 (winter habit) alleles, were chosen to produce reciprocal near-isogenic lines (NILs). These lines were then used to determine the relationship between rate of phenological development and the degree and duration of LT tolerance gene expression. Each allele was isolated in the genetic backgrounds of the non-hardy spring wheat 'Manitou' and the very cold-hardy winter wheat 'Norstar'. The effects of each allele on phenological development and low-temperature tolerance (LT50) were determined at regular intervals over a 4 degrees C acclimation period of 0-98 d. The vegetative/reproductive transition, as determined by final leaf number (FLN), was found to be a major developmental factor influencing LT tolerance. Possession of a vernalization requirement increased both the length of the vegetative growth phase and LT tolerance. Similarly, increased FLN in spring Norstar and winter Manitou NILs delayed their vegetative/reproductive transition and increased their LT tolerance relative to Manitou. Although the winter Manitou NILs had a lower FLN than the spring Norstar NILs, they were able to extend their vegetative stage to a similar length by increasing the phyllochron (interval between the appearance of successive leaves). Cereal plants have four ways of increasing the length of the vegetative phase, all of which extend the time that low-temperature tolerance genes are more highly expressed: (1) vernalization; (2) photoperiod responses; (3) increased leaf number; and (4) increased length of the phyllochron.

Acclimatization↗
PubMed2003

[Analysis of photoperiod-sensitivity genes in Minghui63, an restorer line of indica rice(Oryza sativa L.)].

Hybrid rice is very important in agriculture production in China. Its selecting property makes it significant to study the genetic performance of F1's date to heading (DH). Minghui63, an indica rice restorer line, has been widdly applied to hybrid rice seed production in China, but the photoperiod-sensitivity gene of heading date in this restorer line is still unknown. This definitely limited the further use of this restorer line in breeding practice and re-production of hybrid seeds. To solve this problem, using heading time nearly isogenic lines EGO-EG7, ER-LR and two heading date QTL-isogenic lines, NIL (Hd1) and NIL (Hd4), with the genes of Nipponbare but Hd1 (Se-1) and Hd4 (E1) genes from Kasalath, respectively, we performed a genetic analysis of Minghui63 with special reference to photoperiod-sensitivity loci, using natural long days in Nanjing(32 degrees N) and natural short days in Linshui county, Hainan province (18 degrees 29'N), where the average day-length is about 14 h and 11.6 h during the course of rice growing, respectively. The F1 and F2 generations from the crosses "heading time nearly isogenic lines x Minghui63" were subjected to genetic analyses. Experimental results showed that Minghui63 carries photoperiod-sensitivity allele gene E1 and E3 in E1 and E3 loci, respectly, and a photoperiod insensitivity allele Se-1e in Se-1 locus, and it also carries a recessive inhibitor for photoperiod-sensitivity gene E1. Meanwhile, the photoperiod-sensitive genes, E1 and the photoperiod-insensitive genes, Se-1e, in Minghui63 were also identified by crossing with the nearly isogenic lines for heading time QTLs, NIL (Hd1) and NIL(Hd4). The results indicated that Minghui63's genotype of heading date was: E1E1e2e2E3E3Se-1eSe-1e. The result from this research indicated that Minghui63 carries a major dominant photoperiod-sensitive gene E1 in E1 locus, and our previous researches indicated that Zhenshan97A carried a major dominant photoperiod-sensitive gene Se-1n in Se-1 locus and a recessive inhibitor gene i-Se-1. The DH of the hybrid rice "Shanyou63" is 94.7 in Nanjing, lying between Zhenshan97A's and Minghui63's, but more nearer to late maturity parent Minghui63. It has been not expressed that E1 gene usually prolongs days to heading by about 20 days when coexisting with Se-1u or Se-1n. This is possibly made by that inhibitor genes exist in respective parents, which make DH transgression of "Shanyou63" not appear. This phenomenon indicated that the heading date of indica hybrid rice is resulted from the interaction among the photoperiod-sensitive genes and their inhibitor genes in the sterile and the restorer lines.

Gene Expression Regulation, Plant↗
PubMed2004

Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene.

Previous quantitative trait loci (QTL) mapping studies document that the distal region of mouse Chromosome (Chr) 1 contains a gene(s) that is in large part responsible for the difference in seizure susceptibility between C57BL/6 (B6) (relatively seizure-resistant) and DBA/2 (D2) (relatively seizure-sensitive) mice. We now confirm this seizure-related QTL ( Szs1) using reciprocal, interval-specific congenic strains and map it to a 6.6-Mb segment between Pbx1 and D1Mit150. Haplotype conservation between strains within this segment suggests that Szs1 may be localized more precisely to a 4.1-Mb critical interval between Fcgr3 and D1Mit150. We compared the coding region sequences of candidate genes between B6 and D2 mice using RT-PCR, amplification from genomic DNA, and database searching and discovered 12 brain-expressed genes with SNPs that predict a protein amino acid variation. Of these, the most compelling seizure susceptibility candidate is Kcnj10. A survey of the Kcnj10 SNP among other inbred mouse strains revealed a significant effect on seizure sensitivity such that most strains possessing a haplotype containing the B6 variant of Kcnj10 have higher seizure thresholds than those strains possessing the D2 variant. The unique role of inward-rectifying potassium ion channels in membrane physiology coupled with previous strong association between ion channel gene mutations and seizure phenotypes puts even greater focus on Kcnj10 in the present model. In summary, we confirmed a seizure-related QTL of large effect on mouse Chr 1 and mapped it to a finely delimited region. The critical interval contains several candidate genes, one of which, Kcnj10, exhibits a potentially important polymorphism with regard to fundamental aspects of seizure susceptibility.

Amino Acid Sequence↗
PubMed2006

Identification of a novel A1v-O1v hybrid allele with G829A mutation in a chimeric individual of AelBel phenotype.

BACKGROUND: Many A and B suballeles responsible for ABO subgroup formation have been identified. Some of these minor alleles have mutations in the ABO gene coding sequence. Most of these mutations are due to single-nucleotide substitution and lead to amino acid alteration. Several alleles at the ABO locus appear to be caused by crossing over between dissimilar alleles. STUDY DESIGN AND METHODS: Blood samples were collected from an individual with AelBel phenotype and her family members. Sequencing of the seven ABO exons was performed on these samples. The following was performed for the samples from the AelBel proposita: cloning and sequencing of the genomic DNA of the ABO gene, reverse transcription-polymerase chain reaction (PCR) analysis of cDNA transcript of the ABO gene, sequence-specific priming (SSP)-PCR analysis and direct sequencing of the ABO gene, SSP-PCR DNA typing of generic HLA-ABC and HLA-DRB, and short-tandem repeat (STR)-PCR typing on 15 autosomal, 2 X-chromosomal, and 6 Y-chromosomal loci. RESULTS: The proposita with AelBel phenotype has blood group chimerism with a major group of A1v-O1v/O1(O01) and a minor group of B(B101)/O1v(O02). Additional haplotypes on HLA-ABC, HLA-DR-B, STR loci, and Y-chromosome STR loci were present on the proposita. The paternal genotype is B(B101)/O1(O01) and the maternal genotype is A1v(A102)/O1v(O02). No other siblings have the A1v-O1v hybrid allele. Parentage was confirmed with the paternity STR-PCR test. Full-length cDNA transcripts of the B(B101) allele and alternately spliced cDNA transcripts of the hybrid A1v-O1v, O(1), and O1v alleles were cloned from the proposita. The A1v-O1v hybrid gene contains two missense mutations: C467T and G829A, resulting in Pro156Leu and Val277Met substitution. CONCLUSION: Formation of the A1v-O1v hybrid allele appears to result from de novo recombination in the germ line of the mother during meiosis. G829A with Val277Met appears to be responsible for the decrease in A-transferase activity and Ael phenotypic expression in the proposita. The chimeric minor population of B(B101)/O1v is responsible for Bel phenotypic expression in the proposita.

ABO Blood-Group System↗