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Results for “expression quantitative trait loci”

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PubMed1996

Quantitative trait loci and metabolic pathways: genetic control of the concentration of maysin, a corn earworm resistance factor, in maize silks.

Interpretation of quantitative trait locus (QTL) studies of agronomic traits is limited by lack of knowledge of biochemical pathways leading to trait expression. To more fully elucidate the biological significance of detected QTL, we chose a trait that is the product of a well-characterized pathway, namely the concentration of maysin, a C-glycosyl flavone, in silks of maize, Zea mays L. Maysin is a host-plant resistance factor against the corn earworm, Helicoverpa zea (Boddie). We determined silk maysin concentrations and restriction fragment length polymorphism genotypes at flavonoid pathway loci or linked markers for 285 F2 plants derived from the cross of lines GT114 and GT119. Single-factor analysis of variance indicated that the p1 region on chromosome 1 accounted for 58.0% of the phenotypic variance and showed additive gene action. The p1 locus is a transcription activator for portions of the flavonoid pathway. A second QTL, represented by marker umc 105a near the brown pericarp1 locus on chromosome 9, accounted for 10.8% of the variance. Gene action of this region was dominant for low maysin, but was only expressed in the presence of a functional p1 allele. The model explaining the greatest proportion of phenotypic variance (75.9%) included p1, umc105a, umc166b (chromosome 1), r1 (chromosome 10), and two epistatic interaction terms, p1 x umc105a and p1 x r1. Our results provide evidence that regulatory loci have a central role and that there is a complex interplay among different branches of the flavonoid pathway in the expression of this trait.

Journal Article↗

PubMed2006

Identifying genes associated with a quantitative trait or quantitative trait locus via selective transcriptional profiling.

Genetical genomics is an approach that blends the mapping of quantitative trait loci (QTL) with microarray analysis. The approach can be used to identify associations between the allelic state of a genomic region and a gene's transcript abundance. However, the large number of microarrays required for adequate power results in high material and labor costs that prevent wide adoption of the genetical genomics strategy outside of some well-funded laboratories. We present a method called selective transcriptional profiling that involves selecting an optimal subset of individuals to microarray from a larger set of individuals for which relatively inexpensive quantitative trait and molecular marker data are available. We show how to use microarray data from the selected individuals, along with the trait and marker data from all individuals, to identify genes whose transcript abundance is associated with a quantitative trait of interest through linkage to a trait QTL or correlation with the trait. Our methods for selection and analysis are derived within a missing data framework.

Alleles↗

PubMed2002

An improved genetic model generates high-resolution mapping of QTL for protein quality in maize endosperm.

The genetic mapping of polymorphic markers in a cross between two inbred plant lines has proven to be a powerful method for detecting quantitative trait loci (QTL) underlying complex traits. However, existing methods of QTL mapping were developed for disomic inheritance of both marker and QTL loci in a diploid population. To map QTL influencing traits expressed in the endosperm, a triploid embryo-nourishing tissue resulting from double fertilization, existing QTL mapping models require modification to consider the trisomic inheritance of the endosperm and the generation difference between the mapping population and the endosperm. Such a model requires simultaneous use of two successive generations, which theoretically can lead to an increase in resolution for QTL mapping compared with the use of a single backcross or F(2) generation. Using a newly developed model based on these considerations, we demonstrate the improved resolution of QTL, influencing protein quality traits in maize endosperm. The increased resolution made possible with this approach makes identified QTL accessible to positional cloning.

Chromosome Mapping↗

PubMed1999

Chromosome regions between centromeres and proximal crossovers are the physical sites of major effect loci for yield in potato: genetic analysis employing meiotic mutants.

Meiotic mutant (2n) gametes formed by first-division restitution without crossover (FDR-NCO) are expected to be superior to FDR with crossover (FDR-CO) because they transmit to the progeny, without disruption by recombination, almost 100% of the parental genotype. FDR-CO transfers approximately 80% of the parental heterozygosity and a large fraction of the epistatic interactions. Another genetic expectation associated with both FDR gametes is their equivalence for the phenotypic expression of traits controlled by genes residing between centromeres and proximal crossover sites. This set of unique cytogenetic features of FDR mutants was employed here as a tool to infer physical location of quantitative trait loci controlling total tuber yield (TTY) in potato. Two assays were conducted to verify the superiority of FDR-NCO over FDR-CO gametes for TTY by using progenies from 4x-2x factorial crosses. Male clones were 2n-pollen producers by either FDR-CO or FDR-NCO mechanisms. Compared with the 4x parents, TTY of the progenies ranged from 41% to 175% (i.e., high-parent heterosis). However, no significant TTY differences were observed between FDR-CO and FDR-NCO families. In addition, the size of variance components of males was smaller than females and near zero. Our results reinforce the hypothesis that genes controlling yielding ability have a predominant physical location between centromeres and proximal chiasmata. Quantitative trait loci in chromosome regions with reduced levels of recombination may provide a partial explanation for the slow progress in increasing TTY through conventional 4x-4x crosses and for the often high degree of heterosis obtained by introgressing genetic diversity via 4x-2x crosses in potato.

Journal Article↗

PubMed2003

Dietary fat interacts with QTLs controlling induction of Pgc-1 alpha and Ucp1 during conversion of white to brown fat.

To identify novel regulatory factors controlling induction of the brown adipocyte-specific mitochondrial uncoupling protein (Ucp1) mRNA in the retroperitoneal white fat depot, we previously mapped quantitative trait loci (QTLs) that control this trait to chromosomes 2, 3, 8, and 19. Since the peroxisome proliferator activator receptor-gamma coactivator-1alpha (PGC-1alpha) regulates Ucp1 and other genes of energy metabolism, we have evaluated whether the QTLs controlling Ucp1 mRNA levels also modulate Pgc-1alpha mRNA levels by analysis of backcross progeny from the A/J and C57BL/6J strains of mice. The results indicate that a locus on chromosome 3 orchestrates expression of Pgc-1alpha and Ucp1 in retroperitoneal fat of mice fed a low-fat diet; however, the effect of this locus on Pgc-1alpha is lost, and a significant correlation between Ucp1 and Pgc-1alpha is severely reduced in mice fed a high-fat diet. An additional QTL located on chromosome 5 has also been identified for the selective regulation of Ucp1 mRNA levels. Similar to the effects of a high-fat diet on the chromosome 3 QTL, linkage of the chromosome 5 QTL is also lost in mice on a high-fat diet. Thus dietary fat has a profound influence on PGC-1alpha-regulated pathways controlling energy metabolism in white fat. The allelic variation observed in the regulation of Ucp1 and Pgc-1alpha expression in brown adipocytes of white fat but not interscapular brown fat suggests that fundamentally different regulatory mechanisms exist to control the thermogenic capacities of these tissues.

Adipocytes↗

PubMed2003

FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice.

BACKGROUND & AIMS: Cholesterol gallstone formation is a complex genetic trait. To identify additional cholesterol gallstone susceptibility loci, we performed a quantitative trait locus analysis using an intercross of PERA/Ei and I/LnJ inbred strains of mice. METHODS: Mice of both sexes were examined for gallstone weight and evaluated according to a scoring system for the physical chemistry of cholelithiasis during feeding of a lithogenic diet. Intercross offspring were genotyped, and linkage analysis was performed by interval mapping. Differences in messenger RNA expression of positional candidate genes were determined using reverse-transcription and real-time polymerase chain reaction. RESULTS: We identified significant loci associated with gallstone weight on chromosomes 10 and 4, named Lith7 and Lith8, respectively (both susceptibility alleles conferred by strain I/LnJ). Positional candidate genes with higher expression in I/LnJ mice are Fxr (official symbol, Nr1h4), encoding the nuclear bile salt receptor, on chromosome 10 and Shp1 (official symbol, Nr0b2), encoding the small heterodimer partner 1, on chromosome 4. A significant locus associated with gallstone score on chromosome 17, named Lith9 (susceptibility allele conferred by strain PERA/Ei), colocalizes with the genes Abcg5 and Abcg8 that encode the canalicular cholesterol transporter. Higher hepatic messenger RNA expression of Abcg5 and Abcg8 in strain PERA/Ei correlates positively with higher biliary cholesterol levels. CONCLUSIONS: Our findings suggest a primary role of the nuclear bile salt receptor FXR and the canalicular cholesterol transporter ABCG5/ABCG8 in the genetic susceptibility and pathogenesis of cholesterol cholelithiasis in these strains of inbred mice.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2002

Molecular characterization of the equine AEG1 locus.

Acidic epididymal glycoprotein 1 (AEG1), also called cysteine-rich secretory protein 1 (CRISP1), is a member of the CRISP protein family which is characterized by 16 conserved cysteine residues at the C-terminus. The CRISP proteins are expressed in the male genital tract and are thought to be involved in sperm-egg fusion. Therefore, their genes are of interest as candidate genes for inherited male fertility dysfunctions and as putative quantitative trait loci for male fertility traits. In this report, the cloning and DNA sequence of 90 kb of horse genomic DNA from equine chromosome 20q22 containing the complete equine AEG1 gene are described. The equine AEG1 gene consists of eight exons spanning 31 kb. Analysis of equine AEG1 transcripts did not reveal any evidence for alternative splicing, however three different transcription start sites are used. The first transcription start site is located 20 nt downstream of a TATA box motif. Reverse transcription polymerase chain reaction analysis demonstrated that AEG1 is expressed in different parts of the epididymis, whereas it is hardly detectable in the testis. The naturally occurring diversity of the equine AEG1 gene in different horse breeds was investigated and several polymorphisms are reported, including one that affects the amino acid sequence. Finally, sequence comparisons revealed that the intronless equine PGK2 gene for the testis-specific phosphoglycerate kinase is located approximately 39 kb downstream of AEG1.

5' Flanking Region↗

PubMed2006

QTL analysis of body weight and conformation score in commercial broiler chickens using variance component and half-sib analyses.

The aim of the study was to investigate quantitative trait loci (QTL) in previously identified regions of chicken chromosomes 1, 4 and 5 relating to 40-day body weights and conformation scores. Half-sib (HS) and variance component analyses were implemented and compared using QTL Express software. Data were from a two-generation design and consisted of 100 dam families nested in 46 sire families with trait values for 2,708 offspring. Chicken chromosome 4 showed nominal significance for QTL affecting body weight and conformation, and linkage was confirmed for both traits on chromosome 5. Results varied according to method of analysis and with common parent in the HS method.

Animals↗

PubMed2025

Role of HLA-DRA-CREB3L4 regulatory axis in the pathogenesis of ovarian endometriosis: Inhibition of CREB3L4 expression by HLA-DRA increases the risk of disease.

BACKGROUND: Ovarian endometriosis is a common gynecological condition characterized by the abnormal growth of endometrial-like tissue in locations outside the uterus, and its development remains poorly understood. This study aims to investigate potential protein regulatory networks and assess their impact on disease risk using both protein quantitative trait locus (pQTL) analysis and Mendelian randomization (MR) techniques. METHODS: This study systematically integrates two major genome-wide pQTL databases, UKB-PPP and deCODE, to identify pQTL signals associated with ovarian endometriosis. Additionally, we utilized the GEO database to validate differences in protein expression. We conducted a Mendelian randomization analysis to further explore the regulatory relationships between proteins and their roles in disease development. RESULTS: After the Bonferroni correction, we identified 33 pQTL signals from UKB-PPP and 19 pQTL signals from deCODE. Among these, 8 signals from UKB-PPP and 3 signals from deCODE were validated based on expression differences. The mediation analysis results indicate that HLA-DRA significantly increases the risk of developing ovarian endometriosis by inhibiting the expression of CREB3L4 (with a mediation proportion of 13.99 %), and the direction of the mediation effect is consistent with the total effect. CONCLUSION: This study provides new insights that HLA-DRA downregulates the expression of CREB3L4, which may affect the risk of developing endometriosis. The results provide new evidence for understanding the genetic and molecular basis of ovarian endometriosis and establish a theoretical foundation for the development of future diagnostic markers and targeted treatment strategies.

Humans↗

PubMed2006

Comparative genomics for the investigation of autoimmune diseases.

The complete DNA sequence of the human genome and of several related mammals are now available, due to the investments of enormous resources and advances in sequencing technology. Novel technologies have been developed to compare multiple genomes with each other, thus specifying regions of sequence similarity among mammals and with their pathogens. Larger blocks of sequence similarity (syntenic regions) have been determined and made publicly available. In many ways, novel insights can be gained by such data when combining external genetic or clinical information for these syntenic loci. These novel tools have proven to be successful in inferring functional equivalence between loci of multiple genomes. This review reports on the role of comparative genomics in research on autoimmune diseases, a field with strong dependencies on animal models of human diseases and the problem of an adequate information transfer between multiple organisms and research areas.

Animals↗

PubMed2006

Positional relationships between photoperiod response QTL and photoreceptor and vernalization genes in barley.

Winterhardiness has three primary components: photoperiod (day length) sensitivity, vernalization response, and low temperature tolerance. Photoperiod and vernalization regulate the vegetative to reproductive phase transition, and photoperiod regulates expression of key vernalization genes. Using two barley mapping populations, we mapped six individual photoperiod response QTL and determined their positional relationship to the phytochrome and cryptochrome photoreceptor gene families and the vernalization regulatory genes HvBM5A, ZCCT-H, and HvVRT-2. Of the six photoreceptors mapped in the current study (HvPhyA and HvPhyB to 4HS, HvPhyC to 5HL, HvCry1a and HvCry2 to 6HS, and HvCry1b to 2HL), only HvPhyC coincided with a photoperiod response QTL. We recently mapped the candidate genes for the 5HL VRN-H1 (HvBM5A) and 4HL VRN-H2 (ZCCT-H) loci, and in this study, we mapped HvVRT-2, the barley TaVRT-2 ortholog (a wheat flowering repressor regulated by vernalization and photoperiod) to 7HS. Each of these three vernalization genes is located in chromosome regions determining small photoperiod response QTL effects. HvBM5A and HvPhyC are closely linked on 5HL and therefore are currently both positional candidates for the same photoperiod effect. The coincidence of photoperiod-responsive vernalization genes with photoperiod QTL suggests vernalization genes should also be considered candidates for photoperiod effects.

Alleles↗

PubMed2006

Transcriptional alterations in the left ventricle of three hypertensive rat models.

Left ventricular hypertrophy (LVH) is commonly associated with hypertension and represents an independent cardiovascular risk factor. The aim of this study was to test the hypothesis that the cardiac overload related to hypertension is associated to a specific gene expression pattern independently of genetic background. Gene expression levels were obtained with microarrays for 15,866 transcripts from RNA of left ventricles from 12-wk-old rats of three hypertensive models [spontaneously hypertensive rat (SHR), Lyon hypertensive rat (LH), and heterozygous TGR(mRen2)27 rat] and their respective controls. More than 60% of the detected transcripts displayed significant changes between the three groups of normotensive rats, showing large interstrain variability. Expression data were analyzed with respect to hypertension, LVH, and chromosomal distribution. Only four genes had significantly modified expression in the three hypertensive models among which a single gene, coding for sialyltransferase 7A, was consistently overexpressed. Correlation analysis between expression data and left ventricular mass index (LVMI) over all rats identified a larger set of genes whose expression was continuously related with LVMI, including known genes associated with cardiac remodeling. Positioning the detected transcripts along the chromosomes pointed out high-density regions mostly located within blood pressure and cardiac mass quantitative trait loci. Although our study could not detect a unique reprogramming of cardiac cells involving specific genes at early stage of LVH, it allowed the identification of some genes associated with LVH regardless of genetic background. This study thus provides a set of potentially important genes contained within restricted chromosomal regions involved in cardiovascular diseases.

Animals↗

PubMed2004

[Approach to depressogenic genes from genetic analyses of animal models].

Human depression or mood disorder is defined as a complex disease, making positional cloning of susceptibility genes a formidable task. We have undertaken genetic analyses of three different animal models for depression, comparing our results with advanced database resources. We first performed quantitative trait loci (QTL) analysis on two mouse models of "despair", namely, the forced swim test (FST) and tail suspension test (TST), and detected multiple chromosomal loci that control immobility time in these tests. Since one QTL detected on mouse chromosome 11 harbors the GABA A receptor subunit genes, we tested these genes for association in human mood disorder patients. We obtained significant associations of the alpha 1 and alpha 6 subunit genes with the disease, particularly in females. This result was striking, because we had previously detected an epistatic interaction between mouse chromosomes 11 and X that regulates immobility time in these animals. Next, we performed genome-wide expression analyses using a rat model of depression, learned helplessness (LH). We found that in the frontal cortex of LH rats, a disease implicated region, the LIM kinase 1 gene (Limk 1) showed greatest alteration, in this case down-regulation. By combining data from the QTL analysis of FST/TST and DNA microarray analysis of mouse frontal cortex, we identified adenylyl cyclase-associated CAP protein 1 (Cap 1) as another candidate gene for depression susceptibility. Both Limk 1 and Cap 1 are key players in the modulation of actin G-F conversion. In summary, our current study using animal models suggests disturbances of GABAergic neurotransmission and actin turnover as potential pathophysiologies for mood disorder.

Actins↗

PubMed2002

Identification of multiple genetic loci linked to the propensity for "behavioral despair" in mice.

The forced swim test (FST) and tail suspension test (TST) are widely used and well established screening paradigms for antidepressants. A variety of antidepressive agents are known to reduce immobility time in both FST and TST. To identify genetic determinants of immobility duration in both tests, we analyzed 560 F2 mice from an intercross between C57BL/6 (B6) and C3H/He (C3) strains. Composite interval mapping revealed five major loci (suggestive and significant linkage) affecting immobility in the FST, and four loci for the TST. The quantitative trait loci (QTL) on chromosomes 8 and 11 overlap between the two behavioral measures. Genome-wide interaction analysis, which was developed to identify locus pairs that may contribute epistatically to a phenotype, detected two pairs of chromosomal loci for the TST. The QTL on chromosome 11 and its associated epistatic TST-QTL on chromosome X encode gamma-aminobutyric acid type A (GABA(A)) receptor subunits as candidates. Sequence and expression analyses of these genes from the two parental strains revealed a significantly lower expression of the alpha1 subunit gene in the frontal cortex of B6 mice compared to C3 mice. The present quantitative trait study should open up avenues for identifying novel molecular targets for antidepressants and unraveling the complex genetic mechanisms of depressive and anxiety disorders.

Animals↗

PubMed2007

Genomics of sleep-disordered breathing.

The technologies of genomics and proteomics are powerful tools for discovering novel gene and protein expression responses to disease. Considerable evidence indicates that a genetic basis exists to the causes of sleep-disordered breathing, in particular its most common form of obstructive sleep apnea (OSA), which is characterized by periods of intermittent hypoxia and disrupted sleep. However, the genetic contribution to the pathogenesis of OSA has largely been determined using traditional genetic approaches of family, twin, and linkage studies in clinical populations and quantitative trait loci and targeted gene procedures in animal models of OSA. In contrast to the pathogenesis of OSA, the consequences or sequelae of OSA are highly amenable to genomic and proteomic approaches. Animal studies have assessed changes in gene and protein expression in multiple organ systems in response to intermittent hypoxia and sleep deprivation and uncovered novel gene activation paradigms. The first tentative steps have been made toward applying proteomic analyses of blood and urine from patients with OSA as a potential screening tool for diagnosis in the clinical setting. It is anticipated that genomic and proteomic technologies will become increasingly used in the area of OSA with the unprecedented access to tissue in procedures such as bariatric surgery. OSA represents a severe insult to the oxygenation of tissues and the homeostasis of sleep, and genomic and proteomic approaches hold promise for defining previously unexplored mechanisms and pathways that lead to downstream pathologies, including hypertension, insulin resistance, and neurocognitive dysfunction.

Animals↗

PubMed2004

Analysis of transcripts that are differentially expressed in three sectors of the rice root system under water deficit.

Short periods of water deprivation can stimulate the growth of seminal and lateral roots in rice, and inhibit the emergence of adventitious roots. Identification of genes in the different tissues that respond to a water deficit may help us to understand the mechanism underlying root growth under conditions when water is scarce. cDNA-amplified fragment length polymorphism (AFLP) analysis was used to profile gene expression upon imposition of water deficit in three types of root tissue from the upland rice variety Azucena: seminal root tips, lateral root zones and adventitious root primordial zones. In all, 121 unique transcript-derived fragments (TDFs) were cloned, and Northern analysis was carried out for 30 TDFs to confirm their expression patterns. Sixty-six TDFs were differentially expressed in all three root samples. Four (AC2, D6, L22 and T23) were up-regulated by water deficit in seminal root tips and lateral root zones, and down-regulated in adventitious root primordial zones, an expression pattern which reflects the phenotypic changes observed in the different root sectors. In contrast, T17 and T37 showed the opposite expression pattern in Azucena: up-regulation in adventitious roots and repression in the other two zones. Functions could be assigned to five of these six TDFs on the basis of homology: they encode an expansin (T37), a fruit-ripening protein similar to ASR (T23), submergence-induced protein 2A (T17), a dehydrin (D6) and a 9- cis -epoxycarotenoid dioxygenase1 (L22), respectively. AC2 did not show a significant match to any known gene. Northern analysis showed that these six clones exhibited expression patterns that differed between the two cultivars tested (Azucena and the lowland variety IR1552) with respect to regulation by water limitation. Furthermore, T17, T37, D6 and T23 mapped within intervals known to contain QTLs (quantitative trait loci) for root growth in rice under water deficit. These genes may regulate or co-regulate the growth and development of the three root zones in a tissue-specific manner, and may play a role in the processes that underlie the early changes in root architecture under conditions of water deprivation.

Blotting, Northern↗

PubMed2004

Recent progress in the characterization of molecular determinants in the Xanthomonas axonopodis pv. manihotis-cassava interaction.

Cassava bacterial blight, caused by Xanthomonas axonopodis pv. manihotis (Xam), is a widespread disease that affects cassava (Manihot esculenta Crantz). Studies on the pathogen population structure, pathogen diagnosis, identification and expression of plant genes involved in resistance have been carried out. Different molecular techniques were developed to assess the genetic diversity among the Xampopulations. Characterization of Xam population dynamics over time had enable us to determine the different factors that are associated with resistance breakdown and those that influence the genetic structure or virulence phenotypes of the pathogen's population. Methods for detecting the pathogen in vegetative planting materials and true seeds were developed and contributed to reduce the impact of the disease. To better understand the genetics of resistance a quantitative trait loci (QTLs) approach was developed. Using a PCR-based strategy with degenerate primers we isolated two resistance gene candidates in cassava. We also characterized a region of a chromosome rich in R-gene like sequence. In this review we also report the main results obtained by transcript profiling methodologies, cDNA-AFLP and ESTs developed by the authors to characterize the genes involved in disease resistance. All together these techniques allowed the identification of molecular markers either associated to CBB resistance or that may represent putative genes involved in disease resistance. This article reviews current knowledge on the molecular cassava-Xam interactions.

Chromosome Mapping↗

PubMed2006

Virulence attributes and hyphal growth of C. neoformans are quantitative traits and the MATalpha allele enhances filamentation.

Cryptococcus neoformans is a fungal human pathogen with a bipolar mating system. It undergoes a dimorphic transition from a unicellular yeast to hyphal filamentous growth during mating and monokaryotic fruiting. The traditional sexual cycle that leads to the production of infectious basidiospores involves cells of both alpha and a mating type. Monokaryotic fruiting is a modified form of sexual reproduction that involves cells of the same mating type, most commonly alpha, which is the predominant mating type in both the environment and clinical isolates. However, some a isolates can also undergo monokaryotic fruiting. To determine whether mating type and other genetic loci contribute to the differences in fruiting observed between alpha and a cells, we applied quantitative trait loci (QTL) mapping to an inbred population of F2 progeny. We discovered that variation in hyphal length produced during fruiting is a quantitative trait resulting from the combined effects of multiple genetic loci, including the mating type (MAT) locus. Importantly, the alpha allele of the MAT locus enhanced hyphal growth compared with the a allele. Other virulence traits, including melanization and growth at 39 degrees C, also are quantitative traits that share a common QTL with hyphal growth. The Mac1 transcription factor, encoded in this common QTL, regulates copper homeostasis. MAC1 allelic differences contribute to phenotypic variation, and mac1Delta mutants exhibit defects in filamentation, melanin production, and high temperature growth. Further characterization of these QTL regions will reveal additional quantitative trait genes controlling biological processes central to fungal development and pathogenicity.

Alleles↗