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PubMed1998

Linkage analysis in tetraploid potato and association of markers with quantitative resistance to late blight (Phytophthora infestans).

We have constructed a partial linkage map in tetraploid potato which integrates simplex, duplex and double-simplex AFLP markers. The map consists of 231 maternal and 106 paternal markers with total map lengths of 990.9 cM and 484.6 cM. The longer of the two cumulative map lengths represents approximately 25% coverage of the genome. In tetraploids, much of the polymorphism between parental clones is masked by 'dosage' which significantly reduces the number of individual markers that can be scored in a population. Consequently, the major advantage of using AFLPs--their high multiplex ratio--is reduced to the point where the use of alternative multi-allelic marker types would be significantly more efficient. The segregation data and map information have been used in a QTL analysis of late blight resistance, and a multi-allelic locus at the proximal end of chromosome VIII has been identified which contributes significantly to the expression of resistance. No late blight resistance genes or QTLs have previously been mapped to this location.

Chromosome Mapping↗

PubMed2004

Use of the Serial Analysis of Gene Expression (SAGE) method in veterinary research: A concrete application in the study of the bovine trypanotolerance genetic control.

New postgenomic biotechnologies, such as transcriptome analyses, are now able to characterize the full complement of genes involved in the expression of specific biological functions. One of these is the Serial Analysis of Gene Expression (SAGE) technique, which consists of the construction of transcripts libraries for a quantitative analysis of the entire gene(s) expressed or inactivated at a particular step of cellular activation. Bioinformatic comparisons in the bovine genomic databases allow the identification of several up- and downregulated genes, expressed sequence tags, and unknown functional genes directly involved in the genetic control of the studied biological mechanism. We present and discuss the preliminary results in comparing the expressed genes in two total mRNA transcripts libraries obtained during an experimental Trypanosoma congolense infection in one trypanotolerant N'Dama animal cow. Knowing all the functional genes involved in the trypanotolerance control will permit validation of some results obtained with the quantitative trait locus approach, to set up specific microarrays sets for further metabolic and pharmacological studies, and to design field marker-assisted selection by introgression programs.

Animals↗

PubMed2002

A quantitative trait locus on chromosome 22 for serum leptin levels adjusted for serum testosterone.

OBJECTIVE: Studies have reported the existence of marked sexual dimorphism in serum leptin levels in humans with women having approximately two to three times the levels of men. We have shown that this sexual dimorphism has a strong genetic component arising from a genotype by sex interaction, but adjusting leptin levels for testosterone eliminates this interaction. Because interactions such as genotype x sex can confound the detection of quantitative trait loci (QTLs), we wanted to determine if there are QTLs associated with the expression of leptin adjusted for testosterone. RESEARCH METHODS AND PROCEDURES: We performed a genome-wide scan using multipoint linkage analysis and implemented a general pedigree-based variance-component approach to identify genes with measurable effects on variation in leptin levels independent of testosterone in 318 Mexican Americans from the San Antonio Family Heart Study. RESULTS: We detected significant evidence of linkage (log of the odds ratio = 3.44) for a QTL on chromosome 22. DISCUSSION: Given these results, we hypothesize that a QTL on chromosome 22 may influence the level of leptin adjusted for testosterone.

Adult↗

PubMed2026

First genomic insights into the introgression of almond PPV-Marcus resistance into peach.

AIM: Sharka, caused by Plum pox virus (PPV), is one of the most damaging viral diseases of stone fruit crops, with peach among the most susceptible cultivated Prunus species. Almond is a promising source of resistance, but its genetic architecture and expression in a peach genetic background remain largely unknown. This study aimed to construct parental genetic linkage maps and identify genomic regions associated with PPV response in almond × peach interspecific populations. METHODS: Progenies derived from the almond cultivars 'Del Cid', 'Garrigues', and 'Mono' were evaluated by RT-PCR after graft inoculation with the PPV-Marcus (PPV-M) strain over consecutive infection cycles. Phenotypic data were summarized for each genotype using best linear unbiased estimates (BLUEs). High-density SNP almond and peach arrays were used to construct parental maps for 'Garrigues' and 'Mono' and perform quantitative trait locus (QTL) analysis. RESULTS: Phenotypic variation was observed among and within families. 'Del Cid'-derived progenies showed the greatest resistance, 'Garrigues'-derived progenies displayed intermediate responses, and 'Mono'-derived progenies showed greater susceptibility and variability. The parental maps covered 546.69 cM in 'Mono' and 521.72 cM in 'Garrigues', with average intervals of 0.61 and 1.26 cM per unique marker position, respectively, and showed strong collinearity with the reference genome. QTL associated with PPV-M response were detected on linkage groups (LG) 1 and 6 in 'Garrigues' and LG2 in 'Mono'. The main QTL in 'Garrigues' peaked near 22.39 Mb on LG1, whereas the 'Mono' QTL was located at 22.27-22.62 Mb on LG2; a weaker QTL was detected near 25.38 Mb on LG6 in 'Garrigues'. The results support a quantitative and genetic-background-dependent architecture of PPV resistance. CONCLUSION: This study provides the first evidence of genomic regions associated with PPV-Marcus response in almond × peach populations. The detected QTLs provide an initial basis to support the introgression of almond-derived resistance into peach breeding material.

Prunus↗

PubMed2002

Congenic mapping of alcohol and pentobarbital withdrawal liability loci to a <1 centimorgan interval of murine chromosome 4: identification of Mpdz as a candidate gene.

Risk for onset of alcoholism is related to genetic differences in acute alcohol withdrawal liability. We previously mapped a locus responsible for 26% of the genetic variance in acute alcohol withdrawal convulsion liability to a >35 centimorgan (cM) interval of murine chromosome 4. Here, we narrow the position of this locus to a <1 cM interval (approximately 1.8 megabase, containing 15 genes and/or predicted genes) using a combination of novel, interval-specific congenic strains and recombinant progeny testing. We report the development of a small-donor-segment congenic strain, which confirms capture of a gene affecting alcohol withdrawal within the <1 cM interval. We also confirm a pentobarbital withdrawal locus within this interval, suggesting that the same gene may influence predisposition to physiological dependence on alcohol and a barbiturate. This congenic strain will be invaluable for determining whether this interval also harbors a gene(s) underlying other quantitative trait loci mapped to chromosome 4, including loci affecting voluntary alcohol consumption, alcohol-induced ataxia, physical dependence after chronic alcohol exposure, and seizure response to pentylenetetrazol or an audiogenic stimulus. To date, Mpdz, which encodes the multiple PSD95/DLG/ZO-1 (PDZ) domain protein (MPDZ), is the only gene within the interval shown to have allelic variants that differ in coding sequence and/or expression. Sequence analysis of 15 standard inbred mouse strains identifies six Mpdz haplotypes that predict three MPDZ protein variants. These analyses, and evidence using interval-specific congenic lines, show that alcohol withdrawal severity is genetically correlated with MPDZ status, indicating that MPDZ variants may influence alcohol withdrawal liability.

Alleles↗

PubMed2026

Multi-omics Mendelian Randomization Prioritizes Neutrophil Extracellular Trap-related Genes Associated with Atrial Fibrillation Risk.

BACKGROUND: Neutrophil extracellular traps (NETs) participate in thrombosis, inflammation, and cardiovascular remodeling, yet whether NET-related genes (NRGs) are associated with atrial fibrillation (AF) risk across multiple molecular layers remains unclear. This study used a multiomics Mendelian randomization framework to prioritize NRGs supported by methylation, expression, and protein quantitative trait loci (QTL) data. METHODS: Genome-wide significant cis instruments (P < 5 × 10-8) were obtained for 90 methylation QTLs (mQTLs), 100 expression QTLs (eQTLs), and 38 protein QTLs (pQTLs) mapped to 137 literature- curated NRG entries. Summary-data-based Mendelian randomization (SMR) coupled with the heterogeneity in dependent instruments (HEIDI) test was applied using whole-blood mQTL data (n = 1,980), eQTLGen blood eQTL data (n = 31,684), and deCODE plasma pQTL data (n = 35,559). AF outcome data were obtained from a meta-analysis including 60,620 cases and 970,216 controls of European ancestry. RESULTS: At the methylation level, 21 CpG-feature associations across 13 genes remained significant after HEIDI filtering and false discovery rate (FDR) correction. Expression-level analysis identified eight significant gene-AF associations, whereas protein-level analysis identified seven significant features representing five unique proteins. Cross-omics integration prioritized C3, MAPK3, and STAT3 as Tier 1 genes, CTSC, LPAR3, and THBD as Tier 2 genes, and fourteen additional genes as Tier 3 candidates. C3 showed risk-increasing protein-level associations together with multiple significant CpG signals, whereas MAPK3 and STAT3 showed directionally protective expression/protein or methylation/protein patterns. DISCUSSION: The cross-omics convergence on C3, MAPK3, and STAT3 is consistent with complement activation, immune-fibrotic signaling, and cytokine-regulatory pathways implicated in AF biology, but the findings should be interpreted as genetic prioritization rather than definitive intervention-ready causality. CpG-level heterogeneity at the C3 locus and the blood/plasma origin of the QTL resources further support a cautious interpretation. Modest colocalization support and the unresolved possibility of pQTL sample overlap further support this cautious, hypothesis-generating interpretation. CONCLUSION: Multi-omics SMR prioritizes C3, MAPK3, and STAT3 as the most consistently supported NET-related genes associated with AF risk. These findings provide a framework for atrialtissue replication and mechanistic validation of NET-related pathways in AF.

Atrial fibrillation↗

PubMed2003

Molecular marker dissection of rice (Oryza sativa L.) plant architecture under temperate and tropical climates.

Rice ( Oryza sativa L.) plants develop vertically with shoot elongation and horizontally with tillering. The purpose of this study was to identify and characterize genomic regions influencing the rice plant architecture by quantitative trait locus (QTL) analysis for the component traits: culm length (CL), panicle length (PnL), panicle number (PnN) and tiller number (TN). For this QTL analysis, 191 recombinant inbred lines (F(7)) derived from a cross of Milyang 23 (M23) and Akihikari (AK) were grown in 1995, 1996 and 1997 (May-Oct) in Joetsu, Japan (temperate climate), and in the 2000 dry season (Jan-Apr), the 2000 wet season (Jun-Oct) and the 2001 dry season in Los Baños, The Philippines (tropical climate). Results showed that rice plant architecture was influenced by 19 genomic regions categorized into five groups. In Group I, two regions (on chrs. 6 and 11) affected shoot elongation (CL and PnL) and tillering (PnN and TN) in opposite directions more significantly in Los Baños than in Joetsu. In Group II, two regions (chrs. 3 and 12) affected shoot elongation, whereas in Group III, five regions [chrs. 1 (two), 2, 3 and 9] affected only culm length (CL). Expressions of four regions of Group III were influenced by either tropical or temperate environments. In Group IV, seven regions (chrs. 1, 2, 4, 5, 6, 8 and 9) controlled panicle development (PnN or PnL), and in Group V, three regions (chrs. 1, 2 and 3) regulated tillering (PnN or TN). Characterizing these 19 genomic regions provided a detailed analysis of rice plant architecture with emphasis on the multiple effect and environmental responsive regions.

Genetic Markers↗

PubMed2005

Activation of the ALT pathway for telomere maintenance can affect other sequences in the human genome.

Immortal human cells maintain telomere length by the expression of telomerase or through the alternative lengthening of telomeres (ALT). The ALT mechanism involves a recombination-like process that allows the rapid elongation of shortened telomeres. However, it is not known whether activation of the ALT pathway affects other sequences in the genome. To address this we have investigated, in ALT-expressing cell lines and tumours, the stability of tandem repeat sequences known to mutate via homologous recombination in the human germline. We have shown extraordinary somatic instability in the human minisatellite MS32 (D1S8) in ALT-expressing (ALT+) but not in normal or telomerase-expressing cell lines. The MS32 mutation frequency varied across 15 ALT+ cell lines and was on average 55-fold greater than in ALT- cell lines. The MS32 minisatellite was also highly unstable in three of eight ALT+ soft tissue sarcomas, indicating that somatic destabilization occurs in vivo. The MS32 mutation rates estimated for two ALT+ cell lines were similar to that seen in the germline. However, the internal structures of ALT and germline mutant alleles are very different, indicating differences in the underlying mutation mechanisms. Five other hypervariable minisatellites did not show elevated instability in ALT-expressing cell lines, indicating that minisatellite destabilization is not universal. The elevation of MS32 instability upon activation of the ALT pathway and telomere length maintenance suggests there is overlap between the underlying processes that may be tractable through analysis of the D1S8 locus.

Cell Line, Tumor↗

PubMed2000

Inheritance and mapping of 2n-egg production in diploid alfalfa.

The production of eggs with the sporophytic chromosome number (2n eggs) in diploid alfalfa (Medicago spp.) is mainly associated with the absence of cytokinesis after restitutional meiosis. The formation of 2n eggs through diplosporic apomeiosis has also been documented in a diploid mutant of M. sativa subsp. falcata (L.) Arcang. (2n = 2x = 16), named PG-F9. Molecular tagging of 2n-egg formation appears to be an essential step towards marker-assisted breeding and map-based cloning strategies aimed at investigating and manipulating reproductive mutants of the M. sativa complex. We made controlled crosses between PG-F9 and three wild type plants of M. sativa subsp. coerulea (Less.) Schm. (2n = 2x = 16) and then hand-pollinated the F1 progenies with tetraploid plants of M. sativa subsp. sativa L. (2n = 4x = 32). As a triploid embryo block prevents the formation of 3x progenies in alfalfa because of endosperm imbalance, and owing to the negligible selfing rate, seed set in 2x-4x crosses was used to discriminate the genetic capacity for 2n-egg production. F1 plants that exhibited null or very low seed sets were classified as normal egg producers and plants with high seed sets as 2n-egg producers. A bulked segregant analysis (BSA) with RAPD (random amplified polymorphic DNA), ISSR (inter-simple sequence repeat), and AFLP (amplified fragment length polymorphism) markers was employed to identify a genetic linkage group related to the 2n-egg trait using one of the three F1 progenies. This approach enabled us to detect a paternal ISSR marker of 610 bp, generated by primer (CA)8-GC, located 9.8 cM from a putative gene (termed Tne1, two-n-eggs) that in its recessive form determines 2n eggs and a 30% recombination genomic window surrounding the target locus. Eight additional RAPD and AFLP markers, seven of maternal, and one of paternal origin, significantly co-segregated with the trait under investigation. The minimum number of quantitative trait loci (QTLs) controlling seed set in 2x-4x crosses was estimated by ANOVA and regression analysis. Four maternal and three paternal independent molecular markers significantly affected the trait. A paternal RAPD marker allele, mapped in the same linkage group of Tne1, explained 43% of the variation for seed set in 2x-4x crosses indicating the presence of a major QTL. A map of the PG-F9 chromosome regions carrying the minor genes that determine the expression level of 2n eggs was constructed using selected RAPD and AFLP markers. Two of these genes were linked to previously mapped RFLP loci belonging to groups 1 and 8. Molecular and genetic evidence support the involvement of at least five genes.

Chromosome Mapping↗

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↗

PubMed2001

Linkage analysis of asthma and atopy including models with genomic imprinting.

Asthma and atopy are two closely related, common complex traits in which a number of genetic and environmental factors are suspected to play a role. We have performed parametric and nonparametric multi-marker linkage analysis for the Busselton data set, which is part of problem 1 of Genetic Analysis Workshop 12. In particular, we have focused on the dichotomous trait atopy, as well as on dichotomized versions of the quantitative traits RASTI and loge slope. The lod score analysis with adequate modeling of a parent-of-origin effect, by use of the program GENEHUNTER-IMPRINTING, was a special interest. The most prominent findings are a multipoint mod score of 3.12 at D13S153 for RASTI, and a multipoint mod score of 4.32 at the same locus for atopy, both with four-penetrance imprinting models that point to a gene subject to maternal imprinting. In addition, there are marked differences between imprinting and non-imprinting mod scores. These results corroborate earlier findings of linkage between atopy and D13S153, but add the aspect of paternal gene expression. Furthermore, suggestive evidence for linkage to atopy is found near D6S291, D7S530, and D14S74. The best-fitting models for chromosome 6 and 14 may suggest that genomic imprinting takes plae at these two loci as well.

Adult↗

PubMed2006

Genetic and structural analysis of the basolateral amygdala complex in BXD recombinant inbred mice.

The amygdala integrates and coordinates emotional and autonomic responses. The genetics that underlie variation in amygdala structure may be coupled to variation in levels of aggression, fear, anxiety, and affiliated behaviors. We systematically quantified the volume and cell populations of the basolateral amygdala complex (BLAc) across 35 BXD recombinant inbred (RI) lines, the parental strains--C57BL/6J (B6) and DBA/2J (D2)--and F1 hybrids (n cases=199, bilateral analysis). Neuron number and volume vary 1.7- to 2-fold among strains (e.g., neuron number ranged from 88,000 to 170,000). Glial and endothelial populations ranged more widely (5- to 8-fold), in part because of higher technical error. A quantitative trait locus (QTL) for the BLAc size is located on chromosome (Chr) 8 near the Large gene. This locus may also influence volume of other regions including hippocampus and cerebellum. Cell populations in the BLAc appear to be modulated more weakly by loci on Chrs 11 and 13. Candidate genes were selected on the basis of correlation with BLAc traits, chromosomal location, single nucleotide polymorphism (SNP) density, and expression patterns in the Allen Brain Atlas. Neurod2, a gene shown to be significant for the formation of the BLAc by knockout studies, is among the candidates genes. Other candidates include Large, and Thra. Responses to drugs of abuse and locomotor activity were the most notable behavioral correlates of the BLAc traits.

Amygdala↗

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↗

PubMed2026

AKR7A3 rs1738023 association with susceptibility to female hepatocellular carcinoma and its role in AFB1 metabolism and tumor.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. In this study, we performed a two-stage exome-chip association analysis and found that the aldo-keto reductase family7 member A3 (AKR7A3) rs1738023 may be a potential susceptibility locus for HCC in females. We aimed to explore its role and mechanism. METHODS: The association between genotype and phenotype was analyzed through GWAS method. The expression of AKR7A3 in cancer tissue and blood analysis by qRT-PCR. The relationship of AKR7A3 and aflatoxin B1 (AFB1) was also analyzed. The effect of AKR7A3 on the biological behavior of HCC cell line was investigated on proliferation and invasion. The potential mechanism was analyzed by transcriptome analysis and western blot. RESULTS: Through genome-wide association analysis (GWAS), AKR7A3 (rs1738023), KIF2C (rs4342887), and CYP3A5 (rs6977165 and rs4646450) were found to be associated with susceptibility to hepatocellular carcinoma (HCC) in women. Further expression quantitative trait loci (eQTL) analysis showed that only AKR7A3 (rs1738023) was significantly associated with gene expression. The expression of AKR7A3 was significantly lower in HCC than adjacent non-tumorous tissues (P < 0.001). The genotype of rs1738023 was significantly associated with AKR7A3 expression (P = 0.0085). Rs1738023[C] genotype had a low AKR7A3 expression level and limited detoxification ability of AFB1. Literature data showed that AKR7A3 is involved in the metabolism of aflatoxin B1 (AFB1). Functional experimental results showed that overexpression of AKR7A3 in the normal liver cell line HL-7702 could significantly reduce AFB1-induced ROS levels and DNA adduct formation, suggesting that it plays a protective role in AFB1 metabolic detoxification. Cell function test showed that overexpression of AKR7A3 inhibit the proliferation, migration and invasion of HCC cells, and block the cell cycle. Transcriptome sequencing and KEGG pathway enrichment analysis revealed that overexpression of AKR7A3 affected the PI3K signaling pathway and led to downregulation of HIF1A and its downstream VEGFA protein expression. The validation results were confirmed in HCC cell lines Huh-7 and SUN-387. CONCLUSION: Overexpression of AKR7A3 contributes to inhibition of HCC progression and reduction of aflatoxin toxicity. AKR7A3 may serve as a potential prognostic and therapeutic target for HCC patients, although further validation is needed.

AKR7A3↗

PubMed2005

A rice quantitative trait locus for salt tolerance encodes a sodium transporter.

Many important agronomic traits in crop plants, including stress tolerance, are complex traits controlled by quantitative trait loci (QTLs). Isolation of these QTLs holds great promise to improve world agriculture but is a challenging task. We previously mapped a rice QTL, SKC1, that maintained K(+) homeostasis in the salt-tolerant variety under salt stress, consistent with the earlier finding that K(+) homeostasis is important in salt tolerance. To understand the molecular basis of this QTL, we isolated the SKC1 gene by map-based cloning and found that it encoded a member of HKT-type transporters. SKC1 is preferentially expressed in the parenchyma cells surrounding the xylem vessels. Voltage-clamp analysis showed that SKC1 protein functions as a Na(+)-selective transporter. Physiological analysis suggested that SKC1 is involved in regulating K(+)/Na(+) homeostasis under salt stress, providing a potential tool for improving salt tolerance in crops.

Base Sequence↗

PubMed2002

Differential conservation of transcriptional domains of mammalian Prophet of Pit-1 proteins revealed by structural studies of the bovine gene and comparative functional analysis of the protein.

The Prophet of Pit-1 (PROP1) gene encodes a paired class homeodomain transcription factor that is exclusively expressed in the developing mammalian pituitary gland. PROP1 function is essential for anterior pituitary organogenesis, and heritable mutations in the gene are associated with combined pituitary hormone deficiency in human patients and animals. By cloning the bovine PROP1 gene and by comparative analysis, we demonstrate that the homeodomains and carboxyl termini of mammalian PROP1 proteins are highly conserved while the amino termini are diverged. Whereas the carboxyl termini of the human and bovine PROP1 proteins contain potent transcriptional activation domains, the amino termini and homeodomains have repressive activities. The bovine PROP1 gene has four exons and three introns and maps to a region of chromosome seven carrying a quantitative trait locus affecting ovulation rate. Two alleles of the bovine gene were found that encode distinct protein products with different DNA binding and transcriptional activities. These experiments demonstrate that mammalian PROP1 genes encode proteins with complex regulatory capacities and that modest changes in protein sequence can significantly alter the activity of this pituitary developmental transcription factor.

Alleles↗

PubMed2002

Combining mapping and arraying: An approach to candidate gene identification.

A combination of quantitative trait locus (QTL) mapping and microarray analysis was developed and used to identify 34 candidate genes for ovariole number, a quantitative trait, in Drosophila melanogaster. Ovariole number is related to evolutionary fitness, which has been extensively studied, but for which few a priori candidate genes exist. A set of recombinant inbred lines were assayed for ovariole number, and QTL analyses for this trait identified 5,286 positional candidate loci. Forty deletions spanning the QTL were employed to further refine the map position of genes contributing to variation in this trait between parental lines, with six deficiencies showing significant effects and reducing the number of positional candidates to 548. Parental lines were then assayed for expression differences by using Affymetrix microarray technology, and ANOVA was used to identify differentially expressed genes in these deletions. Thirty-four genes were identified that showed evidence for differential expression between the parental lines, one of which was significant even after a conservative Bonferroni correction. The list of potential candidates includes 5 genes for which previous annotations did not exist, and therefore would have been unlikely choices for follow-up from mapping studies alone. The use of microarray technology in this context allows an efficient, objective, quantitative evaluation of genes in the QTL and has the potential to reduce the overall effort needed in identifying genes causally associated with quantitative traits of interest.

Analysis of Variance↗

PubMed2005

Gene expression profiling of arthritis using a QTL chip reveals a complex gene regulation of the Cia5 region in mice.

One of the major quantitative trait loci (QTLs) associated with arthritis in crosses between B10.RIII and RIIIS/J mice is the Cia5 on chromosome 3. Early in the congenic mapping process it was clear that the locus was complex, consisting of several subloci with small effects. Therefore, we developed two novel strategies to dissect a QTL: the partial advanced inter-cross (PAI) strategy, with which we recently found the Cia5 region to consist of three loci, Cia5, Cia21 and Cia22, and now we introduce the QTL-chip strategy, where we have combined congenic mapping with a QTL-restricted expression profiling using a novel microarray design. The expression of QTL genes was compared between parental and congenic mice in lymph node, spleen and paw samples in five biological replicates and in dye-swapped experiments at three time points during the induction phase of arthritis. The QTL chip approach revealed 4 genes located in Cia21, differently expressed in lymph nodes, and 14 genes in Cia22, located within two clusters. One cluster contains six genes, differently expressed in spleen, and the second cluster contains eight genes, differently expressed in paws. We conclude the QTL-chip strategy to be valuable in the selection of candidate genes to be prioritized for further investigation.

Animals↗