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PubMed1997

Interval-specific congenic strains (ISCS): an experimental design for mapping a QTL into a 1-centimorgan interval.

A general experimental design that allows mapping of a quantitative trait locus (QTL) into a 1-cM interval is presented. The design consists of a series of strains, termed "interval-specific congenic strains (ISCS)". Each ISCS is recombinant at a specific 1-cM sub-interval out of an ordered set of sub-intervals, which together comprise a wider interval, to which a QTL was previously mapped. It is shown that a specific and previously detected QTL of moderate or even small effect can be accurately mapped into a 1-cM interval in a program involving a total of no more than 1000 individuals. Consequently, ISCS can serve as the ultimate genetic mapping procedure before the application of physical mapping tools for positional cloning of a QTL.

Chromosome Mapping↗

PubMed1998

Linkage mapping of fifty-eight new rat microsatellite markers.

Fifty-eight new anonymous simple sequence repeats (SSR) were generated and mapped to various rat chromosomes. Among them two genes (rat homologs for human cadherin-14 and mouse fibroblast growth factor-related protein) were mapped on Chromosomes (Chrs) 2 and 11 respectively. The majority of markers were generated from a small insert genomic library specific to Chr 11, 13, 14, and 15. Twenty new markers were mapped to Chr 13, which is known to contain a blood pressure quantitative trait locus (QTL). Several approaches to obtain microsatellite markers are described. The protocols and newly generated markers should be useful for ongoing rat genome project.

Animals↗

PubMed1998

The effect of genotype on response thresholds to sucrose and foraging behavior of honey bees (Apis mellifera L.).

Honey bee foragers were tested for their proboscis extension response (PER) to water and varying solutions of sucrose. Returning pollen and nectar foragers were collected at the entrance of a colony and were assayed in the laboratory. Pollen foragers had a significantly higher probability of responding to water and to lower concentrations of sucrose. Bees derived from artificially selected high- and low-pollen-hoarding strains were also tested using the proboscis extension assay. Returning foragers were captured and tested for PERs0 to 30% sucrose. Results demonstrated a genotypic effect on PERs of returnining foragers. The PERs of departing high- and low-strain foragers were consistent with those of returning foragers. The PERs were related to nectar and water reward perception of foragers. High strain bees were more likely to return with loads of water and lower concentrations of sucrose than foragers from low pollen strain. Low-strain bees were more likely to return empty. We identified a previously mapped genomic region that contains a variable quantitative trait locus that appears to influence sucrose response thresholds. These studies demonstrate a gene-brain-behavior pathway that can be altered as a consequence of colony-level selection for quantities of stored food.

Animals↗

PubMed2003

Susceptibility of heat shock protein 70.1-deficient C57BL/6 J, wild-type C57BL/6 J and A/J mice to Trypanosoma congolense infection.

The heat shock protein (HSP) 70.1 gene lies on mouse chromosome 17 among the candidates for Tir1, the major quantitative trait locus associated with response to Trypanosoma congolense infection. To evaluate whether the HSP70.1 gene is involved in the response, we compared the susceptibility of HSP70.1-deficient C57BL/6 J, resistant wild-type C57BL/6 J and susceptible A/J mice. No differences were observed between HSP70.1-deficient and wild-type C57BL/6 J mice in survival time, levels of parasitemia and anemia, suggesting that there is no involvement of the HSP70.1 gene in control of T. congolense infection. The course of infection was markedly different between A/J and C57BL/6 J mice. A/J mice showed a bi-phasic survival pattern, which seemed to be associated with two waves of high parasitemia, but developed only moderate anemia. C57BL/6 J mice controlled parasitemia well but developed severe anemia in the late stage of infection.

Animals↗

PubMed2004

The (GT)n polymorphism and haplotype of the COL1A2 gene, but not the (AAAG)n polymorphism of the PTHR1 gene, are associated with bone mineral density in Chinese.

Collagen type I alpha2 (COL1A2) and parathyroid hormone (PTH)/PTH-related peptide receptor (PTHR1) are two prominent candidate genes for bone mineral density (BMD). To test their importance for BMD variation in Chinese, we recruited 388 nuclear families composed of both parents and at least one healthy daughter with a total of 1,220 individuals, and simultaneously analyzed population stratification, total-family association, and within-family association between BMD at the spine and hip and the (GT)n marker in the intron 1 of the COL1A2 gene and the (AAAG)n marker in the P3 promoter of PTHR1 gene. We also performed these association analyses with haplotypes of the MspI and (GT)n polymorphisms in the COL1A2 gene. Significant within-family association was found between the M(GT)12 haplotype and trochanter BMD (P<0.001). Individuals with this haplotype have, on average, 9.53% lower trochanter BMD than the non-carriers. Suggestive evidence of the within-family association was detected between the (GT)17 allele and BMD at the spine (P=0.012), hip (P=0.011), femoral neck (P=0.032), trochanter (P=0.023), and intertrochanter (P=0.034). The association was confirmed by subsequent permutation tests. For the association, the proportion of phenotypic variance explained by the detected markers ranged from 1.2 to 3.9%, with the highest 3.9% at the trochanter for the M(GT)12 haplotype. This association indicates that there is strong linkage disequilibrium between the polymorphisms (MspI and GT repeat polymorphism) in the COL1A2 gene and a nearby quantitative trait locus (QTL) underlying BMD variation in Chinese, or the markers themselves may have an important effect on the variation of BMD. On the other hand, no significant within-family association, population stratification and total-family association between the PTHR1 polymorphism and BMD were found in our Chinese population.

Adult↗

PubMed2004

Mapping of putative ether-anesthesia resistance gene using C57BL/6J and MSM/Ms mouse strains.

PURPOSE: We attempted to identify the locations of major mouse genes responsible for sensitivity to diethylether (ether) anesthesia, using microsatellite linkage analyses including Quantitative Trait Locus (QTL) analysis. METHODS: To determine the locations of ether anesthesia resistance genes on chromosomes, an ether anesthesia-resistant mouse strain, C57BL/6J (C57BL), and an ether anesthesia-sensitive mouse strain, MSM/Ms (MSM), were used. The sensitivity of mice to ether anesthesia was determined from the latency time required to lose the righting reflex during exposure to 4% ether vapor in air. The (C57BL x MSM) F(1) mice were found to be resistant to ether, showing that the resistant phenotype is genetically dominant. Twelve resistant and 12 sensitive mice were then selected from the 196 backcrossed F(2) mice (F(1) x MSM) at 11-16 weeks of age. Genomic DNA samples were extracted from the tails for mapping ether anesthesia-related genes using microsatellite linkage analyses. RESULTS: One major putative gene related to resistance to ether anesthesia was restricted in the region 23 to 37 cM from the centromere in chromosome 7 by primary and secondary linkage analyses. The QTL analysis narrowed the position of the gene to 29.0 cM, with a maximum logarithm of odds (LOD) score of 3.03, and it was termed Etan1 ( ether-anesthesia 1). CONCLUSION: Microsatellite linkage analyses, including QTL analysis, determined the location of the ether-resistance gene, Etan1, within a narrow range. Our findings should be helpful for further experiments, such as cloning of the gene governing the sensitivity to ether anesthesia in mice.

Anesthesia↗

PubMed2004

Attention-Deficit Hyperactivity Disorder in the post-genomic era.

BACKGROUND: ADHD is a common and complex genetic disorder. Genetic risk factors are expected to be multiple, have small effect sizes when considered individually and to interact with each other and with environmental factors. OBJECTIVE: To describe the difficulties involved in the genetic investigation of such a complex disorder and give a prospective for the future. METHODS: Review based on empirical literature and project description. RESULTS: Considerable progress has been achieved through the association analysis of candidate gene loci. Linkage scans using affected sibling pairs have identified a number of potential loci that may lead to the identification of novel genes of moderate effect size. Quantitative trait locus (QTL) approaches provide powerful complementary strategies that have the potential to link the categorical disorder to continuously distributed traits associated more closely with underlying genetic liability in the general population. Success in identifying some associated genes has been complemented by functional studies that seek to understand the mode of action of such genes. CONCLUSION: Progress in understanding the mechanisms involved has not been straightforward and many inconsistencies have arisen. In order to take advantage of the potential for progress that stems from the genetic findings it will be important to draw upon a variety of approaches and experimental paradigms. A functional genomic approach to ADHD means that investigation of gene function is carried out at various levels of analysis, not only at the level of molecular and cellular function but also at the level of psychological processes, neuronal networks, environmental interactions and behavioural outcomes.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Development of congenic rat strains for alcohol consumption derived from the alcohol-preferring and nonpreferring rats.

A genome scan of the F2 generation from an inbred alcohol-preferring (iP) and inbred alcohol-nonpreferring (iNP) rat cross identified a significant quantitative trait locus (QTL) on chromosome 4 with a lod score of 9.2. To confirm this QTL and to create animals for fine mapping of the QTL region, chromosome 4 reciprocal congenic strains were developed by transferring the chromosome 4 QTL interval into the respective iP or iNP backgrounds. The iP strain was crossed with the iNP strain to create iPiNP F1 animals, which were backcrossed to either iNP or iP animals to produce the N2 generation. Using marker-assisted selection, 10 generations of backcrossing were performed. The selection was followed by an intercross between the N10 animals to produce homozygous animals (N10F1), resulting in the finished congenic strains. Congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP (NP.P) and the iNP chromosome 4 QTL was transferred to the iP (P.NP) exhibited the expected effect on alcohol consumption of the donor strain. Development of these congenic strains further indicates that the chromosome 4 QTL region is, in part, responsible for the disparate alcohol consumption observed between the iP and iNP rats. These congenic animals will be an invaluable resource for fine mapping the QTL region and for the identification of the gene(s) that influences the drinking behavior of the iP and iNP rats.

Alcohol Drinking↗

PubMed2025

Development of recombinant inbred lines and QTL analysis of plant height and fruit shape-related traits in Cucurbita pepo L.

UNLABELLED: Zucchini (Cucurbita pepo subsp. pepo) stands as an economically vital crop in China. In zucchini breeding, plant architectural patterns and fruit morphological characteristics serve as pivotal traits. In this study, we employed quantitative trait locus (QTL) analysis using recombinant inbred lines (RILs) derived from two distinct inbred lines, JinGL (subsp. ovifera) and HM-S2 (subsp. pepo), in conjunction with a high-density genetic map. Our investigation focused on ten QTLs associated with six horticulturally significant traits, including hypocotyl length (HL), plant height (PH), and four fruit-related traits: fruit length (FL), fruit diameter (FD), fruit shape index (FSI), and fruit weight (FW). The QTLs governing HL and PH were mapped to Chr03/LG10 and named qhl3.1 and qph3.1, respectively. The candidate gene Cp4.1LG10g05910/CpDw for qph3.1 was successfully identified. Additionally, three novel QTLs related to fruit size and shape were discovered. Among them, qfsi8.1/qfl8.1, demarcated by Marker238258 and Marker240069 on Chromosome 08/Linkage group 17 (Chr08/LG17), is a new major QTL regulating the fruit shape of zucchini. Through genomic insertion-deletion (InDel) and qRT-PCR analyses, we predicted genes within the qfsi8.1/qfl8.1 candidate interval, uncovering Cp4.1LG17g02030/CpIAA12 and Cp4.1LG17g02010/CpCalB as potential candidate genes. We developed molecular markers tightly linked to qph3.1 and qfl8.1 and validated them in 171 and 224 Cucurbita pepo germplasms, achieving accuracy rates of 96% and 100%, respectively. This study deepens our understanding of the genetic basis of key traits and provides valuable references for molecular breeding in Cucurbita pepo. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11032-025-01592-y.

Cucurbita pepo↗

PubMed2005

Angiogenesis in prolactinomas: regulation and relationship with tumour behaviour.

Tumours are dependent on angiogenesis for growth and inhibition of angiogenesis has become a target for antineoplastic therapy. In the pituitary, unlike other tissues, vascularization is lower in adenomas compared to the normal gland. Despite this finding, a relationship between increased vascularity and several aspects of prolactinoma behaviour such as size, invasiveness, surgical outcome and malignancy, has been demonstrated. The process of angiogenesis is the result of a balance of stimulating and inhibiting factors. It is likely that an interaction between gene expression (such as pituitary tumour transforming gene (PTTG) and a novel gene located within the Edpm5 quantitative trait locus), hormonal stimuli including oestrogens, dopamine, 16 kDa fragments of prolactin and proangiogenic and antiangiogenic growth factors (for example, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2), determine the final angiogenic phenotype of prolactinomas, and thus subsequent tumour behaviour. The elucidation of all the factors involved in the regulation of angiogenesis and their interactions might open new possibilities in the treatment of prolactinomas, especially in those cases with resistance or intolerance to dopamine agonists.

Dopamine↗

PubMedDate not supplied

Linkage mapping for hypertension susceptibility genes.

Several approaches based on linkage methods have been used to identify susceptibility genes for hypertension. Tests of candidate genes for essential hypertension have generally relied on the combination of linkage and association studies, and have given mostly negative or relatively conflicting results between studies. The detailed exploration of a candidate region, eg, a region of human homology to a principal quantitative trait locus for blood pressure variation in the rat, has led to the identification of linkage to a susceptibility locus for hypertension in humans. Studies of rare Mendelian forms of hypertension have enabled us to identify causative genes in several instances, and to detect mere linkages to chromosomal regions in other instances. Whether molecular variants at these genes are pathophysiologically involved in the common form of hypertension remains to be established. Finally, genome-wide linkage studies for essential hypertension are currently in progress. Confirming linkage to particular regions or genes with a high statistical significance in essential hypertension may prove difficult, therefore, other lines of evidence for a particular gene's role in hypertension susceptibility, derived from either studies in animal models, studies of Mendelian forms of hypertension, or from association studies, may prove to be crucial.

Animals↗

PubMed2005

Genetic epidemiology of osteoporosis: past, present, and future.

Research during the past several decades has unequivocally established a role of heredity in the etiology of osteoporosis. Major efforts are currently underway to identify the genes and allelic variants that confer genetic susceptibility to this common and disabling condition. Genome-wide linkage mapping in families, candidate gene association studies in unrelated individuals, and quantitative trait locus mapping in animal models are the primary strategies being used to search for the genetic contributors to osteoporosis. Genome-wide mapping efforts have identified the low-density lipoprotein receptor-related protein 5, bone morphogenetic protein 2, and 15-lipoxygenase as potential susceptibility genes for osteoporosis in the past few years, providing a rich new base for understanding bone biology. Candidate gene association analyses have also provided evidence for a modest role of allelic variants in several additional genes including collagen type Ialpha1, vitamin D receptor, and estrogen receptor-alpha. With the development of a high-density genome-wide polymorphism and haplotype map and continued improvements in high-throughput and cost-effective genotyping technologies, many more genetic contributors to osteoporosis will probably be identified in the near future. The results of this research should facilitate the development of new methods for diagnosing, preventing, and treating the growing clinical and public health problem of osteoporosis.

Animals↗

PubMed1994

Genetic aspects and risk factors in alcoholism and alcoholic liver disease.

There is a great deal of evidence for genetic predisposition to alcoholism; considerably less is known regarding predisposition to alcoholic liver disease. The specific genes involved in either disorder are not well understood, although the enzymes of alcohol metabolism appear to play some role. It will be interesting to determine whether genetic factors that alter the expression of these enzymes, in addition to altering the kinetics of the enzymes, could modify responses to drinking. Work in the next few years will include determination of which responses to alcohol are indeed genetically influenced in twin studies, testing additional candidate genes for alcohol-related traits in populations and families, as well as the application of genomic mapping methodologies to alcoholic pedigrees. The latter strategy will be integrated into the larger number of studies that will grow from the Human Genome Project. Animal studies with selectively bred lines of rodents that differ in voluntary alcohol consumption will lead the way to define the neuronal and behavioral substrates responsible for differences in alcohol-drinking behavior. The use of the quantitative trait locus (QTL) mapping approach in F2 intercross between two inbred strains of rodents with opposite alcohol-response characteristics and in recombinant inbred strains derived from F2 intercross already has and will continue to help identify chromosomal locations of genes relevant to voluntary alcohol consumption. Perhaps in the future selective breeding of rodents and QTL mapping strategies can also be used to determine the biology and genetics of alcohol-induced liver injury.

Adenylyl Cyclases↗

PubMed1995

Chromosomal localization of opioid peptide and receptor genes in the mouse.

Opiate receptors are the primary targets for the drugs of abuse morphine and heroin. In this study, we completed the localization on mouse chromosomes of the genes encoding mu (Oprm) and kappa (Oprk) receptors, as well as the genes for the opioid propeptides proenkephalin (Penk) and prodynorphin (Pdyn). The genetic mapping was performed using a panel of DNA samples from an interspecific cross [C3H/HeJ-gld and (C3H/HeJ-gld x Mus spretus)F1] that has been characterized for more than 800 markers throughout the genome. The genes are localized on mouse Chr 1 (Oprk, 10 cM from the centromere), Chr 2 (Pdyn, 75 cM from the centromere), Chr 4 (Penk, 1 cM from the centromere) and Chr 10 (Oprm, 10 cM from the centromere). Interestingly, the gene for the mu receptor is located in the same region as a Quantitative Trait Locus for high morphine consumption, thus raising the possibility of its direct role in drug abuse mechanisms.

Animals↗

PubMedDate not supplied

Quantitative trait loci associated with brain weight in the BXD/Ty recombinant inbred mouse strains.

Adult C57BL/6J (B6) male mice had 37% heavier brains than did DBA/2J (D2) mice, while their body weights did not differ. The BXD recombinant inbred (RI) series of 20 strains, derived from a cross between B6 and D2 inbred strains, was used as the initial screen to determine significant associations between male brain weight and brain:body weight ratio, with allelic variation at 360 known marker gene loci. For brain weight, this yielded five candidate chromosome regions, each reflecting a possible quantitative trait locus (QTL) site affecting brain weight. The second step was to test as many of these five as possible using standard (non-RI) inbred strain data for brain weight previously reported in the literature. For this purpose, only strains possessing the same alleles as the B6 or D2 strains were used. Sufficient data to test two of the five candidate QTL were available. Of these, one was strongly supported as a site affecting brain weight--the D7rp2 region of chromosome 7. For the brain to body weight ratio, four chromosome regions emerged as significantly associated in the BXD series, but none were amenable to testing due to a lack of allelic information for the standard inbred strains. However, two of these regions showed highly significant associations (p less than 0.001, single test) that merit consideration as QTL sites for future testing. These two are the Hba region on chromosome 11 and the D17Tu7 region on chromosome 17. The genetic correlation between brain and body weight was low (r = 0.28), indicating that these two traits are largely genetically independent in the BXD RI series.

Animals↗

PubMed1993

Sequence and single-base polymorphisms of the bovine alpha-lactalbumin 5'-flanking region.

The alpha-lactalbumin (alpha LA)-encoding gene is a potential quantitative trait locus in dairy animals. In cattle, the production of alpha LA is tightly coupled to the onset of lactation and it serves as a regulatory subunit of the enzyme responsible for lactose synthesis. Lactose is the major osmole controlling water movement in the mammary gland. To better understand the control of bovine alpha LA expression, the 5'-flanking region of a Holstein alpha LA gene was cloned and sequenced. The sequenced clone contains 1952 bp of 5'-flanking region and 66-bp of the protein-coding region. Three single-bp polymorphisms were identified within this region. These polymorphisms occur at positions +15, +21 and +54 relative to the mRNA transcription start point (tsp). The +15 and +21 variations occur in the region encoding the 5'-untranslated region of the mRNA-coding sequence. The +54 polymorphism is a silent mutation in the SP-coding region of the gene. A polymerase chain reaction (PCR, Cetus)-based screening method has been employed to analyze the genotype of cattle at the +15 position. A total of 501 randomly selected cattle from seven breeds were screened for this allele. Of these animals, only the Holstein breed of cattle was found to contain the +15 variation and it occurs at a gene frequency of 32%. Sequence comparisons were conducted between the 5'-flanking regions of the bovine-milk-protein encoding genes, alpha LA, beta-casein and alpha S1-casein, which are coordinately expressed. Regions of similarity extending to 350 bp in length were observed between these sequences.

Animals↗

PubMed2006

Peripheral blood alpha-synuclein mRNA levels are elevated in cynomolgus monkeys that chronically self-administer ethanol.

The gene SNCA (or NACP), which codes for alpha-synuclein, a small synaptic protein involved in dopaminergic neurotransmission, maps to a quantitative trait locus for alcohol preference and is differentially expressed in specific brain regions in alcohol-preferring versus -nonpreferring rats. Moreover, elevated alpha-synuclein messenger RNA (mRNA) and protein levels in peripheral blood have been shown to be associated with craving in patients with alcoholism. The focus of this study was to evaluate gene expression, including the levels of alpha-synuclein mRNA, in peripheral blood in nonhuman primates that were induced to drink ethanol (4 months) and then allowed 14 months of 22-h/day access to ethanol (4% wt/vol) or water compared to alcohol-naïve controls. Differential gene expression, including alpha-synuclein mRNA levels, was measured in 18 cynomolgus macaque monkeys, 8 that had been chronically self-administering ethanol for 18 months and 10 that were alcohol naïve. Cynomolgus monkeys in this study self-administered ethanol at average rates of between 1.2 and 4.2g/kg/day. This group of ethanol-drinking monkeys had a highly significant 3.21-fold higher level of alpha-synuclein mRNA in peripheral blood than alcohol-naïve controls. These data agree with recent reports of elevated alpha-synuclein mRNA and protein in the blood of human alcoholics, support the concept of an association between alpha-synuclein and alcoholism, and demonstrate, for the first time, a biomarker present in rats, monkeys, and humans for the consumption of ethanol.

Alcoholism↗

PubMed2026

Fourier-transform infrared-based genome-wide association study identifies candidate genes and variants for sow colostrum composition.

Sows with high prolificacy and better lactation traits are beneficial for weaned piglet number. Because the genetic basis of sow lactation traits remains elusive, genetic improvement for lactation traits lags behind that for litter traits, constraining the full realisation of genetic potential for large litters. Here, we measured 1 060 Fourier-transform infrared (FTIR) wavenumbers and five predicted colostrum composition traits from sow colostrum samples. Heritability estimates for both the FTIR spectra and predicted traits ranged from moderate to high. Correlation analysis revealed that lactose percentage was negatively genetically correlated with the other four predicted traits (fat percentage, protein percentage, total solid content, and urea nitrogen content) and with 24 h litter weight, which was positively genetically correlated with both protein and total solid content. Genome-wide association studies on the FTIR spectra and predicted traits identified 134 significant single-nucleotide polymorphisms (SNPs) (False discovery rate < 0.05), with most clustering on Sus scrofa chromosomes (SSC) 5 and 7. Among the candidate genes, two expressed in lactating mammary tissue have established roles in milk trait determination: (1) LALBA, which encodes a major colostrum protein and is responsible for lactose synthesis, and (2) BTN1A1, which mediates milk fat secretion. Additionally, the study detected two important candidate variants on SSC7: (1) rs691487382, which was colocalised with the expression quantitative trait locus signal for TRIM26 in the liver, a key metabolic organ supporting lactation, and (2) rs327923027, a missense variant located in a phylogenetically conserved domain of TRIM26, an E3 ubiquitin ligase implicated in liver homeostasis. Taken together, this study identifies, for the first time, candidate genes and variants for sow colostrum, providing genomic markers useful for genetic improvement.

Association analysis↗