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PubMed2006

Transcriptome profile of macrophages from atherosclerosis-sensitive and atherosclerosis-resistant mice.

We performed a strain intercross between two apoE-deficient mouse strains with a large difference in lesion susceptibility and measured aortic root lesion area in 98 female F(2) progeny. Total RNA was prepared from bone marrow-derived macrophages, and RNA from the five mice with the smallest and largest lesions were used for microarray gene expression profiling. Remarkably, approximately 5% of the 12,288 expressed transcripts were differentially expressed in the atherosclerosis-susceptible and atherosclerosis-resistant bone marrow-derived macrophages (unadjusted p < 0.05), thus defining the transcriptome of macrophages associated with atherosclerosis susceptibility. Using more stringent criteria of twofold or greater change and p < 0.01, 116 and 70 transcripts were overexpressed in lesion-prone and lesion-resistant bone marrow-derived macrophages, respectively. Transcription factor binding site analysis identified two promoter elements that were found more often in the genes overexpressed in the large-lesion group, and one promoter element that was found more often in the small-lesion group. The combination of this expression profiling data with the genetic method of quantitative trait locus mapping should give powerful insights into the genes that affect atherosclerosis susceptibility in mice.

Alternative Splicing↗

PubMed2006

Mind the gap: analysis of marker-assisted breeding strategies for inbred mouse strains.

The development of congenic mouse strains is the principal approach for confirming and fine mapping quantitative trait loci, as well as for comparing the phenotypic effect of a transgene or gene-targeted disruption between different inbred mouse strains. The traditional breeding scheme calls for at least nine consecutive backcrosses before establishing a congenic mouse strain. Recent availability of genome sequence and high-throughput genotyping now permit the use of polymorphic DNA markers to reduce this number of backcrosses, and empirical data suggest that marker-assisted breeding may require as few as four backcrosses. We used simulation studies to investigate the efficiency of different marker-assisted breeding schemes by examining the trade-off between the number of backcrosses, the number of mice produced per generation, and the number of genotypes per mouse required to achieve a quality congenic mouse strain. An established model of crossover interference was also incorporated into these simulations. The quality of the strain produced was assessed by the probability of an undetected region of heterozygosity (i.e., "gaps") in the recipient genetic background, while maintaining the desired donor-derived interval. Somewhat surprisingly, we found that there is a relatively high probability for undetected gaps in potential breeders for establishing a congenic mouse strain. Marker-assisted breeding may decrease the number of backcross generations required to generate a congenic strain, but only additional backcrossing will guarantee a reduction in the number and length of undetected gaps harboring contaminating donor alleles.

Animals↗

PubMed1998

Identification of a RAPD marker linked to progressive rod-cone degeneration in dogs.

Random amplified polymorphic DNA (RAPD) analysis has been used widely in plant and fungi for identification of markers linked to genetic traits and mapping, but its use is limited to identification of intra- and inter-species difference in domestic mammals. We report here identification of a RAPD-derived marker linked to progressive rod-cone degeneration (prcd), an inherited autosomal recessive retinal disease of dogs. A total of 400 standard 10-mer primers were used for amplification by use of DNA samples from normal (+/+) and affected (prcd/prcd) dogs. A single primer was identified which amplified a 1.5-kb DNA fragment only from normal dogs. PCR with longer primers designed from the sequence-characterized amplified region of the 1.5-kb DNA fragment identified a co-dominant multi-allelic polymorphism in the prcd-informative pedigree. Three recombinants were identified among 34 informative offsprings, yielding a LOD score of 5.568 at theta = 0.091. This marker was mapped to two canine-rodent hybrid cell lines in which two genes (canine homologues of human breast cancer 1 susceptibility gene, and cGMP phosphodiesterase gamma-subunit gene), and three anonymous microsatellites have been identified. This is the first reported identification of a RAPD-derived marker with multiple alleles linked to a mammalian disease locus.

Alleles↗

PubMed1998

Inheritance and usefulness of AFLP markers in channel catfish (Ictalurus punctatus), blue catfish (I. furcatus), and their F1, F2, and backcross hybrids.

Eight primer combinations were used to investigate the application of amplified fragment length polymorphism (AFLP) markers in catfish for genetic analysis. Intraspecific polymorphism was low among channel catfish or blue catfish strains. Interspecific AFLP polymorphism was high between the channel catfish and blue catfish. Each primer combination generated from 70 to more than 200 bands, of which 38.6 75.7% were polymorphic between channel catfish and blue catfish. On average, more than 20 polymorphic bands per primer combination were produced as quality markers suitable for genetic analysis. All AFLP markers were transmitted into channel catfish x blue catfish F1 hybrids, except rare markers that were heterozygous in the parents and therefore were segregating in F1 hybrids. The two reciprocal channel catfish x blue catfish F1 hybrids (channel catfish female x blue catfish male; blue catfish female x channel catfish male) produced identical AFLP profiles. The AFLP markers were inherited and segregated in expected Mendelian ratios. At two loci, E8-b9 and E8-b2, markers were found at significantly lower frequencies than expected with F2 and backcross hybrids which had been selected for increased growth rates. The reproducibility of AFLP was excellent. These characteristics of the catfish AFLP markers make them highly useful for genetic analysis of catfish, especially for construction of genetic linkage and quantitative trait loci maps, and for marker-assisted selection.

Animals↗

PubMed1993

Genetic diagnostics in plant breeding: RAPDs, microsatellites and machines.

The science of mapping genetic traits, including those of agronomic interest, is well established and many genetic marker systems are available. However, the application of genetic diagnostics in plant breeding is in its infancy. The sample throughput and cost requirements are very different from those of medical DNA diagnostics. It will be necessary to automate the DNA isolation process, DNA amplification-based allele identification and data handling. Here, we discuss recent progress in the development of molecular technology for plant breeding.

Breeding↗

PubMed2006

Mouse bone marrow and peripheral blood erythroid cell counts are regulated by different autosomal genetic loci.

Erythropoiesis is under fine control and genetic loci that affect it are likely to be important in a range of conditions. To assess the relative contributions of different genetic loci to parameters of erythropoiesis, we have measured RBC counts in the peripheral circulation and committed erythroid cells (RBC and small normoblasts) in the bone marrow in a cohort of (CBA/H x C57BL/6) F2 mice to map quantitative trait loci (QTL). Candidate genes were assessed using bioinformatics and DNA sequencing. Different autosomal loci affect bone marrow (chromosomes 5, 11 and 19) and peripheral blood (chromosome 4) erythroid cell counts but there may be a common chromosome X locus. Spleen weight QTL were found on chromosomes 3, 15 and 17. Surprisingly, erythropoietin (Epo) is the best candidate quantitative trait gene (QTG) in the chromosome 5 locus that affects bone marrow but not peripheral blood erythroid cell counts. Epo gene expression is known to be genetically regulated in mice, but our data suggest a tissue-specific role for epo in mouse erythropoiesis that is also genetically determined. The identity of the other QTG will be important both to further knowledge of the control of erythropoiesis and as potential modifier genes for haematological disorders.

Animals↗

PubMed2005

Genotyping single nucleotide polymorphisms by MALDI mass spectrometry in clinical applications.

Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry has become one of the most powerful and widely applied technologies for SNP scoring and determination of allele frequencies in the post-genome sequencing era. Although different strategies for allele discrimination combined with MALDI were devised, in practice only primer extension methods are nowadays routinely used. This combination enables the rapid, quantitative, and direct detection of several genetic markers simultaneously in a broad variety of biological samples. In the field of molecular diagnostics, MALDI has been applied to the discovery of genetic markers, that are associated with a phenotype like a disease susceptibility or drug response, as well as an alternative means for diagnostic testing of a range of diseases for which the responsible mutations are already known. It is one of the first techniques with which whole genome scans based on single nucleotide polymorphisms were carried out. It is equally well suited for pathogen identification and the detection of emerging mutant strains as well as for the characterization of the genetic identity and quantitative trait loci mapping in farm animals. MALDI can also be used as a detection platform for a range of novel applications that are more demanding than standard SNP genotyping such as mutation/polymorphism discovery, molecular haplotyping, analysis of DNA methylation, and expression profiling. This review gives an introduction to the application of mass spectrometry for DNA analysis, and provides an overview of most studies using SNPs as genetic markers and MALDI mass spectrometric detection that are related to clinical applications and molecular diagnostics. Further, it aims to show specialized applications that might lead to diagnostic applications in the future. It does not speculate on whether this methodology will ever reach the diagnostic market.

Animals↗

PubMed2026

Deep learning and statistical methods identify novel asthma risk variants in Europeans.

BACKGROUND: Asthma is a common heritable respiratory disorder with a complex genetic basis. Although large-scale genome-wide association studies have identified many risk loci, the full spectrum of its polygenic architecture remains to be defined. OBJECTIVE: We refined the genetic landscape of asthma in individuals of European ancestry and improve polygenic risk prediction through statistical and deep learning-based methods. METHODS: We conducted the largest genome-wide association study meta-analysis of asthma in individuals of European ancestry, combining data from the Global Biobank Meta-analysis Initiative (121,940 cases, 1,254,131 controls) and the Million Veteran Program (36,823 cases, 398,278 controls). To enhance discovery, we applied pleiotropy-informed multitrait analysis and conditional false discovery rate approaches, each incorporating eosinophil counts as a secondary trait. In parallel, we used a Transformer-based deep learning framework to further prioritize variants and improve polygenic risk prediction. RESULTS: The meta-analysis identified 69 independent genome-wide significant loci (P < 5 × 10-8) not previously reported in asthma. Multitrait analysis of genome-wide association studies, conditional false discovery rate, and deep learning approaches uncovered additional candidate loci. Functional annotation and expression quantitative trait locus mapping implicated novel genes in immune regulation, airway remodeling, and metabolic processes. Polygenic risk score models derived from deep learning-prioritized variants outperformed those based on conventional genome-wide association study and standard statistical approaches. CONCLUSIONS: Our study yields a comprehensive map of asthma-associated loci in European ancestry populations, improves genetic risk prediction, and informs future mechanistic studies.

Humans↗

PubMed2005

Developing salt-tolerant crop plants: challenges and opportunities.

Soil salinity, one of the major abiotic stresses reducing agricultural productivity, affects large terrestrial areas of the world; the need to produce salt-tolerant crops is evident. Two main approaches are being used to improve salt tolerance: (i) the exploitation of natural genetic variations, either through direct selection in stressful environments or through mapping quantitative trait loci and subsequent marker-assisted selection; and (ii) the generation of transgenic plants to introduce novel genes or to alter expression levels of the existing genes to affect the degree of salt stress tolerance. Here, we discuss the challenges and opportunities provided by recently developed functional tools for the development of salt-tolerant crops.

Adaptation, Physiological↗

PubMed2000

Pharmacogenomics and addiction to opiates.

The risk of initiating and maintaining the use of opiates up to the point of abuse and dependence is to a large degree genetically transmitted and is separate from genetic risk factors for addiction to other drugs of abuse. Pharmacogenetic studies have so far focused on obvious candidate genes that are expected to be involved either in the pharmacokinetics or in the pharmacodynamics of opioids in the mesolimbic reward system of the brain. The few findings of a positive allelic association rarely withstand replication in independent case-control or less stratification-prone family-based association samples. A pharmacogenomic approach in the best sense of the word, however, involves an unbiased, genome-wide, parallel search for risk genes and gene expression patterns. So far, only quantitative trait loci mapping studies of inbred rodent strains and differential expression studies using high-density DNA microarrays fulfill these requirements. The present state of pharmacogenomic and pharmacogenetic studies in animals and humans with respect to opiate addiction is reviewed in this paper.

Animals↗

PubMed1996

Genetic models in the study of anesthetic drug action.

This chapter reviews the use of genetic models in the study of anesthetic drug action. Genetic model systems provide a novel approach to understanding mechanisms of anesthetic drug action. Many models have been derived using selection processes that emphasize differential drug sensitivity, producing animal lines that differ in their CNS drug response. Studies of vertebrate (rodent) and invertebrate (Drosophila, Caenorhabditis elegans) animal model systems are covered. The review discusses studies employing lines derived from spontaneous and induced mutagenic processes, selectively bred lines, and inbred lines possessing inherent differential drug sensitivities. The primary focus of included studies is the general anesthetic drugs that are commonly used in the clinical setting. These are drugs such as the inhalational agents (halothane, enflurane, isoflurane, nitrous oxide) and the intravenous induction agents (propofol and diazepam). Rodent lines with differential sensitivity to opiates are also discussed. Finally, an approach to identifying and isolating the genes that control anesthetic sensitivity is discussed in a section on mapping quantitative trait loci (QTL) in recombinant inbred lines.

Anesthetics↗

PubMed2002

The tau H1 haplotype is associated with Parkinson's disease in the Norwegian population.

We investigated the association of Parkinson's disease (PD) with tau gene H1 haplotypes in the Norwegian population. In a sample of 96 unrelated PD cases and 68 control subjects, we observed an increased risk of PD for persons with the tau H1 haplotype (odds ratio=5.52; 95% confidence interval: 2.64-11.10; P=2.17x10(-6)). Findings provide evidence that tau participates in the PD pathogenic process and demonstrate the value of isolated populations in mapping complex traits.

Adult↗

PubMed2005

Schizophrenia, antipsychotics and diabetes: Genetic aspects.

The relatively high comorbidity of type 2 diabetes and schizophrenia may suggest a shared biological susceptibility to these two conditions. Family studies have demonstrated an increased risk of diabetes in unaffected relatives of patients with schizophrenia, consistent with a heritable susceptibility trait. Linkage analyses have identified several loci that are associated with schizophrenia and some of these, notably those on chromosomes 2p22.1-p13.2 and 6g21-824.1 have also been observed in linkage studies in type 2 diabetes. In addition, the dopamine D5 receptor on chromosome 5 and the tyrosine hydroxylase gene on chromosome 11 have both been suggested as candidate genes in schizophrenia and may also be implicated in susceptibility to poor glycaemic control. In addition, an increased rate of type II diabetes has been observed in some patients treated with antipsychotics. Potential neurochemical substrates of this effect include the histamine H1 receptor, the 5-HT2C serotonin receptor or the beta3 adrenoreceptor. However, the search for a genetic basis to the association between diabetes and schizophrenia is still in its infancy, and much further work needs to be performed, including the systematic screening of all confirmed susceptibility loci and quantitative trait locus mapping of glycaemic control.

Chromosomes, Human, Pair 11↗

PubMed2000

Insulin-like growth factor I and bone: from mouse to man.

Serum insulin-like growth factor I (IGF-I) is regulated by numerous variables, including growth hormone (GH), nutritional status, gonadal steroids and other hormones. However, the circulating IGF-I phenotype is also under heritable regulation, and several genetic determinants may be important in defining tissue-specific expression of the gene encoding this peptide. A very strong correlation has been found between serum IGF-I concentration and bone acquisition in both mice and humans. Based on previous studies as well as ongoing work with mice, it has been hypothesized that regulation of the serum IGF-I phenotype includes non-GH-dependent factors and, furthermore, that these determinants are also involved in the acquisition of bone mass. This paper reports that, by performing intercrosses between two inbred strains of mice of similar age, size and length, but with different serum levels of IGF-I, we have identified regulatory loci for serum IGF-I and established their relationship to putative quantitative trait loci for bone mineral density. Mapping these quantitative trait loci will help refine our understanding of disorders related to IGF-I.

Animals↗

PubMed2003

Polygalacturonase: a candidate gene for the soft flesh and deciduous fruit mutation in Capsicum.

The soft flesh and deciduous fruit of pepper (Capsicum spp.) originated from the wild C. frutescens BG 2816 accession is a complete dominant trait controlled by the S gene. We constructed an F2 population from a cross of BG 2816 (SS) and the bell-type C. annuum cultivar Maor (ss) and determined that S cosegregated with the tomato fruit-specific endo-polygalacturonase (PG) gene. The soft flesh and deciduous fruit phenotypes were observed together in all F2 individuals, indicating a pleiotropic effect of PG on the two traits. We mapped S to pepper chromosome 10 in the region corresponding to that in which PG was previously mapped in tomato. Northern, RT-PCR and western analyses and enzyme activity assays, collectively, indicated that PG is not detected in green, breaker or red fruits of Maor, nor in green fruits of BG 2816. Accumulation of PG mRNA and protein was detected in the fruits of BG 2816, and it increased during ripening from breaker to red stages. The sequence analysis of partial PG cDNA isolated from BG 2816 revealed high homology (87% identity) with the tomato PG. The resemblance of the soft flesh and deciduous fruit phenotypes to PG-associated phenotypes in other fruit crops, the complete linkage between S and PG, and the greater expression of PG in the fruits of BG 2816 than in those of Maor, all strongly indicate that PG is a candidate gene for S.

Capsicum↗

PubMed2005

Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics'.

We combined large-scale mRNA expression analysis and gene mapping to identify genes and loci that control hematopoietic stem cell (HSC) function. We measured mRNA expression levels in purified HSCs isolated from a panel of densely genotyped recombinant inbred mouse strains. We mapped quantitative trait loci (QTLs) associated with variation in expression of thousands of transcripts. By comparing the physical transcript position with the location of the controlling QTL, we identified polymorphic cis-acting stem cell genes. We also identified multiple trans-acting control loci that modify expression of large numbers of genes. These groups of coregulated transcripts identify pathways that specify variation in stem cells. We illustrate this concept with the identification of candidate genes involved with HSC turnover. We compared expression QTLs in HSCs and brain from the same mice and identified both shared and tissue-specific QTLs. Our data are accessible through WebQTL, a web-based interface that allows custom genetic linkage analysis and identification of coregulated transcripts.

Carrier Proteins↗

PubMed2003

A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan.

We conducted a 10 centimorgan (cM) linkage genome scan in a set of American extended pedigrees ascertained through probands with panic disorder. Several anxiety disorders segregate in these families. In this article, we describe results for simple phobia from 14 of these families (including 129 subjects of whom 57 are affected). A total of 422 markers were genotyped. Multipoint lod score analyses (fully parametric and simple parametric models) and nonparametric analyses were completed using ALLEGRO. We observed significant linkage of simple phobia to chromosome 14 markers. The highest lod score under a fully parametric model was 3.17, at marker D14S75, under a dominant model. Under a fully parametric recessive model, the maximum lod score, also at D14S75, was 2.86. Analysis under a simple parametric model resulted in lod scores of 3.70 (dominant model) or 3.30 (recessive model). The highest Zlr score observed was 3.93 (P = 4.1 x 10(-5)). The Zlr score was >1 for an extensive region, >77 cM. In all, 12 of the 14 families studied provided positive or zero lod scores at marker D14S75 (dominant model). The homologous genomic region has been implicated by studies mapping quantitative trait loci for a mouse model of fear. The linkage peak may be regarded as highly promising, owing to the breadth of the peak, the convergence of results under different models of inheritance and different analysis methods, and the support from an animal model. This is the first genome scan linkage study for simple phobia, a common disorder that causes high morbidity in the US population.

Anxiety↗

PubMed2003

Genetic control of susceptibility to bacterial infections in mouse models.

Historically, the laboratory mouse (Mus musculus) has been the experimental model of choice to study pathophysiology of infection with bacterial pathogens, including natural and acquired host defence mechanisms. Inbred mouse strains differ significantly in their degree of susceptibility to infection with various human pathogens such as Mycobacterium, Salmonella, Legionella and many others. Segregation analyses and linkage studies have indicated that some of these differences are under simple genetic control whereas others behave as complex traits. Major advances in genome technologies have greatly facilitated positional cloning of single gene effects. Thus, a number of genes playing a key role in initial susceptibility, progression and outcome of infection have been uncovered and the functional characterization of the encoded proteins has provided new insight into the molecular basis of antimicrobial defences of polymorphonuclear leukocytes, macrophages, as well as T and B lymphocytes. The multigenic control of susceptibility to infection with certain human pathogens is beginning to be characterized by quantitative trait locus mapping in genome wide scans. This review summarizes recent progress on the mapping, cloning and characterization of genes and proteins that affect susceptibility to infection with major intracellular bacterial pathogens.

Agammaglobulinaemia Tyrosine Kinase↗