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PubMed2006

In search of new targets for plasma high-density lipoprotein cholesterol levels: promise of human-mouse comparative genomics.

Many lines of evidence suggest that raising plasma high-density lipoprotein cholesterol (HDL-C) levels may inhibit, perhaps even reverse, atherosclerosis. Quantitative trait locus (QTL) analysis has been performed in both humans and mice. So far, approximately 40 high-density lipoprotein (HDL)-regulating QTLs have been identified in each species. To compare human and mouse HDL-C QTLs, we generate human-mouse comparative chromosome maps based on homologous genes in humans and mice. The comparative maps reveal that most human and mouse HDL-C QTLs are concordant, which suggests that identifying the underlying QTL genes in mice will facilitate identifying their homologs in humans. The maps also help to narrow QTLs by mouse-human homologous QTL comparison. By using a combination of classic genetic approaches and newer bioinformatics tools (including comparative genomics as highlighted in this study), identifying new drug targets for plasma HDL-C levels holds more promise than ever.

Animals↗
PubMed2002

[Molecular genetics of cholesterol cholelithiasis: identification of human and murine gallstone genes].

Cholesterol cholelithiasis is one of the most common gastroenterological diseases in Western countries. It is a polygenic disease resulting from disturbed biliary cholesterol homeostasis. Association studies identified six human gallstone candidate genes. Polymorphisms in the genes encoding the apolipoproteins B and E, phospholipid flippase ( ABCB4), cholesterol ester transfer protein ( CETP), cholesterol-7alpha-hydroxylase ( CYP7A1) and ileal bile acid transporter ( SLC10A2) are correlated with gallstone prevalence. Quantitative Trait Locus (QTL) analysis localises additional unknown gallstone genes in inbred mice. Based on the natural variation of cholesterol gallstone susceptibility among different inbred strains, 5 lithogenic ( Lith) loci have been identified. Hepatobiliary transporters (e. g. bile salt export pump Abcb11) and key proteins of the lipoprotein metabolism (e. g. hepatic lipase Lipc) could be established as creedal candidate genes for Lith loci. The rapid progress of mouse and human genome projects provides the basis for the analysis of orthologous human LITH genes in gallstone patients, which might offer new prospects for individual risk assessment and molecular targets for stone prevention.

Animals↗
PubMed2005

Single and interacting QTLs for cholesterol gallstones revealed in an intercross between mouse strains NZB and SM.

Quantitative trait locus (QTL) mapping was employed to investigate the genetic determinants of cholesterol gallstone formation in a large intercross between mouse strains SM/J (resistant) and NZB/B1NJ (susceptible). Animals consumed a gallstone-promoting diet for 18 weeks. QTL analyses were performed using gallstone weight and gallstone absence/presence as phenotypes; various models were explored for genome scans. We detected seven single QTLs: three new, significant QTLs were named Lith17 [chromosome (Chr) 5, peak=60 cM, LOD=5.4], Lith18 (Chr 5, 76 cM, LOD=4.3), and Lith19 (Chr 8, 0 cM, LOD=5.3); two confirmed QTLs identified previously and were named Lith20 (Chr 9, 44 cM, LOD=2.7) and Lith21 (Chr 10, 24 cM, LOD=2.9); one new, suggestive QTL (Chr 17) remains unnamed. Upon searching for epistatic interactions that contributed to gallstone susceptibility, the final suggestive QTL on Chr 7 was determined to interact significantly with Lith18 and, therefore, was named Lith22 (65 cM). A second interaction was identified between Lith19 and a locus on Chr 11; this QTL was named Lith23 (13 cM). mRNA expression analyses and amino acid haplotype analyses likely eliminated Slc10a2 as a candidate gene for Lith19. The QTLs identified herein largely contributed to gallstone formation rather than gallstone severity. Cloning the genes underlying these murine QTLs should facilitate prediction and cloning of the orthologous human genes.

Animals↗
PubMed2004

Quantitative trait analysis reveals transforming growth factor-beta2 as a positive regulator of early hematopoietic progenitor and stem cell function.

Elucidation of pathways involved in mouse strain-dependent variation in the hematopoietic stem cell (HSC) compartment may reveal novel mechanisms relevant in vivo. Here, we demonstrate genetically determined variation in the proliferation of lin-Sca1++kit+ (LSK) primitive hematopoietic progenitor cells in response to transforming growth factor-beta (TGF-beta) 2, the dose response of which was biphasic with a stimulatory effect at low concentrations. In contrast, the dose responses of TGF-beta1 or -beta3 were inhibitory and did not show mouse strain-dependent variation. A quantitative trait locus (QTL) for the effect of TGF-beta2 was identified on chromosome 4 overlapping with a QTL regulating the frequency of LSK cells. These overlapping QTL were corroborated by the observation that the frequency of LSK cells is lower in adult Tgfb2+/- mice than in wild-type littermates, indicating that TGF-beta2 is a genetically determined positive regulator LSK number in vivo. Furthermore, adult Tgfb2+/- mice have a defect in competitive repopulation potential that becomes more pronounced upon serial transplantation. In fetal TGF-beta2-deficient HSCs, a defect only appears after serial reconstitution. These data suggest that TGF-beta2 can act cell autonomously and is important for HSCs that have undergone replicative stress. Thus, TGF-beta2 is a novel, genetically determined positive regulator of adult HSCs.

Animals↗
PubMed2001

The molecular neurobiology of stress--evidence from genetic and epigenetic models.

Knowledge of the genetic and molecular events underlying the neuroendocrine and behavioural sequelae of the response to stress has advanced rapidly over recent years. The response of an individual to a stressful experience is a polygenic trait, but also involves non-genetic sources of variance. Using a combination of top-down (quantitative trait locus [QTL] and microarray analysis) and bottom-up (gene targeting, transgenesis, antisense technology and random mutagenesis) strategies, we are beginning to dissect the molecular players in the mediation of the stress response. Given the wealth of the data obtained from mouse mutants, this review will primarily focus on the contributions made by transgenesis and knockout studies, but the relative contribution of QTL studies and microarray studies will also be briefly addressed. From these studies it is evident that several neuroendocrine and behavioural alterations induced by stress can be modelled in mouse mutants with alterations in hypothalamic-pituitary-adrenal axis activity or other, extrahypothalamic, neurotransmitter systems known to be involved in the stress response. The relative contribution of these models to understanding the stress response and their limitations will be discussed.

Animals↗
PubMed2006

Genomic regulation of natural variation in cortical and noncortical brain volume.

BACKGROUND: The relative growth of the neocortex parallels the emergence of complex cognitive functions across species. To determine the regions of the mammalian genome responsible for natural variations in cortical volume, we conducted a complex trait analysis using 34 strains of recombinant inbred (Rl) strains of mice (BXD), as well as their two parental strains (C57BL/6J and DBA/2J). We measured both neocortical volume and total brain volume in 155 coronally sectioned mouse brains that were Nissl stained and embedded in celloidin. After correction for shrinkage, the measured cortical and noncortical brain volumes were entered into a multiple regression analysis, which removed the effects of body size and age from the measurements. Marker regression and interval mapping were computed using WebQTL. RESULTS: An ANOVA revealed that more than half of the variance of these regressed phenotypes is genetically determined. We then identified the regions of the genome regulating this heritability. We located genomic regions in which a linkage disequilibrium was present using WebQTL as both a mapping engine and genomic database. For neocortex, we found a genome-wide significant quantitative trait locus (QTL) on chromosome 11 (marker D11Mit19), as well as a suggestive QTL on chromosome 16 (marker D16Mit100). In contrast, for noncortex the effect of chromosome 11 was markedly reduced, and a significant QTL appeared on chromosome 19 (D19Mit22). CONCLUSION: This classic pattern of double dissociation argues strongly for different genetic factors regulating relative cortical size, as opposed to brain volume more generally. It is likely, however, that the effects of proximal chromosome 11 extend beyond the neocortex strictly defined. An analysis of single nucleotide polymorphisms in these regions indicated that ciliary neurotrophic factor (Cntf) is quite possibly the gene underlying the noncortical QTL. Evidence for a candidate gene modulating neocortical volume was much weaker, but Otx1 deserves further consideration.

Animals↗
PubMed1999

Bayesian mapping of multiple quantitative trait loci from incomplete outbred offspring data.

A general fine-scale Bayesian quantitative trait locus (QTL) mapping method for outcrossing species is presented. It is suitable for an analysis of complete and incomplete data from experimental designs of F2 families or backcrosses. The amount of genotyping of parents and grandparents is optional, as well as the assumption that the QTL alleles in the crossed lines are fixed. Grandparental origin indicators are used, but without forgetting the original genotype or allelic origin information. The method treats the number of QTL in the analyzed chromosome as a random variable and allows some QTL effects from other chromosomes to be taken into account in a composite interval mapping manner. A block-update of ordered genotypes (haplotypes) of the whole family is sampled once in each marker locus during every round of the Markov Chain Monte Carlo algorithm used in the numerical estimation. As a byproduct, the method gives the posterior distributions for linkage phases in the family and therefore it can also be used as a haplotyping algorithm. The Bayesian method is tested and compared with two frequentist methods using simulated data sets, considering two different parental crosses and three different levels of available parental information. The method is implemented as a software package and is freely available under the name Multimapper/outbred at URL http://www.rni.helsinki.fi/mjs/.

Algorithms↗
PubMed2006

Influence of Slc11a1 on the outcome of Salmonella enterica serovar Enteritidis infection in mice is associated with Th polarization.

Genetic analyses identified Ses1 as a significant quantitative trait locus influencing the carrier state of 129S6 mice following a sublethal challenge with Salmonella enterica serovar Enteritidis. Previous studies have determined that Slc11a1 was an excellent candidate gene for Ses1. Kinetics of infection in 129S6 mice and Slc11a1-deficient (129S6-Slc11a1(tm1Mcg)) mice demonstrated that the wild-type allele of Slc11a1 contributed to the S. enterica serovar Enteritidis carrier state as early as 7 days postinfection. Gene expression profiling demonstrated that 129S6 mice had a significant up-regulation of proinflammatory genes associated with macrophage activation at day 10 postinfection, followed by a gradual increase in immunoglobulin transcripts, whereas 129S6-Slc11a1(tm1Mcg) mice had higher levels of immunoglobulins earlier in the infection. Quantitative reverse transcription-PCR revealed an increase in Th1 cytokine (Ifng and Il12) and Th1-specific transcription factor Tbx21 expression during infection in both the 129S6 and 129S6-Slc11a1(tm1Mcg) strains. However, the expression of Gata3, a transcription factor involved in Th2 polarization, Cd28, and Il4 was markedly increased in Slc11a1-deficient mice during infection, suggesting a predominant Th2 phenotype in 129S6-Slc11a1(tm1Mcg) animals following S. enterica serovar Enteritidis infection. A strong immunoglobulin G2a response, reflecting Th1 activity, was observed only in 129S6 mice. All together, these results are consistent with an impact of Slc11a1 on Th cell differentiation during chronic S. enterica serovar Enteritidis infection. The presence of a Th2 bias in Slc11a1-deficient mice is associated with improved bacterial clearance.

Animals↗
PubMed2003

QTL mapping reveals a two-step model for the evolutionary reduction of inner microsporangia within the asteracean genus Microseris.

The reduction of inner (adaxial) pollen sacs (microsporangia, MS) as a diagnostic character for the three asteracean species, Microseris bigelovii, Microseris elegans and Microseris pygmaea, was analysed in an interspecific cross between Microseris douglasii and Microseris bigelovii with 4 MS and 2 MS, respectively, using the average number of MS per plant as a quantitative character. A previous QTL (Quantitative Trait Locus) analysis had revealed one major QTL (3B) and three modifier QTLs (3A, 4A, 7A) with epistatic effects only on the homozygous recessive 2 MS genotype of QTL 3B. Here we performed a bulked segregant analysis on four 2 MS and four 4 MS DNA-bulks with 407 EcoRI/ MseI AFLP-primer combinations each. In this way additional AFLP markers were mapped close to QTL 3B and QTL 3A. Three of them were converted to SCAR (Sequence Characterized Amplified region) markers. All markers were tested in natural populations of the disporangiate (2 MS) species M. bigelovii, M. elegans and M. pygmaea, and in different populations of tetrasporangiate (4 MS) M. douglasii. The marker distribution suggests that locus 3B mutated in a progenitor of the disporangiate species. QTL 3A has evolved in the 2 MS background of the major gene in the disporangiate species. Since M. pygmaea and M. bigelovii are the sister group to M. elegans, the 4 MS genotype for (markers of) QTL 3A in M. pygmaea populations is most likely due to a back mutation to the 4 MS state and could explain the slight instability of the 2 MS phenotype in this species.

Base Sequence↗
PubMed1997

A variance component approach to dichotomous trait linkage analysis using a threshold model.

We developed and utilized a multipoint variance components method to test for linkage between a disease trait and markers on chromosome 5 in the simulated data provided in GAW10 Problem 2. We demonstrated that the discrete trait variance components method recovers unbiased estimates of quantitative trait locus (QTL) location and reasonable estimates of effect size. We also showed that dichotomization of (a continuous trait such as) Q1 diminished the power to detect linkage compared to direct analysis of Q1, and that extended pedigree analyses provided superior power to detect linkage compared to those in nuclear families.

Analysis of Variance↗
PubMed2005

Pleiotropic effects of the duplicate maize FLORICAULA/LEAFY genes zfl1 and zfl2 on traits under selection during maize domestication.

Phenotypic variation on which selection can act during evolution may be caused by variation in activity level of developmental regulatory genes. In many cases, however, such genes affect multiple traits. This situation can lead to co-evolution of traits, or evolutionary constraint if some pleiotropic effects are detrimental. Here, we present an analysis of quantitative traits associated with gene copy number of two important maize regulatory genes, the duplicate FLORICAULA/LEAFY orthologs zfl1 and zfl2. We found statistically significant associations between several quantitative traits and copy number of both zfl genes in several maize genetic backgrounds. Despite overlap in traits associated with these duplicate genes, zfl1 showed stronger associations with flowering time, while zfl2 associated more strongly with branching and inflorescence structure traits, suggesting some divergence of function. Since zfl2 associates with quantitative variation for ear rank and also maps near a quantitative trait locus (QTL) on chromosome 2 controlling ear rank differences between maize and teosinte, we tested whether zfl2 might have been involved in the evolution of this trait using a QTL complementation test. The results suggest that zfl2 activity is important for the QTL effect, supporting zfl2 as a candidate gene for a role in morphological evolution of maize.

Biological Evolution↗
PubMed2004

Disease-associated qualitative and quantitative trait loci in proteoglycan-induced arthritis and collagen-induced arthritis.

Two autoimmune murine models--proteoglycan (aggrecan)-induced arthritis (PGIA) and collagen-induced arthritis (CIA)--were developed in parent strains, F1 and F2 hybrids of major histocompatibility complex (MHC)-matched (H-2) BALB/c x DBA/2 and MHC-unmatched (H-2/H-2) BALB/c x DBA/1 intercrosses. The major goal of this comparative study was to identify disease (model)-specific (PGIA or CIA) and shared clinical and immunologic loci in 2 types of genetic intercrosses. Qualitative (binary/susceptibility) and quantitative (severity and onset) clinical trait loci were separated and analyzed independently or together with various pathophysiologic/immunologic traits, such as antigen-specific T- and B-cell responses and cytokine production. The major quantitative trait locus (QTL) was the MHC on chromosome 17, which was especially dominant in CIA. In addition, chromosomes 3, 5, 10, and X contained shared clinical loci in both models, and a total of 8 QTLs (clinical traits together with immunologic traits) were colocalized in PGIA and CIA.

Animals↗
PubMed2002

A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility.

Activated protein C resistance (APCR) is the most prevalent risk factor for thrombosis, accounting for 20% to 60% of familial thrombophilia. A mutation in the F5 gene, factor V Leiden (FVL), is a major determinant of pathological APCR in some populations. However, APCR predicts risk for thrombosis independently of FVL. This suggests that other genetic factors may influence risk of thrombosis through quantitative variation in APCR. To search for these unknown loci, we conducted a genome-wide linkage screen for genes affecting normal variation in APCR in the 21 Spanish families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project. Conditional on FVL, the strongest linkage signal for APCR was found on chromosome 18 near D18S53. Bivariate linkage analyses with a genetically correlated trait, levels of clotting factor VIII, strengthened evidence for the chromosome 18 quantitative trait locus (QTL; logarithm of the odds [LOD], 4.5; P = 3.08 x 10(-5)). However, the region on chromosome 1 that contains the F5 structural gene showed little evidence of linkage to APCR (LOD, < 1). This indicates that apart from the FVL, the F5 locus itself plays a relatively minor role in normal variation in APCR, including the HR2 haplotype polymorphisms. A second bivariate analysis of APCR with thrombosis liability suggested that this QTL also influences the risk of thrombosis (P =.0016). These results indicate that a locus on chromosome 18 pleiotropically influences normal variation in the APCR phenotype and factor VIII (FVIII) levels as well as susceptibility to thrombosis. Importantly, there are no known thrombosis-related candidate genes in this region, implying that this QTL represents a completely novel thrombosis risk factor.

Activated Protein C Resistance↗
PubMed2003

Power of QTL detection using association tests with family controls.

The power of testing for a population-wide association between a biallelic quantitative trait locus and a linked biallelic marker locus is predicted both empirically and deterministically for several tests. The tests were based on the analysis of variance (ANOVA) and on a number of transmission disequilibrium tests (TDT). Deterministic power predictions made use of family information, and were functions of population parameters including linkage disequilibrium, allele frequencies, and recombination rate. Deterministic power predictions were very close to the empirical power from simulations in all scenarios considered in this study. The different TDTs had very similar power, intermediate between one-way and nested ANOVAs. One-way ANOVA was the only test that was not robust against spurious disequilibrium. Our general framework for predicting power deterministically can be used to predict power in other association tests. Deterministic power calculations are a powerful tool for researchers to plan and evaluate experiments and obviate the need for elaborate simulation studies.

Analysis of Variance↗
PubMed2001

Modulations in gene expression and mapping of genes associated with cyst nematode infection of soybean.

Infection of the soybean root by the soybean cyst nematode (SCN) (Heterodera glycines Ichinohe) induces a well-documented, yet poorly understood, response by the host plant. The plant response, involving the differentiation of a feeding structure, or "syncytium," facilitates the feeding and reproduction of the nematode to the detriment of the host. We used a genetic system involving a single dominant soybean gene conferring susceptibility to an inbred nematode strain, VL1, to characterize the nematode-host interaction in susceptible line PI 89008. The restriction fragment length polymorphism marker pB053, shown to map to a major SCN resistance locus, cosegregates with resistance among F2 progeny from the PI 89008 x PI 88287 cross. Cytological examination of the infection process confirmed that syncytium development in this genetic system is similar to that reported by others who used noninbred nematode lines. Our study of infected root tissue in the susceptible line PI 89008 revealed a number of genes enhanced in expression. Among these are catalase, cyclin, elongation factor 1alpha, beta-1,3-endoglucanase, hydroxy-methylglutaryl coenzyme A reductase, heat shock protein 70, late embryonic abundant protein 14, and formylglycinamidine ribonucleotide synthase, all of which we have genetically positioned on the public linkage map of soybean. Formylglycinamidine ribonucleotide synthase was found to be tightly linked with a major quantitative trait locus for SCN resistance. Our observations are consistent with the hypothesis proposed by others that feeding site development involves the dramatic modulation of gene expression relative to surrounding root cells.

Animals↗
PubMed2006

Genome-wide search for nevus density shows linkage to two melanoma loci on chromosome 9 and identifies a new QTL on 5q31 in an adult twin cohort.

The density of acquired melanocytic nevi represents an important risk factor for malignant melanoma. Total body nevus counts were collected in a cross-sectional study of 1730 healthy females from the UK Adult twin registry comprising 709 dizygous and 156 monozygous pairs. Nevus density (ND) increased up to the age of 35 years and then gradually declined. Quantitative genetic analysis showed a smaller genetic influence (36%) on ND up to 35 years, compared with after 35 years where it rose to 59%. Using a sub-sample of 1238 genotyped individuals, we performed distinct genome-wide scans for individuals above and below 35 separately. In the younger sub-sample, we confirmed a quantitative trait locus (QTL) for ND on chromosomes 9p21 (LOD=2.54), a region already linked to both familial melanoma and ND. We also observed a linkage signal on 9q21 (LOD=2.55) overlapping a recently reported susceptibility locus for ocular and cutaneous melanoma in Danish families. The strongest evidence of linkage identified a novel QTL on chromosome 5q31-32 (LOD=3.47). None of these linkages was observed in the group aged 35 years and over, which showed suggestive linkage on chromosome 2p24 (LOD=2.75). To the best of our knowledge, this is the first genome-wide search for ND in a large sample of healthy adults. The results suggest that different sets of genes are likely to influence the processes leading to the appearance of nevi and their involution. They provide both novel and replicated QTLs for nevus development, some of which might overlap with those for melanoma and warrant detailed investigation.

Adult↗
PubMed2006

Of flies and man: Drosophila as a model for human complex traits.

Understanding the genetic and environmental factors affecting human complex genetic traits and diseases is a major challenge because of many interacting genes with individually small effects, whose expression is sensitive to the environment. Dissection of complex traits using the powerful genetic approaches available with Drosophila melanogaster has provided important lessons that should be considered when studying human complex traits. In Drosophila, large numbers of pleiotropic genes affect complex traits; quantitative trait locus alleles often have sex-, environment-, and genetic background-specific effects, and variants associated with different phenotypic are in noncoding as well as coding regions of candidate genes. Such insights, in conjunction with the strong evolutionary conservation of key genes and pathways between flies and humans, make Drosophila an excellent model system for elucidating the genetic mechanisms that affect clinically relevant human complex traits, such as alcohol dependence, sleep, and neurodegenerative diseases.

Animals↗
PubMed2002

Congenic mapping of a blood pressure QTL on chromosome 16 of Dahl rats.

A Chromosome (Chr) 16 segment of the Dahl salt-sensitive (S) rat was shown by linkage to contain a blood pressure (BP) quantitative trait locus (QTL). To verify and further narrow down the region harboring the QTL, we made two congenic strains by replacing two segments of the S rats with the homologous segments of the Lewis (LEW) rats. The construction of these congenic strains was facilitated by a genome-wide marker screening. The two congenic strains contained a segment in common, and BPs of both were significantly lower than that of the S strain. Consequently, a BP QTL could be localized to the overlapping region of about 49.4 centiRay (cR) including the telomere on a radiation hybrid map. Heart weights, left and right ventricular weights, kidney weights, and aortic weights over length were all significantly decreased in the congenic strains compared with the S strain. Thus, there appeared to exist an association between the effects of the QTL on BP and on cardiac, renal, and vascular hypertrophy.

Animals↗