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PubMed2006

A novel nuclear-encoded mitochondrial poly(A) polymerase PAPD1 is a potential candidate gene for the extreme obesity related phenotypes in mammals.

People with obesity, especially extreme obesity, are at risk for many health problems. However, the responsible genes remain unknown in >95% of severe obesity cases. Our previous genome-wide scan of Wagyu x Limousin F2 cattle crosses with extreme phenotypes revealed a molecular marker significantly associated with intramuscular fat deposition. Characterization of this marker showed that it is orthologous to the human gene KIAA1462 located on HSA10p11.23, where a major quantitative trait locus for morbid obesity has been reported. The newly identified mitochondrial poly(A) polymerase associated domain containing 1 (PAPD1) gene, which is located near this marker, is particularly interesting because the polymerase is required for the polyadenylation and stabilization of mammalian mitochondrial mRNAs. In the present study, both cDNA and genomic DNA sequences were annotated for the bovine PAPD1 gene and ten genetic markers were detected in the promoter and exon 1 region. Among seven markers assayed on approximately 250 Wagyu x Limousin F2 animals, two single nucleotide polymorphisms (SNPs) in the promoter region were significantly associated with intramuscular fat (P<0.05). However, there was a significant interaction (P<0.05) between a third SNP, which causes an amino acid change in coding exon 1, and each of these two promoter SNPs on intramuscular fat deposition. In particular, the differences between double heterozygous animals at two polymorphic sites and the slim genotype animals exceeded 2.3 standard deviations for the trait in both cases. Our study provides evidence for a new mechanism--the involvement of compound heterosis in extreme obesity, which warrants further examination.

Adipose Tissue↗
PubMed1999

Mild association between the A/G polymorphism in the promoter of the apolipoprotein A-I gene and apolipoprotein A-I levels: a meta-analysis.

A polymorphism caused by a G-to-A substitution in the promoter area (-75 bp) of the apolipoprotein AI (apo A-I) bene is common in the general population. Several studies have investigated its association with apo A-I levels, but the results were conflicting. Here, we undertook meta-analyses to increase the statistical power to further detect this association. Meta-analyses were first performed for each gender and then on the combined data. The overall sample in this meta-analysis included over 3,000 healthy individuals. Results from healthy individuals suggest that the rare allele A is associated with mildly increased apo A-I levels by about 5 mg/dl (95% CI 2.84 - 6.94). This association is weaker among healthy females than males. The present study cannot determine whether this small but significant association was due to a small genetic effect of the A/G polymorphism, or whether the A/G polymorphism is in linkage disequilibrium with a true mutant allele at a quantitative trait locus controlling apo A-I levels. Although smoking status may interact with genotypes, only three studies investigated this interaction and thus no conclusion could be drawn in this regard.

Adolescent↗
PubMed2000

Physical localization of single-copy sequences on pachytene chromosomes in maize (Zea mays L.) by chromosome in situ suppression hybridization.

A new approach for locating single-copy DNA sequences on pachytene chromosomes of maize (Zea mays L.) was developed. A cosmid clone with homologous sequences to a molecular marker (umc105a) linked to a quantitative trait locus (QTL) for resistance against sugarcane borer (SCB) was physically mapped by fluorescence in situ hybridization (FISH) to the short arm of chromosome 9. The marker umc105a was genetically placed in the centromeric region. To suppress signals generated by maize repetitive DNA, competitive in situ suppression (CISS) hybridization was necessary to obtain specific signals from umc105a. A centromere specific DNA probe (CentC) was used in a double-labeling technique as a reference marker. Fluorescence signals generated by umc105a cosmid and CentC were specific and highly reproducible. Thus the single-copy DNA sequence of umc105a was physically localized on the short arm of chromosome 9 near the telomere. This is the first report of physical localization of single-copy DNA sequence by CISS hybridization to a maize pachytene chromosome.

Chromosome Mapping↗
PubMed2001

Molecular genetics of salt-sensitivity and hypertension.

For the past decade, hypertension research has shifted strongly in the direction of molecular genetics. The success stories are the monogenic hypertensive syndromes. Classic linkage analyses have located the responsible genes for glucocorticoid-remediable aldosteronism, Liddle syndrome, and apparent mineralocorticoid excess. Furthermore, a recent gain-of-function mutation has recently been described in the gene for the mineralocorticoid receptor. These genes have been cloned and their functions elucidated. Other monogenic syndromes are currently being intensively studied. However, in the area of primary hypertension, the successes have relied on the candidate gene approach. Allelic variants in the genes for angiotensinogen, alpha-adducin, the beta2-adrenergic receptor, the G-protein beta3-subunit, and the T594M mutation in the beta-subunit of the epithelial sodium channel have been identified; however, the importance of these allelic variants to primary hypertension as a whole is not yet clear. Recently, an association approach was employed to implicate the mineralocorticoid receptor gene in salt-sensitivity. Linkage approaches have been attempted and the beta-subunit of the epithelial sodium channel has been linked to hypertension and to blood pressure as a quantitative trait locus. New approaches are necessary to elucidate salt-sensitive hypertension. The analysis of multiple genes simultaneously in terms of a metabolic control analysis may provide a more promising approach.

Genetic Predisposition to Disease↗
PubMed2002

Animal models for the genetic study of human alcohol phenotypes.

Researchers are increasingly using animal models to study the genetic basis of complex human behaviors, such as alcoholism. The most commonly used animal species are rodents, but other species, such as nonhuman primates, fruit flies, and zebrafish, can also provide important information. A variety of approaches are employed in these studies, particularly knockout and transgenic mice as well as specially bred animal lines that can be used for various genetic analyses, including quantitative trait locus mapping. Other strategies applied in genetic studies in animal models include random mutagenesis, virus-mediated gene transfer, and gene expression profiling.

Alcoholism↗
PubMed2001

Genetic verification of the role of CCK-AR in pancreatic proliferation and blood glucose and insulin regulation using a congenic rat carrying CCK-AR null allele.

A number of studies have indicated that cholecystokinin type A receptor (CCK-AR) plays a crucial role in postnatal pancreatic proliferation and blood glucose regulation through stimulating insulin secretion. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat has been shown to possess poor pancreatic proliferation (PPP) capability after pancreatectomy (Px). Here we have constructed a congenic strain which introgressed an OLETF-derived 18.5 cM genomic fragment identified in our previous quantitative trait locus (QTL) analysis as a locus responsible for PPP into normoglycemic F344 genetic background The introgressed region includes CCK-AR null mutation. After Px, the congenic rat showed weak pancreatic proliferation equivalent to that of the OLETF rat. Furthermore, post-surgery non-fasting blood glucose levels for the congenic rats are significantly higher in comparison with the F344 rats. At 28 days after Px, the congenic rats also showed lower blood insulin levels than the F344 rats. These results further provide the genetic evidence that 1) CCK-AR is essential for pancreatic regeneration; 2) impaired pancreatic proliferation mediates the development of hyperglycemia.

Alleles↗
PubMed2002

Genetic regulation of bone mineral density in mice.

Peak bone mass is a major determinant of risk of osteoporotic fracture. Family and twin studies have found a strong genetic component to the determination of bone mineral density (BMD). However, BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. The number, locations and effects of the individual genes contributing to natural variation in this trait are all unknown. The extreme difficulty of dissecting out environmental factors from genetic ones in humans has motivated the investigation of animal models. Genetically distinct animal strains raised under strict environmental control are critical tools for defining genetic regulation. The availability of inbred strains, combined with its relative fecundity, has established the mouse as the best model system for the study of mammalian genetics and physiology. Importantly, genes identified in murine analyses can usually be readily mapped to particular human chromosomal regions because of the high degree of synteny that exists between the mouse and human genomes. We employed quantitative trait locus (QTL) analysis to examine peak BMD in 24 recombinant inbred (RI) mouse strains, derived from a cross between C57BL/6 (B6) and DBA/2 (D2) progenitors (BXD RI). The distribution of BMD values among these strains clearly indicated the presence of strong genetic influences, with an estimated narrow sense heritability of 35%. The differences in peak whole body BMD in the BXD strains were integrated with a large database of genetic markers previously defined in the RI BXD strains to generate chromosome map sites for QTL locations. This QTL analysis provisionally identified a number of chromosomal sites linked to BMD. In the second phase of our BMD QTL mapping efforts, we used three independent mouse populations (all derived from B6 and D2 progenitor strains) to confirm and narrow the genetic locations of 4 QTLs (on chromosomes 1, 2, 4, and 11) that strongly influence the acquisition of peak BMD in mice. Using a novel, fine-mapping approach (recombinant inbred segregation testing), we have succeeded in narrowing two of the BMD-related chromosomal regions and in the process eliminated a number of candidate genes. The homologous regions in the human genome for each of these murine QTLs have been identified in recent human genetic studies. In light of this, we believe that findings in mice should aid in the identification of specific candidate genes for study in humans.

Journal Article↗
PubMed2003

[Molecular epidemiology of osteoporosis].

Recently, molecular epidemiological studies have been performed in order to identify genetic factors associated with osteoporosis. Linkage analysis and association study are useful methods in molecular epidemiology. Quantitative trait locus (QTL) analysis, an effective technique of linkage analysis has been performed for loci linked to bone mineral density (BMD). Association studies between bone mass and a number of polymorphisms in candidate genes were carried out, including vitamin D receptor (VDR) gene. However, one problem has been poor reproducibility of the results. Genome-wide linkage screens with a dense set of single nucleotide polymorphism (SNP) markers are currently being conducted.

English Abstract↗
PubMed2005

Association of ACE polymorphisms with left ventricular hypertrophy.

The angiotensin converting enzyme gene (ACE) is a candidate gene for an individual's genetic susceptibility to left ventricular hypertrophy (LVH). LVH has long been thought to be an end point of essential hypertension (EH), rather than a separate entity, though it is influenced by a unique set of hormonal, vascular and genetic factors. In this study, we attempted to determine whether two representative polymorphisms of the ACE gene, ACE I/D and 2350 G>A, known to be associated with EH and to influence plasma ACE levels most significantly, could implicate ACE as a quantitative trait locus (QTL) for LVH. We carried out a retrospective, case-control study of the two ACE polymorphisms amongst 180 nationals (50 LVH patients and 130 controls) from the United Arab Emirates--an ethnic group characterized by no alcohol intake and no cigarette smoking--for correlations with LVH. Clinical diagnosis of LVH was based on echocardiographic and ECG criteria. ACE I/D and 2350 G>A genotypes were determined by PCR and restriction digestion. Univariate and multivariate logistic regression analyses revealed an association between ACE polymorphisms and LVH. Haplotype analysis further supported this finding. ACE I/D and ACE 2350 G>A polymorphisms are in strong linkage disequilibrium and are associated with LVH, suggesting that ACE is likely to be a QTL for LVH.

Adult↗
PubMedDate not supplied

The search for human osteoporosis genes.

Osteoporosis is the most prevalent metabolic bone disease and a major clinical and public health problem. Heredity plays an important and well-established role in determining the lifetime risk of this disease. Major efforts are currently underway to identify the specific genes and their allelic variations that contribute to the heritable component to osteoporosis. A number of laboratories are using quantitative trait locus (QTL) methods of genome scanning in families and animal models to identify candidate genomic regions and, ultimately, the genes and genetic variations that lead to osteoporosis. Several chromosomal regions of the human genome have now been linked to osteoporosis-related phenotypes. Although the specific genes contributing to the majority of these linkage signals have not been identified, two positional candidate genes have now been identified: low density lipoprotein receptor-related protein 5 (LRP5) and bone morphogenetic protein 2 (BMP2). A number of QTL has also been identified by cross-breeding strains of mice with variable bone density and several of these QTL have been fine mapped, providing a rich new base for understanding osteoporosis. Genetic association analyses have also provided evidence for a modest relationship between allelic variants in several biological candidate genes and bone mass and the risk of fracture. These ongoing animal and human studies will provide a continuing source of new insight into the genetic regulation of bone and mineral metabolism and the molecular etiology of osteoporosis. The new insight that will emerge from this ongoing research should lead to new ways of diagnosing, preventing and treating the growing clinical and public health problem of osteoporosis.

Animals↗
PubMed1994

A multivariate analysis of repeated measures: linkage of the albinism gene (Tyr) to a QTL influencing ethanol-induced anesthesia in laboratory mice.

We propose the use of multivariate analysis of variance in order to address linkage relationships between a genetic marker and a phenotype that is specified by multiple variables. Moreover, enhanced power of a linkage model that simultaneously accounts for environmental factors is demonstrated in the present study. This strategy was used to establish linkage of a quantitative trait locus influencing ethanol-induced anesthesia to the albinism gene (Tyr) in mouse. This approach, which can be implemented immediately with most statistical packages, provides the extreme flexibility of multivariate analysis of variance for analyzing complex questions of linkage regarding either animal or human research paradigms.

Albinism↗
PubMed1994

A sib-pair approach to interval mapping of quantitative trait loci.

An interval mapping procedure based on the sib-pair method of Haseman and Elston is developed, and simulation studies are carried out to explore its properties. The procedure is analogous to other interval mapping procedures used with experimental material, such as plants and animals, and yields very similar results in terms of the location and effect size of a quantitative trait locus (QTL). The procedure offers an advantage over the conventional Haseman and Elston approach, in terms of power, and provides useful information concerning the location of a QTL. Because of its simplicity, the method readily lends itself to the analysis of selected samples for increased power and the evaluation of multilocus models of complex phenotypes.

Alleles↗
PubMed1993

Recent developments in alcoholism:genetic transmission.

This chapter is an overview of developments in the study of genetic factors in vulnerability in alcoholism. The focus is on recent developments, including heritability studies in twins and transmission studies in families, both of which have continued to reveal evidence for a substantial role for genetic factors but also for etiologic complexity and variation in vulnerability across generations and across cultures. Studies are discussed which utilized psychophysiological and neurochemical markers for alcoholism for analysis of genetic association, transmission, and linkage. These markers include the low P300 event-related potential, sensitivity to ethanol's intoxicating and euphoric effects, platelet adenylate cyclase, and neurotransmitter metabolite concentrations. Although it is highly likely that many alcoholism-associated physiologic phenotypes are secondary traits, these approaches have increased the specificity of genetic analyses and genetic analyses are clarifying their relationship to alcoholism. For example, early efforts to study, in families, the co-occurrence of the P300 marker and alcoholism have yielded results indicating that the P300 abnormality precedes significant exposure to alcohol and that relatives of alcoholics are more likely to have this trait. In the area of animal models, two nonhuman primate species, the vervet monkey and the rhesus macaque, were shown to willingly consume alcohol to intoxicating blood levels. Also, linkage studies using the quantitative trait locus (QTL) mapping strategy were attempted for phenotypes relevant for alcoholism. The QTL strategy is theoretically capable of identifying determinant genes which contribute only a small portion of the variance. In human linkage studies, a genetic association was found to the DRD2 dopamine receptor. The DRD2 finding generated controversy, as a number of other groups failed to replicate it, and also focused attention on the advantages and pitfalls of the population association approach for detecting genes influencing behavior. The relationship of the alcohol metabolic gene variants to alcoholism was clarified by the finding that functional variants of alcohol and aldehyde dehydrogenases can act additively to determine vulnerability to alcoholism.

Alcoholism↗
PubMed1995

Genetic mapping of quantitative trait loci for traits with ordinal distributions.

Statistical methods for mapping quantitative trait loci relative to genetic markers are now well established for continuous traits with normal distributions. However, many traits of economic importance are recorded on a discrete, ordinal scale. Here we describe a model developed for the analysis of ordinal traits, such as degree of difficulty in calving or categories of plant disease resistance. The model estimates the distance from the quantitative trait locus to neighbouring genetic markers, and also genetic parameters, either as gene effects on an underlying continuous scale or as probabilities of the observed categories. The model is tested on simulated data and is compared with an analysis based on mixtures of normal distributions. The ordinal model is found to estimate the parameters more accurately, especially when the number of categories is small or when only one linked marker is available.

Animal Husbandry↗
PubMed1996

Defective Fc gamma RII gene expression in macrophages of NOD mice: genetic linkage with up-regulation of IgG1 and IgG2b in serum.

A quantitative trait locus for increased IgG serum levels in the NOD mouse strain was mapped to distal chromosome 1, close to the fcgr2 locus encoding the low-affinity type II receptor for the Fc portion of IgG (Fc gamma RII). Expression of membrane-inserted (b2) and soluble (b3) isoforms of Fc gamma RII was strongly decreased in macrophages of NOD compared with C57BL/6 (B6) mice. In contrast, B cell-specific (Fc gamma RIIb1) isoform was only slightly decreased and Fc gamma RIII was not altered. This Fc gamma RII regulatory defect was cis-encoded by fcgr2 or by a closely linked locus, occurred at the mRNA level, and was associated with multiple mutations in the fcgr2 gene promoter. In relation with this defect, binding of IgG1- and IgG2b- but not IgG2a-opsonized RBC by macrophages of NOD and congenic B6.NOD-fcgr2 mice was severely impaired, but was normal in macrophages of NOD.B6-fcgr2 congenic mice, indicating that Fc gamma RII plays a nondispensable role in binding of IgG1 and IgG2b isotypes. Likewise, serum levels of IgG1 and IgG2b but not IgG2a were up-regulated in NOD compared with NOD.B6-fcgr2 congenic mice. These findings indicate that macrophage Fc gamma RII may regulate serum IgG1 and IgG2b through their catabolism, and validate the NOD strain as a model to investigate the functions of Fc gamma RII isoforms.

Animals↗
PubMed1997

Genetic analysis of the components of winterhardiness in barley (Hordeum vulgar L.).

Winterhardiness in cereals is the consequence of a number of complex and interacting components: cold tolerance, vernalization requirement and photoperiod sensitivity. An understanding of the genetic basis of these component traits should allow for more effective selection. Genome map-based analyses hold considerable promise for dissecting complex phenotypes. A 74-point linkage map was developed from one hundred double haploid lines derived from a winter x spring barley cross and used as the basis for quantitative trait locus (QTL) analyses to determine the chromosome location of genes controlling components of winterhardiness. Despite the greater genome coverage provided by the current map, a previously-reported interval on chromosome 7 remains the only region where significant QTL effects for winter survival were detected in this population. QTLs for heading date under 24 h light map to the same region. A QTL for heading date under this photoperiod regime also maps to chromosome 2. A distinct set of QTLs mapping to chromosomes 1, 2, 3 and 5 determined heading date under 8 h light. Patterns of differential QTL expression underscore the complexity of Winterhardiness.

Acclimatization↗
PubMed1997

Genetic and molecular dissection of quantitative traits in rice.

Recent progress in the generation of a molecular genetic map and markers for rice has made possible a new phase of mapping individual genes associated with complex traits. This type of analysis is often referred to as quantitative trait locus (QTL) analysis. Increasing numbers of QTL analyses are providing enormous amounts of information about QTLs, such as the numbers of loci involved, their chromosomal locations and gene effects. Clarification of genetic bases of complex traits has a big impact not only on fundamental research on rice plant development, but it also has practical benefits for rice breeding. In this review, we summarize recent progress of QTL analysis of several complex traits in rice. A strategy for positional cloning of genes at QTLs is also discussed.

Chromosome Mapping↗
PubMed1997

Personality genetics.

Although 30-60% of the variance in many personality traits is inherited, until recently little was known about the responsible genes. Preliminary studies of family history in bipolar disorder and of X-linkage of personality traits in color-blindness suggested a "quantitative trait locus" (QTL) approach to the genetics of normal personality. In methodically similar but independent studies of 124 Israeli and 315 American normal volunteers we showed an association between the dopamine D4 receptor gene (D4DR) and the personality trait of novelty seeking. In the Israeli sample we also found an interaction between the D4DR gene and the serotonin 2C receptor gene (5-HT2C) with a marked effect on the trait of reward dependence. Further investigation of genes for personality traits may suggest links between normal personality and psychiatric illness.

Bipolar Disorder↗