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PubMed1989

Immunoblot analysis of the antibody response to murine cytomegalovirus in genetically resistant and susceptible mice.

The murine of human cytomegalovirus infection was employed to analyse the kinetics of antibody production to murine cytomegalovirus (MCMV) structural and immediate early (IE) polypeptides following MCMV infection of genetically resistant and susceptible strains of mice. A total of 22 structural and six non-structural. IE proteins were identified. Analysis of immunoblots by densitometry identified four patterns of antibody reactivity to MCMV structural polypeptides during primary and secondary antibody responses over a period of 5 weeks post-infection (p.i.). Firstly, antibodies were strongly reactive with an 83K protein soon after infection, with levels which decreased with time: antibodies to a second group of viral proteins were also recognized soon after infection, but consistent levels of reactivity were maintained. Viral proteins that were recognized beyond day 14 p.i. or following a second MCMV infection formed the third group; the fourth consisted of viral proteins that were detected at variable times p.i. by antisera different mouse strains. The kinetics and intensity of the antibody response to individual viral proteins were influenced by virus dose, time p.i. and by a second MCMV infection. In addition, the genetic constitution of the host influenced the antibody response to MCMV proteins both quantitatively and qualitatively. In particular, sera from mice possessing C57BL but not BALB/c genes detected a 56K Mr viral during seroconversion. Antibody reactivity to this protein was shown to segregate among sera from CXB mice, with a strain distribution pattern which indicated a linkage with the b locus on chromosome 4. Finally, expression of the 56K protein was detected in B10. BR but not BALB/c embryo fibroblasts in vitro, with expression being a dominant trait in (BALB/c x B10.BR) F1 embryo fibroblasts. Thus, host genes may influence the expression of this structural viral protein.

Animals↗

PubMed2006

Development of overt proteinuria in the Munich Wistar Frömter rat is suppressed by replacement of chromosome 6 in a consomic rat strain.

In a cross between the Munich Wistar Frömter (MWF) rat and spontaneously hypertensive rats (SHR), a major quantitative trait locus (QTL) was identified on rat chromosome 6 (RNO6) that demonstrated the strongest linkage to albuminuria among several QTL identified. The QTL represented the only locus that is linked to both early-onset albuminuria and increased renal interstitial fibrosis in adult animals. A consomic MWF-6(SHR) strain in which chromosome 6 from SHR was introgressed into the MWF background therefore was generated to test the relevance of this QTL. Phenotype analysis at 8 wk of age revealed that early onset of albuminuria in MWF with a 55-fold elevation of urinary albumin excretion compared with SHR (P < 0.0001) was completely abolished in MWF-6(SHR). Time-course analysis until week 24 demonstrated only a moderate increase of urinary albumin excretion in MWF-6(SHR), whereas MWF reached levels in the nephrotic range (16.6 +/- 3.5 versus 162.6 +/- 16.0 mg/24 h; P < 0.0001). At this age, analysis of glomerulosclerosis, tubulointerstitial damage, renal interstitial fibrosis, and renal collagen III mRNA expression revealed a significant improvement of all parameters in MWF-6(SHR) compared with MWF (P < 0.05). At 32 wk, MWF but not MWF-6(SHR) demonstrated overt proteinuria (354.6 +/- 37.6 versus 48.8 +/- 13.2; P < 0.0001), whereas serum urea, cholesterol, and triglyceride concentrations were lower and creatinine clearance was higher in MWF-6(SHR) compared with MWF (P < 0.05). Therefore, although albuminuria in MWF is determined by a complex interplay of several QTL, our data demonstrate that genetic exchange of one locus on RNO6 leads to marked suppression of early-onset albuminuria and renal damage in MWF.

Albuminuria↗

PubMed1999

Linkage between IgE receptor-mediated histamine releasability from basophils and gene marker of chromosome 11q13.

BACKGROUND: The genetics of the regulation of the release of mediators involving the interaction of IgE with cells and their ability to release mediators have not been extensively investigated. With use of the candidate gene approach, it was reported that the gene regulating the beta chain of the high-affinity receptor for IgE is on chromosome 11q13. OBJECTIVE: To determine whether gene(s) in chromosome 11q13 may control the expression of maximal histamine release from basophil to anti-IgE stimuli, linkage analysis between this phenotype and the gene marker of chromosome 11q13 was performed. METHODS: Maximal histamine release to anti-IgE and calcium ionophore A23187 and genotyping chromosome 11q13 with use of microsatellite marker (D11S97) were performed in 56 probands with asthma and 59 of their siblings. The linkage was analyzed by affected sib-pair analysis and the quantitative trait locus approach. RESULTS: Maximal histamine release (mean +/- SE) to anti-IgE and A23187 was 43.3% +/- 3.5% and 30.9 +/- 3.4% in probands and 29.5% +/- 2.6% and 22.2% +/- 2.7 in siblings, respectively. Of 20 sib-pairs with the maximal histamine release to anti-IgE more than 33% (mean plus 1 SD of nonasthmatic controls), 11 (55%) shared 2 D11S97 alleles, 9 (45%) shared 1 allele, and neither sib-pair shared identical alleles, which indicates a significant linkage of maximal histamine to anti-IgE and gene marker of chromosome 11q13 (P =.02). The difference (mean +/- SE) of the maximal histamine release to anti-IgE between each proband and sibling was smaller in sib-pairs with 2 identical alleles than in those with 1 identical allele and with no identical allele (14.1% +/- 2.6% vs 25.8% +/- 3.1% vs 41.0% +/- 4.9%). However, the difference (mean +/- SE) to A23187 between each proband and sibling was not different among the 3 groups (9.7% +/- 1.8% vs 17.9% +/- 3.6% vs 10.4% +/- 4.8%). CONCLUSION: Maximal histamine release from basophils to anti-IgE stimuli was linked to the gene marker of chromosome 11q13.

Adolescent↗

PubMed2001

Modifying with mitochondria.

An elegant set of mouse crosses has been used to identify a mitochondrial variant that interacts with a nuclear locus on chromosome 10, Ahl, to modify age-related hearing loss. This discovery sets the stage for the identification of factors that modify expression levels and variability of human hearing impairments.

Age Factors↗

PubMed2002

Lith genes control mucin accumulation, cholesterol crystallization, and gallstone formation in A/J and AKR/J inbred mice.

We recently identified 2 Lith genes that determine cholesterol gallstone formation in C57L/J inbred mice, which show a gallstone prevalence of approximately 80% on feeding 1.0% cholesterol and 0.5% cholic acid. The aim of this study was to explore if the same Lith loci contribute to the variation in gallstone susceptibility in a new experimental cross. After 12 weeks of feeding the lithogenic diet to inbred mice of strains A/J and AKR/J as well as their F(1) progeny, we used microscopy of bile to assess mucin accumulation, crystallization pathways, and stone formation. Backcross progeny (n = 225) were phenotyped and genotyped selectively for microsatellite markers spanning the genome. Quantitative trait loci (QTL) affecting gallstone phenotypes were identified by linkage analysis. Both inbred strains showed accumulation of mucin gel and cholesterol supersaturation. However, only strain AKR developed gallstones (prevalence of 20%), whereas strain A showed a stable liquid crystalline state and no stones. QTL analysis identified a gallstone locus on chromosome 17 (Lith3). A second gene locus on chromosome 15 that controls mucin accumulation harbors the mucin gene Glycam1, which was shown to be expressed in gallbladder epithelia by immunohistochemistry. Gallstone and mucin loci colocalized with potential QTLs affecting the formation of cholesterol crystals. In conclusion, QTL analysis identified specific gene loci determining mucin accumulation, cholesterol crystallization, and gallstone formation. Characterization of the pathophysiologic roles of Lith3 and the new biliary mucin gene Glycam1 might provide insights into primary defects of human cholelithiasis and lead to new therapeutic strategies for prestone intervention.

Animals↗

PubMed1999

Linkage of a candidate gene locus to familial combined hyperlipidemia: lecithin:cholesterol acyltransferase on 16q.

Familial combined hyperlipidemia (FCHL) is a common lipid disorder characterized by elevated levels of plasma cholesterol and triglycerides that is present in 10% to 20% of patients with premature coronary artery disease. To study the pathophysiological basis and genetics of FCHL, we previously reported recruitment of 18 large families. We now report linkage studies of 14 candidate genes selected for their potential involvement in the aspects of lipid and lipoprotein metabolism that are altered in FCHL. We used highly polymorphic markers linked to the candidate genes, and these markers were analyzed using several complementary, nonparametric statistical allele-sharing linkage methodologies. This current sample has been extended over the one in which we identified an association with the apolipoprotein (apo) AI-CIII-AIV gene cluster. We observed evidence for linkage of this region and FCHL (P<0.001), providing additional support for its involvement in FCHL. We also identified a new locus showing significant evidence of linkage to the disorder: the lecithin:cholesterol acyltransferase (LCAT) locus (P<0.0006) on chromosome 16. In addition, analysis of the manganese superoxide dismutase locus on chromosome 6 revealed a suggestive linkage result in this sample (P<0.006). Quantitative traits related to FCHL also provided some evidence of linkage to these regions. No evidence of linkage to the lipoprotein lipase gene, the microsomal triglyceride transfer protein gene, or several other genes involved in lipid metabolism was observed. The data suggest that the lecithin:cholesterol acyltransferase and apolipoprotein AI-CIII-AIV loci may act as modifying genes contributing to the expression of FCHL.

Adult↗

PubMed2025

Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits.

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with transcriptomic and proteomic measure using multi-omics data from a Hispanic/Latino population. Using this approach, we identify genes linked to type 2 diabetes and lipid/lipoprotein traits, including TMEM205 and NEDD9 for HDL cholesterol, TREH for triglycerides, and ANXA4 for type 2 diabetes.

Female↗

PubMed2005

A comprehensive radiation hybrid map of the bovine genome comprising 5593 loci.

A bovine whole genome 7000-rad radiation hybrid (RH) panel, SUNbRH(7000-rad), was constructed to build a high-resolution RH map. The Shirakawa-USDA linkage map served as a scaffold to construct a framework map of 3216 microsatellites on which 2377 ESTs were ordered. The resulting RH map provided essentially complete coverage across the genome, with 1 cR7000 corresponding to 114 kb, and a cattle-human comparative map of 1716 bovine genes and sequences annotated in the human genome, which covered 79 and 72% of the bovine and human genomes, respectively. We then integrated the bovine RH and comparative maps with BAC fingerprint information in to construct a detailed, BAC-based physical map covering a reported 40-cM quantitative trait locus region for intramuscular fat or "marbling" on BTA 4. In summary, the new, high-resolution SUNbRH7000-rad, comparative, Shirakawa-USDA linkage, and BAC fingerprint maps provide a set of genomic tools for fine mapping regions of interest in cattle.

Animals↗

PubMed2002

Genetic analysis of pod dehiscence in pea (Pisum sativum L.).

The inheritance of the dehiscent pod character was investigated in two recombinant inbred populations using a simplified correlation analysis. The approach identified three regions on the pea genome that affect the expression of pod dehiscence. The region on linkage group III corresponded to the expected position of Dpo, a gene known to influence pod dehiscence. A locus on linkage group V appeared to have a slightly smaller effect on expression of the phenotype. The third region was observed only in one cross, had a greater effect than Dpo, and was postulated to be yellow pod allele at the Gp locus

Chromosome Mapping↗

PubMedDate not supplied

A further look at quantitative trait loci affecting growth and fatness in a cross between Meishan and Large White pig populations.

A detailed quantitative trait locus (QTL) analysis of growth and fatness data from a three generation experimental cross between Large White (LW) and Meishan (MS) pig breeds was carried out to search for sex x QTL interactions, imprinting effects and multiple linked QTLs. A total of 530 F(2) males and 573 F(2) females issued from 6 F(1) boars and 23 F(1) sows were typed for a total of 137 markers covering the entire porcine genome. Nine growth traits and three backfat thickness measurements were analysed. All analyses were performed using line cross regression procedures. A QTL with sex-specific expression was revealed in the proximal region of chromosome 8, although some confusion between herd and sex effects could not be discarded. This previously undetected QTL affected male growth during the fattening period, with a favourable additive effect of the LW allele. The analyses also revealed the presence of two linked QTLs segregating on chromosome 1, affecting growth traits during the post-weaning period. The first QTL, previously detected using a single QTL model, was located at the end of the q arm of chromosome 1 and had a favourable MS allele. The second QTL had a favourable LW allele and was located in the proximal extremity of the q arm of chromosome 1. Suggestive genomic imprinting was found in the distal region of chromosome 9 affecting growth during the fattening period.

Adipose Tissue↗

PubMed2004

Altering the expression in mice of genes by modifying their 3' regions.

Polymorphic differences altering expression of genes without changing their products probably underlie human quantitative traits affecting risks of serious diseases, but methods for investigating such quantitative differences in animals are limited. Accordingly, we have developed a procedure for changing the expression in mice of chosen genes over a 100-fold range while retaining their chromosomal location and transcriptional controls. To develop the procedure, we first dissected the effects in embryonic stem (ES) cells of elements within and downstream of the 3' untranslated region (UTR) of a single copy transgene at the Hprt locus. As expected, protein expression varied with the steady-state level and half-life of the mRNA. The rank order of expression with various tested 3' regions is the same in ES cells, and in cardiomyocytes and trophoblastocytes derived from them. In mice having two functionally different native genes with modified 3'UTRs, the desired expression was obtained.

3' Untranslated Regions↗

PubMed2006

AtALMT1, which encodes a malate transporter, is identified as one of several genes critical for aluminum tolerance in Arabidopsis.

Aluminum (Al) tolerance in Arabidopsis is a genetically complex trait, yet it is mediated by a single physiological mechanism based on Al-activated root malate efflux. We investigated a possible molecular determinant for Al tolerance involving a homolog of the wheat Al-activated malate transporter, ALMT1. This gene, named AtALMT1 (At1g08430), was the best candidate from the 14-member AtALMT family to be involved with Al tolerance based on expression patterns and genomic location. Physiological analysis of a transferred DNA knockout mutant for AtALMT1 as well as electrophysiological examination of the protein expressed in Xenopus oocytes showed that AtALMT1 is critical for Arabidopsis Al tolerance and encodes the Al-activated root malate efflux transporter associated with tolerance. However, gene expression and sequence analysis of AtALMT1 alleles from tolerant Columbia (Col), sensitive Landsberg erecta (Ler), and other ecotypes that varied in Al tolerance suggested that variation observed at AtALMT1 is not correlated with the differences observed in Al tolerance among these ecotypes. Genetic complementation experiments indicated that the Ler allele of AtALMT1 is equally effective as the Col allele in conferring Al tolerance and Al-activated malate release. Finally, fine-scale mapping of a quantitative trait locus (QTL) for Al tolerance on chromosome 1 indicated that AtALMT1 is located proximal to this QTL. These results indicate that AtALMT1 is an essential factor for Al tolerance in Arabidopsis but does not represent the major Al tolerance QTL also found on chromosome 1.

Aluminum↗

PubMed2003

Analysis of quantitative trait loci that influence animal behavior.

Behavioral differences between inbred strains of mice and rats have a genetic basis that can now be dissected using quantitative trait locus (QTL) analysis. Over the last 10 years, a large number of genetic loci that influence behavior have been mapped. In this article I review what that information has revealed about the genetic architecture of behavior. I show that most behaviors are influenced by QTL of small effect, each contributing to less than 10% of the variance of a behavioral trait. The small effect of each QTL on behavioral variation suggests that the mutational spectrum is different from that which results in Mendelian disorders. Regions of DNA should be appropriately prioritized to find the molecular variants, for instance by looking at sequences that control the level of gene expression rather than variants in coding regions. While the number of allelic loci that can contribute to a trait is large, this is not necessarily the case: the analysis of selected strains shows that a remarkably small number of QTL can explain the bulk of the genetic variation in behavior. I conclude by arguing that genetic mapping has more to offer than a starting point for positional cloning projects. With advances in multivariate analyses, mapping can also test hypotheses about the psychological processes that give rise to behavioral variation.

Animals↗

PubMed2005

Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice.

To examine further the genetic determinants of cholesterol gallstone susceptibility in inbred mice, we performed quantitative trait locus (QTL) analysis of an intercross of gallstone-susceptible PERA/EiJ and gallstone-resistant DBA/2J inbred mice. Three hundred twenty-four F2 offspring were phenotyped for cholelithiasis during consumption of a lithogenic diet and genotyped using microsatellite markers. Linkage analysis was performed by interval mapping. In addition, we analyzed the combined datasets from this cross and from an independent cross of strain PERA and gallstone-resistant I/Ln mice. QTL mapping detected one significant new gallstone susceptibility (Lith) locus on Chromosome 13 (Lith15). A second significant QTL on Chr 6 (Lith16) confirmed a previous QTL. Furthermore, suggestive QTLs confirmed Lith loci from previous crosses on Chromosomes 1, 2, 5, 16 and X. QTL analysis of the dataset derived from the combined crosses increased the detection power and narrowed confidence intervals of Lith loci on Chromosomes 2, 6, 13, and 16. Moreover, the analysis of combined datasets revealed a shared QTL between both crosses on Chromosome 17 (Lith9). Significantly higher mRNA expression of Abcg5 and Abcg8 in strain PERA compared with strains I/Ln and DBA/2 further substantiated that the PERA allele of Abcg5/Abcg8 was responsible for lithogenicity underlying Lith9.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2005

Expansion and diversification of KRAB zinc-finger genes within a cluster including Regulator of sex-limitation 1 and 2.

The genomic locus on mouse chromosome 13 called Regulator of sex-limitation (Rsl) accentuates sex differences in hepatic gene expression. Females homozygous for variant rsl alleles express some otherwise male-specific liver proteins, such as sex-limited protein (Slp), major urinary proteins (MUPs), and members of the cytochrome P450 (cyp) 2d subfamily. We recently identified mutations in two genes, Rsl1 and Rsl2, accounting for the rsl phenotype. These genes encode KRAB zinc-finger proteins (KRAB-ZFPs) and are embedded within a cluster of over 20 similar genes. Mammalian genomes contain over 200 KRAB-ZFP genes, which act biochemically to repress transcription, but the Rsl genes are the first to have their biological functions elucidated. Here we compare Rsl1 and Rsl2 with their neighboring genes, tracing a series of duplication, inversion, and gene conversion events that have created subfamilies within the locus. Polymorphisms among inbred mouse strains and feral species suggest that mutations responsible for the rsl phenotype arose during the creation of inbred strains. Comparisons among mouse, rat, and human sequences show that the Rsl genes, like members of certain other multigene families, have diversified in a species-specific manner. The targets of Rsl regulation also vary between species, occurring in gene families with functions in steroid and xenobiotic metabolism (Cyp2d), reproduction (MUPs), and immunity (Slp). This suggests that the Rsl locus in mouse, and comparable KRAB-ZFP genes in other mammals, may play a role in speciation via modulation of expression of genes influencing reproductive fitness or behavior.

Animals↗

PubMed2005

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice.

Potentially, autoimmune diseases develop from a combination of multiple genes with allelic polymorphisms. An MRL/Mp-Fas(lpr) (/) (lpr) (MRL/lpr) strain of mice develops autoimmune diseases, including lupus nephritis, but another lpr strain, C3H/HeJ-Fas(lpr) (/) (lpr) (C3H/lpr) does not. This indicates that MRL polymorphic genes are involved in the development of the diseases. By quantitative trait loci (QTL) analysis using 527 of the (MRL/lpr x C3H/lpr)F(2) mice, we identified a novel locus for susceptibility to lupus nephritis at map position D5Mit115 on chromosome 5, the same alias of the osteopontin (Opn) gene (LOD score =4.0), susceptible in the MRL allele. In functional analyses of the MRL and C3H Opn alleles using synthetic osteopontin (OPN) made with a new method "cell-free system" with wheat germ ribosomes, the MRL-OPN induced higher expression and production of immunoglobulins as well as cytokines including TNF-alpha, IL-1beta and IFN-gamma in splenocytes and/or macrophages than that of the C3H allele. These findings suggest that allelic polymorphism of OPN causes the functional differences in antibody production and macrophage activation between MRL and C3H strains, possibly involved in the development of lupus nephritis.

Alleles↗

PubMed2002

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

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

Adult↗

PubMedDate not supplied

QTL analysis of proteome and transcriptome variations for dissecting the genetic architecture of complex traits in maize.

In this review, we present some studies on genetic analysis of proteome and transcriptome variations, which exemplify new strategies for a better understanding of the molecular and genetic bases of complex traits. A large genetic variability was revealed at the proteome expression level, which raised the possibility to predict phenotypical performance on the basis of gene product variability. This approach yielded limited results, but could be re-newed by extensive identification of proteins now allowed by mass spectrometry. The dissection of the genetic basis of the variation of individual protein amounts proves very powerful to select 'candidate' proteins, physiologically relevant for a given phenotypical trait, as shown by a study on the effect of water stress in maize. In order to investigate factors of grain quality in maize, we selected a regulatory locus known to control the expression of several storage protein genes, Opaque-2, and investigated the relationships between variability in zein amount and composition and the molecular polymorphism at this locus. Moreover, a QTL analysis revealed that the variability in Opaque-2 transcript abundance was controlled by several polymorphic trans-acting regulators unlinked to the Opaque-2 structural gene. Such genetic approaches should represent additional tools for physiological analysis of the huge amounts of data generated by transcritome and proteome projects.

DNA-Binding Proteins↗