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PubMed2002

Evidence of genetic interaction between the beta-globin complex and chromosome 8q in the expression of fetal hemoglobin.

During human development, the switch from fetal to adult hemoglobin (Hb) is not complete with the residual gamma-globin expression being restricted to a subset of erythrocytes termed "F cells" (FC). Statistical analyses have shown the FC trait to be influenced by a common sequence variant (C-->T) at position -158 upstream of the Ggamma-globin gene, termed the "XmnI-Ggamma polymorphism." The XmnI-Ggamma site is believed to be involved in the expression of the Ggamma-globin gene through interaction with transcription factors, and polymorphisms in the transcription factors could be influencing fetal Hb expression, conditional on the XmnI-Ggamma site. Using a two-locus model, in which the second locus was the known quantitative-trait locus (QTL) at the XmnI-Ggamma site, we showed suggestive linkage to chromosome 8q. A maximum single-point LOD score of 4.33 and a multipoint LOD score of 4.75 were found in a 15-20 cM region of chromosome 8q. A single-locus analysis failed to show linkage of FC to the region when the XmnI-Ggamma site was accounted for by removing its effects from the data or including it as a covariate. Results of the single-locus analysis were significant when the effects of the XmnI-Ggamma site were not accounted for in any way. The results of analysis in a large Indian kindred indicate that there is an interaction between the XmnI-Ggamma site and a QTL on chromosome 8q that is influencing the production of fetal Hb.

Chromosome Mapping↗
PubMed2001

Genetic interactions in the pathogenesis of neonatal hyperbilirubinemia: Gilbert's Syndrome and glucose-6-phosphate dehydrogenase deficiency.

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is a common condition with a worldwide distribution that has the potential for causing severe hyperbilirubinemia with bilirubin encephalopathy. Hemolysis resulting from identifiable triggers may be the cause of the jaundice in some cases, but in many, jaundice continues to occur despite avoidance of contact with known hemolytic triggers. In some G-6-PD-deficient population groups, carboxyhemoglobin studies have indicated exaggerated hemolysis; but in others, increased hemolysis has not correlated with serum total bilirubin values. As hyperbilirubinemia results from an imbalance between bilirubin production and bilirubin elimination, diminished bilirubin conjugation was suspected to contribute to the pathogenesis of hyperbilirubinemia. Serum-conjugated bilirubin fractions, reflecting intrahepatocytic bilirubin conjugation, were low in G-6-PD-deficient neonates who developed hyperbilirubinemia. This conjugated bilirubin profile was similar to that seen in adults with Gilbert's Syndrome, a condition associated with promoter polymorphism for the gene encoding the bilirubin-conjugating enzyme, UGT glucuronosyltransferase 1A1 (UGT). Whereas G-6-PD deficiency or Gilbert's Syndrome, alone, did not predispose to hyperbilirubinemia, G-6-PD-deficient neonates who also were heterozygotes or homozygotes for the variant UGT gene promoter did have significantly increased incidences of hyperbilirubinemia. Additional conditions which predispose to neonatal jaundice in the presence of Gilbert's Syndrome, include Coombs' negative ABO blood group heterospecificity, hereditary spherocytosis, and prolonged breastfeeding.Gilbert's Syndrome and G-6-PD deficiency are both common, inherited conditions. Individually, and in the absence of additional genetic or environmental factors, both are benign, and should result in minimal health disturbance or interference with the quality of life of affected individuals. However, in combination, or following exposure to environmental or other genetic factors, these benign conditions may have severe manifestations, with potentially dangerous and possibly life-threatening consequences. This review highlights the major clinical features of both Gilbert's Syndrome and G-6-PD deficiency, and surveys a series of studies related to neonatal jaundice in G-6-PD-deficient neonates culminating in the documentation of an interaction between the two conditions that is crucial to the pathogenesis of hyperbilirubinemia.

Bilirubin↗
PubMed1999

Treatment of dyslipidemia: genetic interactions with diet and drug therapy.

Coronary heart disease (CHD) is multifactorial, and its manifestation is determined by multiple gene loci and their interaction with a cohort of environmental factors. Variation at several candidate gene loci has already been shown to have a significant effect over the spectrum of plasma lipid levels observed in the population. Moreover, some variants are known to influence the interindividual variability in response to dietary and pharmacologic interventions aimed to reduce atherogenic lipoproteins. The continuous progress in this area of research is getting us closer to the development of genetic screening panels that will allow a more precise assessment of individual CHD risk and response to therapeutic interventions.

Anticholesteremic Agents↗
PubMed2005

The CRAL/TRIO and GOLD domain protein CGR-1 promotes induction of vulval cell fates in Caenorhabditis elegans and interacts genetically with the Ras signaling pathway.

Ras-mediated signaling is necessary for the induction of vulval cell fates during Caenorhabditis elegans development. We identified cgr-1 by screening for suppressors of the ectopic vulval cell fates caused by a gain-of-function mutation of the let-60 ras gene. Analysis of two cgr-1 loss-of-function mutations indicates that cgr-1 positively regulates induction of vulval cell fates. cgr-1 is likely to function at a step in the Ras signaling pathway that is downstream of let-60, which encodes Ras, and upstream of lin-1, which encodes a transcription factor, if these genes function in a linear signaling pathway. These genetic studies are also consistent with the model that cgr-1 functions in a parallel pathway that promotes vulval cell fates. Localized expression studies suggest that cgr-1 functions cell autonomously to affect vulval cell fates. cgr-1 also functions early in development, since cgr-1 is necessary for larval viability. CGR-1 contains a CRAL/TRIO domain likely to bind a small hydrophobic ligand and a GOLD domain that may mediate interactions with proteins. A bioinformatic analysis revealed that there is a conserved family of CRAL/TRIO and GOLD domain-containing proteins that includes members from vertebrates and Drosophila. The analysis of cgr-1 identifies a novel in vivo function for a member of this family and a potential new regulator of Ras-mediated signaling.

Amino Acid Sequence↗
PubMed2001

Genetic interactions within TFIIIC, the promoter-binding factor of yeast RNA polymerase III.

TFIIIC is a heteromultimeric protein, made of six distinct subunits in Saccharomyces cerevisiae, that binds to RNA polymerase III promoters and triggers the assembly of the transcription complex. The largest yeast subunit tau138, encoded by TFC3, binds to the B-box promoter element. This binding is defective in the temperature-sensitive mutant tfc3-G349E; the mutation responsible is located in one of two conserved motifs shared with the B-binding component of human TFIIIC. Rare dominant gain-of-function mutations that restore growth at high temperature were obtained following ultraviolet mutagenesis of tfc3-G349E. All of them resulted from single amino acid substitutions that alter the structure of TFIIIC. Three were due to reversion or intragenic suppression (TFC3-K754E and TFC3-L804H) events. Three were identical isolates of TFC6-E330K, a previously described mutation of the tau91 subunit. The remaining suppressors mapped in TFC4, and resulted in amino acid replacements in the second largest subunit of TFIIIC (tau131). With the exception TFC4-E711K, these affect positions that are invariant between the S. cerevisiae and Homo sapiens proteins, and are localised in conserved tetratricopeptide motifs. These findings demonstrate a close functional interaction between the two largest subunits of TFIIIC and underscore the importance of the tetratricopeptide motif of tau131.

Amino Acid Motifs↗
PubMedDate not supplied

[The Delta locus in Drosophila virilis: alleles, wing phenotypes and genetic interactions].

A considerable number of Delta (D1) alleles resulting from spontaneous mutation or induced by following X-ray irradiation have been isolated on the basis of the dominant phenotype consisting of disrupted wing venation and associated with heterozygosity for different D1 alleles. The L2 "delta" forming at the wing margin is the most characteristic fully penetrant phenotype of D1-heterozygous adults. The structure disruption of all other longitudinal (L3-L5) and cross (C1 and C2) veins including formation of "deltas" and other additional vein material, have been characterized as the irregular bilaterally asymmetrical nondirectional fluctuations of D1 phenotype expression. The phenotypic interactions between Delta and two D1 phenotype enhancer mutations, L2 fork and gap L2, have been found. Possible participation of Delta, one of the elements of Notch signaling system, in the structure formation is discussed.

Alleles↗
PubMedDate not supplied

Effect of environmental-genetic interactions on Mycobacterium avium challenge infection.

Chickens from lines selectively bred for either a high-antibody (HA) or low-antibody (LA) response to sheep erythrocytes were injected intravenously with Mycobacterium avium while being held in low, medium, or high levels of social stress for 5 days (first environment). During the remaining 6 weeks, they were held under either low or medium levels of social stress (second environment). Infection led to lesions consisting of granulomas, some of which had necrotic centers. There was a positive correlation between numbers of lesions with necrotic centers and M. avium cells recovered from livers. The numbers and nature of lesions were influenced by both genetic and environmental factors. Numbers of necrotizing lesions increased with stressfulness of the first environment. Total numbers of lesions were reduced by the medium-stress second environment, and the total number of necrotizing lesions was reduced among LA chickens in the low-stress second environment.

Animals↗
PubMed2005

Overexpression of TAPETUM DETERMINANT1 alters the cell fates in the Arabidopsis carpel and tapetum via genetic interaction with excess microsporocytes1/extra sporogenous cells.

Previously, we reported that the TAPETUM DETERMINANT1 (TPD1) gene is required for specialization of tapetal cells in the Arabidopsis (Arabidopsis thaliana) anther. The tpd1 mutant is phenotypically identical to the excess microsporocytes1 (ems1)/extra sporogenous cells (exs) mutant. The TPD1 and EMS1/EXS genes may function in the same developmental pathway in the Arabidopsis anther. Here, we further report that overexpression of TPD1 alters the cell fates in the Arabidopsis carpel and tapetum. When TPD1 was expressed ectopically in the wild-type Arabidopsis carpel, the number of cells in the carpel increased significantly, showing that the ectopic expression of TPD1 protein could activate the cell division in the carpel. Furthermore, the genetic analysis showed that the activation of cell division in the transgenic carpel by TPD1 was dependent on EMS1/EXS, as it did not happen in the ems1/exs mutant. This result further suggests that TPD1 regulates cell fates in coordination with EMS1/EXS. Moreover, overexpression of TPD1 in tapetal cells also delayed the degeneration of tapetum. The TPD1 may function not only in the specialization of tapetal cells but also in the maintenance of tapetal cell fate.

Arabidopsis↗
PubMed1996

Genetic interactions among cytoplasmic dynein, dynactin, and nuclear distribution mutants of Neurospora crassa.

Cytoplasmic dynein is a multisubunit, microtubule-associated, mechanochemical enzyme that has been identified as a retrograde transporter of various membranous organelles. Dynactin, an additional multisubunit complex, is required for efficient dynein-mediated transport of vesicles in vitro. Recently, we showed that three genes defined by a group of phenotypically identical mutants of the filamentous fungus Neurospora crassa encode proteins that are apparent subunits of either cytoplasmic dynein or dynactin. These mutants, designated ropy (ro), display abnormal hyphal growth and are defective in nuclear distribution. We propose that mutations in other genes encoding dynein/dynactin subunits are likely to result in a ropy phenotype and have devised a genetic screen for the isolation of additional ro mutants. Cytoplasmic dynein/dynactin is the largest and most complex of the cytoplasmic motor proteins, and the genetic system described here is unique in its potentiality for identifying mutations in undefined genes encoding dynein/dynactin subunits or regulators. We used this screen to isolate > 1000 ro mutants, which were found to define 23 complementation groups. Unexpectedly, interallelic complementation was observed with some allele pairs of ro-1 and ro-3, which are predicted to encode the largest subunits of cytoplasmic dynein and dynactin, respectively. The results suggest that the Ro1 and Ro3 polypeptides may consist of multiple, functionally independent domains. In addition, approximately 10% of all newly isolated ro mutantsdisplay unlinked noncomplementation with two or more of the mutants that define the 23 complementation groups. The frequent appearance of ro mutants showing noncomplementation with multiple ro mutants having unlinked mutations suggests that nuclear distribution in filamentous fungi is a process that is easily disrupted by affecting either dosage or activity of cytoplasmic dynein, dynactin, and perhaps other cytoskeletal proteins or regulators.

Alleles↗
PubMed2002

Genetic interaction between integrins and moleskin, a gene encoding a Drosophila homolog of importin-7.

The Drosophila PS1 and PS2 integrins are required to maintain the connection between the dorsal and ventral wing epithelia. If alphaPS subunits are inappropriately expressed during early pupariation, the epithelia separate, causing a wing blister. Two lines of evidence indicate that this apparent loss-of-function phenotype is not a dominant negative effect, but is due to inappropriate expression of functional integrins: wing blisters are not generated efficiently by misexpression of loss-of-function alphaPS2 subunits with mutations that inhibit ligand binding, and gain-of-function, hyperactivated mutant alphaPS2 proteins cause blistering at expression levels well below those required by wild-type proteins. A genetic screen for dominant suppressors of wing blisters generated null alleles of a gene named moleskin, which encodes the protein DIM-7. DIM-7, a Drosophila homolog of vertebrate importin-7, has recently been shown to bind the SHP-2 tyrosine phosphatase homolog Corkscrew and to be important in the nuclear translocation of activated D-ERK. Consistent with this latter finding, homozygous mutant clones of moleskin fail to grow in the wing. Genetic tests suggest that the moleskin suppression of wing blisters is not directly related to inhibition of D-ERK nuclear import. These data are discussed with respect to the possible regulation of integrin function by cytoplasmic ERK.

Animals↗
PubMed1999

Allele-specific genetic interactions between Prp8 and RNA active site residues suggest a function for Prp8 at the catalytic core of the spliceosome.

The highly conserved spliceosomal protein Prp8 is known to cross-link the critical sequences at both the 5' (GU) and 3' (YAG) ends of the intron. We have identified prp8 mutants with the remarkable property of suppressing exon ligation defects due to mutations in position 2 of the 5' GU, and all positions of the 3' YAG. The prp8 mutants also suppress mutations in position A51 of the critical ACAGAG motif in U6 snRNA, which has been observed previously to cross-link position 2 of the 5' GU. Other mutations in the 5' splice site, branchpoint, and neighboring residues of the U6 ACAGAG motif are not suppressed. Notably, the suppressed residues are specifically conserved from yeast to man, and from U2- to U12-dependent spliceosomes. We propose that Prp8 participates in a previously unrecognized tertiary interaction between U6 snRNA and both the 5' and 3' ends of the intron. This model suggests a mechanism for positioning the 3' splice site for catalysis, and assigns a fundamental role for Prp8 in pre-mRNA splicing.

Alleles↗
PubMed2004

Dissecting complex genetic interactions that influence the Engrailed-1 limb phenotype.

Engrailed-1, a homeobox containing transcriptional repressor, is known to play an important role in the development of the vertebrate limb. In its absence, mouse limbs develop with improper specification of dorsal identity and digit abnormalities. We report here that specific malformations in the mutant limb are dependent on strain background. We have subdivided these defects on the basis of morphology to define five independent traits. Each of these shows marked differences in prevalence among the 129/S1 and C57BL/6J strains carrying the En1(hd) mutation. In a genome-wide scan using SSLP markers, we have determined the location of one significant modifier and several additional suggestive loci responsible for these traits, each a facet of the En1(-/-) phenotype. We propose this type of sensitized genetic screen as a model approach for the discovery and mapping of quantitative loci that affect the subtle details of limb pattern formation.

Alleles↗
PubMed2006

Oral, post-oral and genetic interactions in sweet appetite.

Inbred mouse strains differ in their preferences for sweeteners, due in part to variations in their T1R3 sweet taste receptor. Recent studies of sweet sensitive C57BL/6J (B6) and subsensitive 129P3/J (129) mice indicate that experiential and post-oral effects of sugar substantially modify sweetener preference. In fact, the strain difference in sucrose preference disappeared after the mice were given 23 h/day tests with sucrose at ascending concentrations (0.5-32%). Intragastric infusions of sucrose (16%) also conditioned increased preference for and absolute intake of flavored sweet solutions in B6 and 129 mice. An operant analysis of sweetener appetite revealed, unexpectedly, that sugar-experienced 129 mice respond more vigorously than B6 mice for 16% sucrose rewards. These findings indicate that experiential and nutritional factors can, to some degree, override genetic differences in peripheral taste sensitivity in determining food appetite.

Animals↗
PubMed1997

SRO9, a multicopy suppressor of the bud growth defect in the Saccharomyces cerevisiae rho3-deficient cells, shows strong genetic interactions with tropomyosin genes, suggesting its role in organization of the actin cytoskeleton.

RHO3 encodes a Rho-type small GTPase in the yeast Saccharomyces cerevisiae and is involved in the proper organization of the actin cytoskeleton required for bud growth. SRO9 (YCL37c) was isolated as a multicopy suppressor of a rho3delta mutation. An Sro9p domain required for function is similar to a domain in the La protein (an RNA-binding protein). Disruption of SRO9 did not affect vegetative growth, even with the simultaneous disruption of an SRO9 homologue, SRO99. However, sro9delta was synthetically lethal with a disruption of TPM1, which encodes tropomyosin; sro9delta tpm1delta cells did not distribute cortical actin patches properly and lysed. We isolated TPM2, the other gene for tropomyosin, as a multicopy suppressor of a tpm1delta sro9delta double mutant. Genetic analysis suggests that TPM2 is functionally related to TPM1 and that tropomyosin is important but not essential for cell growth. Overexpression of SRO9 suppressed the growth defect in tpm1delta tpm2delta cells, disappearance of cables of actin filaments in both rho3delta cells and tpm1delta cells, and temperature sensitivity of actin mutant cells (act1-1 cells), suggesting that Sro9p has a function that overlaps or is related to tropomyosin function. Unlike tropomyosin, Sro9p does not colocalize with actin cables but is diffusely cytoplasmic. These results suggest that Sro9p is a new cytoplasmic factor involved in the organization of actin filaments.

Actins↗
PubMed1997

The Schizosaccharomyces pombe spindle checkpoint protein mad2p blocks anaphase and genetically interacts with the anaphase-promoting complex.

The spindle checkpoint monitors mitotic spindle integrity and the attachment of kinetochores to the spindle. Upon sensing a defect the checkpoint blocks cell cycle progression and thereby prevents chromosome missegregation. Previous studies in budding yeast show that the activated spindle checkpoint inhibits the onset of anaphase by an unknown mechanism. One possible target of the spindle checkpoint is anaphase promoting complex (APC), which controls all postmetaphase events that are blocked by spindle checkpoint activation. We have isolated mad2, a spindle checkpoint component in fission yeast, and shown that mad2 overexpression activates the checkpoint and causes a cell cycle arrest at the metaphase-to-anaphase transition. In addition to the observation that mad2-induced arrest can be partially relieved by mitosis-promoting factor inactivation, we present genetic evidence consistent with the hypothesis that the spindle checkpoint imposes a cell cycle arrest by inhibiting APC-dependent proteolysis.

Amino Acid Sequence↗
PubMed1999

Dietary and genetic interactions in the regulation of plasma lipoprotein(a).

Lipoprotein(a) is a plasma particle which is considered to be a risk factor for the development of coronary heart disease. Plasma levels of lipoprotein(a) are affected by different types of dietary fat and steroid hormones. Two regions upstream of the apolipoprotein(a) promoter have been isolated which could be the site of regulation of apolipoprotein(a) gene transcription.

Coronary Disease↗
PubMed2000

Genetic interactions during root hair morphogenesis in Arabidopsis.

Root hairs are a major site for the uptake of water and nutrients into plants and form an increasingly important model system for studies of development of higher plants and cell biology. We have identified loss-of-function mutations in eight new genes required for hair growth in Arabidopsis: SHAVEN1 (SHV1), SHV2, and SHV3; CENTIPEDE1 (CEN1), CEN2, and CEN3; BRISTLED1 (BST1); and SUPERCENTIPEDE1 (SCN1). We combined mutations in 79 pairs of genes to determine the stages at which these and six previously known genes contribute to root hair formation. Double mutant phenotypes revealed roles for several genes that could not have been predicted from the single mutant phenotypes. For example, we show that TIP1 and RHD3 are required much earlier in hair formation than previous studies have suggested. We present a genetic model for root hair morphogenesis that defines the roles of each gene, and we suggest hypotheses about functional relationships between genes.

Arabidopsis↗
PubMed1987

Cellular site of expression and genetic interaction of the rd and the rds loci in the retina of the mouse.

In the retina of mice, the two genes, rd and rds, produce retinal degeneration. Depending on allelic combination and gene dosage at these loci, four different genotypes with distinct phenotypic traits and rates of photoreceptor cell loss are recognized. The cellular site of gene action and the nature of interaction, resulting in the variegation of the retinal phenotypes have been analyzed by comparing gene expression in the retina of pure line (unigenotypic) mice, and in the retina of chimaeric mice, experimentally produced by aggregating embryos of different genotypic constitution. The findings suggest that both rd and rds genes act intracellularly within the photoreceptor cells. The primary expression of the genes, producing specific phenotypic alterations of the photoreceptor cells, are invariant and are not affected by extracellular factors. The lethal effects of the genes, on the other hand, resulting in specified rates of photoreceptor cell death, are influenced by both genetic (intracellular), and environmental factors.

Alleles↗