Browsing by Subject "Epistasis, Genetic"

Now showing 1 - 9 of 9

Open Access
A genome-wide RNAi screen reveals multiple regulators of caspase activation.
(The Journal of cell biology, 2007-11-12) Yi, Caroline H; Sogah, Dodzie K; Boyce, Michael; Degterev, Alexei; Christofferson, Dana E; Yuan, Junying
Apoptosis is an evolutionally conserved cellular suicide mechanism that can be activated in response to a variety of stressful stimuli. Increasing evidence suggests that apoptotic regulation relies on specialized cell death signaling pathways and also integrates diverse signals from additional regulatory circuits, including those of cellular homeostasis. We present a genome-wide RNA interference screen to systematically identify regulators of apoptosis induced by DNA damage in Drosophila melanogaster cells. We identify 47 double- stranded RNA that target a functionally diverse set of genes, including several with a known function in promoting cell death. Further characterization uncovers 10 genes that influence caspase activation upon the removal of Drosophila inhibitor of apoptosis 1. This set includes the Drosophila initiator caspase Dronc and, surprisingly, several metabolic regulators, a candidate tumor suppressor, Charlatan, and an N-acetyltransferase, ARD1. Importantly, several of these genes show functional conservation in regulating apoptosis in mammalian cells. Our data suggest a previously unappreciated fundamental connection between various cellular processes and caspase-dependent cell death.
Open Access
Assessment of LD matrix measures for the analysis of biological pathway association.
(Stat Appl Genet Mol Biol, 2010) Crosslin, David R; Qin, Xuejun; Hauser, Elizabeth R
Complex diseases will have multiple functional sites, and it will be invaluable to understand the cross-locus interaction in terms of linkage disequilibrium (LD) between those sites (epistasis) in addition to the haplotype-LD effects. We investigated the statistical properties of a class of matrix-based statistics to assess this epistasis. These statistical methods include two LD contrast tests (Zaykin et al., 2006) and partial least squares regression (Wang et al., 2008). To estimate Type 1 error rates and power, we simulated multiple two-variant disease models using the SIMLA software package. SIMLA allows for the joint action of up to two disease genes in the simulated data with all possible multiplicative interaction effects between them. Our goal was to detect an interaction between multiple disease-causing variants by means of their linkage disequilibrium (LD) patterns with other markers. We measured the effects of marginal disease effect size, haplotype LD, disease prevalence and minor allele frequency have on cross-locus interaction (epistasis). In the setting of strong allele effects and strong interaction, the correlation between the two disease genes was weak (r=0.2). In a complex system with multiple correlations (both marginal and interaction), it was difficult to determine the source of a significant result. Despite these complications, the partial least squares and modified LD contrast methods maintained adequate power to detect the epistatic effects; however, for many of the analyses we often could not separate interaction from a strong marginal effect. While we did not exhaust the entire parameter space of possible models, we do provide guidance on the effects that population parameters have on cross-locus interaction.
Open Access
Associations of PI3KR1 and mTOR polymorphisms with esophageal squamous cell carcinoma risk and gene-environment interactions in Eastern Chinese populations.
(Scientific reports, 2015-01) Zhu, Jinhong; Wang, Mengyun; Zhu, Meiling; He, Jin; Wang, Jiu-Cun; Jin, Li; Wang, Xiao-Feng; Xiang, Jia-Qing; Wei, Qingyi
Single nucleotide polymorphisms (SNPs) in the PI3K/PTEN/AKT/mTOR signaling pathway may contribute to carcinogenesis. We genotyped five potentially functional PIK3R1 and mTOR SNPs in 1116 esophageal squamous cell cancer (ESCC) patients and 1117 cancer-free controls to assess their associations with ESCC risk. We observed no association with ESCC risk for any of the selected SNPs. However, the combined analysis of these SNPs revealed that subjects with one-to-three risk genotypes had an increased ESCC risk. Stratified analysis by body mass index (BMI) found that ESCC risk was significantly associated with each of three mTOR SNPs among subjects with BMI < 25.0. Specifically, we found that subjects carrying ≥ 1 risk genotypes had significantly increased ESCC risk, particularly for males, ever-smokers, ever-drinkers, and those with age > 60, or BMI < 25.0. Moreover, three mTOR haplotypes were associated with an increase in ESCC risk. Our meta-analysis of mTOR rs2295080 and cancer risk provided further evidence that mTOR SNPs might modulate cancer susceptibility. In this population, such risk effects might be modified by other risk factors, highlighting the importance of gene-environment interaction in esophageal carcinogenesis. Additional, larger studies are warranted to validate our findings.
Open Access
Cytokinesis proteins Tum and Pav have a nuclear role in Wnt regulation.
(J Cell Sci, 2010-07-01) Jones, Whitney M; Chao, Anna T; Zavortink, Michael; Saint, Robert; Bejsovec, Amy
Wg/Wnt signals specify cell fates in both invertebrate and vertebrate embryos and maintain stem-cell populations in many adult tissues. Deregulation of the Wnt pathway can transform cells to a proliferative fate, leading to cancer. We have discovered that two Drosophila proteins that are crucial for cytokinesis have a second, largely independent, role in restricting activity of the Wnt pathway. The fly homolog of RacGAP1, Tumbleweed (Tum)/RacGAP50C, and its binding partner, the kinesin-like protein Pavarotti (Pav), negatively regulate Wnt activity in fly embryos and in cultured mammalian cells. Unlike many known regulators of the Wnt pathway, these molecules do not affect stabilization of Arm/beta-catenin (betacat), the principal effector molecule in Wnt signal transduction. Rather, they appear to act downstream of betacat stabilization to control target-gene transcription. Both Tum and Pav accumulate in the nuclei of interphase cells, a location that is spatially distinct from their cleavage-furrow localization during cytokinesis. We show that this nuclear localization is essential for their role in Wnt regulation. Thus, we have identified two modulators of the Wnt pathway that have shared functions in cell division, which hints at a possible link between cytokinesis and Wnt activity during tumorigenesis.
Open Access
Epistasis among Drosophila persimilis factors conferring hybrid male sterility with D. pseudoobscura bogotana.
(PLoS One, 2010-10-27) Chang, AS; Bennett, SM; Noor, MAF
The Bateson-Dobzhansky-Muller model posits that hybrid incompatibilities result from genetic changes that accumulate during population divergence. Indeed, much effort in recent years has been devoted to identifying genes associated with hybrid incompatibilities, often with limited success, suggesting that hybrid sterility and inviability are frequently caused by complex interactions between multiple loci and not by single or a small number of gene pairs. Our previous study showed that the nature of epistasis between sterility-conferring QTL in the Drosophila persimilis-D. pseudoobscura bogotana species pair is highly specific. Here, we further dissect one of the three QTL underlying hybrid male sterility between these species and provide evidence for multiple factors within this QTL. This result indicates that the number of loci thought to contribute to hybrid dysfunction may have been underestimated, and we discuss how linkage and complex epistasis may be characteristic of the genetics of hybrid incompatibilities. We further pinpoint the location of one locus that confers hybrid male sterility when homozygous, dubbed "mule-like", to roughly 250 kilobases.
Open Access
Integrated pathway and epistasis analysis reveals interactive effect of genetic variants at TERF1 and AFAP1L2 loci on melanoma risk.
(Int J Cancer, 2015-10-15) Brossard, Myriam; Fang, Shenying; Vaysse, Amaury; Wei, Qingyi; Chen, Wei V; Mohamdi, Hamida; Maubec, Eve; Lavielle, Nolwenn; Galan, Pilar; Lathrop, Mark; Avril, Marie-Françoise; Lee, Jeffrey E; Amos, Christopher I; Demenais, Florence
Genome-wide association studies (GWASs) have characterized 13 loci associated with melanoma, which only account for a small part of melanoma risk. To identify new genes with too small an effect to be detected individually but which collectively influence melanoma risk and/or show interactive effects, we used a two-step analysis strategy including pathway analysis of genome-wide SNP data, in a first step, and epistasis analysis within significant pathways, in a second step. Pathway analysis, using the gene-set enrichment analysis (GSEA) approach and the gene ontology (GO) database, was applied to the outcomes of MELARISK (3,976 subjects) and MDACC (2,827 subjects) GWASs. Cross-gene SNP-SNP interaction analysis within melanoma-associated GOs was performed using the INTERSNP software. Five GO categories were significantly enriched in genes associated with melanoma (false discovery rate ≤ 5% in both studies): response to light stimulus, regulation of mitotic cell cycle, induction of programmed cell death, cytokine activity and oxidative phosphorylation. Epistasis analysis, within each of the five significant GOs, showed significant evidence for interaction for one SNP pair at TERF1 and AFAP1L2 loci (pmeta-int = 2.0 × 10(-7) , which met both the pathway and overall multiple-testing corrected thresholds that are equal to 9.8 × 10(-7) and 2.0 × 10(-7) , respectively) and suggestive evidence for another pair involving correlated SNPs at the same loci (pmeta-int = 3.6 × 10(-6) ). This interaction has important biological relevance given the key role of TERF1 in telomere biology and the reported physical interaction between TERF1 and AFAP1L2 proteins. This finding brings a novel piece of evidence for the emerging role of telomere dysfunction into melanoma development.
Open Access
Mutation accumulation may be a minor force in shaping life history traits.
(PLoS One, 2012) Dańko, Maciej Jan; Kozłowski, Jan; Vaupel, James Walton; Baudisch, Annette
Is senescence the adaptive result of tradeoffs between younger and older ages or the nonadaptive burden of deleterious mutations that act at older ages? To shed new light on this unresolved question we combine adaptive and nonadaptive processes in a single model. Our model uses Penna's bit-strings to capture different age-specific mutational patterns. Each pattern represents a genotype and for each genotype we find the life history strategy that maximizes fitness. Genotypes compete with each other and are subject to selection and to new mutations over generations until equilibrium in gene-frequencies is reached. The mutation-selection equilibrium provides information about mutational load and the differential effects of mutations on a life history trait--the optimal age at maturity. We find that mutations accumulate only at ages with negligible impact on fitness and that mutation accumulation has very little effect on the optimal age at maturity. These results suggest that life histories are largely determined by adaptive processes. The non-adaptive process of mutation accumulation seems to be unimportant at evolutionarily relevant ages.
Open Access
Regulation of growth-defense balance by the JASMONATE ZIM-DOMAIN (JAZ)-MYC transcriptional module.
(The New phytologist, 2017-09) Major, Ian T; Yoshida, Yuki; Campos, Marcelo L; Kapali, George; Xin, Xiu-Fang; Sugimoto, Koichi; de Oliveira Ferreira, Dalton; He, Sheng Yang; Howe, Gregg A
The plant hormone jasmonate (JA) promotes the degradation of JASMONATE ZIM-DOMAIN (JAZ) proteins to relieve repression on diverse transcription factors (TFs) that execute JA responses. However, little is known about how combinatorial complexity among JAZ-TF interactions maintains control over myriad aspects of growth, development, reproduction, and immunity. We used loss-of-function mutations to define epistatic interactions within the core JA signaling pathway and to investigate the contribution of MYC TFs to JA responses in Arabidopsis thaliana. Constitutive JA signaling in a jaz quintuple mutant (jazQ) was largely eliminated by mutations that block JA synthesis or perception. Comparison of jazQ and a jazQ myc2 myc3 myc4 octuple mutant validated known functions of MYC2/3/4 in root growth, chlorophyll degradation, and susceptibility to the pathogen Pseudomonas syringae. We found that MYC TFs also control both the enhanced resistance of jazQ leaves to insect herbivory and restricted leaf growth of jazQ. Epistatic transcriptional profiles mirrored these phenotypes and further showed that triterpenoid biosynthetic and glucosinolate catabolic genes are up-regulated in jazQ independently of MYC TFs. Our study highlights the utility of genetic epistasis to unravel the complexities of JAZ-TF interactions and demonstrates that MYC TFs exert master control over a JAZ-repressible transcriptional hierarchy that governs growth-defense balance.
Open Access
Sex-specific incompatibility generates locus-specific rates of introgression between species.
(Genetics, 2011-09) Fusco, Diana; Uyenoyama, Marcy K
Disruption of interactions among ensembles of epistatic loci has been shown to contribute to reproductive isolation among various animal and plant species. Under the Bateson-Dobzhansky-Muller model, such interspecific incompatibility arises as a by-product of genetic divergence in each species, and the Orr-Turelli model indicates that the number of loci involved in incompatible interactions may "snowball" over time. We address the combined effect of multiple incompatibility loci on the rate of introgression at neutral marker loci across the genome. Our analysis extends previous work by accommodating sex specificity: differences between the sexes in the expression of incompatibility, in rates of crossing over between neutral markers and incompatibility loci, and in transmission of markers or incompatibility factors. We show that the evolutionary process at neutral markers in a genome subject to incompatibility selection is well approximated by a purely neutral process with migration rates appropriately scaled to reflect the influence of selection targeted to incompatibility factors. We confirm that in the absence of sex specificity and functional epistasis among incompatibility factors, the barrier to introgression induced by multiple incompatibility factors corresponds to the product of the barriers induced by the factors individually. A new finding is that barriers to introgression due to sex-specific incompatibility depart in general from multiplicativity. Our partitioning of variation in relative reproductive rate suggests that such departures derive from associations between sex and incompatibility and between sex and neutral markers. Concordant sex-specific incompatibility (for example, greater impairment of male hybrids or longer map lengths in females) induces lower barriers (higher rates of introgression) than expected under multiplicativity, and discordant sex-specific incompatibility induces higher barriers.