Baldspot/ELOVL6 is a conserved modifier of disease and the ER stress response

Palu, Rebecca A.S.; Chow, Clement Y.

doi:10.1371/journal.pgen.1007557

Cited by 22 publications

(17 citation statements)

References 58 publications

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“…Ultimately, our goal is not to treat these associations as definitive, but to use these variants to nominate candidate modifier genes or pathways for subsequent functional validation. Despite the weak signals, this approach has been used to successfully identify bona fide modifier genes in previous work (Chow et al 2013, 2015, 2016; Palu and Chow 2018, 2019; Lavoy et al 2018; Ahlers et al 2019). Here again, this genome-wide association analysis yields a number of genes that potentially underlie the variable expressivity of degenerative phenotypes induced by these models of apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Natural Genetic Variation Screen inDrosophilaIdentifies Wnt Signaling, Mitochondrial Metabolism, and Redox Homeostasis Genes as Modifiers of Apoptosis

Palu

Ong

Stevens

et al. 2019

G3 Genes|Genomes|Genetics

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Apoptosis is the primary cause of degeneration in a number of neuronal, muscular, and metabolic disorders. These diseases are subject to a great deal of phenotypic heterogeneity in patient populations, primarily due to differences in genetic variation between individuals. This creates a barrier to effective diagnosis and treatment. Understanding how genetic variation influences apoptosis could lead to the development of new therapeutics and better personalized treatment approaches. In this study, we examine the impact of the natural genetic variation in the Drosophila Genetic Reference Panel (DGRP) on two models of apoptosis-induced retinal degeneration: overexpression of p53 or reaper (rpr). We identify a number of known apoptotic, neural, and developmental genes as candidate modifiers of degeneration. We also use Gene Set Enrichment Analysis (GSEA) to identify pathways that harbor genetic variation that impact these apoptosis models, including Wnt signaling, mitochondrial metabolism, and redox homeostasis. Finally, we demonstrate that many of these candidates have a functional effect on apoptosis and degeneration. These studies provide a number of avenues for modifying genes and pathways of apoptosis-related disease.

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Section: Resultsmentioning

confidence: 99%

Natural Genetic Variation Screen inDrosophilaIdentifies Wnt Signaling, Mitochondrial Metabolism, and Redox Homeostasis Genes as Modifiers of Apoptosis

Palu

Ong

Stevens

et al. 2019

G3 Genes|Genomes|Genetics

Self Cite

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show abstract

“…For example, candidate gene association and phenotypic correlation can be preserved among GWAS from different labs and using different populations of inbred fly lines ( Everman et al 2019 ; Pitchers et al 2019 ). Furthermore, weak DGRP signals have been used to identify genes that genuinely regulate the phenotypic output of the DGRP studies ( Chow et al 2016 ; Palu and Chow 2018 ; Ahlers et al 2019 ; Palu et al 2020 ). Nevertheless, we calculated FDR corrections that would result in an equivalent P -value cutoff of P < 10 −5 for each of our GWA analyses ( Benjamini and Hochberg 1995 ; Pinheiro et al 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Natural genetic variation inDrosophila melanogasterreveals genes associated withCoxiella burnetiiinfection

et al. 2021

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The gram-negative bacterium Coxiella burnetii is the causative agent of Query (Q) fever in humans and coxiellosis in livestock. Host genetics are associated with Coxiella burnetii pathogenesis both in humans and animals; however, it remains unknown if specific genes are associated with severity of infection. We employed the Drosophila Genetics Reference Panel to perform a genome-wide association study to identify host genetic variants that affect host survival to Coxiella burnetii infection. The genome-wide association study identified 64 unique variants (P < 10−5) associated with 25 candidate genes. We examined the role each candidate gene contributes to host survival during Coxiella burnetii infection using flies carrying a null mutation or RNAi knockdown of each candidate. We validated 15 of the 25 candidate genes using at least one method. This is the first report establishing involvement of many of these genes or their homologs with Coxiella burnetii susceptibility in any system. Among the validated genes, FER and tara play roles in the JAK/STAT, JNK, and decapentaplegic/TGF-β signaling pathways which are components of known innate immune responses to Coxiella burnetii infection. CG42673 and DIP-ε play roles in bacterial infection and synaptic signaling but have no previous association with Coxiella burnetii pathogenesis. Furthermore, since the mammalian ortholog of CG13404 (PLGRKT) is an important regulator of macrophage function, CG13404 could play a role in host susceptibility to Coxiella burnetii through hemocyte regulation. These insights provide a foundation for further investigation regarding the genetics of Coxiella burnetii susceptibility across a wide variety of hosts.

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“…We obtained 20 RNAi lines from the Bloomington Drosophila Stock Center. Ovary/germline specific RNAi knockdowns were performed using Gal4 DNA-binding protein and Upstream Activator Sequence ( GAL4/UAS ) technology, as previously described 61 . We crossed flies carrying the Maternal Triple Driver-GAL4 ( MTD-GAL4 ; BDSC 31777) transgene to flies carrying each respective UAS-RNAi transgene to generate female flies with ovary specific knockdown of each gene.…”

Section: Methodsmentioning

confidence: 99%

Causal and Candidate Gene Variants in a Large Cohort of Women with Primary Ovarian Insufficiency

Gorsi

Hernandez

Moore

et al. 2021

Preprint

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A genetic etiology accounts for unexplained primary ovarian insufficiency (POI; amenorrhea with an elevated FSH level). Subjects with POI (n=291) and controls recruited for health in old age or 1000 Genomes (n=233) underwent whole exome or whole genome sequencing. Data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1 and BOD1L1). Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.

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Baldspot/ELOVL6 is a conserved modifier of disease and the ER stress response

Cited by 22 publications

References 58 publications

Natural Genetic Variation Screen inDrosophilaIdentifies Wnt Signaling, Mitochondrial Metabolism, and Redox Homeostasis Genes as Modifiers of Apoptosis

Natural Genetic Variation Screen inDrosophilaIdentifies Wnt Signaling, Mitochondrial Metabolism, and Redox Homeostasis Genes as Modifiers of Apoptosis

Natural genetic variation inDrosophila melanogasterreveals genes associated withCoxiella burnetiiinfection

Causal and Candidate Gene Variants in a Large Cohort of Women with Primary Ovarian Insufficiency

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