Genetic Architectures of Quantitative Variation in RNA Editing Pathways

Gu, Tongjun; Gatti, Daniel M.; Srivastava, Anuj; Snyder, Elizabeth M.; Raghupathy, Narayanan; Šimeček, Petr; Svenson, Karen L.; Dotú, Iván; Chuang, Jeffrey H.; Keller, Mark P.; Attie, Alan D.; Braun, Robert E.; Churchill, Gary A.

doi:10.1534/genetics.115.179481

Cited by 25 publications

(34 citation statements)

References 43 publications

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“…Given the lack of editing changes with global A1CF loss, it appears as though while A1CF is capable of complementing APOBEC1-mediated editing in vitro, A1CF is not required for that function in vivo. This conclusion is supported by a failure to find genetic variation in C-to-U editing linked to either A1CF, or the mooring sequence for A1CF, in a genetically diverse multiparent mouse population (Gu et al 2016). Altered editing efficiencies at the ApoB locus and 49 other C-to-U edited sites appeared to be solely driven by linkage to four functional Apobec1 alleles segregating within the population.…”

Section: Discussionmentioning

confidence: 94%

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APOBEC1 complementation factor (A1CF) is dispensable for C-to-U RNA editing in vivo

Snyder

McCarty

Mehalow

et al. 2017

RNA

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Editing of the human and murine ApoB mRNA by APOBEC1, the catalytic enzyme of the protein complex that catalyzes C-to-U RNA editing, creates an internal stop codon within the APOB coding sequence, generating two protein isoforms. It has been long held that APOBEC1-mediated editing activity is dependent on the RNA binding protein A1CF. The function of A1CF in adult tissues has not been reported because a previously reported null allele displays embryonic lethality. This work aimed to address the function of A1CF in adult mouse tissues using a conditional A1cf allele. Unexpectedly, A1cf-null mice were viable and fertile with modest defects in hematopoietic, immune, and metabolic parameters. C-to-U RNA editing was quantified for multiple targets, including ApoB, in the small intestine and liver. In all cases, no changes in RNA editing efficiency were observed. Blood plasma analysis demonstrated a male-specific increase in solute concentration and increased cellularity in the glomeruli of male A1cf-null mice. Urine analysis showed a reduction in solute concentration, suggesting abnormal water homeostasis and possible kidney abnormalities exclusive to the male. Computational identification of kidney C-to-U editing sites from polyadenylated RNA-sequencing identified a number of editing sites exclusive to the kidney. However, molecular analysis of kidney C-to-U editing showed no changes in editing efficiency with A1CF loss. Taken together, these observations demonstrate that A1CF does not act as the APOBEC1 complementation factor in vivo under normal physiological conditions and suggests new roles for A1CF, specifically within the male adult kidney.

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Section: Discussionmentioning

confidence: 94%

“…In contrast, C-to-U editing is highly tissue and target dependent. Although genetic regulation of A-to-I editing is primarily dependent on cis-acting factors within the target RNAs themselves, C-to-U editing appears to be regulated by a limited number of trans-acting factors (Gu et al 2016). …”

Section: Introductionmentioning

confidence: 99%

APOBEC1 complementation factor (A1CF) is dispensable for C-to-U RNA editing in vivo

Snyder

McCarty

Mehalow

et al. 2017

RNA

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“…At 21 generations, the DO mouse population has proven to be a valuable resource for genetic mapping (Recla et al 2014; Smallwood et al 2014; Church et al 2015; French et al 2015; Gu et al 2016) and systems genetics (Kelly et al 2015; Chick et al 2016). However, an ongoing selective sweep driven by the R2d2 locus occurred in the DO breeding colony and threatened to eliminate genetic variation across a large region of chromosome 2.…”

Section: Discussionmentioning

confidence: 99%

Diversity Outbred Mice at 21: Maintaining Allelic Variation in the Face of Selection

Chesler

Gatti

Morgan

et al. 2016

G3 Genes|Genomes|Genetics

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Multi-parent populations (MPPs) capture and maintain the genetic diversity from multiple inbred founder strains to provide a resource for high-resolution genetic mapping through the accumulation of recombination events over many generations. Breeding designs that maintain a large effective population size with randomized assignment of breeders at each generation can minimize the impact of selection, inbreeding, and genetic drift on allele frequencies. Small deviations from expected allele frequencies will have little effect on the power and precision of genetic analysis, but a major distortion could result in reduced power and loss of important functional alleles. We detected strong transmission ratio distortion in the Diversity Outbred (DO) mouse population on chromosome 2, caused by meiotic drive favoring transmission of the WSB/EiJ allele at the R2d2 locus. The distorted region harbors thousands of polymorphisms derived from the seven non-WSB founder strains and many of these would be lost if the sweep was allowed to continue. To ensure the utility of the DO population to study genetic variation on chromosome 2, we performed an artificial selection against WSB/EiJ alleles at the R2d2 locus. Here, we report that we have purged the WSB/EiJ allele from the drive locus while preserving WSB/EiJ alleles in the flanking regions. We observed minimal disruption to allele frequencies across the rest of the autosomal genome. However, there was a shift in haplotype frequencies of the mitochondrial genome and an increase in the rate of an unusual sex chromosome aneuploidy. The DO population has been restored to genome-wide utility for genetic analysis, but our experience underscores that vigilant monitoring of similar genetic resource populations is needed to ensure their long-term utility.

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“…They found that the status of the editing efficiency matches the expression of the corresponding enzyme in the populations they studied 7 , indicating that the underlying genetics can affect both editing efficiency and gene expression. In our previous and several other groups' studies [8][9][10] , a strong genetic effect on RNA editing was identified. Here we developed a two-step generalized linear regression model to detect the novel genes potentially involved in the RNA editing process based on the association of gene expression with editing sites using hundreds of cancer samples.…”

Section: Introductionmentioning

confidence: 75%

Systematic identification of A-to-I editing associated regulators from multiple human cancers

Bolt

Zhao

2019

Preprint

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A-to-I editing is the most common editing type in human that is catalyzed by ADAR family members (ADARs), ADAR1 and ADAR2. Millions of A-to-I editing sites have been discovered recently, however, the regulation mechanisms of the RNA editing process are still not clear. Here we developed a two-step logistic regression model to identify genes that are potentially involved in RNA editing process in four human cancers. The first step by classifying the editing sites into different categories assists the analysis at the second step. In the first step, ADAR1 was identified as the enzyme that associated with the majority of the A-to-I editing sites. Thus, ADAR1 was taken as a control gene in the second step to identify genes that have a stronger effect on editing sites than ADAR1. In addition, the detectable interferons and their receptors were used as covariates in the both steps to account for potential association caused by interferons. Using our advanced method, we successfully found a set of genes that were significantly positively or negatively associated (PA or NA) with specific sets of RNA editing sites. We highlighted two genes, SRSF5and MIR22HG which were supported by multiple evidences. Most PA and NA genes were unique to each cancer, and only a few shared across two cancers. Pathway enrichment analysis showed that the PA genes from the four cancer types were enriched in Immune System, while the NA genes were enriched in two pathways: Metabolism of RNA, and Metabolism. The functional similarity of the PA and NA genes across all the four cancers indicates that even though most of the editing associated genes were unique to each cancer, they may impact on editing process through common pathways. Interestingly, the PA genes from kidney cancer were enriched for survival-associated genes while the NA genes were depleted of these genes, indicating that the PA genes may play more important roles in kidney cancer development.

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Genetic Architectures of Quantitative Variation in RNA Editing Pathways

Cited by 25 publications

References 43 publications

APOBEC1 complementation factor (A1CF) is dispensable for C-to-U RNA editing in vivo

APOBEC1 complementation factor (A1CF) is dispensable for C-to-U RNA editing in vivo

Diversity Outbred Mice at 21: Maintaining Allelic Variation in the Face of Selection

Systematic identification of A-to-I editing associated regulators from multiple human cancers

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