Cyclin B3 and dynein heavy chain cooperate to increase fitness in the absence of<i>mdf-1/MAD1</i>in<i>Caenorhabditis elegans</i>

Tarailo‐Graovac, Maja; Wong, Tammy; Qin, Zhaozhao; Flibotte, Stéphane; Taylor, John; Moerman, Donald G.; Rose, Ann M.; Chen, Nansheng

doi:10.4161/15384101.2014.949491

Cited by 2 publications

(1 citation statement)

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“…The experimental challenge includes establishing high-throughput forward genetic screening techniques utilizing model organisms as current mutagenesis and screening techniques often take years to identify modifiers [152][153][154]. On the other hand, the computational challenge exists in identifying genetic modifiers by comprehensively analyzing all the variants from an individual genome [155,156].…”

Section: Discussionmentioning

confidence: 99%

Genetic Modifiers and Rare Mendelian Disease

Rahit

Tarailo‐Graovac

2020

Genes

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Despite advances in high-throughput sequencing that have revolutionized the discovery of gene defects in rare Mendelian diseases, there are still gaps in translating individual genome variation to observed phenotypic outcomes. While we continue to improve genomics approaches to identify primary disease-causing variants, it is evident that no genetic variant acts alone. In other words, some other variants in the genome (genetic modifiers) may alleviate (suppress) or exacerbate (enhance) the severity of the disease, resulting in the variability of phenotypic outcomes. Thus, to truly understand the disease, we need to consider how the disease-causing variants interact with the rest of the genome in an individual. Here, we review the current state-of-the-field in the identification of genetic modifiers in rare Mendelian diseases and discuss the potential for future approaches that could bridge the existing gap.

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Section: Discussionmentioning

confidence: 99%

Genetic Modifiers and Rare Mendelian Disease

Rahit

Tarailo‐Graovac

2020

Genes

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120

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Spectrum of variations in dog-1/FANCJ and mdf-1/MAD1 defective Caenorhabditis elegans strains after long-term propagation

et al. 2015

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BackgroundWhole and partial chromosome losses or gains and structural chromosome changes are hallmarks of human tumors. Guanine-rich DNA, which has a potential to form a G-quadruplex (G4) structure, is particularly vulnerable to changes. In Caenorhabditis elegans, faithful transmission of G-rich DNA is ensured by the DOG-1/FANCJ deadbox helicase.ResultsTo identify a spectrum of mutations, after long-term propagation, we combined whole genome sequencing (WGS) and oligonucleotide array Comparative Genomic Hybridization (oaCGH) analysis of a C. elegans strain that was propagated, in the absence of DOG-1 and MDF-1/MAD1, for a total of 470 generations, with samples taken for long term storage (by freezing) in generations 170 and 270. We compared the genomes of F170 and F470 strains and identified 94 substitutions, 17 InDels, 3 duplications, and 139 deletions larger than 20 bp. These homozygous variants were predicted to impact 101 protein-coding genes. Phenotypic analysis of this strain revealed remarkable fitness recovery indicating that mutations, which have accumulated in the strain, are not only tolerated but also cooperate to achieve long-term population survival in the absence of DOG-1 and MDF-1. Furthermore, deletions larger than 20 bp were the only variants that frequently occurred in G-rich DNA. We showed that 126 of the possible 954 predicted monoG/C tracts, larger than 14 bp, were deleted in unc-46 mdf-1 such-4; dog-1 F470 (JNC170).ConclusionsHere, we identified variants that accumulated in C. elegans’ genome after long-term propagation in the absence of DOG-1 and MDF-1. We showed that DNA sequences, with G4-forming potential, are vulnerable to deletion-formation in this genetic background.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1402-y) contains supplementary material, which is available to authorized users.

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Cyclin B3 and dynein heavy chain cooperate to increase fitness in the absence ofmdf-1/MAD1inCaenorhabditis elegans

Cited by 2 publications

References 32 publications

Genetic Modifiers and Rare Mendelian Disease

Genetic Modifiers and Rare Mendelian Disease

Spectrum of variations in dog-1/FANCJ and mdf-1/MAD1 defective Caenorhabditis elegans strains after long-term propagation

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