Publications by authors named "Ryan J McGinty"
Article Synopsis
- CANVAS is a genetic disorder linked to expansions of a specific DNA repeat in the RFC1 gene, with pathogenic (A2G3)n and nonpathogenic (A4G)n repeats present in the human population.
- Research showed that the pathogenic (A2G3)n repeat blocks DNA replication in vitro, while the benign (A4G)n repeat does not, suggesting that the former can form unusual DNA structures like triplexes or quadruplexes in the presence of certain ions.
- In experimental models, the harmful (A2G3)n repeat was found to disrupt normal DNA replication in both yeast and human cells, indicating it poses challenges to genome stability.
CANVAS is a recently characterized repeat expansion disease, most commonly caused by homozygous expansions of an intronic (AG) repeat in the gene. There are a multitude of repeat motifs found in the human population at this locus, some of which are pathogenic and others benign. In this study, we conducted structure-functional analyses of the main pathogenic (AG) and the main nonpathogenic (AG) repeats.
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- - The study explores how double-strand breaks (DSBs) created by Cas9 in the retrotransposon Ty1 in yeast can lead to significant genomic changes, such as deletions and rearrangements of chromosomes.
- - Researchers found that most of these rearrangements occurred through non-allelic homologous recombination at Ty1 elements, showing that certain Ty clusters are hotspots for these genetic changes.
- - The results indicate differences in repair pathways used by haploid and diploid yeast strains, underscoring the role of retrotransposons in genome evolution through DNA damage and repair mechanisms.
Article Synopsis
- - Biological mechanisms behind human germline mutations are not well understood, but recent analysis has identified nine processes that influence mutation rates and types through a deep dive into genomic variation.
- - Using data from a large sequencing study (TOPMed), researchers interpreted seven of these processes, linking them to factors like DNA damage resolution and the effects of DNA replication timing and direction.
- - They discovered specific mutagenic effects related to DNA regulation and certain DNA elements, highlighting a unique mutagenic process in oocytes that shows transcriptional asymmetry.
Article Synopsis
- * Research on Friedreich's ataxia (GAA repeats) revealed that large-scale deletions and repeat expansions occur in nondividing cells during aging, driven by the activity of specific DNA repair complexes and polymerases.
- * The study highlights that the mechanisms of repeat instability differ significantly between dividing and non-dividing cells, suggesting these variations could impact the development of diseases like Friedreich's ataxia.
Article Synopsis
- * Genetic variants can influence these diseases both nearby (cis) and far (trans) from the repeat regions, but our understanding is limited by discrepancies between model studies and human genetic diversity.
- * The authors suggest using SNP-based screening in model systems to better identify and understand genetic modifiers that can impact these diseases and improve patient care.
Article Synopsis
- Improper repair of DNA double-strand breaks (DSBs) can lead to complex genomic rearrangements (CGRs) associated with various cancers and genetic disorders, such as Friedreich's ataxia and fragile X syndrome.
- Recent advances in long-read DNA sequencing technologies, like Nanopore sequencing, allow for quicker and more precise mapping of CGRs at the single base pair level.
- By applying whole-genome Nanopore sequencing, researchers have characterized CGRs from DSBs at (GAA) microsatellites, providing valuable insights into the mechanisms behind DSB repair that lead to these genomic changes.
Article Synopsis
- Repetitive DNA sequences, especially trinucleotide repeats, can lead to various hereditary disorders in humans due to their instability.
- This study presents a new method to analyze the instability of these triplet repeats using yeast as a model organism.
- The researchers utilize a fluctuation assay combined with a software called FluCalc to measure the rates of repeat expansions and associated genetic mutations.
Article Synopsis
- Expansions of microsatellite repeats are linked to hereditary diseases like myotonic dystrophy and Friedreich's ataxia, with repeat length being a key factor in disease inheritance.
- Recent findings suggest that additional genomic factors, known as trans modifiers, can influence the likelihood of these expansions and how the diseases progress.
- This study introduces a method for quickly identifying these trans modifiers in yeast, discovering that mutations in a specific protein (Ysh1) increase the rate of certain repeat expansions when they are being actively transcribed, indicating a connection between RNA processing and genetic stability.
Article Synopsis
- - The study investigates how simple DNA repeat expansions contribute to hereditary disorders like Friedreich's ataxia, focusing on whether replication or transcription plays a bigger role in this process.
- - The researchers created two yeast genetic systems to compare repeat expansions in both transcribed and non-transcribed regions, discovering that large expansions can happen without transcription and that transcription significantly increases the rate of expansions.
- - They propose a model suggesting that the transcriptional state of DNA, influenced by nucleosomal density, regulates the frequency of large-scale repeat expansions, with replication defects also boosting these rates regardless of transcription.