Biology subjects

Yamrom, B.

Publications and source records attributed to Yamrom, B..

4 recordsLinked to original sources

bioRxiv2026

PAXIP1-PAGR1 directs cohesin recruitment during break-induced telomere repair

Cohesin is a conserved multiprotein complex (SMC1, SMC3, RAD21, and either STAG1 or STAG2) that organizes three-dimensional genome architecture and regulates chromosome segregation, gene expression, and DNA damage repair (1-4). Following double-strand breaks (DSBs), cohesin is recruited to sites of DNA damage - a process considered essential for efficient homologous recombination (5-15). Yet how DSB signaling elicits cohesin recruitment and subsequent cohesion establishment remains poorly understood. Here we show that telomere replication stress activates de novo STAG2-cohesin loading, thereby promoting break-induced telomeric DNA repair. We demonstrate that this DNA break-elicited cohesin recruitment is strictly controlled by the BRCT domain-containing DNA damage recognition factor PAXIP1 and its functional partner PAGR1. Cryo-electron microscopy structure reveals that PAGR1, together with PAXIP1, physically binds to a composite interface formed by the STAG2-RAD21 cohesin subcomplex. Complementary mutational and biochemical analyses define the molecular basis of this interaction and establish its essential role in break-induced cohesion establishment. Furthermore, we show that PAXIP1-PAGR1-enacted STAG2-cohesin recruitment complements with the PML body-associated pathway in orchestrating break-induced alternative lengthening of telomeres (ALT). Concurrent depletion of PML together with PAXIP1, PAGR1 or STAG2 disrupts ALT-mediated telomere maintenance, leading to end-to-end chromosomal fusion and mitotic cell death. Collectively, these findings uncover a distinctive molecular mechanism through which DSB signaling directs de novo cohesion establishment, and highlight its critical importance in break-induced telomere repair.

molecular biology↗

bioRxiv2024

The Genotype and Phenotypes in Families (GPF) platform manages the large and complex data at SFARI

The exploration of genotypic variants impacting phenotypes is a cornerstone in genetics research. The emergence of vast collections containing deeply genotyped and phenotyped families has made it possible to pursue the search for variants associated with complex diseases. However, managing these large-scale datasets requires specialized computational tools tailored to organize and analyze the extensive data. GPF (Genotypes and Phenotypes in Families) is an open-source platform (https://github.com/iossifovlab/gpf) that manages genotypes and phenotypes derived from collections of families. The GPF interface allows interactive exploration of genetic variants, enrichment analysis for de novo mutations, and phenotype/genotype association tools. In addition, GPF allows researchers to share their data securely with the broader scientific community. GPF is used to disseminate two large-scale family collection datasets (SSC, SPARK) for the study of autism funded by the SFARI foundation. However, GPF is versatile and can manage genotypic data from other small or large family collections. Our GPF-SFARI GPF instance (https://gpf.sfari.org/) provides protected access to comprehensive genotypic and phenotypic data for the SSC and SPARK. In addition, GPF-SFARI provides public access to an extensive collection of de novo mutations identified in individuals with autism and related disorders and to gene-level statistics of the protected datasets characterizing the genes roles in autism. Here, we highlight the primary features of GPF within the context of GPF-SFARI.

bioinformatics↗

bioRxiv2022

Snakeobjects: an object-oriented workflow management system

Snakemake is one of the most popular workflow management systems, particularly in biological sciences. Snakemake workflows are highly portable, scalable, and transparent. Moreover, they enable the painless reproduction of published results and adaption to similar data processing and analysis projects. Here we present Snakeobjects, an extension of Snakemake that considerably simplifies the development of workflows and improves their readability and adaptability while preserving all the benefits of Snakemake that ensure the large and growing community of its users.

bioinformatics↗

bioRxiv2017

De novo indels within introns contribute to ASD incidence

Copy number profiling and whole-exome sequencing has allowed us to make remarkable progress in our understanding of the genetics of autism over the past ten years, but there are major aspects of the genetics that are unresolved. Through whole-genome sequencing, additional types of genetic variants can be observed. These variants are abundant and to know which are functional is challenging. We have analyzed whole-genome sequencing data from 510 of the Simons Simplex Collections quad families and focused our attention on intronic variants. Within the introns of 546 high-quality autism target genes, we identified 63 de novo indels in the affected and only 37 in the unaffected siblings. The difference of 26 events is significantly larger than expected (p-val = 0.01) and using reasonable extrapolation shows that de novo intronic indels can contribute to at least 10% of simplex autism. The significance increases if we restrict to the half of the autism targets that are intolerant to damaging variants in the normal human population, which half we expect to be even more enriched for autism genes. For these 273 targets we observe 43 and 20 events in affected and unaffected siblings, respectively (p-value of 0.005). There was no significant signal in the number of de novo intronic indels in any of the control sets of genes analyzed. We see no signal from de novo substitutions in the introns of target genes.

genetics↗