Biology subjects

Ferraj, A.

Publications and source records attributed to Ferraj, A..

3 recordsLinked to original sources

bioRxiv2025

Segmental duplication-mediated rearrangements alter the landscape of mouse genomes

Segmental duplications (SDs) are dynamic regions of mammalian genomes that drive structural variation and phenotypic diversity. However, genome-wide characterization of the SD landscape and the rearrangements mediated by SD paralogs in mouse genomes has been limited by the near-exclusive reliance on short-read sequencing technologies. Here, we integrate long-read genome assemblies, optical mapping, and k-mer based copy number analysis across eight genetically diverse inbred mouse strains to identify and characterize SD-mediated rearrangements. We identify 223 rearrangements affecting over 14 Mb of sequence and reveal substantial variation in gene content. These rearrangements affect loci involved in immunity, sensory perception, and gene regulation, including variation in the amylase gene cluster (Amy2a) and KRAB-zinc finger genes. We observed that SD flanks in mouse genomes are significantly enriched for young LINE-1 transposable elements, suggesting a potential role for transposons in promoting recombination and generating SDs within mice. Our findings highlight the contribution of SDs to genome structure and intra-species variation, and provide a resource for identifying regions prone to rearrangement in a critical model organism for biomedical research.

genomics↗

bioRxiv2024

Anapc5 and Anapc7 as genetic modifiers of KIF18A function in fertility and mitotic progression

The kinesin family member 18A (KIF18A) is an essential regulator of microtubule dynamics and chromosome alignment during mitosis. Functional dependency on KIF18A varies by cell type and genetic context but the heritable factors that influence this dependency remain unknown. To address this, we took advantage of the variable penetrance observed in different mouse strain backgrounds to screen for loci that modulate germ cell depletion in the absence of KIF18A. We found a significant association at a Chr5 locus where anaphase promoting complex subunits 5 (Anapc5) and 7 (Anapc7) were the top candidate genes. We found that both genes were differentially expressed in a sensitive strain background when compared to resistant strain background at key timepoints in gonadal development. We also identified a novel retroviral insertion in Anapc7 that may in part explain the observed expression differences. In cell line models, we found that depletion of KIF18A induced mitotic arrest, which was partially rescued by co-depletion of ANAPC7 (APC7) and exacerbated by co-depletion of ANAPC5 (APC5). These findings suggest that differential expression and activity of Anapc5 and Anapc7 may influence sensitivity to KIF18A depletion in germ cells and CIN cells, with potential implications for optimizing antineoplastic therapies.

cell biology↗

bioRxiv2022

Resolution of structural variation in diverse mouse genomes reveals chromatin remodeling due to transposable elements

Diverse inbred mouse strains are among the foremost models for biomedical research, yet genome characterization of many strains has been fundamentally lacking in comparison to human genomics research. In particular, the discovery and cataloging of structural variants is incomplete, limiting the discovery of potentially causative alleles for phenotypic variation across individuals. Here, we utilized long-read sequencing to resolve genome-wide structural variants (SVs, variants [≥] 50 bp) in 20 genetically distinct inbred mice. We report 413,758 site-specific SVs that affect 13% (356 Mbp) of the current mouse reference assembly, including 510 previously unannotated variants which alter coding sequences. We find that 39% of SVs are attributed to transposable element (TE) variation accounting for 75% of bases altered by SV. We then utilized this callset to investigate the impact of TE heterogeneity on mouse embryonic stem cells (mESCs), and find multiple TE classes that influence chromatin accessibility across loci. We also identify strain-specific transcription start sites originating in polymorphic TEs that modify gene expression. Our work provides the first long-read based analysis of mouse SVs and illustrates that previously unresolved TEs underlie epigenetic and transcriptome differences in mESCs.

genomics↗