👤 Matthieu Schapira

Sequence alignment is essential for genomic research and clinical diagnostics, yet detecting complex rearrangements such as inversions, duplications, and gene conversions remains challenging due to allele complexity and limitations of current methods. We introduce VACmap, a non-linear mapping approach to enhance the detection and representation of all genetic variations. VACmap improves duplication detection from 20% to 90% in the Challenging Medically-Relevant Genes (CMRG) benchmark and improves characterization of complex inversions in repetitive regions and gene conversion events. It improves resolving clinically significant loci, including the LPA gene (with repetitive KIV-2 units linked to coronary heart disease), GBA1 and STRC genes (risk factors for Parkinson's disease and hearing loss, respectively, affected by pseudogene recombination with GBAP1 and STRCP1). Here, we show that VACmap delivers better alignment accuracy and SV detection, providing a robust tool for genomic analysis and clinical insights, with potential to advance understanding of genetic diversity and disease mechanisms. Show less

The eight mammalian Cbx proteins are chromodomain-containing proteins involved in regulation of heterochromatin, gene expression, and developmental programs. They are evolutionarily related to the Drosophila HP1 (dHP1) and Pc (dPc) proteins that are key components of chromatin-associated complexes capable of recognizing repressive marks such as trimethylated Lys-9 and Lys-27, respectively, on histone H3. However, the binding specificity and function of the human homologs, Cbx1-8, remain unclear. To this end we employed structural, biophysical, and mutagenic approaches to characterize the molecular determinants of sequence contextual methyllysine binding to human Cbx1-8 proteins. Although all three human HP1 homologs (Cbx1, -3, -5) replicate the structural and binding features of their dHP counterparts, the five Pc homologs (Cbx2, -4, -6, -7, -8) bind with lower affinity to H3K9me3 or H3K27me3 peptides and are unable to distinguish between these two marks. Additionally, peptide permutation arrays revealed a greater sequence tolerance within the Pc family and suggest alternative nonhistone sequences as potential binding targets for this class of chromodomains. Our structures explain the divergence of peptide binding selectivity in the Pc subfamily and highlight previously unrecognized features of the chromodomain that influence binding and specificity. Show less