Bakar, A. | bioRxiv Science

bioRxiv2026

GenoSim: A Forward-Time Genotype Simulator for Clinical and Population Genetics with Population Stratification

MotivationNext-generation sequencing studies in clinical genetics are often limited by the scarcity of human genotype data, which stems from ethical, regulatory, and economic barriers. The shortfall is sharpest in consanguineous populations, which are common in South Asia and the Middle East, where family-based designs need large pedigrees that are rarely sequenced in full. Existing simulators do not combine pedigree-aware propagation, realistic population stratification, and clinical export formats in one tool. ResultsWe present GenoSim, an R package for forward-time simulation of diploid SNP genotypes. It runs in two modes: a population mode implementing inbreeding-adjusted Hardy-Weinberg sampling, Wright-Fisher drift, directional selection, recurrent mutation, and Haldane recombination across multiple generations; and a pedigree-constrained mode that ingests real family VCFs and a pedigree, reconstructs phase where the pedigree makes it identifiable, propagates genotypes through the observed family structure, and appends synthetic generations. Version 1.1.1 adds population stratification through the Balding-Nichols model parameterised by gnomAD v3.1 fixation indices (Fsr) for eight ancestry groups (AFR, AMR, EAS, EUR, FIN, MID, SAS, ASJ), empirical allele-frequency loading from external reference panels, and admixed-cohort simulation. Analysis functions cover Hardy-Weinberg testing, linkage disequilibrium, runs of homozygosity, principal component analysis, founder-referenced and between-generation F-statistics, and Nei gene diversity. Output is compatible with VCFv4.2, PLINK PED/MAP/RAW, and tidy CSV. Availability and implementationGenoSim is available as an R package at https://github.com/malikbak/GenoSim under the MIT licence. It requires R [≥]4.0.0 and depends only on base R packages (stats, utils, graphics, grDevices, tools). Contactmalikabubakar279@gmail.com

bioinformatics↗

bioRxiv2025

Identification of Novel Fusion Genes in Pediatric B-ALL patients Using Whole Transcriptome Sequencing

BackgroundFusion genes (FGs), serving as diagnostic, prognostic, and therapeutic markers, are key molecular aberrations in acute leukemia. They are also essential for risk stratification and measurable residual disease (MRD) monitoring. This study aimed to characterize the distribution of FGs using whole transcriptome sequencing (WTS). Materials and MethodsA total of 12 newly diagnosed treatment naive pediatric B-ALL cases from a local tertiary care hospital were enrolled in this study. Following the nucleic acids isolation procedures, the RNA sequencing was done for 12 B-ALL patients to find the fusion genes. ResultsIn the present cohort of 12 pediatric B-ALL patients, 19 high-confidence in-frame gene fusion events were identified involving 29 unique partner genes. The commonly reported sub-type defining rearrangements in B-ALL, including ETV6-RUNX1, TCF3-PBX1 and BCR-ABL1, were found in 8.3 % of the patients whereas the rearrangements in commonly prevalent genes in B-ALL like PAX5, ABL1 and ATXN3 were also found in 8.3 % of the patients with different unreported partner genes but reported earlier in various studies i.e. PAX-ETV6 (8.3%), ABL1-SNX2 (8.3%) and CMC2-ATXN3. ConclusionThe present work expands the scope of fusions in pediatric B-ALL by revealing unreported and domain-retaining fusions, as well as co-occurring rearranged fusions with possible combinatorial outcomes. By introducing WTS into clinical workflows, the genetic classification can be done more accurately and new pathogenic drivers missed by traditional methods can be identified, highlighting the increased significance of transcriptomic profiling in the diagnosis, prognosis, and personalized therapy of leukemia.

genomics↗