Hinson, S. | Search bioRxiv

bioRxiv2025

Non-uniform chromosomal SNP density biases sites of meiotic crossovers in Drosophila melanogaster

Here we localize a genetic suppressor that enhances the reduced locomotor activity phenotype of flies lacking brain dopamine. We utilized a non-bulked segregant analysis using whole genome sequencing (WGS), mapping the trait to a roughly 3.5 mega-base (Mb) region of the X-chromosome. However, this mapping yielded [~]5-fold lower resolution than anticipated, due to an uneven distribution of Single Nucleotide Polymorphisms (SNPs) between the X-chromosomes of the two recombining lines. This uneven SNP distribution was associated with recombination events biased towards regions of low SNP density, and away from the more SNP dense regions associating with the activity phenotype. We find that nearly perfect mapping of X-chromosome visible markers occurs only in historical data from a time before the establishment of discrete genetic background strains. This suggests that genetic uniformity in early Drosophila studies may have contributed to more consistent recombination frequencies, whereas modern mapping efforts are complicated by variability in SNP distribution across recombining strains. These findings highlight challenges in Drosophila genetic mapping in situations where altered SNP density can skew recombination, complicating trait localization. Article SummaryGenetic mapping studies generally assume uniform crossover distribution across chromosomes. However, this study demonstrates that an uneven density of single nucleotide polymorphism (SNP) is associated with biased sites of meiotic recombination. Using brain dopamine-deficient Drosophila, SNP dense regions show reduced crossover frequency, which reduced the mapping resolution, complicating genetic trait localization. These findings highlight the need to consider parental chromosome SNP distribution and its impact on recombination when designing genetic mapping studies. Future studies should consider chromosome structure, parental haplotype, and sequence heterogeneity to enhance mapping accuracy and resolution.

genetics↗

bioRxiv2025

Integrative Functional Genomics Identifies ARHGAP10 in the 4q31.2 Locus as a Novel Congenital Heart Disease and Ciliopathy Gene.

Congenital heart disease (CHD) remains a major cause of pediatric morbidity and mortality, yet its genetic underpinnings are not fully understood. Two studies independently identified rare deletions in ARHGAP10 (GAP10), a Rho GTPase-activating protein located at 4q31.2 in individuals with heterotaxy and atrial septal defects (n=2 rare copy number variants (CNVs)), highlighting GAP10 as a new candidate CHD gene. While the 4q31.2 locus is implicated in CHD, the function of GAP10 has not been investigated. Here, using Xenopus tropicalis as a model, we demonstrate that gap10 deletion disrupts morphogenetic movements critical for body axis extension, left-right organizer (LRO) formation, and ciliogenesis, leading to severe cardiac looping defects that closely mirror human CHD phenotypes. Moreover, gap10 localizes to basal bodies of motile cilia in multiciliated cells, where it regulates basal body organization and apical actin enrichment by recruiting focal adhesion kinase (FAK) to specialized ciliary adhesion complexes. In summary, our findings implicate GAP10 as a clinically relevant, genetically supported, and functionally validated regulator of CHD and ciliogenesis, underscoring the power of integrative functional genomics in the discovery of rare disease genes.

developmental biology↗