Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/429472

Evolutionary rate covariation analysis of E-cadherin identifies Raskol as regulator of cell adhesion and actin dynamics in Drosophila

Raza, Q.·Choi, J. Y.·Li, Y.·O'Dowd, R. M.·Watkins, S. C.·Hong, Y.·Clark, N. L.·Kwiatkowski, A. V.
View original source ↗Export metadata ↓

Abstract

The adherens junction couples the actin cytoskeletons of neighboring cells to provide the foundation for multicellular organization. The core of the adherens junction is the cadherin-catenin complex that arose early in the evolution of multicellularity to link cortical actin to intercellular adhesions. Over time, evolutionary pressures have shaped the signaling and mechanical functions of the adherens junction to meet specific developmental and physiological demands. Evolutionary rate covariation (ERC) identifies genes with correlated fluctuations in evolutionary rate that can reflect shared selective pressures and functions. Here we use ERC to identify genes with evolutionary histories similar to shotgun (shg), which encodes the Drosophila E-cadherin (DE-Cad) ortholog. Core adherens junction components -catenin and p120-catenin displayed strong ERC correlations with shg, indicating that they evolved under similar selective pressures during evolution between Drosophila species. Further analysis of the shg ERC profile revealed a collection of genes not previously associated with shg function or cadherin-mediated adhesion. We then analyzed the function of a subset of ERC-identified candidate genes by RNAi during border cell (BC) migration and identified novel genes that function to regulate DE-Cad. Among these, we found that the gene CG42684, which encodes a putative GTPase activating protein (GAP), regulates BC migration and adhesion. We named CG42684 raskol (\"to split\" in Russian) and show that it regulates DE-Cad levels and actin protrusions in BCs. We propose that Raskol functions with DE-Cad to restrict Ras/Rho signaling and help guide BC migration. Our results demonstrate that a coordinated selective pressure has shaped the adherens junction and this can be leveraged to identify novel components of the complexes and signaling pathways that regulate cadherin-mediated adhesion.\n\nAuthor SummaryThe establishment of intercellular adhesions facilitated the genesis of multicellular organisms. The adherens junction, which links the actin cytoskeletons of neighboring cells, arose early in the evolution of multicellularity and selective pressures have shaped its function and molecular composition over time. In this study, we used evolutionary rate covariation (ERC) analysis to examine the evolutionary history of the adherens junction and to identify genes that coevolved with the adherens junction gene shotgun, which encodes the Drosophila E-cadherin (DE-Cad). ERC analysis of shotgun revealed a collection of genes with similar evolutionary histories. We then tested the role of these genes in border cell migration in the fly egg chamber, a process that requires the coordinated regulation of cell-cell adhesion and cell motility. Among these, we found that a previously uncharacterized gene CG42684, which encodes a putative GTPase activating protein (GAP), regulates the collective cell migration of border cells, stabilizes cell-cell adhesions and regulates the actin dynamics. Our results demonstrate that components of the adherens junction share an evolutionary history and that ERC analysis is a powerful method to identify novel components of cell adhesion complexes in Drosophila.

Source connections

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Raza, Q., Choi, J. Y., Li, Y., O'Dowd, R. M., Watkins, S. C., Hong, Y., Clark, N. L., Kwiatkowski, A. V.. 2018-09-27. Evolutionary rate covariation analysis of E-cadherin identifies Raskol as regulator of cell adhesion and actin dynamics in Drosophila. https://doi.org/10.1101/429472

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Mapping, stacking and characterization of a novel resistance haplotype against GpaVvrn-virulent Globodera pallida derived from wild potato relative Solanum brevicaule

Potato production is threatened by pests and pathogens. Among the most harmful are the potato cyst nematodes (PCN), including Globodera pallida. The major control measures are potato cultivars harbouring resistance genes. However, virulent nematode populations are breaking through the most broadly applied resistance genes, and therefore novel resistance genes are required to keep control of G. pallida. In this study we map a resistance locus in wild potato relative Solanum brevicaule to the bottom of chromosome 11 (42.83 - 42.85 Mb) using a k-mer based bulked segregant analysis and name the resistant haplotype GpaXIbrc. The presence of the GpaXIbrc marker in the potato genome significantly increases resistance against a GpaVvrn-virulent G. pallida population (AMPOP01). Furthermore, the GpaXIbrc haplotype was stacked with three other resistance haplotypes: GpaXItar, GpaVvrn, and GpaIXvrn. Stacking of the novel GpaXIbrc haplotype to these other resistance haplotypes resulted in a significant increase in resistance. The largest effect was seen in combinations with 'major' resistance haplotypes GpaVvrn + GpaIXvrn and GpaXItar + GpaXIbrc. To determine whether we are dealing with a novel allele, the resistance mechanism underlying the GpaXIbrc haplotype was described after performing an in vitro bioassay. The resistance mechanism was different from GpaXIspl as described in literature, which is also localized at the bottom of chromosome 11. Therefore, we conclude that we found a novel resistance allele originating from S. brevicaule.

genetics↗
bioRxiv2026

Cellular context shapes the transcriptomic impact of somatic variants

Somatic SNVs are commonly prioritized by recurrence or sequence annotation, leaving the molecular consequences of private variants unresolved. We developed PrismSNV and Ligo-Seq, a single-cell full-length transcriptome sequencing platform, to quantify transcriptomic displacement associated with within-cell SNV-state toggling. Across 26 samples from three cancer types, more than 60% of candidate SNVs showed significant cell-type-specific displacement with over 30% variation in magnitude. Sequence-based deleteriousness was poorly aligned with cellular displacement, and fewer than 3% of top-displacement SNVs across six tumor types were catalogued in ClinVar. Displacement was strongest in transcriptionally plastic, less differentiated states. Analysis of 655,349 CD4+ T-cell transcriptomes further showed that SNV-gene associations changed in magnitude and sometimes direction during activation. Lack of recurrence or clinical annotation does not imply transcriptomic inertness; variant impact is shaped by cellular context rather than sequence alone, establishing the variant-cell pair as a critical unit for interpreting somatic variation.

genetics↗
bioRxiv2026

Genetic and Epigenetic Landscape of Self-Identified Hispanics/Latino in All Of Us

Human genetic studies still underrepresent many populations, limiting discovery and interpretation of medically relevant variation. Extensive admixture in self-identified Hispanic/Latino populations increases the need for representative reference data and ancestry-aware interpretation of medically relevant variation. We used long-read sequencing to analyze genetic variation, ancestry, and DNA methylation in 1,490 self-identified Hispanic/Latino participants from the All of Us Research Program. We identified 10 million novel variants and more than 100 candidate phenotype associations, with fine-mapping prioritizing structural variants over nearby single-nucleotide variants in more than half. We linked 3,329 tandem repeats to DNA methylation, resolved widespread allele-specific methylation, and identified ancestry-linked regulation across paralogous genes. These results reveal previously inaccessible genetic and regulatory variation and show the value of long-read sequencing for diverse populations.

genetics↗