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Cross, R.

Publications and source records attributed to Cross, R..

3 recordsLinked to original sources

Complex structural variation and behavioral interactions underpin a balanced sexual mimicry polymorphism

How phenotypic diversity originates and persists within populations are classic puzzles in evolutionary biology. While polymorphisms hypothesized to be under balancing selection segregate within many species, it remains rare for the genetic basis and the selective forces to both be known for the same trait, leading to an incomplete understanding of many classes of polymorphisms. Here, we uncover the genetic architecture of a balanced sexual mimicry polymorphism and identify behavioral mechanisms that may be involved in its maintenance in the swordtail fish Xiphophorus birchmanni. We find that [~]40% of X. birchmanni males develop a "false gravid spot", a melanic pigmentation pattern that mimics the "pregnancy spot" associated with sexual maturity in female live-bearing fish. Using genome-wide association mapping, we detect a single intergenic region associated with variation in the false gravid spot, which is upstream of kitlga, a gene involved in melanophore patterning. By performing long-read sequencing within and across populations, we identify complex structural rearrangements between alternate alleles at this locus. The false gravid spot haplotype drives increased allele-specific expression of kitlga, which provides a mechanistic explanation for the increased melanophore abundance that causes the spot. By studying social interactions in the laboratory and in nature, we find that males with the false gravid spot experience less aggression; however, they also receive increased attention from other males and are disdained by females. These behavioral interactions may play a role in maintaining this phenotypic polymorphism in natural populations. We speculate that structural variants affecting gene regulation may be an underappreciated driver of balanced polymorphisms across diverse species.

evolutionary biology↗

DNA demethylation switches the drivers of Foxp3 expression to maintain regulatory T cell identity

Maintenance of differentiated cellular states is crucial for numerous biological processes, yet its molecular basis remains unclear. Here, we investigate how mechanistically regulatory T (Treg) cell fate is "locked in" during lineage commitment via transcriptional regulation of its lineage-specifying factor Foxp3. Tet-mediated DNA demethylation of Foxp3 enhancer CNS2 was proposed to be a key mechanism maintaining Foxp3 transcription. However, this model has not been directly tested. Therefore, we integrated genetic, pharmacological, and epigenetic approaches to examine the function and mechanism of DNA demethylation in Treg lineage maintenance. We observed an abrupt switch of the transcriptional drivers of Foxp3 upon DNA demethylation, which was abolished by CNS2 deficiency. Demethylation of CNS2 increased chromatin accessibility and protein binding, conferring on Treg fate substantial resistance to adverse environments. Thus, our study consolidated the role of DNA demethylation in stabilizing Foxp3 expression in cis and revealed a novel regulatory mode governing Treg identity.

immunology↗

Near-atomic cryo-EM structure of yeast kinesin 5-microtubule complex reveals a distinct binding footprint

Kinesin-5s are essential members of the superfamily of microtubule-dependent motors that undertake conserved roles in cell division. We investigated coevolution of the motor-microtubule interface using cryo-electron microscopy to determine the near-atomic structure of the motor domain of Cut7, the fission yeast kinesin-5, bound to fission yeast microtubules. AMPPNP-bound Cut7 adopts a kinesin-conserved ATP-like conformation, with a closed nucleotide binding pocket and docked neck linker that supports cover neck bundle formation. Compared to mammalian tubulin microtubules, Cut7s footprint on S. pombe microtubule surface is subtly different because of their different architecture. However, the core motor-microtubule interaction that stimulates motor ATPase is tightly conserved, reflected in similar Cut7 ATPase activities on each microtubule type. The S. pombe microtubules were bound by the drug epothilone, which is visible in the taxane binding pocket. Stabilization of S. pombe microtubules is mediated by drug binding at this conserved site despite their noncanonical architecture and mechanochemistry.\n\nHighlightsO_LIS. pombe Cut7 has a distinct binding footprint on S. pombe microtubules\nC_LIO_LIThe core interface driving microtubule activation of motor ATPase is conserved\nC_LIO_LIThe neck linker is docked in AMPPNP-bound Cut7 and the cover neck bundle is formed\nC_LIO_LIEpothilone binds at the taxane binding site to stabilize S. pombe microtubules\nC_LI\n\neTOC textTo investigate coevolution of the motor-microtubule interface, we used cryo-electron microscopy to determine the near-atomic structure of the motor domain of Cut7, the fission yeast kinesin-5, bound to microtubules polymerized from natively purified fission yeast tubulin and stabilised by the drug epothilone.

biophysics↗