Kean, C. M. | bioRxiv Science

bioRxiv2022

Decreasing Wapl dosage partially corrects transcriptome phenotypes in Nipbl-/+ embryonic mouse brain

Cohesin rings interact with DNA and modulate expression of thousands of genes. NIPBL loads cohesin onto chromosomes and WAPL takes it off. Heterozygous mutations in NIPBL lead to a developmental disorder called Cornelia de Lange syndrome. Nipbl heterozygous mice are a good model for this disease but mutations in WAPL were not known to cause disease or gene expression changes in mammals. Here we show dysregulation of >1000 genes in Wapl{Delta}/+ embryonic mouse brains. The patterns of dysregulation are highly similar to Nipbl heterozygotes, suggesting that Wapl mutations may also cause disease in humans. Since WAPL and NIPBL have opposite effects on cohesins association with DNA, we asked whether a heterozygous Wapl mutation could correct phenotypes seen in Nipbl heterozygous mice. In fact, both gene expression and embryonic growth are partially corrected. Our data are consistent with the view that cohesin dynamics play a key role in regulating gene expression.

genetics↗

bioRxiv2022

Testing the Drosophila maternal haploid gene for functional divergence and a role in hybrid incompatibility

Crosses between D. simulans females and D. melanogaster males produce viable F1 sons and poorly viable F1 daughters. Unlike most hybrid incompatibilities, this hybrid incompatibility violates Haldanes rule, the observation that incompatibilities preferentially affect the heterogametic sex. Further, it is important to understand fully the genetic basis of this incompatibility because the causal allele in D. melanogaster is a large species-specific block of complex satellite DNA on its X chromosome known as the 359-bp satellite, rather than a protein-coding locus. The causal allele(s) in D. simulans are unknown but likely involve maternally expressed genes or factors since the F1 females die during early embryogenesis. The maternal haploid (mh) gene is an intriguing candidate because it is expressed maternally and its protein product localizes to the 359-bp repeat. We found that this gene has diverged extensively between D. melanogaster and D. simulans. This observation led to the hypothesis that D. melanogaster mh may have co-evolved with the 359-bp repeat, and that hybrid incompatibility thus results from the absence of a co-evolved mh allele in D. simulans. We tested for functional divergence of mh by creating matched transformants of D. melanogaster and D. simulans orthologs in both D. melanogaster and D. simulans strains. Surprisingly, we find that D. simulans mh fully complements the female sterile phenotype of D. melanogaster mh mutations. Contrary to our hypothesis, we find no evidence that adding a D. melanogaster mh gene to D. simulans increases hybrid viability.

evolutionary biology↗