Biology subjects

Davis, E. E.

Publications and source records attributed to Davis, E. E..

2 recordsLinked to original sources

bioRxiv2018

Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remains unclear. We performed a systematic secondary-variant burden analysis of two independent Bardet-Biedl syndrome (BBS) cohorts with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We observed a significant enrichment of trans-acting rare nonsynonymous secondary variants compared to either population controls or to a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, we found a significant over-representation of secondary alleles in chaperonin-encoding genes, a finding corroborated by the observation of epistatic interactions involving this complex in vivo. These data indicate a complex genetic architecture for BBS that informs the biological properties of disease modules and presents a model paradigm for secondary-variant burden analysis in recessive disorders.

genetics↗

bioRxiv2017

Actin Impacts The Late Stages Of Prion Formation And Prion Propagation

In yeast, the [PSI+] and [PIN+] prions are aggregated forms of the Sup35 and Rnq1 proteins, respectively. The cellular mechanisms that underlie the formation and propagation of these prion states are not clearly understood. Our previous work suggested that actin networks play a role in early and late steps of the formation of [PSI+]. To further explore how actin impacts yeast prions, we turned to a set of actin point mutants. We found that the disruption of actin cables, either by an actin destabilizing drug or the act1-101 mutant, can enhance prion formation during the later stages of prion formation. Our data suggest that under normal conditions, actin cables play a role in limiting the inheritance of newly made prion particles to daughter cells. We also found actin can impact prion propagation. The act1-122 mutant, which contains a substitution in the fimbrin binding region, destabilized the [PIN+] prion over time. This is the first evidence that actin has a role in [PIN+] propagation. Taken together, our findings reveal novel roles for actin in the formation and propagation of prions.

cell biology↗