Biology subjects

Parsons, L. R.

Publications and source records attributed to Parsons, L. R..

4 recordsLinked to original sources

bioRxiv2024

Integrative Computational Framework, Dyscovr, Links Mutated Driver Genes to Expression Dysregulation Across 19 Cancer Types

Mutations within cancer driver genes induce widespread transcriptional changes that reflect altered cellular states and can reveal associated genetic vulnerabilities. However, it remains challenging to determine which genes are dysregulated as a consequence of cancer alterations, and of these, which represent therapeutic opportunities. Here, we present Dyscovr, an integrative computational framework that leverages somatic mutation, gene expression, copy number alteration, methylation, and clinical data from primary tumors to identify driver-associated transcriptional changes. Dyscovr then uses these transcriptional changes as a biologically grounded starting point, integrating them with cancer cell line data to prioritize genes whose inhibition is predicted to reduce viability either specifically in driver-mutant contexts or in combination with driver inhibition. Applied both pan-cancer and across 19 tumor types, Dyscovr uncovers hundreds of such conditional vulnerabilities. As a case study, we newly implicate--and experimentally validate--KBTBD2 as a gene whose inhibition enhances the efficacy of PI3K inhibitors in PIK3CA-mutant breast cancer cell lines. The Dyscovr software (github.com/Singh-Lab/Dyscovr) and predictions (dyscovr.princeton.edu) provide a platform and resource for linking mutated driver genes to conditional genetic vulnerabilities and for prioritizing these relationships for experimental and therapeutic investigation.

systems biology↗

bioRxiv2021

Convergent selection on juvenile hormone signaling is associated with the evolution of eusociality in bees

Sweat bees have repeatedly gained and lost eusociality, a transition from individual to group reproduction. Here, we generate chromosome-length genome assemblies for 17 species and identify genomic signatures of evolutionary trade-offs associated with transitions between social and solitary living. Both young genes and regulatory regions show enrichment for these molecular patterns. We also identify loci that show evidence of complementary signals of positive and relaxed selection linked specifically to the convergent gains and losses of eusociality in sweat bees. This includes two proteins that bind and transport juvenile hormone (JH) - a key regulator of insect development and reproduction. We find one of these JH binding proteins is primarily expressed in subperineurial glial cells that form the insect blood-brain barrier and that brain levels of JH vary by sociality. Our findings are consistent with a role of JH in modulating social behavior and suggest eusocial evolution was facilitated by alteration of the proteins that bind and transport JH, revealing how an ancestral, developmental hormone may have been co-opted during one of lifes major transitions. More broadly, our results highlight how trade-offs have structured the molecular basis of eusociality in these bees and demonstrate how both directional selection and release from constraint can shape trait evolution.

evolutionary biology↗

bioRxiv2020

Horizontal and vertical transmission of transgenerational memories via the Cer1 transposon

Animals face both external and internal dangers: pathogens threaten from the environment, and unstable genomic elements threaten from within. Previously, we discovered that C. elegans protects itself from pathogens by "reading" bacterial small RNAs and using this information to both induce avoidance and transmit memories for several generations. Here we found that these memories can be transferred to naive animals via Cer1 retrotransposon-encoded capsids. Cer1 functions at the step of transmission of information from the germline to neurons, and is required for C. elegans learned avoidance ability and for mothers to pass this information on to progeny. The presence of the Cer1 retrotransposon in wild C. elegans strains correlates with the ability to learn and inherit small RNA-induced pathogen avoidance. Together, these results suggest that C. elegans has co-opted a potentially dangerous retrotransposon to instead protect itself and its progeny from a common pathogen through its inter-tissue signaling ability, hijacking this genomic element for its own adaptive immunity benefit.

genetics↗

bioRxiv2019

Cross-kingdom recognition of bacterial small RNAs induces transgenerational pathogenic avoidance

We recently discovered that C. elegans can pass on a learned avoidance of pathogenic Pseudomonas aeruginosa (PA14) to four generations of its progeny. This transgenerational inheritance is bacterial species-specific, but how C. elegans recognizes and distinguishes different bacteria and transmits this information to future generations is not apparent. Here we show that small RNAs purified from pathogenic PA14 are sufficient not only to induce avoidance of pathogens in mothers, but also to confer transgenerational inheritance of this species-specific behavior for four generations, all without direct contact with pathogenic bacteria. This behavior requires the small RNA transporters SID-1 and SID-2, RNA interference pathway components, the piRNA Piwi/Argonaute pathway, a functioning germline, and TGF-{beta} ligand daf-7 expression in the ASI sensory neuron. Our results suggest that C. elegans \"reads\" small RNAs expressed by pathogenic bacteria, and uses this information to induce an escape behavior that lasts for four additional generations. C. elegans may have evolved this trans-kingdom signaling system to avoid pathogens in abundant classes of bacteria in its environment and its microbiome.

genetics↗