Characterizing the research mentorship experience of genetic counseling students.

The Accreditation Council for Genetic Counseling's Practice-Based Competencies include research-related skills, which are taught in master's level genetic counseling programs through didactic coursework and completion of mentored research experiences. It is known that research mentors can impact student work environments, create positive perceptions of the research process, and increase students' likelihood of future involvement in research. However, few studies have characterized the experiences of GC students in receiving research mentorship. It is crucial to understand these experiences from student perspectives to better inform stakeholders about factors that impact mentorship. Using a mixed-methods approach, this study explored GC students' experiences receiving research mentorship and their thoughts regarding the successful qualities of research mentors. GC students (N = 165) who graduated between 2019 and 2022 responded to an online survey measuring the mentorship relationship, defined by the Advisory Working Alliance Inventory (AWAI). On average, participants scored 3.96/5 on the AWAI, where higher scores indicate stronger working alliances. When asked to describe their overall research experience in three words, 75.7% of participants used at least one negatively connotated descriptor. Thematic analysis of semi-structured interviews obtained via purposive sampling of highest and lowest scoring participants on the AWAI (N = 14) revealed the following five themes related to successful qualities of a research mentor: (1) communication; (2) rapport building and relationship; (3) engagement and guidance; (4) expertise and connections; and (5) mentors with different roles. Of note, many of these qualities are foundational skills in genetic counseling. Thus, genetic counselors who may be strong in these areas who do not identify as "researchers" ought to consider becoming a research committee member. Additionally, education programs could consider implementing research committee member evaluations and/or student research self-efficacy surveys to evaluate how these relationships may be shaping research experiences for students within their program.

Exploring collaboration models between geneticists and intensivists for implementing rapid genome sequencing in critical care settings.

The availability of rapid genome sequencing (rGS) for children in a critical-care setting is increasing. This study explored the perspectives of geneticists and intensivists on optimal collaboration and division of roles when implementing rGS in neonatal and pediatric intensive care units (ICUs). We conducted an explanatory mixed methods study involving a survey embedded within an interview with 13 genetics and intensive care providers. Interviews were recorded, transcribed, and coded. Geneticists endorsed higher confidence in performing a physical exam and interpreting/communicating positive results. Intensivists endorsed highest confidence in determining whether genetic testing was appropriate, communicating negative results, and consenting. Major qualitative themes that emerged were: (1) concerns with both "genetics-led" and "intensivist-led" models with workflows and sustainability (2) shift the role of determining rGS eligibility to ICU medical professionals, (3) continued role of geneticists to assess phenotype, and (4) include genetic counselors (GCs) and neonatal nurse practitioners to enhance workflow and care. All geneticists supported shifting decisions regarding eligibility for rGS to the ICU team to minimize time cost for the genetics workforce. Exploring models of geneticist-led phenotyping, intensivist-led phenotyping for some indications, and/or inclusion of a dedicated inpatient GC may help offset the time burden of consenting and other tasks associated with rGS.

Transcriptome changes during the initiation and progression of Duchenne muscular dystrophy in Caenorhabditis elegans.

Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease characterized by progressive muscle degeneration. The condition is driven by nonsense and missense mutations in the dystrophin gene, leading to instability of the sarcolemma and skeletal muscle necrosis and atrophy. Resulting changes in muscle-specific gene expression that take place in dystrophin's absence remain largely uncharacterized, as they are potentially obscured by the chronic inflammation elicited by muscle damage in humans. Caenorhabditis elegans possess a mild inflammatory response that is not active in the muscle, and lack a satellite cell equivalent. This allows for the characterization of the transcriptome rearrangements affecting disease progression independently of inflammation and regeneration. In effort to better understand these dynamics, we have isolated and sequenced body muscle-specific transcriptomes from C. elegans lacking functional dystrophin at distinct stages of disease progression. We have identified an upregulation of genes involved in mitochondrial function early in disease progression, and an upregulation of genes related to muscle repair in later stages. Our results suggest that in C. elegans, dystrophin may have a signaling role early in development, and its absence may activate compensatory mechanisms that counteract muscle degradation caused by loss of dystrophin. We have also developed a temperature-based screening method for synthetic paralysis that can be used to rapidly identify genetic partners of dystrophin. Our results allow for the comprehensive identification of transcriptome changes that potentially serve as independent drivers of disease progression and may in turn allow for the identification of new therapeutic targets for the treatment of DMD.

The C. elegans 3' UTRome v2 resource for studying mRNA cleavage and polyadenylation, 3'-UTR biology, and miRNA targeting.

3' Untranslated regions (3' UTRs) of mRNAs emerged as central regulators of cellular function because they contain important but poorly characterized cis-regulatory elements targeted by a multitude of regulatory factors. The model nematode Caenorhabditis elegans is ideal to study these interactions because it possesses a well-defined 3' UTRome. To improve its annotation, we have used a genome-wide bioinformatics approach to download raw transcriptome data for 1088 transcriptome data sets corresponding to the entire collection of C. elegans trancriptomes from 2015 to 2018 from the Sequence Read Archive at the NCBI. We then extracted and mapped high-quality 3'-UTR data at ultradeep coverage. Here, we describe and release to the community the updated version of the worm 3' UTRome, which we named 3' UTRome v2. This resource contains high-quality 3'-UTR data mapped at single-base ultraresolution for 23,084 3'-UTR isoform variants corresponding to 14,788 protein-coding genes and is updated to the latest release of WormBase. We used this data set to study and probe principles of mRNA cleavage and polyadenylation in C. elegans The worm 3' UTRome v2 represents the most comprehensive and high-resolution 3'-UTR data set available in C. elegans and provides a novel resource to investigate the mRNA cleavage and polyadenylation reaction, 3'-UTR biology, and miRNA targeting in a living organism.

ALG-1 Influences Accurate mRNA Splicing Patterns in the Caenorhabditis elegans Intestine and Body Muscle Tissues by Modulating Splicing Factor Activities.

MicroRNAs (miRNAs) are known to modulate gene expression, but their activity at the tissue-specific level remains largely uncharacterized. To study their contribution to tissue-specific gene expression, we developed novel tools to profile putative miRNA targets in the Caenorhabditis elegans intestine and body muscle. We validated many previously described interactions and identified ∼3500 novel targets. Many of the candidate miRNA targets curated are known to modulate the functions of their respective tissues. Within our data sets we observed a disparity in the use of miRNA-based gene regulation between the intestine and body muscle. The intestine contained significantly more putative miRNA targets than the body muscle highlighting its transcriptional complexity. We detected an unexpected enrichment of RNA-binding proteins targeted by miRNA in both tissues, with a notable abundance of RNA splicing factors. We developed in vivo genetic tools to validate and further study three RNA splicing factors identified as putative miRNA targets in our study (asd-2, hrp-2, and smu-2), and show that these factors indeed contain functional miRNA regulatory elements in their 3'UTRs that are able to repress their expression in the intestine. In addition, the alternative splicing pattern of their respective downstream targets (unc-60, unc-52, lin-10, and ret-1) is dysregulated when the miRNA pathway is disrupted. A reannotation of the transcriptome data in C. elegans strains that are deficient in the miRNA pathway from past studies supports and expands on our results. This study highlights an unexpected role for miRNAs in modulating tissue-specific gene isoforms, where post-transcriptional regulation of RNA splicing factors associates with tissue-specific alternative splicing.