Biology subjects

Bresnahan, S. T.

Publications and source records attributed to Bresnahan, S. T..

4 recordsLinked to original sources

bioRxiv2025

Quantification method affects replicability of eQTL analysis, colocalization, and TWAS

eQTL mapping and TWAS are widely used to contextualize GWAS, yet the impact of RNA-seq processing choices remains unexplored. We find that RNA-seq quantification method and transcriptomic reference substantially affect eQTL detection and gene expression prediction with significant downstream impact on colocalization and TWAS results. Our findings demonstrate that seemingly minor methodological decisions substantially affect these common analyses, highlighting the need for standardized practices to ensure reproducible genetic association studies.

genomics↗

bioRxiv2025

Long-read transcriptome assembly reveals vast isoform diversity in the placenta associated with metabolic and endocrine function

The placenta is critical for fetal development and mediates the effects of pregnancy complications on offspring metabolic health, yet it is often poorly characterized in genomic studies. Existing transcriptomic analyses rely on adult tissue-based references, which overlook developmentally important isoform diversity. We used largest-in-class long-read RNA-seq (N=72) to create a comprehensive placental transcriptome reference, identifying 37,661 high-confidence isoforms (14,985 novel) across 12,302 genes (2,759 novel). Contrary to characterizations of the placenta as a "transcriptomic void," we found transcriptional breadth and complexity comparable to adult tissues, with extraordinary splicing diversity in genes controlling obesity, lactogen production and growth, including 108 distinct CSH1 (placental lactogen) isoforms. This improved reference offers two advantages: First, it reduced inferential uncertainty in isoform quantification by 30% and increased the yield of high-confidence transcripts. Applying this reference to short-read RNA-seq datasets (N=344) of gestational diabetes mellitus (GDM), we found that placental transcription mediated 36% of GDM effects on birth weight, with novel CSH1 isoforms identified as key mediators. We further uncovered ancestry-specific effects, with distinct CSH1 isoforms mediating larger effects in European (24.4%) than Asian (13.4%) populations. Our results establish that utilizing long-read-based, tissue-specific transcriptomic annotations is critical, enabling isoform-resolved analyses that provide greater sensitivity than conventional gene-level approaches for understanding placental function and context-specific variation across diverse biobanks.

genomics↗

bioRxiv2024

Intragenomic conflict underlies extreme phenotypic plasticity in queen-worker caste determination in honey bees (Apis mellifera)

Caste determination of honey bees (Apis mellifera) is a prime example of developmental plasticity, where differences in larval diet will result in identical genotypes yielding either long-lived, reproductive queens or short-lived, facultatively sterile workers. Beyond environmental factors, intragenomic conflict between genes inherited from the mother (matrigenes) versus the father (patrigenes) is also hypothesized to generate this plasticity. In honey bees, the Kinship Theory of Intragenomic Conflict predicts selection on patrigenes to enhance traits that result in fitness gained through reproduction, and thus patrigenes should favor the queen caste fate. Here, we conducted allele-specific transcriptome analyses on queen-destined larvae (QL) and worker-destined larvae (WL) at 192 hours post-fertilization (hpf), a critical stage for caste determination. Our findings reveal hundreds of genes with parent-of-origin effects (POEs), with significant patrigene-biased transcription in QL. Genes with POEs in honey bees resemble imprinted genes in other taxa in terms of genomic clustering, recombination rate, intron length and CpG density, and a subset are maintained from 24hpf eggs. Previous studies demonstrated that DNA methylation, the canonical regulatory mechanism underlying transcriptional POEs in placental mammals, angiosperms, and some insects, is not operating in honey bees or other social insects. We use allele-specific ChIP-seq analyses to demonstrate that POEs on caste-specific histone post-translational modification (HPTM) profiles of H3K27me3, H3K4me3 and H3K27ac are associated with POEs on transcription. Together, these findings suggest that parent-of-origin intragenomic conflicts may contribute broadly to phenotypic plasticity and may be associated with HPTMs, suggesting a "non-canonical" genomic imprinting-like system in social insects.

developmental biology↗

bioRxiv2023

Beyond conflict: kinship theory of intragenomic conflict predicts individual variation in altruistic behavior

Studies of the genetic basis of behavioral variation have emphasized gene cooperation within networks, often overlooking gene conflicts. The Kinship Theory of Intragenomic Conflict (KTIC) proposes that conflicts can occur within genes when parent-specific alleles have different strategies for maximizing reproductive fitness. Here, we test a prediction of the KTIC - that selection should favor alleles which promote "altruistic" behaviors that support the reproductive fitness of kin. In honey bee (Apis mellifera) colonies, workers act altruistically when tending to the queen by performing a "retinue" behavior, distributing the queens mandibular pheromone (QMP) throughout the hive. Workers exposed to QMP do not activate their ovaries, ensuring they care for the queens brood instead of competing to lay unfertilized eggs. Thus, the KTIC predicts that response to QMP should be favored by the maternal genome. Using a reciprocal cross design, we tested for parent-of-origin effects on the workers 1) responsiveness to QMP, 2) ovary activation, and 3) brain transcriptome. We hypothesized that QMP-responsive workers have smaller and less active ovaries, influenced by the workers parent-of-origin. With an allele-specific transcriptomic analysis, we tested whether QMP-responsive workers show enriched maternal allele-biased gene expression compared to QMP-unresponsive workers. Finally, we explored how parent-of-origin gene expression patterns are associated with overall gene expression patterns and regulatory networks. We report evidence in support of the KTIC for the retinue behavior and associated conflicts within gene networks. Our study provides new insights into the genetic basis of behavior and the potential for behavioral variation influenced by intragenomic conflict.

animal behavior and cognition↗