Biology subjects

Higgins, D. P.

Publications and source records attributed to Higgins, D. P..

5 recordsLinked to original sources

bioRxiv2025

Inbreeding and resultant homozygosity across key inflammation and DNA repair genes linked to chlamydial infection in New South Wales koalas

Inbreeding and resultant homozygosity can reduce genetic diversity and increase disease susceptibility. Koalas (Phascolarctos cinereus) are one species suffering genomic diversity loss and inbreeding and concurrent significant disease pressure (particularly chlamydiosis). Using 259 whole genomes with a pathogen sampling regime we identify potential links between inbreeding, genome-wide variation and chlamydial infection. We found a general trend of reduced genomic diversity and increased inbreeding from north to south across six sites in New South Wales. A genome-wide association study of 153 individuals from sites with known Chlamydia pecorum presence were used to investigate the potential relationship between inbreeding and infection. Chlamydia positive individuals (average FH = 0.026) were significantly more inbred than Chlamydia negative individuals (average FH= -0.0051) (t = - 2.31, df = 151, p-value = 0.022). We identified several genes involved in host-pathogen interactions and DNA mismatch repair within in runs of homozygosity that were unique to Chlamydia positive individuals. Interestingly, populations considered putatively Chlamydia-free had similar allele frequencies across candidate loci as Chlamydia positive individuals. Combined with gene flow analyses, this result suggests that isolation may have protected these populations more than harbouring alleles conferring infection resilience and supports the concept that disease should be carefully considered in any conservation measures that increase connectivity or translocations. Our genome-wide approach has identified several avenues for investigations into the pathogenesis of Chlamydia infection and chlamydiosis. We showcase the value of high-quality re-sequenced genomes for understanding the implications of inbreeding, genomic diversity loss, and infection susceptibility, all universal problems for threatened species.

genomics↗

bioRxiv2025

Transcriptional responses to prolonged oxidative stress require cholinergic activation of G-protein-coupled receptor signaling

Organisms have evolved protective strategies that are geared toward limiting cellular damage and enhancing organismal survival in the face of environmental stresses, but how these protective mechanisms are coordinated remains unclear. Here, we define a requirement for neural activity in mobilizing the antioxidant defenses of the nematode Caenorhabditis elegans both during chronic oxidative stress and prior to its onset. We show that acetylcholine-deficient mutants are particularly vulnerable to chronic oxidative stress. We find that extended oxidative stress mobilizes a broad transcriptional response which is strongly dependent on both cholinergic signaling and activation of the muscarinic G-protein acetylcholine coupled receptor (mAChR) GAR-3. Gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and gar-3 mAChR mutants, suggesting that muscarinic activation is critical for stress-responsive upregulation of protein degradation pathways. Further, we find that GAR-3 overexpression in cholinergic motor neurons prolongs survival during chronic oxidative stress. Our studies demonstrate neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling pathways, defining new potential links between cholinergic signaling, oxidative damage, and neurodegenerative disease.

neuroscience↗

bioRxiv2021

WormCat 2.0 defines characteristics and conservation of poorly annotated genes in Caenorhabditis elegans

Genome-wide measurement of mRNA or protein levels provides broad data sets for biological discovery. However, subsequent computational methods are essential for uncovering the functional implications of the data as well as intuitively visualizing the findings. Current computational tools are biased toward well-described pathways, limiting their utility for novel discovery. Recently, we developed an annotation and category enrichment tool for Caenorhabditis elegans genomic data, WormCat, that provides an intuitive visualization output. Unlike GO, which excludes genes with no annotation information, WormCat 2.0 retains these genes as a special UNASSIGNED category. Here, we show that the UNASSIGNED gene category enrichment exhibits tissue-specific expression patterns and include genes with biological functions. Poorly annotated genes have previously been considered to lack homologs in closely related species. Instead, we find that around 3% of the UNASSIGNED genes have poorly characterized human orthologs. These human orthologs are themselves have little annotation information. A recently developed method that incorporates lineage relationships (abSENSE) indicates that failure of BLAST to detect homology explains the apparent lineage specificity for many UNASSIGNED genes, suggesting that a larger subset could be related to human genes. WormCat provides an annotation strategy that allows association of UNASSIGNED genes with specific phenotypes and known pathways. Our analysis indicates that the UNASSIGNED gene category contains candidates that merit further functional study which could yield insight into understudied areas of biology.

genomics↗

bioRxiv2019

WormCat: an online tool for annotation and visualization of Caenorhabditis elegans genome-scale data

The emergence of large gene expression datasets has revealed the need for improved tools to identify enriched gene categories and visualize enrichment patterns. While Gene Ontogeny (GO) provides a valuable tool for gene set enrichment analysis, it has several limitations. First, it is difficult to graphically compare multiple GO analyses. Second, genes from some model systems are not well represented. For example, around 30% of Caenorhabditis elegans genes are missing from analysis in commonly used databases. To allow categorization and visualization of enriched C. elegans gene sets in different types of genome-scale data, we developed WormCat, a web-based tool that uses a near-complete annotation of the C. elegans genome to identify co-expressed gene sets and scaled heat map for enrichment visualization. We tested the performance of WormCat using a variety of published transcriptomic datasets and show that it reproduces major categories identified by GO. Importantly, we also found previously unidentified categories that are informative for interpreting phenotypes or predicting biological function. For example, we analyzed published RNA-seq data from C. elegans treated with combinations of lifespan-extending drugs where one combination paradoxically shortened lifespan. Using WormCat, we identified sterol metabolism as a category that was not enriched in the single or double combinations but emerged in a triple combination along with the lifespan shortening. Thus, WormCat identified a gene set with potential phenotypic relevance that was not uncovered with previous GO analysis. In conclusion, WormCat provides a powerful tool for the analysis and visualization of gene set enrichment in different types of C. elegans datasets.

bioinformatics↗

bioRxiv2018

Stress-responsive and metabolic gene regulation are altered in low S-adenosylmethionine

S-adenosylmethionine (SAM) is the methyl donor that modifies proteins such as histones, nucleic acids and produces phosphatidylcholine. Thus variations in SAM levels could affect processes from lipogenesis to epigenetic gene regulation. SAM is hypothesized to link metabolism and chromatin modification, however, its role in acute gene regulation is poorly understood. We recently found that Caenorhabditis elegans with reduced SAM had deficiencies in bacterial-induced H3K4 trimethylation at selected pathogen-response genes, decreasing their expression and limiting survival on the pathogen Pseudomonas aeruginosa. This led us to the hypothesis that SAM may be generally required stress-responsive transcription. Here we show that C. elegans with low SAM fail to activate genome-wide transcriptional programs when exposed to bacterial or xenotoxic stress. However, heat shock responses were unaffected. We also investigated the role of two H3K4 methyltransferases that use SAM, set-2/SET1, and set-16/MLL and found that set-2/SET1 has a specific requirement in bacterial stress responses, whereas set-16/MLL was required for survival in all three stresses. These results define a role for SAM and H3K4 methyltransferases in the acute genome-wide remodeling of gene expression in response to stress. Finally, we find that the ability to modify metabolic gene expression correlates with enhanced survival in stress conditions.

molecular biology↗