School of BioSciences - Research Publications

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    Building an Understanding of Proteostasis in Reproductive Cells: The Impact of Reactive Carbonyl Species on Protein Fate
    Smyth, SP ; Nixon, B ; Skerrett-Byrne, DA ; Burke, ND ; Bromfield, EG (Mary Ann Liebert, 2024)
    Significance: Stringent regulation of protein homeostasis pathways, under both physiological and pathological conditions, is necessary for the maintenance of proteome fidelity and optimal cell functioning. However, when challenged by endogenous or exogenous stressors, these proteostasis pathways can become dysregulated with detrimental consequences for protein fate, cell survival, and overall organism health. Most notably, there are numerous somatic pathologies associated with a loss of proteostatic regulation, including neurodegenerative disorders, type 2 diabetes, and some cancers. Recent Advances: Lipid oxidation-derived reactive carbonyl species (RCS), such as 4-hydroxynonenal (4HNE) and malondialdehyde, are relatively underappreciated purveyors of proteostatic dysregulation, which elicit their effects via the nonenzymatic post-translational modification of proteins. Emerging evidence suggests that a subset of germline proteins can serve as substrates for 4HNE modification. Among these, prevalent targets include succinate dehydrogenase, heat shock protein A2 and A-kinase anchor protein 4, all of which are intrinsically associated with fertility. Critical Issues: Despite growing knowledge in this field, the RCS adductomes of spermatozoa and oocytes are yet to be comprehensively investigated. Furthermore, the manner by which RCS-mediated adduction impacts protein fate and drives cellular responses, such as protein aggregation, requires further examination in the germline. Given that RCS-protein adduction has been attributed a role in infertility, there has been sparked research investment into strategies to prevent lipid peroxidation in germ cells. Future Directions: An increased depth of knowledge regarding the mechanisms and substrates of RCS-mediated protein modification in reproductive cells may reveal important targets for the development of novel therapies to improve fertility and pregnancy outcomes for future generations.
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    Acetylcholine esterase of Drosophila melanogaster: a laboratory model to explore insecticide susceptibility gene drives
    Hernandes, N ; Qi, XM ; Bhide, S ; Brown, C ; Camm, BJ ; Baxter, SW ; Robin, C (JOHN WILEY & SONS LTD, 2024-06)
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    C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line.
    Zoch, A ; Konieczny, G ; Auchynnikava, T ; Stallmeyer, B ; Rotte, N ; Heep, M ; Berrens, RV ; Schito, M ; Kabayama, Y ; Schöpp, T ; Kliesch, S ; Houston, B ; Nagirnaja, L ; O'Bryan, MK ; Aston, KI ; Conrad, DF ; Rappsilber, J ; Allshire, RC ; Cook, AG ; Tüttelmann, F ; O'Carroll, D (Elsevier BV, 2024-03-21)
    In the male mouse germ line, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germ line remain unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility. Through the analysis of these pathogenic alleles, we discovered that the uncharacterized protein C19ORF84 interacts with SPOCD1. DNMT3C, the DNA methyltransferase responsible for transposon methylation, associates with SPOCD1 and C19ORF84 in fetal gonocytes. Furthermore, C19ORF84 is essential for piRNA-directed DNA methylation and male mouse fertility. Finally, C19ORF84 mediates the in vivo association of SPOCD1 with the de novo methylation machinery. In summary, we have discovered a conserved role for the human piRNA pathway in transposon silencing and C19ORF84, an uncharacterized protein essential for orchestrating piRNA-directed DNA methylation.
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    How often are male mosquitoes attracted to humans?
    Paris, V ; Hardy, C ; Hoffmann, A ; Ross, P ( 2023)
    Many mosquito species live close to humans where females feed on human blood. While male mosquitoes do not feed on blood, it has long been recognized that males of some species can be attracted to human hosts. To investigate the frequency of male mosquito attraction to humans, we conducted a literature review and human-baited field trials, as well as laboratory experiments involving males and females of three common Aedes species. Our literature review indicated that male attraction to humans is limited to a small number of species, including Ae. aegypti and Ae. albopictus. In our human-baited field collections, only 4 out of 13 species captured included males. In laboratory experiments, we found that male Ae. notoscriptus and Ae. vigilax showed no attraction to humans, while male Ae. aegypti exhibited persistent attraction for up to 30 minutes. Both male and female Ae. aegypti displayed similar preferences for different human subjects, suggesting that male Ae. aegypti respond to similar cues as females. Additionally, we found that mosquito repellents applied to human skin effectively repelled male mosquitoes. These findings shed light on mosquito behaviour and have implications for mosquito control programs, particularly those involving the release or monitoring of the male mosquito population.
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    Defining and Reducing Variant Classification Disparities.
    Dawood, M ; Fayer, S ; Pendyala, S ; Post, M ; Kalra, D ; Patterson, K ; Venner, E ; Muffley, LA ; Fowler, DM ; Rubin, AF ; Posey, JE ; Plon, SE ; Lupski, JR ; Gibbs, RA ; Starita, LM ; Robles-Espinoza, CD ; Coyote-Maestas, W ; Gallego Romero, I (Cold Spring Harbor Laboratory, 2024-04-12)
    BACKGROUND: Multiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style data may help resolve variant classification disparities between populations, especially for variants of uncertain significance (VUS). METHODS: We analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry from All of Us and the Genome Aggregation Database. Then, we incorporated clinically calibrated MAVE data into the Clinical Genome Resource's Variant Curation Expert Panel rules to automate VUS reclassification for BRCA1, TP53, and PTEN . RESULTS: Using two orthogonal statistical approaches, we show a higher prevalence ( p ≤5.95e-06) of VUS in individuals of non-European-like genetic ancestry across all medical specialties assessed in all three databases. Further, in the non-European-like genetic ancestry group, higher rates of Benign or Likely Benign and variants with no clinical designation ( p ≤2.5e-05) were found across many medical specialties, whereas Pathogenic or Likely Pathogenic assignments were higher in individuals of European-like genetic ancestry ( p ≤2.5e-05). Using MAVE data, we reclassified VUS in individuals of non-European-like genetic ancestry at a significantly higher rate in comparison to reclassified VUS from European-like genetic ancestry ( p =9.1e-03) effectively compensating for the VUS disparity. Further, essential code analysis showed equitable impact of MAVE evidence codes but inequitable impact of allele frequency ( p =7.47e-06) and computational predictor ( p =6.92e-05) evidence codes for individuals of non-European-like genetic ancestry. CONCLUSIONS: Generation of saturation-style MAVE data should be a priority to reduce VUS disparities and produce equitable training data for future computational predictors.
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    Genetic mutation of Cep76 results in male infertility due to abnormal sperm tail composition
    Houston, BJ ; Merriner, DJ ; Stathatos, GG ; Nguyen, JH ; O'Connor, AE ; Lopes, AM ; Conrad, DF ; Baker, M ; Dunleavy, JEM ; O'Bryan, MK (Life Science Alliance LLC, 2024-06)
    The transition zone is a specialised gate at the base of cilia/flagella, which separates the ciliary compartment from the cytoplasm and strictly regulates protein entry. We identified a potential new regulator of the male germ cell transition zone, CEP76. We demonstrated that CEP76 was involved in the selective entry and incorporation of key proteins required for sperm function and fertility into the ciliary compartment and ultimately the sperm tail. In the mutant, sperm tails were shorter and immotile as a consequence of deficits in essential sperm motility proteins including DNAH2 and AKAP4, which accumulated at the sperm neck in the mutant. Severe annulus, fibrous sheath, and outer dense fibre abnormalities were also detected in sperm lacking CEP76. Finally, we identified that CEP76 dictates annulus positioning and structure. This study suggests CEP76 as a male germ cell transition zone protein and adds further evidence to the hypothesis that the spermatid transition zone and annulus are part of the same functional structure.
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    Navigating the transition to online teaching at the University of Melbourne during COVID-19: approaches, reflections and insights.
    MULDER, R ; Bone, E ; FRENCH, S ; Connelly, CF ( 2023-09-07)
    An Occasional Paper at the Melbourne CSHE describing the outcomes from an institution-wide survey distributed to teaching academics that sought to understand their experiences in moving their subjects online during the lockdowns associated with the COVID-19 pandemic.
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    Gut microbiota in the short-beaked echidna (Tachyglossus Aculeatus) shows stability across gestation
    Buthgamuwa, I ; Fenelon, JC ; Roser, A ; Meer, H ; Johnston, SD ; Dungan, AM (Wiley, 2023-12)
    Indigenous gut microbial communities (microbiota) play critical roles in health and may be especially important for the mother and fetus during pregnancy. Monotremes, such as the short-beaked echidna, have evolved to lay and incubate an egg, which hatches in their pouch where the young feeds. Since both feces and eggs pass through the cloaca, the fecal microbiota of female echidnas provides an opportunity for vertical transmission of microbes to their offspring. Here, we characterize the gut/fecal microbiome of female short-beaked echidnas and gain a better understanding of the changes that may occur in their microbiome as they go through pregnancy. Fecal samples from four female and five male echidnas were obtained from the Currumbin Wildlife Sanctuary in Queensland and sequenced to evaluate bacterial community structure. We identified 25 core bacteria, most of which were present in male and female samples. Genera such as Fusobacterium, Bacteroides, Escherichia-Shigella, and Lactobacillus were consistently abundant, regardless of sex or gestation stage, accounting for 58.00% and 56.14% of reads in male and female samples, respectively. The echidna microbiome remained stable across the different gestation stages, though there was a significant difference in microbiota composition between male and female echidnas. This study is the first to describe the microbiome composition of short-beaked echidnas across reproductive phases and allows the opportunity for this novel information to be used as a metric of health to aid in the detection of diseases triggered by microbiota dysbiosis.
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    Ecomorphological correlates of inner ear shape in Australian limb-reduced skinks (Scincidae: Sphenomorphini)
    Camaiti, M ; Wiles, J ; Aguilar, R ; Hutchinson, MN ; Hipsley, CA ; Chapple, DG ; Evans, AR (OXFORD UNIV PRESS, 2023-12-01)
    Abstract The inner ear labyrinth is an organ able to perceive balance and spatial orientation, but the drivers of its morphological variation across and within vertebrate lineages are unclear. We assess two competing hypotheses whether this organ, and specifically the semicircular canals, modifies its shape as a functional adaptation to ecology and locomotion, or according to the constraints of skull morphology. We test these using 52 species of Australian sphenomorphines, a group of scincid lizards that evolved changes in body shape and locomotory adaptations to fossoriality multiple times independently, by reducing their limbs. We find a correlation between semicircular canal shape and degree of limb reduction in these lizards, supporting a functional hypothesis. The interaction between body shape and substrate ecology is also a significant predictor. The wider and more eccentric semicircular canals of limb-reduced skinks indicate higher balance sensitivity and manoeuvrability compared with fully limbed skinks, probably as an adaptation to navigating cluttered environments. Conversely, our results show only a minimal influence of skull constraints on semicircular canal shape, having instead significant effects on size. This supports the hypothesis that in these skinks inner ear shape evolution is driven by specific locomotory strategies more than it is constrained by cranial anatomy.
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    A targeted approach to enrich host-associated bacteria for metagenomic sequencing.
    Dungan, AM ; Tandon, K ; Jameson, V ; Gotze, CR ; Blackall, LL ; van Oppen, MJH (Oxford University Press (OUP), 2024)
    Multicellular eukaryotic organisms are hosts to communities of bacteria that reside on or inside their tissues. Often the eukaryotic members of the system contribute to high proportions of metagenomic sequencing reads, making it challenging to achieve sufficient sequencing depth to evaluate bacterial ecology. Stony corals are one such complex community; however, separation of bacterial from eukaryotic (primarily coral and algal symbiont) cells has so far not been successful. Using a combination of hybridization chain reaction fluorescence in situ hybridization and fluorescence activated cell sorting (HCR-FISH + FACS), we sorted two populations of bacteria from five genotypes of the coral Acropora loripes, targeting (i) Endozoicomonas spp, and (ii) all other bacteria. NovaSeq sequencing resulted in 67-91 M reads per sample, 55%-90% of which were identified as bacterial. Most reads were taxonomically assigned to the key coral-associated family, Endozoicomonadaceae, with Vibrionaceae also abundant. Endozoicomonadaceae were 5x more abundant in the 'Endozoicomonas' population, highlighting the success of the dual-labelling approach. This method effectively enriched coral samples for bacteria with <1% contamination from host and algal symbionts. The application of this method will allow researchers to decipher the functional potential of coral-associated bacteria. This method can also be adapted to accommodate other host-associated communities.