Biology subjects

Fraser, H.

Publications and source records attributed to Fraser, H..

13 recordsLinked to original sources

bioRxiv2026

Quantification of X-chromosome inactivation in fibroblast and iPSC models of UBQLN2 ALS/FTD using allele-selective qPCR

Pathogenic missense variants in the X chromosome gene UBQLN2 cause amyotrophic lateral sclerosis (ALS), often accompanied by frontotemporal dementia (FTD). As an X-linked gene, UBQLN2 is subject to X chromosome inactivation (XCI), a process wherein one X chromosome in each cell is randomly inactivated to a Barr body throughout the body in females, creating a mosaic of allelic expression in the tissues of heterozygotes. Despite heterozygous females constituting a majority of reported cases of UBQLN2-linked ALS/FTD, and the known influence of XCI on neurological disorders at large, no current disease models account for XCI. Here we report the characterisation of 12 iPSC clones carrying the ALS/FTD-causing p.T487I (c.1460C>T) UBQLN2 variant. These clones, originally derived from 3 heterozygous carrier fibroblast lines, underwent validation of homeostatic Barr body retention. Erosion of XCI in a subset of the lines was correlated with biallelic expression (of both wildtype and mutant UBQLN2), as measured through a novel allele-selective qPCR (AS-qPCR) assay and verified by amplicon-based Illumina sequencing and Sanger chromatogram quantification, enabling selection of iPSC clones best retaining XCI. Together, this UBQLN2 AS-qPCR assay and selected iPSC clones will enable studies of the role of XCI and its skew in female resilience to UBQLN2 p.T487I-linked ALS/FTD and enable development of allele-selective therapies.

molecular biology↗

bioRxiv2026

The pattern of mammal change in Garig Gunak Barlu (Cobourg) National Park suggests a fire-mediated pathway to decline and one for recovery

ContextFire is a key driver of wildlife pattern in northern Australia, and in recent decades there has been concerted efforts to return burning practices from unmanaged wildfire to approaches more in tune with traditional approaches to fire management undertaken by First Nations people. AimsWe examined fire pattern (early and late dry season) and distance from coast in relation to mammal pattern on a Cobourg peninsula, as there was some evidence in variable patterns in fire history and mammal persistence in this landscape. MethodsIn this study we examined data collected from Garig Gunak Barlu (Cobourg) National Park, Northern Territory, between 2004 and 2017. We investigated the relationship between all native mammal abundance and species richness, and abundance for eight species, with the three environmental variables (distance from coast, preceding early dry and late dry season burning frequency), using an information theoretic model selection and averaging framework. Key resultsThere is a distinctive change in the fire and mammal pattern with respect to distance from the coast; that is, early and late dry season burning increasing moving inland from the coast, and a concomitant decrease or persistence in some key species on this fire gradient. ConclusionsOur results suggest that fire management in northern Australia still needs targeted research linked to active management to more effectively prevent declines of mammal populations. ImplicationsThe location and shape of Garig Gunak Barlu (Cobourg) National Park provide an excellent opportunity to undertake some natural experiments in strategic burning to investigate improved approaches to conservation in fire-prone landscapes.

ecology↗

bioRxiv2026

Monitoring data indicates some annual change in the mammal fauna at Nitmiluk National Park between 2005 and 2018 but a reduction in effort confounds any interpretation

ContextThe decline, extirpation and extinction of Australias mammal fauna is without peer. In recent decades long term monitoring has revealed tragic patterns in iconic locations such as Kakadu National Park. AimsPast studies have described universal patterns across multiple national parks in the Northern Territory, linking the declines to fire management; however, much of the data in Nitmiluk National Park do not cover the period that encompasses this decline. We examine this data separately to look for patterns with respect to fire history. MethodsWe examined standardised mammal survey data collected in Nitmiluk from 2005 to 2018, to look for correlates with year of survey, time since last burnt, and the frequency of early season and late season burns. Key resultsDespite subtle difference in methods over the years, we found there were some annual changes in the mammals, but little discernible pattern of change correlated to fire regime (which itself indicated an improvement in seasonality, and the extent of burning overall over this period). Instead, there was a distinct reduction in the survey effort. ConclusionsOur study provides further support for the pitfalls of ecological monitoring losing focus, being decoupled from management actions, and allowing ill-conceived changes in design. We recommend that future monitoring at Nitmiluk should focus on key management questions (i.e., fire), best methods for target taxa (i.e. camera traps), more regular and flexible sampling linked to a conceptual model, and integration and co-design with the local land managers, rangers and Traditional Owners. Short SummaryRe-examination of the mammal data collected in monitoring sites at Nitmiluk National Park between 2005 to 2018 indicated little pattern with fire regime over time, and instead indicated that a reduction in effort, had reduced the ability to find pattern With sparse and declining mammal population in northern Australia, future monitoring needs to be focused on key management questions.

ecology↗

bioRxiv2026

The causes and consequences of human-specific DNA methylation

The vast collection of human-specific traits- such as our unique morphology, cognition, behavior, and diseases- has long been attributed to gene expression divergence between us and our closest living relatives, chimpanzees. Theory suggests that changes to cis-regulatory elements such as promoters and enhancers may drive evolutionary adaptation, and DNA methylation is a key factor in transcriptional cis-regulation. However, we still lack an understanding of 1) how species-specific methylation patterns arise; 2) their downstream effects; and 3) whether they are a common target of natural selection. In this study, we investigated these three questions. By combining a novel hypothesis testing framework with DNA methylation data from six human and chimpanzee cell types, as well as fused interspecies hybrid cells, we disentangled cis- vs. trans-acting methylation divergence across the genome. Across cell types, we found that methylation divergence is primarily driven in cis, which can be linked in some cases to nearby sequence variants such as CpG gains and losses. Although less common, regions with trans-acting methylation divergence were enriched for specific transcription factor (TF) binding motifs, suggesting a role of TFs such as FOXM1 in these differences. Having established these causes of methylation divergence, we then examined the functional consequences of differential methylation. Although methylation lacks a consistent relationship with transcription, we observed that associations between methylation and gene expression are stronger for genes with cis-regulatory divergence. Moreover, we identified lineage-specific selection shaping promoter methylation at the level of entire pathways including those associated with human-specific traits such as speech, cognition, and susceptibility to infection with hepatitis C. Collectively, our findings provide a mechanistic framework suggesting that DNA methylation may occupy a key position, mediating the effects of both cis- and trans-acting factors on transcriptional networks, including those contributing to human-specific traits.

evolutionary biology↗

bioRxiv2025

A typology of Australian terrestrial bird communities

AimIncreasing interest in holistic measurement of the response of fauna communities to interventions requires suitable community condition metrics. However, the development of such metrics is hindered by the absence of broad-scale typologies at suitable spatial and ecological resolutions. We aimed to derive a preliminary typology of terrestrial bird communities for Australia, based on bird co-occurrence data, and describe and map the likely distribution of each community type across the continent. LocationMainland Australia, continental islands Time period1973-2022 Major taxa studiedAves MethodsWe used fine-scale co-occurrence data from standard 2-ha surveys in BirdLife Australias citizen-science database. After filtering to reduce bias, we used hierarchical clustering followed by iterative consultation with experts to identify reliably distinct and recognisable terrestrial bird communities across Australia. We used Maxent to model the likely distributions of each community, and developed community descriptions based on each communitys composition and distribution. ResultsThe resultant typology included 29 reliably distinct and recognisable bird communities with major clusters corresponding with seven broad geographical regions. The distributions of bird communities did not correspond tightly to the boundaries of major vegetation groups, with most communities occurring across multiple vegetation types. Main ConclusionsOur preliminary typology of bird communities provides a standard classification at a continental scale. It newly defines distinct bird communities as entities for which condition benchmarks can be established to allow assessment of their conservation status and monitoring of change over time. Refinement will enable cryptic communities in areas with sparse data to be identified. The method could be translated to other regions where adequate coverage of data in the form of standardised surveys of fauna are available. Vast biodiversity datasets delivered through citizen science programs provide the opportunity to develop such typologies for fauna communities, as a precursor to developing targeted and informative community condition metrics.

ecology↗

bioRxiv2024

Loss of O-specific antigen shapes Pseudomonas aeruginosa microbiogeography in murine preclinical pulmonary infection model

Chronic Pseudomonas aeruginosa infections are the hallmark of late-stage lung disease in individuals with cystic fibrosis. During chronic infection P. aeruginosa becomes the dominant bacteria in the airways. Within-host adaptation of P. aeruginosa leads to vast phenotypic and genetic population heterogeneity. In vitro studies show mutations in lipopolysaccharide (LPS) O-specific antigen changes the aggregate formation in P. aeruginosa, however role of these changes in aggregate assembly in vivo is not understood. Using a synthetic CF sputum media and a preclinical murine infection model we assessed how the PAO1 wildtype and O-specific antigen mutants interact with each other, and if P. aeruginosa population heterogeneity affects the colonization of the murine lungs. Our findings suggest that the presence of variants lacking O-specific antigen does not impact the population fitness and size in both in vitro and in vivo, however it can influence the aggregate volume in vivo.

microbiology↗

bioRxiv2024

Disentangling cell-intrinsic and extrinsic factors underlying gene expression evolution

A key goal of developmental biology is to determine the extent to which cells and organs develop autonomously, as opposed to requiring interactions with other cells or environmental factors. Chimeras have played a foundational role in this by enabling qualitative classification of cell-intrinsically vs. extrinsically driven processes. Here, we extend this framework to precisely decompose evolutionary divergence in any quantitative trait into cell-intrinsic, extrinsic, and intrinsic-extrinsic interaction components. Applying this framework to thousands of gene expression levels in reciprocal rat-mouse chimeras, we found that the majority of their divergence is attributable to cell-intrinsic factors, though extrinsic factors also play an integral role. For example, a rat-like extracellular environment extrinsically up-regulates the expression of a key transcriptional regulator of the endoplasmic reticulum (ER) stress response in some but not all cell types, which in turn strongly predicts extrinsic up-regulation of its target genes and of the ER stress response pathway as a whole. This effect is also seen at the protein level, suggesting propagation through multiple regulatory levels. Applying our framework to a cellular trait, neuronal differentiation, revealed a complex interaction of intrinsic and extrinsic factors. Finally, we show that imprinted genes are dramatically mis-expressed in species-mismatched environments, suggesting that mismatch between rapidly evolving intrinsic and extrinsic mechanisms controlling gene imprinting may contribute to barriers to interspecies chimerism. Overall, our conceptual framework opens new avenues to investigate the mechanistic basis of developmental processes and evolutionary divergence across myriad quantitative traits in any multicellular organism.

evolutionary biology↗

bioRxiv2021

Cis-regulatory changes in locomotor genes are associated with the evolution of burrowing behavior

How evolution modifies complex, innate behaviors is largely unknown. Divergence in many morphological traits has been linked, at least in part, to cis-regulatory changes in gene expression, a pattern also observed in some behaviors of recently diverged populations. Given this, we compared the gene expression in the brains of two interfertile sister species of Peromyscus mice, including allele-specific expression (ASE) of their F1 hybrids, that show large and heritable differences in burrowing behavior. Because cis-regulation may contribute to constitutive as well as activity-dependent gene expression, we also captured a molecular signature of burrowing circuit divergence by quantifying gene expression in mice shortly after burrowing. We found that several thousand genes were differentially expressed between the two sister species regardless of behavioral context, with several thousand more showing behavior-dependent differences. Allele-specific expression in F1 hybrids showed a similar pattern, suggesting that much of the differential expression is driven by cis-regulatory divergence. Genes related to locomotor coordination showed the strongest signals of lineage-specific selection on burrowing-induced cis-regulatory changes. By comparing these candidate genes to independent quantitative trait locus (QTL) mapping data, we found that the closest QTL markers to these candidate genes are associated with variation in burrow shape, demonstrating an enrichment for candidate locomotor genes near segregating causal loci. Together, our results provide insight into how cis-regulated gene expression can depend on behavioral context as well as how this dynamic regulatory divergence between species can be integrated with forward genetics to enrich our understanding of the genetic basis of behavioral evolution.

animal behavior and cognition↗

bioRxiv2020

Detecting selection with a genetic cross

Distinguishing which traits have evolved under natural selection, as opposed to neutral evolution, is a major goal of evolutionary biology. Several tests have been proposed to accomplish this, but these either rely on false assumptions or suffer from low power. Here, I introduce a new approach to detecting lineage-specific selection that makes minimal assumptions and only requires phenotypic data from [~]10 individuals. The test compares the phenotypic difference between two populations to what would be expected by chance under neutral evolution, which can be estimated from the phenotypic distribution of an F2 cross between those populations. Simulations show that the test is robust to parameters such as the number of loci affecting the trait, the distribution of locus effect sizes, heritability, dominance, and epistasis. Comparing its performance to the QTL sign test--an existing test of selection that requires both genotype and phenotype data--the new test achieves comparable power with 50- to 100-fold fewer individuals (and no genotype data). Applying the test to empirical data spanning over a century shows strong directional selection in many crops, as well as on naturally selected traits such as head shape in Hawaiian Drosophila and skin color in humans. Applied to gene expression data, the test reveals that the strength of stabilizing selection acting on mRNA levels in a species is strongly associated with that species effective population size. In sum, this test is applicable to phenotypic data from almost any genetic cross, allowing selection to be detected more easily and powerfully than previously possible. Significance StatementNatural selection is the force that underlies the spectacular adaptations of all organisms to their environments. However, not all traits are under selection; a key question is which traits have been shaped by selection, as opposed to the random drift of neutral traits. Here, I develop a test of selection on quantitative traits that can be applied to almost any genetic cross between divergent populations or species. The test is robust to a wide range of potential confounders, and has greater power to detect selection than existing tests. Applied to empirical data, the test reveals widespread selection in both domesticated and wild species, allowing selection to be detected more easily and powerfully than previously possible.

evolutionary biology↗

bioRxiv2018

Tissue-specific cis-regulatory divergence implicates a fatty acid elongase necessary for inhibiting interspecies mating in Drosophila

Pheromones known as cuticular hydrocarbons are a major component of reproductive isolation in Drosophila. Individuals from morphologically similar sister species produce different sets of hydrocarbons that allow potential mates to identify them as a suitable partner. In order to explore the molecular mechanisms underlying speciation, we performed RNA-seq in F1 hybrids to measure tissue-specific cis-regulatory divergence between the sister species D. simulans and D. sechellia. By focusing on cis-regulatory changes specific to female oenocytes, we rapidly identified a small number of candidate genes. We found that one of these, the fatty acid elongase eloF, broadly affects both the complement of hydrocarbons present on D. sechellia females and the propensity of D. simulans males to mate with those females. In addition, knockdown of eloF in the more distantly related D. melanogaster led to a similar shift in hydrocarbons as well as lower interspecific mate discrimination by D. simulans males. Thus, cis-regulatory changes in eloF appear to be a major driver in the sexual isolation of D. simulans from multiple other species. More generally, our RNA-seq approach proved to be far more efficient than QTL mapping in identifying candidate genes; the same framework can be used to pinpoint cis-regulatory drivers of divergence in a wide range of traits differing between any interfertile species.

systems biology↗

bioRxiv2018

Interim impact evaluation of the hepatitis C virus elimination program in Georgia

Background and AimsGeorgia has one of the highest hepatitis C virus (HCV) prevalence rates in the world, with >5% of the adult population (~150,000 people) chronically infected. In April 2015, the Georgian government, in collaboration with CDC and other partners, launched a national program to eliminate HCV through scaling up HCV treatment and prevention interventions, with the aim of achieving a 90% reduction in prevalence by 2020. We evaluate the interim impact of the HCV treatment program as of 31 October 2017, and assess the feasibility of achieving the elimination goal by 2020.\n\nMethodWe developed a dynamic HCV transmission model to capture the current and historical epidemic dynamics of HCV in Georgia, including the main drivers of transmission. Using the 2015 national sero-survey and prior surveys conducted among people who inject drugs (PWID) from 1997-2015, the model was calibrated to data on HCV prevalence by age, gender and PWID status, and the age distribution of PWID. We use the model to project the interim impact of treatment strategies currently being undertaken as part of the ongoing Georgia HCV elimination program, while accounting for treatment failure/loss to follow up, in order to determine whether they are on track to achieving their HCV elimination target by 2020, or whether strategies need to be modified to ensure success.\n\nResultsA treatment rate of 2,050 patients/month was required from the beginning of the national program to achieve a 90% reduction in prevalence by the end of 2020, with equal treatment rates of PWID and the general population. From May 2015 to October 2017, 40,420 patients were treated, an average of ~1,350 per month; although the treatment rate has recently declined from a peak of 4,500/month in September 2016 to 2100/month in November-December 2016, and 1000/month in August-October 2017, with a sustained virological response rate (SVR) of 98% per-protocol or 78% intent to treat. The model projects that the treatments undertaken up to October 2017 have reduced adult chronic prevalence by 26% (18-35%) to 3.7% (2.9-5.1%), reduced total incidence by 25% (15-35%), and prevented 1845 (751-3969) new infections and 93 (31-177) HCV-related deaths. If the treatment rate of 1000 patients initiated per month continues, prevalence will have halved by 2020, and reduce by 90% by 2026. In order to reach a 90% reduction by 2020, the treatment rate must increase 3.5-fold to 4000/month.\n\nConclusionThe Georgia HCV elimination program has accomplished an impressive scale up of treatment, which has already impacted on prevalence and incidence, and averted deaths due to HCV. However, extensive scale up is needed to achieve a 90% reduction in prevalence by 2020.

epidemiology↗

bioRxiv2017

High-Resolution Mapping Of cis-Regulatory Variation In Budding Yeast

Genetic variants affecting gene expression levels are a major source of phenotypic variation. The approximate locations of these variants can be mapped as expression quantitative trait loci (eQTLs); however a major limitation of eQTLs is their low resolution, which precludes investigation of the causal variants and their molecular mechanisms. Here we report RNA-seq and full genome sequences for 85 diverse isolates of the yeast Saccharomyces cerevisiae--including wild, domesticated, and human clinical strains--which allowed us to perform eQTL mapping with 50-fold higher resolution than previously possible. In addition to variants in promoters, we uncovered an important role for variants in 3 untranslated regions, especially those affecting binding of the PUF family of RNA-binding proteins. The eQTLs are predominantly under purifying selection, particularly those affecting essential genes and conserved genes. However, applying the sign test for lineage-specific selection revealed the polygenic up-regulation of dozens of biofilm suppressor genes in strains isolated from human patients, consistent with the key role of biofilms in fungal pathogenicity. In addition, a single variant in the promoter of a biofilm suppressor, NIT3, showed the strongest genome-wide association with clinical origin. Altogether our results demonstrate the power of high-resolution eQTL mapping in understanding the molecular mechanisms of regulatory variation, as well as the natural selection acting on this variation that drives adaptation to environments ranging from laboratories to vineyards to the human body.

genetics↗

bioRxiv2017

Genetic control of age-related gene expression and complex traits in the human brain

Age is the primary risk factor for many of the most common human diseases--particularly neurodegenerative diseases--yet we currently have a very limited understanding of how each individuals genome affects the aging process. Here we introduce a method to map genetic variants associated with age-related gene expression patterns, which we call temporal expression quantitative trait loci (teQTL). We found that these loci are markedly enriched in the human brain and are associated with neurodegenerative diseases such as Alzheimers disease and Creutzfeldt-Jakob disease. Examining potential molecular mechanisms, we found that age-related changes in DNA methylation can explain some cis-acting teQTLs, and that trans-acting teQTLs can be mediated by microRNAs. Our results suggest that genetic variants modifying age-related patterns of gene expression, acting through both cis- and trans-acting molecular mechanisms, could play a role in the pathogenesis of diverse neurological diseases.

genetics↗