Biology subjects

Rice, A. M.

Publications and source records attributed to Rice, A. M..

6 recordsLinked to original sources

bioRxiv2024

Evolution of dosage-sensitive genes by tissue-restricted expression changes

Dosage-sensitive genes have characteristic patterns of evolution that include being refractory to small-scale duplication, depleted on human benign copy number variants (CNVs) and enriched on pathogenic CNVs. This intolerance to copy number change is likely due to an expression constraint that exists in one or more tissues. While genomic copy number changes alter the encompassed genes expression across all tissues, expression quantitative trait loci (eQTLs) -genomic regions harbouring sequence variants that influence the expression level of one or more genes- can act in a tissue-specific manner. In this work we examine expression variation of presumed dosage-sensitive and non-dosage-sensitive genes to discover how the locus duplicability constraints translate into gene expression constraints. Here we test the hypothesis that expression changes due to the presence of eQTLs acting in unconstrained tissues will not be deleterious and thus allow dosage-sensitive genes to vary expression while obeying constraints in other tissues. Using eQTLs across 48 human tissues from The Genotype-Tissue Expression (GTEx) project, we find that dosage-sensitive genes are enriched for being affected by eQTLs and that the eQTLs affecting dosage-sensitive genes are biased towards having narrow tissue-specificity with these genes having fewer eQTL-affected tissues than non-dosage-sensitive genes. Additionally, we find that dosage-sensitive genes are depleted for being affected by broad tissue breadth eQTLs, likely due to the increased chance of these eQTLs conflicting with expression constraints and being removed by purifying selection. These patterns suggest that dosage-sensitivity shapes the evolution of these genes by precluding copy number evolution and restricting their evolutionary trajectories to changes in expression regulation compatible with their functional constraints. Thus deeper interpretation of the patterns of constraints can be informative of the temporal or spatial location of the gene dosage sensitivity and contribute to our understanding of functional genomics. Author summaryGene duplication is an important and powerful evolutionary force that is responsible for the expansion of the coding capacity of genomes ultimately resulting in great genetic novelty. However, the opportunity for this evolutionary change can be limited by dosage constraints on some genes, meaning they are not normally duplicable, except in a balanced, whole genome event. This results in important, biologically relevant, differences between genes that are retained from whole genome duplication events versus those retained from small scale duplications, especially in terms of dosage sensitivity. We explored how the different dosage sensitivity in these sets of genes relates to quantitative expression variation present in populations. We found that while dosage-sensitive genes are more likely to have their expression levels influenced by genetic variation, these changes are often specific a small number of tissues. In contrast, genes that are less sensitive to dosage changes show greater variation in expression levels across multiple tissues. Our findings suggest that dosage-sensitive genes evolve through fine-tuned adjustments in their expression levels in specific tissues, thus bypassing constraints operating on other tissues. This understanding sheds light on how dosage-sensitive genes evolve and could have implications for understanding human diseases caused by these genes.

evolutionary biology↗

bioRxiv2023

Regulatory network structure and environmental signals constrain transcription factor innovation

Evolutionary innovation of transcription factors frequently drives phenotypic diversification and adaptation to environmental change. Rewiring - that is gaining or losing connections to transcriptional target genes - is a key mechanism by which transcription factors evolve and innovate. However the frequency of functional adaptation varies between different regulators, even when they are closely related. To identify factors influencing propensity for rewiring, we utilise a Pseudomonas fluorescens SBW25 strain rendered incapable of flagellar mediated motility in soft-agar plates via deletion of the flagellar master regulator (fleQ). This bacterium can evolve to rescue flagellar motility via gene regulatory network rewiring of an alternative transcription factor to rescue activity of FleQ. Previously, we have identified two members (out of 22) of the RpoN-dependent enhancer binding protein (RpoN-EBP) family of transcription factors (NtrC and PFLU1132) that are capable of innovating in this way. These two transcription factors rewire repeatably and reliably in a strict hierarchy - with NtrC the only evolved rewiring route in a {Delta}fleQ background, and PFLU1132 the only evolved rewiring route in a {Delta}fleQ{Delta}ntrC background. However, why other members in the same transcription factor family have not been observed to rescue flagellar activity is unclear. Previous work shows that protein homology cannot fully explain this pattern, and mutations in rewired strains suggested high levels of transcription factor expression and activation drive rewiring. We predict that mutations that increase expression of the rewired transcription factor are vital to unlock rewiring potential. Here, we construct titratable expression mutant lines for 11 of the RpoN-EBPs in P. fluorescens. We show that in 5 additional RpoN-EBPs (HbcR, GcsR, DctD, AauR and PFLU2209), high expression levels result in different mutations conferring motility rescue, suggesting alternative rewiring pathways. Our results indicate that expression levels (and not protein homology) of RpoN-EBPs are a key constraining factor in determining rewiring potential. This suggests that transcription factors that can achieve high expression through few mutational changes, or transcription factors that are active in the selective environment, are more likely to innovate and contribute to adaptive gene regulatory network rewiring.

evolutionary biology↗

bioRxiv2022

Thermal acclimation in a non-migratory songbird occurs via changes to thermogenic capacity, but not conductance

Thermoregulatory performance can be modified through changes in various subordinate traits, including thermal conductance, basal and summit metabolic rates, and body composition. We investigated physiological differences between black-capped chickadees (Poecile atricapillus) acclimated for six weeks to cold (-5{degrees}C) or control (25{degrees}C) environments (n = 7 per treatment) by measuring traits that affect thermal balance. We made repeated measurements of basal and summit metabolic rates via flow-through respirometry and body composition using quantitative magnetic resonance of live birds. At the end of the acclimation, we measured thermal conductance of the combined feathers and skins. Cold-acclimated birds had a higher summit metabolic rate, reflecting a greater capacity for endogenous heat generation, and an increased lean mass. However, birds did not alter their thermal conductance. These results suggest that, while birds can use multiple mechanisms to acclimate to their thermal environment, they use a subset of potential changes over varying timescales.

physiology↗

bioRxiv2021

Poly-glutamine-dependent self-association as a potential mechanism for regulation of androgen receptor activity

The androgen receptor (AR) plays a central role in prostate cancer. Development of castration resistant prostate cancer (CRPC) requires androgen-independent activation of AR, which involves its large N-terminal domain (NTD) and entails dramatic epigenetic changes depending in part on histone lysine demethylases (KDMs) that interact with AR. The AR-NTD is rich in low-complexity sequences, including a polyQ repeat. Longer polyQ sequences were reported to decrease transcriptional activity and to protect against prostate cancer. However, the molecular mechanisms underlying these observations are unclear. Using NMR spectroscopy, here we identify weak interactions between the AR-NTD and the KDM4A catalytic domain, and between the AR ligand-binding domain and a central KDM4A region that also contains low-complexity sequences. We also show that the AR-NTD can undergo liquid-liquid phase separation in vitro, with longer polyQ sequences phase separating more readily. Moreover, longer polyQ sequences hinder nuclear localization in the absence of hormone and increase the propensity for formation of AR-containing puncta in the nucleus of cells treated with dihydrotestosterone. These results lead us to hypothesize that polyQ-dependent liquid-liquid phase separation may provide a mechanism to decrease the transcriptional activity of AR, potentially opening new opportunities to design effective therapies against CRPC.

cancer biology↗

bioRxiv2020

Evidence for strong mutation bias towards, and selection against, T/U content in SARS-CoV2: implications for attenuated vaccine design.

Large-scale re-engineering of synonymous sites is a promising strategy to generate attenuated viruses for vaccines. Attenuation typically relies on de-optimisation of codon pairs and maximization of CpG dinculeotide frequencies. So as to formulate evolutionarily-informed attenuation strategies, that aim to force nucleotide usage against the estimated direction favoured by selection, here we examine available whole-genome sequences of SARS-CoV2 to infer patterns of mutation and selection on synonymous sites. Analysis of mutational profiles indicates a strong mutation bias towards T with concomitant selection against T. Accounting for dinucleotide effects reinforces this conclusion, observed TT content being a quarter of that expected under neutrality. A significantly different mutational profile at CDS sites that are not 4-fold degenerate is consistent with contemporaneous selection against T mutations more widely. Although selection against CpG dinucleotides is expected to drive synonymous site G+C content below mutational equilibrium, observed G+C content is slightly above equilibrium, possibly because of selection for higher expression. Consistent with gene-specific selection against CpG dinucleotides, we observe systematic differences of CpG content between SARS-CoV2 genes. We propose an evolutionarily informed gene-bespoke approach to attenuation that, unusually, seeks to increase usage of the already most common synonymous codons. Comparable analysis of H1N1 and Ebola finds that GC3 deviated from neutral equilibrium is not a universal feature, cautioning against generalization of results.

evolutionary biology↗

bioRxiv2017

Hybrid Songbirds are Deficient in Learning and Memory

Identifying the phenotypes underlying postzygotic reproductive isolation is crucial for fully understanding the evolution and maintenance of species. One potential postzygotic isolating barrier that has not yet been examined is learning and memory ability in hybrids. Learning and memory are important fitness-related traits, especially in scatter-hoarding species, where accurate retrieval of hoarded food is vital for winter survival. Here, we test the hypothesis that learning and memory ability can act as a postzygotic isolating barrier by comparing these traits among two scatter-hoarding songbird species, black-capped (Poecile atricapillus), Carolina chickadees (Poecile carolinensis), and their naturally occurring hybrids. In an outdoor aviary setting, we find that hybrid chickadees perform significantly worse on an associative learning spatial task and are worse at solving a novel problem compared to both parental species. Deficiencies in learning and memory abilities could therefore contribute to postzygotic reproductive isolation between chickadee species. Given the importance of learning and memory for fitness, our results suggest that these traits may play an important, but as yet overlooked, role in postzygotic reproductive isolation.

evolutionary biology↗