Biology subjects

Irwin, D.

Publications and source records attributed to Irwin, D..

12 recordsLinked to original sources

bioRxiv2026

Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.

neuroscience↗

bioRxiv2026

Highly inducible transcription is impaired in cells lacking Cyclin T1 (CycT1) of the positive transcription factor b (P-TEFb).

In eukaryotic cells, the positive transcription elongation factor b (P-TEFb) plays a critical role in the transition of RNAPII from the paused state to actively transcribing mode. Although three different cyclin (Cyc) T (CycT1, T2a, and T2b) interact with CDK9 to form functional P-TEFb, a majority of P-TEFb complexes are comprised of the CycT1 and CDK9. To analyze the role of the CycT1 subunit of P-TEFb on cellular transcription, we established HEK293T cells lacking CycT1 proteins (CycT1-KO cells). While no apparent growth defects were observed with CYcT1-KO cells, the level of CDK9 was decreased and no compensatory over-expression of CycT2 was observed, suggesting that the reduced level of functional P-TEFb complexes is sufficient for the normal cell growth. Reporter gene assays indicate that NF-kappaB-dependent transcription induced by PMA was impaired in CycT1-KO cells although the function of NF-kappaB (P65) per se was not affected. On the other hand, AP1-dependent transactivation induced by PMA was unaffected in CycT1-KO cells. Moreover, transcription stimulated by JQ1, a strong P-TEFb inducer, was reduced in CycT1-KO cells. Data of biochemical analysis indicate that P-TEFb with CycT1 (P-TEFb (CDK9:CycT1)) was efficiently released from 7SKsnRNP by JQ1 while P-TEFb (CDK9:CycT2) was not affected by JQ1. Transcriptome analysis indicated that the lack of CycT1 had a minor effect on the steady-state transcription. However, expression of JQ1-dependent genes was severely reduced in CycT1-KO cells. Interestingly, referring to gene expression profiles of 33 different types of cancer revealed that 11 out of 13 top JQ1-dependent genes were also highly upregulated in Pancreatic Adenocarcinoma. From these results, we conclude that although many genes can be regulated by both P-TEFb (CDK9:CycT1) and P-TEFb (CDK9:CycT2), CycT1 plays a critical role in regulating highly inducible genes, which are also aberrantly regulated in a particular type of cancer.

molecular biology↗

bioRxiv2026

Admixture mapping among three hybridizing sapsucker (Sphyrapicus) species shows importance of the Z chromosome in phenotypic differentiation and speciation

Plumage pigmentation is under intense sexual and natural selection and plays an important role in the speciation process in birds, so there is much interest in uncovering the genomic basis of plumage colour differences between populations and species. Three species of North American woodpeckers, the red-breasted (Sphyrapicus ruber), red-naped (S. nuchalis), and yellow-bellied sapsuckers (S. varius), provide a particularly promising opportunity to unravel the genomic mechanisms of plumage colour differentiation. The breeding ranges of the three species are mostly non-overlapping but adjacent, with hybrid zones occurring where the ranges meet. The species pair with the most similar plumage colouration (S. varius and S. nuchalis) is not the most closely related pair genomically (S. nuchalis and S. ruber is), providing an opportunity to determine the subset of the genome that underlies the plumage colour variation. Using admixture mapping of whole genome sequences from each species and hybrids from each species pair, we show close associations between the colour of multiple plumage patches and wide swathes of the Z-chromosome. These results highlight how comparable changes in one sex chromosome can cause either slight plumage pigmentation changes (S. varius vs. S. nuchalis) or large-scale shifts from dimorphism to monomorphism and from primarily black and white to primarily red plumage colouration (S. varius and S. nuchalis vs. S. ruber).

evolutionary biology↗

bioRxiv2026

Magic traits, search costs, and the persistence of species in secondary contact

When two populations come into secondary contact, assortative mating can act as a barrier to gene flow. However, when assortative mating is incomplete, associations between preference and cue loci can break down, eroding assortative mating and collapsing species boundaries. Here, we investigate factors that can contribute to the maintenance of differentiated reproductive populations despite gene flow, resulting in either clinal hybrid zones or overlap zones between distinct populations. By simulating secondary contact on a uniform two-dimensional landscape using an individual-based computer model, we examine how the potential outcomes of secondary contact depend on search costs and/or pleiotropy between various combinations of mating cue, mating preference, and hybrid viability traits. We find that search costs can maintain stable mating trait clines, even in the absence of hybrid inviability traits. Pleiotropy between mating cues and hybrid inviability (i.e., "magic cues") temporarily stabilizes the mating cue cline but fails to maintain mating preference differentiation, since preference is not itself under direct selection. As the preference cline collapses, assortative mating breaks down, and -- absent search costs or very strong hybrid inviability -- the mating cue cline subsequently collapses as well. Thus, without preference-cue or preference-viability pleiotropy, search costs are essential for maintaining mating trait differentiation. Changes to the genetic architecture of mating traits strongly alter the distribution of phenotypes, affecting whether parental populations can coexist spatially. Small parameter changes can abruptly shift outcomes, highlighting the sensitivity of these systems.

evolutionary biology↗

bioRxiv2025

The Driving W Hypothesis for Low Within-Population Mitochondrial DNA Diversity and Between-Population Mitochondrial Capture

The fields of evolutionary biology, molecular ecology, genetics, and taxonomy have been profoundly influenced by studies of variation in mitochondrial DNA (mtDNA), yet there are often surprising differences between mtDNA and nuclear DNA in the within- and between-population relationships that they display. Here I articulate and evaluate a hypothesis that may explain many of the cases in which mtDNA shows little within-population variation and recent movement between populations. Many taxonomic groups (e.g., birds, butterflies and moths; most snakes; some amphibians, fish, and plants) have sex chromosome systems in which females are heterogametic (i.e., ZW females and ZZ males). If a W chromosome undergoes a mutation that gives it a transmission advantage in getting into the one egg produced by female meiosis, it will tend to cause a female-biased sex ratio in the offspring of females that carry that driving W chromosome. This sex ratio bias increases the frequency of the driving W in relation to the non-driving W in the next generation. In the great majority of species in which mitochondria are inherited matrilineally, the spread of the driving W through the population will carry along the particular mitochondrial genome that happens to be associated with the driving W. I summarize evidence in support of the seven components of this W-mtDNA Drive Hypothesis and present simulations and mathematical formulae showing that W drivers spread much more rapidly than equivalent-strength Z or autosomal drivers. Suppressors of W drive spread at a vastly lower rate. I conclude that many cases of low within-population mitochondrial diversity and mitochondrial transfer between species might be explained by the spread of driving W chromosomes.

evolutionary biology↗

bioRxiv2024

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies

AbstractSpread and aggregation of misfolded -synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinsons disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed "strains" for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain (e.g., in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear. Here, we developed assays using monoclonal antibodies selective for two different aSyn species generated in vitro - termed Strain A and Strain B - and used them to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma, through immunohistochemistry, enzyme-linked immunoassay, and immunoblotting. Surprisingly, we found that plasma aSyn species detected by these antibodies differentiated individuals with PD vs. DLB in a discovery cohort (UPenn, n=235, AUC 0.83) and a multi-site replication cohort (Parkinsons Disease Biomarker Program, or PDBP, n=200, AUC 0.72). aSyn plasma species detected by the Strain A antibody also predicted rate of cognitive decline in PD. We found no evidence for aSyn strains in CSF, and ability to template aSyn fibrillization differed for species isolated from plasma vs. brain, and in PD vs. DLB. Taken together, our findings suggest that aSyn conformational differences may impact clinical presentation and cortical spread of pathological aSyn. Moreover, the enrichment of these aSyn strains in plasma implicates a non-central nervous system source.

neuroscience↗

bioRxiv2024

Cytoarchitectonic gradients of laminar degeneration in behavioral variant frontotemporal dementia

Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation. Here, we tested this hypothesis in a frontal cortical gradient consisting of five cytoarchitectonic types (i.e., periallocortex, agranular mesocortex, dysgranular mesocortex, eulaminate-I isocortex, eulaminate-II isocortex) spanning anterior cingulate, paracingulate, orbitofrontal, and mid-frontal gyri in bvFTD-tau (n=27), bvFTD-TDP (n=47), and healthy controls (HC; n=32). We immunostained all tissue for total neurons (NeuN; neuronal-nuclear protein) and pyramidal neurons (SMI32; non-phosphorylated neurofilament) and digitally quantified NeuN-immunoreactivity (ir) and SMI32-ir in supragranular II-III, infragranular V-VI, and all I-VI layers in each cytoarchitectonic type. We used linear mixed-effects models adjusted for demographic and biologic variables to compare SMI32-ir between groups and examine relationships with the cortical gradient, long-range pathways, and clinical symptoms. We found regional and laminar distributions of SMI32-ir expected for HC, validating our measures within the cortical gradient framework. While SMI32-ir loss was not related to the cortical gradient in bvFTD-TDP, SMI32-ir progressively decreased along the cortical gradient of bvFTD-tau and included greater SMI32-ir loss in supragranular eulaminate-II isocortex in bvFTD-tau vs bvFTD-TDP (p=0.039). In a structural model for long-range laminar connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio of mesocortex-to-isocortex SMI32-ir in bvFTD-tau vs bvFTD-TDP (p=0.019), suggesting select long-projecting pathways may contribute to isocortical-predominant degeneration in bvFTD-tau. In cytoarchitectonic types with the highest NeuN-ir, we found lower SMI32-ir in bvFTD-tau vs bvFTD-TDP (p=0.047), suggesting pyramidal neurodegeneration may occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir related to behavioral severity and frontal-mediated letter fluency, not temporal-mediated confrontation naming, demonstrating the clinical relevance and specificity of frontal pyramidal neurodegeneration to bvFTD-related symptoms. Our data suggest loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that selectively worsens along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration may preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients may be an important neuroanatomical framework for identifying which types of cells and pathways are differentially involved between proteinopathies.

neuroscience↗

bioRxiv2023

Macrophage Xanthine Oxidoreductase Links LPS Induced Lung Inflammatory Injury to NLRP3 Inflammasome Expression and Mitochondrial Respiration

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) remain poorly treated inflammatory lung disorders. Both reactive oxygen species (ROS) and macrophages are involved in the pathogenesis of ALI/ARDS. Xanthine oxidoreductase (XOR) is an ROS generator that plays a central role in the inflammation that contributes to ALI. To elucidate the role of macrophage-specific XOR in endotoxin induced ALI, we developed a conditional myeloid specific XOR knockout in mice. Myeloid specific ablation of XOR in LPS insufflated mice markedly attenuated lung injury demonstrating the essential role of XOR in this response. Macrophages from myeloid specific XOR knockout exhibited loss of inflammatory activation and increased expression of anti-inflammatory genes/proteins. Transcriptional profiling of whole lung tissue of LPS insufflated XORfl/fl//LysM-Cre mice demonstrated an important role for XOR in expression and activation of the NLRP3 inflammasome and acquisition of a glycolytic phenotype by inflammatory macrophages. These results identify XOR as an unexpected link between macrophage redox status, mitochondrial respiration and inflammatory activation.

immunology↗

bioRxiv2023

Evidence for a chromosomal inversion maintaining divergent plumage phenotypes between extensively hybridizing yellowhammers (Emberiza citrinella) and pine buntings (E. leucocephalos)

In an allopatric speciation model, populations of a species become isolated by a geographic barrier and develop reproductive isolation through genetic differentiation. When populations meet in secondary contact, the strength of evolved reproductive barriers determines the extent of hybridization and whether the populations will continue to diverge or merge back together. The yellowhammer (Emberiza citrinella) and pine bunting (E. leucocephalos) are avian sister species that diverged in allopatry during the Pleistocene glaciations. Though they differ greatly in plumage and form distinct genetic clusters in allopatry, these taxa show negligible mitochondrial DNA differentiation and hybridize extensively in sympatry lending uncertainty to the state of reproductive isolation in the system. To assess the strength of reproductive barriers between taxa, we examined genomic differentiation across the yellowhammer and pine bunting system. We found that extensive admixture has occurred in sympatry, indicating that reproductive barriers between taxa are weak. We also identified a putative Z chromosome inversion that underlies plumage variation in the system, with the "pine bunting" inversion form showing dominance over the "yellowhammer" form. Our results suggest that yellowhammers and pine buntings are currently at a crossroads and that evolutionary forces may push this system towards either continued differentiation or population merging. However, even if these taxa merge, recombination suppression between chromosome Z inversion forms may maintain divergent plumage phenotypes within the system. In this way, our findings highlight the important role hybridization plays in increasing the genetic and phenotypic variation as well as the evolvability of a system.

evolutionary biology↗

bioRxiv2022

Geographic variability of hybridization between Red-breasted and Red-naped Sapsuckers

Hybrid zones reveal the strength of reproductive isolation between populations undergoing speciation and are thus a key tool used in evolutionary biology research. Multiple replicate transects across the same hybrid zone offer further insight into the dynamics of hybridization in different environments, clarifying the role of extrinsic forces on the speciation process. Red-breasted and Red-naped Sapsuckers (Sphyrapicus ruber and S. nuchalis) have a long zone of contact over approximately 1,600 km from central British Columbia, Canada to central California, USA. We compared Genotyping-by-Sequencing data from three independent sapsucker hybrid zone transects to compare hybridization dynamics between the same species under variable geoclimatic conditions. We then generated geographic clines of the genomic data to compare hybrid zone widths and used Random Forest models and linear regression to assess the relationship between climate and sapsucker ancestry along each transect. Our results show variation in symmetry and directionality of back crossing, patterns often indicative of moving hybrid zones. We note variable cline widths among transects, indicating differences in the selection maintaining hybrid zone dynamics. Furthermore, Random Forest models identified different variables in close association with sapsucker ancestry across each transect. These results indicate a lack of repeatability across replicate transects and a strong influence of the local environment on hybrid zone dynamics.

evolutionary biology↗

bioRxiv2021

Mitonuclear co-introgression opposes genetic differentiation between phenotypically divergent songbirds

Comparisons of genomic variation among closely related species often show more differentiation in mitochondrial DNA (mtDNA) and sex chromosomes than in autosomes, a pattern expected due to the differing effective population sizes and evolutionary dynamics of these genomic components. Yet, introgression can cause species pairs to deviate dramatically from general differentiation trends. The yellowhammer (Emberiza citrinella) and the pine bunting (E. leucocephalos) are hybridizing avian sister species that differ greatly in appearance and moderately in nuclear DNA, but that show no mtDNA differentiation. This mitonuclear discordance is best explained by adaptive mtDNA introgression--a process that can select for co-introgression at nuclear genes with mitochondrial functions (mitonuclear genes). To better understand the extent of mitonuclear discordance and characterize nuclear differentiation patterns in this system, we investigated genome-wide differentiation between allopatric yellowhammers and pine buntings and compared it to what was seen previously in mtDNA. We found significant nuclear differentiation that was highly heterogeneous across the genome, with a particularly wide differentiation peak on the sex chromosome Z. We further tested for preferential introgression of mitonuclear genes and found statistical support for this process in yellowhammers. A role for mitonuclear coevolution in this system is supported by a stronger signal of co-introgression in genes coding for subunits of the mitoribosome and electron transport chain complexes. Altogether, our study emphasizes the extreme variation seen in differentiation across genomic components and study systems as well as highlights the ramifications of this variation in species evolution.

evolutionary biology↗

bioRxiv2021

Hybridization and the coexistence of species

It is thought that two species can coexist if they use different resources present in the environment, yet this assumes that species are completely reproductively isolated. We model coexistence outcomes for two sympatric species that are ecologically differentiated but have incomplete reproductive isolation. The consequences of interbreeding depend crucially on hybrid fitness. When hybrid fitness is high, just a small rate of hybridization can lead to collapse of two species into one. Low hybrid fitness can cause population declines, making extinction of one or both species likely. High intrinsic growth rates result in higher reproductive rates when populations are below carrying capacity, reducing the probability of extinction and increasing the probability of stable coexistence at moderate levels of assortative mating and hybrid fitness. Very strong but incomplete assortative mating can induce low hybrid fitness via a mating disadvantage to rare genotypes, and this can stabilize coexistence of two species at high but incomplete levels of assortative mating. Given these results and evidence that it may take many millions of years of divergence before related species become sympatric, we postulate that coexistence of closely-related species is more often limited by insufficient assortative mating than by insufficient ecological differentiation.

ecology↗