Biology subjects

Kirby, C.

Publications and source records attributed to Kirby, C..

6 recordsLinked to original sources

bioRxiv2026

Mononuclear myeloid cells mount an adaptive protective response to intracerebral haemorrhage by activation of NRF2

Following intracerebral haemorrhage (ICH), secondary injury contributes to negative outcomes. Here, we describe inter-dependent injurious and adaptive-protective pathways that form a therapeutically modifiable ICH response. In perihaematomal tissue from post-mortem ICH patients, transcriptomic analysis pointed to concurrent perihaematomal activation of the cytoprotective stress-induced transcription factor NRF2 and activation of interferon responses, with mononuclear myeloid cells (microglia and monocyte-derived cells, MMCs) and astrocytes contributing to this signature. In vitro, microglia-astrocyte-neuron co-culture studies revealed that microglial NRF2 activation was induced by clot-conditioned medium and could influence the interferon pathway in both microglia themselves as well as astrocytes. In vivo, MMC-specific deletion of NRF2 inhibited NRF2 target-gene induction, exacerbated interferon pathway activation following ICH, and impaired functional recovery. Pharmacological NRF2 activation suppressed interferon pathway induction post-ICH, and direct interferon pathway antagonism rescued neurological recovery deficits caused by MMC-specific NRF2 deficiency. Thus, augmenting NRF2- or inhibiting interferon-signalling may improve outcomes after ICH.

neuroscience↗

bioRxiv2026

Pangenome graphs reveal the extent and complexity of genetic variation in North America's most abundant mammal

Pangenome methods reduce reference bias and enable the characterization of previously inaccessible genomic variation within a species, and are thus especially useful for species with high levels of genetic diversity. Here, we constructed a pangenome for the deer mouse (Peromyscus maniculatus), a model for studying local adaptation and a potent reservoir for diverse zoonotic diseases, using long-read assemblies from 14 ecologically and biogeographically diverse populations and 2 outgroup species (totaling 19 haplotypes). The total length of the pangenome is 3.9 Gb, but only 1.4 Gb is shared across all haplotypes, suggesting vast structural diversity. From this pangenome we identified [~]108.3 million single nucleotide polymorphisms (SNPs), [~]23.9 million indels (variants < 50 bp), and [~]2.4 million structural variants (variants > 50 bp) as well as complex genetic variation driven by massive chromosomal rearrangements and an unprecedented diversity of centromeric satellite positions. Furthermore, we uncover widespread gene copy number variation (CNVs)-some genes vary in number by an order of magnitude across deer mouse haplotypes-in addition to several gene-rich loci that display high levels of structural diversity. Such genes are enriched for functions related to sensory perception, environmental interaction, and immune responses and many display signatures of positive selection at the molecular level, suggesting functional diversification. Our work provides important insight into the utility of pangenomes for genetically diverse species and illuminates underappreciated genomic plasticity within a mammalian species.

evolutionary biology↗

bioRxiv2026

Pleistocene climatic oscillations impact the diversification of deer mice (Peromyscus maniculatus) and the independent evolution of ecotypes

A central question in evolutionary biology is whether local adaptation is predictable when a species repeatedly encounters similar environments. The deer mouse, Peromyscus maniculatus, has a range of over 13 million km2 in North America and may be found in nearly every terrestrial habitat. Because of their abundance and wide habitat preference, deer mice and closely related Peromyscus, which we refer to as the P. maniculatus species complex, are at the forefront of studies of biogeography and local adaptation. Here, we undertake a comprehensive survey of genome-wide and phenotypic diversity to characterize the recent evolutionary history of this group. We sequenced whole genomes from 232 individuals across their range, representing the most thorough genetic sampling of the P. maniculatus species complex to date. We identify six geographically delineated clades, several of which encompass both classically recognized P. maniculatus subspecies as well as other recognized species. Ecological niche modelling suggests that this geographic structure resulted from rapid post-LGM range expansion and adaptation to emerging habitats. Our morphological measurements of 979 specimens and field data compiled from over 28,000 museum records show that deer mice in forests across the range consistently have longer tails, larger feet, bigger ears, and elongated whiskers. These traits constitute an arboreal ecotype that has evolved at least three times independently, and was likely lost in other parts of the range as populations moved out of forested habitat. Altogether, these results suggest that post-LGM increases in forested habitat drove the parallel evolution of arboreal ecotypes across the deer mouse range.

evolutionary biology↗

bioRxiv2024

Cellular evolution of the hypothalamic preoptic area of behaviorally divergent deer mice

Genetic variation is known to contribute to the variation of animal social behavior, but the molecular mechanisms that lead to behavioral differences are still not fully understood. Here, we investigate the cellular evolution of the hypothalamic preoptic area (POA), a brain region that plays a critical role in social behavior, across two sister species of deer mice (Peromyscus maniculatus and P. polionotus) with divergent social systems. These two species exhibit large differences in mating and parental care behavior across species and sex. Using single-nucleus RNA-sequencing, we build a cellular atlas of the POA for males and females of both Peromyscus species. We identify four cell types that are differentially abundant across species, two of which may account for species differences in parental care behavior based on known functions of these cell types. Our data further implicate two sex-biased cell types to be important for the evolution of sex-specific behavior. Finally, we show a remarkable reduction of sex-biased gene expression in P. polionotus, a monogamous species that also exhibits reduced sexual dimorphism in parental care behavior. Our POA atlas is a powerful resource to investigate how molecular neuronal traits may be evolving to give rise to innate differences in social behavior across animal species.

evolutionary biology↗

bioRxiv2021

Adaptive tail-length evolution in deer mice is associated with differential Hoxd13 expression in early development

Variation in the size and number of axial segments underlies much of the diversity in animal body plans. Here, we investigate the evolutionary, genetic, and developmental mechanisms driving tail-length differences between forest and prairie ecotypes of deer mice (Peromyscus maniculatus). We first show that long-tailed forest mice perform better in an arboreal locomotion assay, consistent with tails being important for balance during climbing. The long tails of these forest mice consist of both longer and more caudal vertebrae than prairie mice. Using quantitative genetics, we identify six genomic regions that contribute to differences in total tail length, three of which associate with vertebra length and the other three with vertebra number. For all six loci, the forest allele increases tail length, consistent with the cumulative effect of natural selection. Two of the genomic regions associated with variation in vertebra number contain Hox gene clusters. Of those, we find an allele-specific decrease in Hoxd13 expression in the embryonic tail bud of long-tailed forest mice, consistent with its role in axial elongation. Additionally, we find that forest embryos have more presomitic mesoderm than prairie embryos, and that this correlates with an increase in the number of neuromesodermal progenitors (NMPs), which are modulated by Hox13 paralogs. Together, these results suggest a role for Hoxd13 in the development of natural variation in adaptive morphology on a microevolutionary timescale. HIGHLIGHTSO_LIIn deer mice, the long-tailed forest ecotype outperforms the short-tailed prairie ecotype in climbing, consistent with the tails role in balance. C_LIO_LILong tails are due to mutations on distinct chromosomes that affect either length or number of caudal vertebrae. C_LIO_LIQTL mapping identifies Hox clusters, one gene of which - Hoxd13 - shows low allele-specific expression in the embryonic tail bud of forest mice. C_LIO_LIForest mouse embryos have a larger presomitic mesoderm (PSM), likely mediated by a larger progenitor population (NMPs) and lower Hoxd13 levels. C_LI

genetics↗

bioRxiv2019

The Tug1 Locus is Essential for Male Fertility

BackgroundSeveral long noncoding RNAs (lncRNAs) have been shown to function as central components of molecular machines that play fundamental roles in biology. While the number of annotated lncRNAs in mammalian genomes has greatly expanded, their functions remain largely uncharacterized. This is compounded by the fact that identifying lncRNA loci that have robust and reproducible phenotypes when mutated has been a challenge. ResultsWe previously generated a cohort of 20 lncRNA loci knockout mice. Here, we extend our initial study and provide a more detailed analysis of the highly conserved lncRNA locus, Taurine Upregulated Gene 1 (Tug1). We report that Tug1 knockout male mice are sterile with complete penetrance due to a low sperm count and abnormal sperm morphology. Having identified a lncRNA loci with a robust phenotype, we wanted to determine which, if any, potential elements contained in the Tug1 genomic region (DNA, RNA, protein, or the act of transcription) have activity. Using engineered mouse models and cell-based assays, we provide evidence that the Tug1 locus harbors three distinct regulatory activities - two noncoding and one coding: (i) a cis DNA repressor that regulates many neighboring genes, (ii) a lncRNA that can regulate genes by a trans-based function, and finally (iii) Tug1 encodes an evolutionary conserved peptide that when overexpressed impacts mitochondrial membrane potential. ConclusionsOur results reveal an essential role for the Tug1 locus in male fertility and uncover three distinct regulatory activities in the Tug1 locus, thus highlighting the complexity present at lncRNA loci.

genomics↗