Biology subjects

Keane, T. M.

Publications and source records attributed to Keane, T. M..

4 recordsLinked to original sources

bioRxiv2025

The Onychomys pangenome reveals the unique molecular adaptations that confer toxin resistance

Novel traits enable many rodents to thrive in extreme environmental niches. Predatory grasshopper mice (Onychomys sp.) have co-evolved resistance to painful and lethal neurotoxins produced by their scorpion prey. Previous work reported that grasshopper mice have structural and functional modifications in sodium channel Nav1.8 that block the effect of painful toxins. However, key questions remain about the molecular adaptations underlying toxin resistance. We produced the first high-quality reference genomes and annotations for Onychomys species and Peromyscus eremicus. We implemented a comprehensive pipeline to detect positive selection across genome-scale datasets and identified Onychomys-specific mutations in Nav1.3 (Scn3a), a sodium channel gene expressed in the central nervous system and the peripheral sensory system after nerve damage. We detected an Onychomys-specific tandem gene duplication of the Cblif gene, which encodes a glycoprotein crucial for vitamin B12 absorption. This adaptation likely supports the species dietary specialisation and modified stomach morphology, where parietal cells expressing Cblif are especially numerous. Our study provides a key step for establishing the Onychomys species as a model system for studying toxin resistance, alternative pain phenotypes, and behavioural traits related to predator-prey interactions.

genomics↗

bioRxiv2025

The mouse pangenome reveals the structural complexity of the murine protein coding landscape

We present the first mouse pangenome consisting of 17 high-quality inbred mouse strain genomes with complete annotation. This collection includes 12 widely used classical laboratory strains and 5 wild-derived strains. We have fully resolved previously incomplete genomic regions, including the major histocompatibility complex (MHC), the defensin cluster, T-cell receptor, and Ly49 complexes. Hundreds of non-reference genes identified in previous publications not found in GRCm39, like Defa1, Raet1a, and Klra20 (Ly49T), were localised in the new reference genomes. We conducted the first genome-wide scan of variable number tandem repeats (VNTRs) within the coding regions of mice, identifying over 400 genes with VNTR polymorphisms up to more than 600 repeat copies and repeat units reaching 990 nucleotides. Our strain-specific annotations enhance RNA-Seq analyses, as demonstrated in PWK/PhJ, where we observed a 5.1% improvement in read mapping and expression level differences in 2.1% of coding genes compared to using GRCm39.

genomics↗

bioRxiv2025

Young KRAB-zinc finger gene clusters are highly dynamic incubators of ERV-driven genetic heterogeneity in mice

KRAB-zinc finger proteins (KZFPs) comprise the largest family of mammalian transcription factors, rapidly evolving within and between species. Most KZFPs repress endogenous retroviruses (ERVs) and other retrotransposons, with KZFP gene numbers correlating with the ERV load across species, suggesting coevolution. How new KZFPs emerge in response to ERV invasions is currently unknown. Using a combination of long-read sequencing technologies and genome assembly, we present a first detailed comparative analysis of young KZFP gene clusters in the mouse lineage, which has undergone recent KZFP gene expansion and ERV infiltration. Detailed annotation of KZFP genes in a cluster on Mus musculus Chromosome 4 revealed parallel expansion and diversification of this locus in different mouse strains (C57BL/6J, 129S1/SvImJ and CAST/EiJ) and species (Mus spretus and Mus pahari). Our data supports a model by which new ERV integrations within young KZFP gene clusters likely promoted recombination events leading to the emergence of new KZFPs that repress them. At the same time, ERVs also increased their numbers by duplication instead of retrotransposition alone, unraveling a new mechanism for ERV enrichment at these loci.

genetics↗

bioRxiv2024

The structural diversity of telomeres and centromeres across mouse subspecies revealed by complete assemblies

It is over twenty years since the publication of the C57BL/6J mouse reference genome, which has been a key catalyst for understanding mammalian disease biology. However, the mouse reference genome still lacks telomeres and centromeres, contains 281 chromosomal sequence gaps, and only partially represents many biomedically relevant loci. We present the first T2T mouse genomes for two key inbred strains, C57BL/6J and CAST/EiJ. These T2T genomes reveal significant variability in telomere and centromere sizes and structural organisation. We add an additional 213 Mbp of novel sequence to the reference genome containing 517 protein-coding genes. We examined two important but incomplete loci in the mouse genome - the pseudoautosomal region (PAR) on the sex chromosomes and KRAB zinc finger proteins (KZFPs) loci. We identified distant locations of the PAR boundary, different copy number and sizes of segmental duplications, and a multitude of amino acid substitution mutations in PAR genes.

genomics↗