Biology subjects

Harringmeyer, O. S.

Publications and source records attributed to Harringmeyer, O. S..

8 recordsLinked to original sources

bioRxiv2026

Gene flux shapes diversity and evolution of the ancient 17q21.31 inversion polymorphism

A hallmark of chromosomal inversions is that they suppress recombination between haplotypes, allowing inversion haplotypes to persist as single co-inherited units. To determine the extent to which inversions nevertheless permit genetic exchange, we investigated a common 979-kb inversion polymorphism at the human 17q21.31 locus. This locus exhibits deep divergence between the reference (H1) and inverted (H2) haplotypes, extensive segmental duplications (SDs) flanking the inversion, and association with neurodegenerative diseases, developmental disorders, and fertility-related phenotypes. Using single-cell sperm genome sequencing data, we directly measured recombination rates between H1 and H2 haplotypes and found near-complete suppression of single-crossover events between the haplotypes. The rare single crossovers that did occur were mediated by non-allelic homologous recombination between shared H1 and H2 SDs, generating novel duplication architectures. In contrast, two-switch events consistent with gene conversion or double crossovers, spanning 17-150 kb, occurred throughout the inversion at rates exceeding genome-wide estimates for events of comparable size. Consistent with recurring genetic exchange, we identified 99 distinct H1-H2 recombinant haplotypes segregating in All of Us genomes, including 26 with combinations of H1 and H2 SDs. These recombinant haplotypes facilitated dissection of the inversion's effects on fertility-related phenotypes; using a large parent-embryo dataset, we found that H2 additively increases female crossover rates across chromosomes and that KANSL1 duplications do not explain this effect. Finally, ancestral recombination graphs dated H1-H2 gene flux (the exchange of genetic material between alternative arrangements) to approximately 100-500 thousand years ago, revealing that H1 and H2 haplotypes have co-segregated for at least half a million years. Together, these results demonstrate that inversions can be permeable barriers to recombination, with ongoing gene flux influencing the diversity and evolution of inversion polymorphisms.

genomics↗

bioRxiv2026

Sequential accumulation of adaptive alleles forms an inversion supergene in deer mice

Supergenes are clusters of co-inherited loci that affect multiple or complex phenotypes. Despite the growing number of chromosomal inversions identified as supergenes in natural populations, their molecular basis and evolutionary history often remain obscure. Here, we identified two candidate genes, Slc45a2 and Npr3, within a 41-Mb inversion supergene in the deer mouse (Peromyscus maniculatus) that respectively drive darker coats and longer tails - two traits associated with forest adaptation. Mice homozygous for the inversion (inv/inv) exhibit elevated Slc45a2 expression in melanocytes relative to the congenic standard genotype (std/std), disrupting pheomelanin production. In parallel, downregulation of Npr3 in inv/inv mouse growth plates prolongs postnatal growth of caudal vertebrae, resulting in tail elongation. Population-level analyses further implicate that this supergene arose through the subsequent accumulation of the Npr3 allele within the inversion, rather than by capturing all beneficial mutations at its origin.

evolutionary biology↗

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↗

bioRxiv2024

How repeats rearrange chromosomes in deer mice

Large genomic rearrangements, such as chromosomal inversions, can play a key role in evolution and often underlie karyotype variation, but the mechanisms by which these rearrangements arise remain poorly understood. To study the origins of inversions, we generated chromosome-level de novo genome assemblies for four subspecies of deer mice (Peromyscus maniculatus) with known inversion polymorphisms. We identified [~]8,000 inversions, including 47 mega-base scale inversions, that together affect [~]30% of the genome. Analysis of inversion breakpoints suggests that while most small (<1 Mb) inversions arise via ectopic recombination between retrotransposons, large (>1 Mb) inversions are primarily associated with segmental duplications (SDs). Large inversion breakpoints frequently occur near centromeres, which may be explained by an accumulation of transposable elements in pericentromeric regions driving SD formation. Additionally, multiple large inversions likely arose from ectopic recombination between near-identical centromeric satellite arrays located megabases apart, a previously uncharacterized mechanism of inversion formation. Together, our results illuminate how repeats give rise to massive shifts in chromosome architecture.

genomics↗

bioRxiv2023

A single genetic locus lengthens deer mouse burrows via motor pattern evolution

The question of how evolution builds complex behaviors has long fascinated biologists. To address this question from a genetic perspective, we capitalize on variation in innate burrowing behavior between two sister species of Peromyscus mice: P. maniculatus that construct short, simple burrows and P. polionotus that uniquely construct long, elaborate burrows. We identify three regions of the genome associated with differences in burrow length and then narrow in on one large-effect 12-Mb locus on chromosome 4. By introgressing the P. polionotus allele into a P. maniculatus background, we demonstrate this locus, on its own, increases burrow length by 20%. Next, by recording mice digging in a transparent tube, we find this locus has specific effects on burrowing behavior. This locus does not affect time spent digging or latency to dig, but rather affects usage of only two of the primary digging behaviors that differ between the focal species: forelimb digging, which loosens substrate, and hindlimb kicking, which powerfully ejects substrate. This locus has an especially large effect on hindkicking, explaining 56% and 22% of interspecific differences in latency and proportion of hindkicks, respectively. Together, these data provide genetic support for the hierarchical organization of complex behaviors, offering evolution the opportunity to tinker with specific behavioral components.

evolutionary biology↗

bioRxiv2022

Massive inversion polymorphisms shape the genomic landscape of deer mice

Chromosomal inversions are an important form of structural variation that can affect recombination, chromosome structure and fitness. However, because inversions can be challenging to detect, the prevalence and hence significance of inversions segregating within species remains largely unknown, especially in natural populations of mammals. Here, by combining population-genomic and long-read sequencing analyses in a single, widespread species of deer mouse (Peromyscus maniculatus), we identified 21 polymorphic inversions, which are large (1.5-43.8 Mb) and cause near complete suppression of recombination when heterozygous (0-0.03 cM/Mb). We found that inversion breakpoints frequently occur in centromeric and telomeric regions and are often flanked by long inverted repeats (0.5-50 kb), suggesting that they likely arose via ectopic recombination. By genotyping the inversions in populations across the species range, we found that the inversions are often widespread, do not harbor deleterious mutational loads, and many are likely maintained as polymorphisms by divergent selection. Comparisons of forest and prairie ecotypes of deer mice revealed 13 inversions that contribute to differentiation between populations, of which five exhibit significant associations with traits implicated in local adaptation. Together, we found that inversion polymorphisms have a significant impact on recombination, genome structure and genetic diversity in deer mice, and likely facilitate local adaptation across this species widespread range.

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↗

bioRxiv2021

A chromosomal inversion drives evolution of multiple adaptive traits in deer mice

A long-standing question in evolutionary biology is how differences in multiple traits can evolve quickly and be maintained together during local adaptation. Using forest and prairie ecotypes in deer mice, which differ in both tail length and coat color, we discovered a 41 Mb chromosomal inversion that is strongly linked to variation in both traits. The inversion maintains highly divergent loci in strong linkage disequilibrium and likely originated ~170 kya, long before the forest-prairie divergence ~10 kya. Consistent with a role in local adaptation, inversion frequency is associated with phenotype and habitat across both a local transect and the species range. Still, although eastern and western forest subspecies share similar phenotypes, the inversion is absent in eastern North America. This work highlights the significance of inversion polymorphisms for the establishment and maintenance of multiple locally adaptive traits in mammals, and demonstrates that, even within a species, parallel phenotypes may evolve through nonparallel genetic mechanisms.

evolutionary biology↗