Biology subjects

Odenthal-Hesse, L.

Publications and source records attributed to Odenthal-Hesse, L..

7 recordsLinked to original sources

bioRxiv2026

A songbird karyotype: cytogenetic confirmation of a migration-associated region rich in olfactory receptor genes.

The field of genetics of bird migration advances, driven by exponential refinements of sequencing and tracking technologies. In willow warblers (Phylloscopus trochilus), a complex repeat-rich region named MARB (Migration Associated Repeat Block) has recently been found to correlate with the routes taken by individual birds from Europe to their African wintering grounds. However, the genomic location of this region remains unknown. Here, we characterized MARB using a combination of approaches to understand how it evolved. We describe the region using long-read genome assemblies of two willow warbler subspecies (P. t. trochilus and P. t. acredula), two related species, the common chiffchaff (P. collybita) and the greenish warbler (P. trochiloides), and whole genome sequencing data from 76 willow warblers. Finally, we applied karyotyping and fluorescent in situ hybridization techniques on willow warbler spermatocytes to cytogenetically locate MARB. Due to the many repeats, we cannot order scaffolds in silico, but probe hybridization on the karyotype shows that MARB constitutes a single locus (~27.5 Mb) spanning most of the 11th largest chromosome in the willow warbler genome. Interestingly, the MARB regions of all species share several characteristics such as relatively high GC content (50%), a high density of specific repeat families and notably, more than 800 olfactory receptor sequences. Regions homologous to MARB may exist in several migrant bird genomes, though currently unassembled due to their complexity. Resolving these in species with similar migratory polymorphisms to willow warblers will be essential to determine whether MARB influences migratory behaviour across species.

genomics↗

bioRxiv2023

Natural variation in the zinc-finger-encoding exon of Prdm9 affects hybrid sterility phenotypes in mice

PRDM9-mediated reproductive isolation was first described in the progeny of Mus musculus musculus (MUS) PWD/Ph and Mus musculus domesticus (DOM) C57BL/6J inbred strains. These male F1-hybrids fail to complete chromosome synapsis and arrest meiosis at prophase I, due to incompatibilities between the Prdm9 gene and hybrid sterility locus Hstx2. We identified fourteen alleles of Prdm9 in Exon 12, encoding the DNA-binding domain of the PRDM9 protein in outcrossed wild mouse populations from Europe, Asia, and the Middle East, eight of which are novel. The same Prdm9 allele was found in all mice bearing introgressed t-haplotypes, encompassing Prdm9 and inversions preventing recombination with wildtype Chr 17. We asked whether seven novel Prdm9 alleles in MUS populations and the t-haplotype allele in one MUS and three DOM populations induce Prdm9-mediated reproductive isolation. The results show that only combinations of the dom2 allele of DOM origin and the MUS msc1 allele ensure complete infertility of intersubspecific hybrids outside the context of inbred mouse strains. The results further indicate that the erasure of PRDM9 msc1 binding motifs may be shared by MUS mice from populations with different Prdm9 alleles, implicating that erased PRDM9 binding motifs may be uncoupled from their corresponding PRDM9 zinc finger arrays at the population level. Our data corroborate the model of Prdm9-mediated hybrid sterility beyond inbred strains of mice and suggest that sterility alleles of Prdm9 may be rare.

genetics↗

bioRxiv2023

Natural variation in Prdm9 affecting hybrid sterility phenotypes

PRDM9-mediated reproductive isolation was first described in offspring of Mus musculus musculus strain PWD/Ph and Mus musculus domesticus strain C57BL/6J. Male F1-hybrids do not complete chromosome synapsis and arrest meiosis at Prophase I. Currently, all data supports an oligogenic control of hybrid sterility based on incompatibilities between PRDM9 and hybrid-sterility locus Hstx2 in Mus musculus hybrids. Erosion of PRDM9 binding sites was proposed to result in asymmetric binding on diverged homologs of intersubspecific F1 hybrids. Numerous alleles of Prdm9 have been characterized for different subspecies of Mus musculus, but only a few were analyzed for their impact on hybrid sterility. We analyzed Prdm9 diversity in natural wild mouse populations from Europe, Asia, and the Middle East and identified several novel Prdm9 alleles. We established that a single Prdm9 allele is associated with t-haplotype Chromosome 17 in all three subspecies of Mus musculus and characterized the phylogenetic relationships of novel Prdm9 alleles with established sterility alleles. Novel wild Prdm9 alleles produced F1-hybrid male offspring that were either fertile or showed Prdm9-dependent reduction of fertility and high levels of asynapsis. Fertility or sterility phenotypes segregated purely with the Prdm9 genotype, although the Mus musculus musculus background varied. Our data substantiate that hybrid sterility is under oligogenic control with Prdm9 as the leading player but is consistent with a nonbinary regulation of hybrid sterility and gradual fertility decline when homologs diverge.

genetics↗

bioRxiv2021

Extensive variation in the mouse intelectin gene family: recent duplications, deletions and inactivating variants result in diversity in laboratory strains

Intelectins are a family of multimeric secreted proteins that bind microbe-specific glycans. Both genetic and functional studies have suggested that intelectins have an important role in innate immunity and are involved in the etiology of various human diseases, including inflammatory bowel disease. Experiments investigating the role of intelectins in human disease using mouse models are limited by the fact that there is not a clear one-to-one relationship between intelectin genes in humans and mice, and that the number of intelectin genes varies between different mouse strains. In this study we show by gene sequence and gene expression analysis that human intelectin-1 (ITLN1) has multiple orthologues in mice, including a functional homologue Itln1; however, human intelectin-2 has no such orthologue or homologue. We confirm that all sub-strains of the C57-line have a large deletion resulting in retention of only one intelectin gene, Itln1. The majority of laboratory strains have a full complement of six intelectin genes, except wild-derived CAST, SPRET, SKIVE, MOLF and PANCEVO, which are derived from different mouse species/subspecies and encode different complements of intelectin genes. In wild mice, intelectin deletions are polymorphic in Mus musculus castaneus and Mus musculus domesticus. Further sequence analysis shows that Itln3 and Itln5 are polymorphic pseudogenes due to premature truncating mutations, and that mouse Itln1 has undergone recent adaptive evolution. Taken together, our study shows extensive diversity in intelectin genes in both laboratory and wild-mice, suggesting a pattern of birth-and-death evolution. In addition, our data provide a foundation for further experimental investigation of the role of intelectins in disease.

genetics↗

bioRxiv2020

Allelic diversity of the PRDM9 coding minisatellite in minke whales

We explored the structure and variability of the Prdm9 gene, which codes for the PRDM9 protein, in samples of the minke whales from the Atlantic, Pacific and Southern Oceans. The PRDM9 protein controls the reshuffling of parental genomes in most metazoans and we show that minke whale possess all the features characteristic of PRDM9-directed recombination initiation, including complete KRAB, SSXRD and SET domains and a rapidly evolving array of C2H2-type-Zincfingers (ZnF). We uncovered eighteen novel PRDM9 variants and evidence of rapid evolution, particularly at DNA-recognizing positions that evolve under positive selection. At different geographical scales, we observed extensive Prdm9 allelic diversity in Antarctic minke whales (Balaenoptera bonarensis) that, conversely, lack observable population differentiation in mitochondrial DNA and microsatellites. In contrast, a single PRDM9 variant is shared between all Common Minke whales and even across subspecies boundaries of North Atlantic (B. a. acutorostrata) and North Pacific (B. a. scammoni) minke whale, which do show clear population differentiation. PRDM9 variation of whales predicts distinct recombination initiation landscapes genome-wide, which has possible consequences for speciation.

genetics↗

bioRxiv2019

Genomic structure of Hstx2 modifier of Prdm9-dependent hybrid male sterility in mice

F1 hybrids between mouse inbred strains PWD and C57BL/6 represent the most thoroughly genetically defined model of hybrid sterility in vertebrates. Hybrid male sterility can be fully reconstituted from three components of this model, namely the Prdm9 hybrid sterility gene, intersubspecific homeology of Mus musculus musculus and Mus musculus domesticus autosomes, and the X-linked Hstx2 locus. Hstx2 modulates the extent of Prdm9-dependent meiotic arrest and harbors two additional genetic factors responsible for intersubspecific introgression-induced oligospermia (Hstx1) and reduced global meiotic recombination rate (Meir1). To facilitate positional cloning and to overcome the recombination suppression within the 4.3 Mb genomicDob interval encompassing the Hstx2 locus we designed Hstx2-CRISPR and SPO11/Cas9 transgenes aimed to induce DNA double-strand breaks specifically within the Hstx2 locus. The resulting recombinant reduced the Hstx2 locus to 2.70 Mb (Chr X:66.51-69.21 Mb). The newly defined Hstx2 still operates as the major X-linked factor of the F1 hybrid sterility, controls meiotic chromosome synapsis, and modifies meiotic recombination rate. Despite extensive further crosses, the 2.70 Mb Hstx2 interval behaved as a recombination cold spot with reduced PRDM9-mediated H3K4 hotspots and absence of DMC1-defined DNA DSB hotspots. To search for structural anomalies as a possible cause of recombination suppression we used optical mapping of the Hstx2 interval and observed high incidence of subspecies-specific structural variants along the X chromosome, with a striking copy number polymorphism of the microRNA Mir465 cluster. Finally, we analyzed the role of one of the Hstx2 candidate genes, the Fmr1 neighbor (Fmr1nb) gene in male fertility.\n\nArticle summaryEarly meiotic arrest of mouse intersubspecific hybrids depends on the interaction between the Prdm9 gene and Hybrid sterility X2 (Hstx2) locus on chromosome X. Lustyk et al. conducted high-resolution genetic and physical mapping of the Hstx2 locus, reduced it to 2.7 Mb interval within a constitutive recombination cold spot and found that the newly defined Hstx2 still operates as the X-linked hybrid sterility factor, controls meiotic chromosome synapsis, and modifies recombination rate. Optical mapping of the Hstx2 genomic region excluded inversion as a cause of recombination suppression and revealed a striking copy number polymorphism of the microRNA Mir465 cluster.

genetics↗

bioRxiv2018

Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function

The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies. We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test (PRT) and imputed (with validation) CCR5del32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels. We found no evidence for association of CCL3L1 copy number or CCR5del32 genotype with lung function suggesting that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.

genetics↗