Biology subjects

Ullrich, K. K.

Publications and source records attributed to Ullrich, K. K..

13 recordsLinked to original sources

bioRxiv2024

Evolutionary trends in the emergence of skeletal cell types.

The emergence of novel cell types fuels evolutionary innovations and contributes to the diversity of life forms and their morphological and functional traits. Cell types are fundamental functional units of multicellular organisms defined by their specific gene expression programs. The evolution of these transcriptional programs is driven by genetic changes, such as gene co-option and cis- regulatory evolution, known to facilitate the assembly or rewiring of molecular networks and give rise to new cell types with specialized functions. However, the role of novel genes in this complex evolutionary process is underexplored. Here, we examine the trends in skeletal cell type evolution with a focus on lineage-specific genes. We find that immature chondrocytes express the oldest transcriptome and resemble ancestral skeletogenic cell type, supporting the existence of a conserved genetic program for cartilage development in bilaterians. The subsequent acquisition of lineage-restricted genes led to the individuation of the ancient gene expression program and powered the emergence of osteoblasts and hypertrophic chondrocytes. We found a significant enrichment of Vertebrate-specific genes in osteoblasts and Gnathostome-specific genes in hypertrophic chondrocytes. By identifying the functional properties of the recruited genes, coupled with the recently discovered fossil evidence, our findings challenge the long-standing view on the evolution of vertebrate skeletal structures and suggest that endochondral ossification and chondrocyte hypertrophy evolved already in the last common ancestors of gnathostomes. Finally, our findings highlight the critical role of novel genes in shaping cellular diversity.

evolutionary biology↗

bioRxiv2024

Plasticity and evolutionary dynamics of alternative RNA splicing

The ability to generate multiple RNA transcript isoforms from the same gene is a general phenomenon in eukaryotes. However, the complexity and diversity of alternative isoforms in natural populations remain largely unexplored. Using a newly developed full-length transcripts enrichment protocol with 5 CAP selection, we sequenced full-length RNA transcripts of 48 individuals from outbred populations and subspecies of Mus musculus, and from the closely related sister species Mus spretus and Mus spicilegus as outgroups. The dataset represents the most extensive full-length high-quality isoform catalog at the population level to date. In total, we reliably identified 117,728 distinct isoforms, of which only 51% were previously annotated. We show that the population-specific distribution pattern of isoforms is phylogenetically informative and reflects the segregating SNP diversity between the populations. We find that ancient housekeeping genes are a major source of the overall isoform diversity, and that the generation of alternative first exons plays a major role in generating new isoforms. Given that our data allow us to distinguish between population-specific isoforms and isoforms that are conserved across multiple populations, it is possible to refine the annotation of the reference mouse genome to a set of about 40,000 isoforms that should be most relevant for comparative functional analysis across species.

genomics↗

bioRxiv2023

The dimorphic diaspore model Aethionema arabicum (Brassicaceae): Distinct molecular and morphological control of responses to parental and germination temperatures

Plants in habitats with unpredictable conditions are often characterized by diversifying their bet-hedging strategies that ensure fitness over a wider range of variable environmental factors. A striking example is the diaspore (seed and fruit) heteromorphism that evolved to maximize species survival in Aethionema arabicum (Brassicaceae) in which external and endogenous triggers allow the production of two distinct diaspores on the same plant. Using this dimorphic diaspore model, we identified contrasting molecular, biophysical, and ecophysiological mechanisms in the germination responses to different temperatures of the mucilaginous seeds (M+ seed morphs), the dispersed indehiscent fruits (IND fruit morphs), and the bare non-mucilaginous M- seeds obtained by pericarp (fruit coat) removal from IND fruits. Large-scale comparative transcriptome and hormone analyses of M+ seeds, IND fruits, and M- seeds provided comprehensive datasets for their distinct thermal responses. Morph-specific differences in co-expressed gene modules in seeds, as well as seed and pericarp hormone contents identified a role of the IND pericarp in imposing coat dormancy by generating hypoxia affecting ABA sensitivity. This involved expression of morph-specific transcription factors, hypoxia response and cell wall-remodeling genes, as well as altered abscisic acid (ABA) metabolism, transport, and signaling. Parental temperature affected ABA contents and ABA-related gene expression and altered IND pericarp biomechanical properties. Elucidating the molecular framework underlying the diaspore heteromorphism can provide insight into developmental responses to globally changing temperatures. IN A NUTSHELL BackgroundHeteromorphic diaspores (fruits and seeds) are an adaptive bet-hedging strategy to ensure survival in spatiotemporally variable environments. The stone cress Aethionema arabicum, an annual plant native to semi-arid habitats in Anatolia (Turkey), one of the worlds hotspots of biodiversity. It is a close relative of Arabidopsis, rapeseed, cabbage and other Brassica crops, but in contrast to these Ae. arabicum disperses two distinct diaspores from the same plant. These dimorphic diaspores are the mucilaginous seeds (dispersed by pod shatter) and indehiscent fruits (dispersed by abscission). The wing-like pericarp (fruit coat) of the single-seeded indehiscent fruit allows wind dispersal over large distances. The amounts and ratios of the dimorphic diaspores are variable and depend on the environmental conditions. The dimorphic diaspores differ in morphology, dormancy and germination properties and thereby make Ae. arabicum an excellent model for the comparative investigation of the underpinning molecular mechanisms. QuestionWe asked how temperature during fruit and seed formation and during seed germination affect dormancy release and germination speed, and how the morphology, hormonal regulation, and the expression of genes differ between the dimorphic diaspores. FindingsLarge-scale comparative transcriptome and hormone analyses of the mucilaginous seeds and the indehiscent fruits, as well as the seeds artificially extracted from indehiscent fruits by pericarp (fruit coat) removal, provided comprehensive datasets for their distinct thermal responses. Material obtained from plants grown at different temperatures during reproduction was imbibed at different temperatures for germination. This altered the abscisic acid (ABA) metabolism and the pericarp biomechanical properties. Diaspore-specific differences in response to distinct imbibition temperatures identified distinct gene expression patterns in seeds, distinct seed and pericarp hormone contents, and a role of the pericarp in generating hypoxia inside the fruit and imposing coat dormancy. This revealed distinct combinations of specific transcription factors, hypoxia responses and cell wall-remodeling genes, as well as altered signaling pathway genes. Next stepsOur large-scale comparative transcriptome datasets are easily and publicly accessible via the Aethionema arabicum web portal (https://plantcode.cup.uni-freiburg.de/aetar_db/index.php). We plan to expand this by future work on seedlings derived from the dimorphic diaspores, by comparing different Ae. arabicum genotypes, and by studying responses to specific stresses. Understanding the molecular basis of this fascinating example of developmental diversity and plasticity and its regulation by temperature is expected to add insight how plants respond to changing environmental conditions.

plant biology↗

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↗

bioRxiv2022

syntenet: an R/Bioconductor package for the inference and analysis of synteny networks

Interpreting and visualizing synteny relationships across several genomes is a challenging task. We previously proposed a network-based approach for better visualization and interpretation of large-scale microsynteny analyses. Here, we present syntenet, an R package to infer and analyze synteny networks from whole-genome protein sequence data. The package offers a simple and complete framework, including data preprocessing, synteny detection and network inference, network clustering and phylogenomic profiling, and microsynteny-based phylogeny inference. Graphical functions are also available to create publication-ready plots. Synteny networks inferred with syntenet can highlight taxon-specific gene clusters that likely contributed to the evolution of important traits, and microsynteny-based phylogenies can help resolve phylogenetic relationships under debate. Availability and ImplementationThe package is available on Bioconductor (https://bioconductor.org/packages/syntenet), and the source code is available on a GitHub repository (https://github.com/almeidasilvaf/syntenet).

bioinformatics↗

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↗

bioRxiv2020

The mutational load in natural populations is significantly affected by high primary rates of retroposition

Gene retroposition is known to contribute to patterns of gene evolution and adaptations. However, possible negative effects of gene retroposition remain largely unexplored, since most previous studies have focussed on between-species comparisons where negatively selected copies are mostly not observed, as they are quickly lost from the populations. Here, we show for natural house mouse populations that the primary rate of retroposition is orders of magnitude higher than previously thought. Comparisons with SNP distribution patterns in the same populations show that most retroposition events are deleterious. Transcriptomic profiling analysis shows that new retroposed copies become easily subject to transcription and have an influence on the expression level of their parental genes, especially when transcribed in the antisense direction. Our results imply that the impact of retroposition on the mutational load in natural populations has been highly underestimated, which has also implications for strategies of disease allele detection in humans. Significance statementThe phenomenon or retroposition (re-integration of reverse transcribed RNA into the genome), has been well studied in comparisons between genomes and has been identified as a source of evolutionary innovation. However, the negative effects of retroposition have been overlooked so far. Our study makes use of a unique population genomic dataset from natural mouse populations. It shows that the retroposition rate is magnitudes higher than previously suspected. We show that most of the newly transposed retrocopies have a deleterious impact through modifying the expression of their parental genes. In humans, this effect is expected to cause disease alleles and we propose that genetic screening needs to take into account the search for newly transposed retrocopies.

genomics↗

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↗

bioRxiv2019

Studying the dawn of de novo gene emergence in mice reveals fast integration of new genes into functional networks

The de novo emergence of new transcripts has been well documented through genomic analyses. However, a functional analysis, especially of very young protein-coding genes, is still largely lacking. Here we focus on three loci that have evolved from previously intergenic sequences in the house mouse (Mus musculus) and are not present in its closest relatives. We have obtained knockouts and analyzed their phenotypes, including a deep transcriptomic analysis, based on a dedicated power analysis. We show that the transcriptional networks are significantly disturbed in the knockouts and that all three genes have effects on phenotypes that are related to their expression patterns. This includes behavioral effects, skeletal differences and the regulation of the reproduction cycle in females. Substitution analysis suggests that all three genes have directly obtained an activity, without new adaptive substitutions. Our findings support the hypothesis that de novo genes can quickly adopt functions without extensive adaptation.\n\nImpact statementNew protein-coding genes emerging out of non-coding sequences can become directly functional without signatures of adaptive protein changes

evolutionary biology↗

bioRxiv2018

A novel model plant to study the light control of seed germination

Timing of seed germination is crucial for seed plants and coordinated by internal and external cues, reflecting adaptations to different habitats. Physiological and molecular studies with lettuce and Arabidopsis thaliana have documented a strict requirement for light to initiate germination and identified many receptors, signalling cascades, and hormonal control elements. In contrast, seed germination of several other plants is inhibited by light, but the molecular basis of this converse response is unknown. We describe Aethionema arabicum (Brassicaceae) as a suitable model plant to investigate the mechanism of germination inhibition by light, as it comprises accessions with natural variation between light-sensitive and light-neutral responses. Inhibition is independent of light wavelength and increases with light intensity and duration. Gibberellins and abscisic acid are involved in the control of germination as in Arabidopsis, but transcriptome comparisons of light- and dark-exposed Aethionema arabicum seeds revealed that expression of genes for key regulators upon light exposure undergo converse changes, resulting in antipodal hormone regulation. This illustrates that similar modular components of a pathway in light-inhibited, light-neutral and light requiring germination among the Brassicaceae have been assembled by evolution to produce divergent pathways, likely as adaptive traits.\n\nHighlightIn contrast to light requirement for Arabidopsis seed germination, germination of several Aethionema arabicum accessions is inhibited by light, due to antipodal transcriptional regulation of hormone balance.

plant biology↗

bioRxiv2017

Introgression patterns between house mouse subspecies and species reveal genomic windows offrequent exchange

Based on whole genome sequencing data, we have studied the patterns of introgression in a phylogenetically well defined set of populations, sub-species and species of mice (Mus m. domesticus, Mus m. musculus, Mus m. castaneus and Mus spretus). We find that many discrete genomic regions are subject to repeated and mutual introgression and exchange. The majority of these regions code for genes that are involved in parasite defense or genomic conflict. They include genes involved in adaptive immunity, such as the MHC region or antibody coding regions, but also genes involved in innate immune reactions of the epidermis. We find also clusters of KRAB zinc finger proteins that control the spread of transposable elements and genes that are involved in meiotic drive. These findings suggest that even well separated populations and species maintain the capacity to exchange genetic material in a special set of evolutionary active genes.

evolutionary biology↗