Expression of Random Sequences and de novo Evolved Genes From the Mouse in Human Cells Reveals Functional Diversity and Specificity.

Proteins that emerge de novo from noncoding DNA could negatively or positively influence cellular physiology in the sense of providing a possible adaptive advantage. Here, we employ two approaches to study such effects in a human cell line by expressing random sequences and mouse de novo genes that lack homologs in the human genome. We show that both approaches lead to differential growth effects of the cell clones dependent on the sequences they express.

The rate and spectrum of new mutations in mice inferred by long-read sequencing.

All forms of genetic variation originate from new mutations, making it crucial to understand their rates and mechanisms. Here, we use long-read PacBio sequencing to investigate de novo mutations that accumulated in 12 inbred mouse lines derived from three commonly used inbred strains (C3H, C57BL/6, and FVB) maintained for 8-15 generations in a mutation accumulation (MA) experiment. We built chromosome-level genome assemblies based on the MA line founders' genomes, and then employed a combination of read and assembly-based methods to call the complete spectrum of new mutations.

Full-length RNA transcript sequencing traces brain isoform diversity in house mouse natural populations.

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 transcript enrichment protocol with 5' CAP selection, we sequenced full-length RNA transcripts of 48 individuals from outbred populations and subspecies of , and from the closely related sister species and as outgroups.

Variation in the Spectrum of New Mutations among Inbred Strains of Mice.

The mouse serves as a mammalian model for understanding the nature of variation from new mutations, a question that has both evolutionary and medical significance. Previous studies suggest that the rate of single-nucleotide mutations (SNMs) in mice is ∼50% of that in humans. However, information largely comes from studies involving the C57BL/6 strain, and there is little information from other mouse strains.

Experimental Evaluation of a Direct Fitness Effect of the De Novo Evolved Mouse Gene Pldi.

De novo evolved genes emerge from random parts of noncoding sequences and have, therefore, no homologs from which a function could be inferred. While expression analysis and knockout experiments can provide insights into the function, they do not directly test whether the gene is beneficial for its carrier. Here, we have used a seminatural environment experiment to test the fitness of the previously identified de novo evolved mouse gene Pldi, which has been implicated to have a role in sperm differentiation.

Working from home and its challenges for transformational and health-oriented leadership.

The Covid-19 crisis forced many employees to abruptly relocate their workplace from the office to their homes. As working from home is expected to remain part of our working world, consequences for leadership need to be examined. Our study aims to investigate the concrete challenges regarding the feasibility of transformational leadership and health-oriented leadership in this remote setting.

Testing the accuracy of 3D automatic landmarking via genome-wide association studies.

Various advances in 3D automatic phenotyping and landmark-based geometric morphometric methods have been made. While it is generally accepted that automatic landmarking compromises the capture of the biological variation, no studies have directly tested the actual impact of such landmarking approaches in analyses requiring a large number of specimens and for which the precision of phenotyping is crucial to extract an actual biological signal adequately. Here, we use a recently developed 3D atlas-based automatic landmarking method to test its accuracy in detecting QTLs associated with craniofacial development of the house mouse skull and lower jaws for a large number of specimens (circa 700) that were previously phenotyped via a semiautomatic landmarking method complemented with manual adjustment.

Evolution of a New Testis-Specific Functional Promoter Within the Highly Conserved Gene of the Mouse.

(synonym ) is a conserved regulatory kinase gene and a central component of the JNK signaling cascade with key functions during cellular differentiation. It shows complex transcription patterns, and different transcript isoforms are known in the mouse (). We have previously identified a newly evolved testis-specific transcript for the gene in the subspecies .

Effects of the Expression of Random Sequence Clones on Growth and Transcriptome Regulation in .

Comparative genomic analyses have provided evidence that new genetic functions can emerge out of random nucleotide sequences. Here, we apply a direct experimental approach to study the effects of plasmids harboring random sequence inserts under the control of an inducible promoter. Based on data from previously described experiments dealing with the growth of clones within whole libraries, we extracted specific clones that had shown either negative, neutral or positive effects on relative cell growth.

The Effects of Sequence Length and Composition of Random Sequence Peptides on the Growth of Cells.

We study the potential for the evolution of genes from random nucleotide sequences using libraries of expressing random sequence peptides. We assess the effects of such peptides on cell growth by monitoring frequency changes in individual clones in a complex library through four serial passages. Using a new analysis pipeline that allows the tracing of peptides of all lengths, we find that over half of the peptides have consistent effects on cell growth.

Tracing the Origin and Evolutionary Fate of Recent Gene Retrocopies in Natural Populations of the House Mouse.

Although the contribution of retrogenes to the evolution of genes and genomes has long been recognized, the evolutionary patterns of very recently derived retrocopies that are still polymorphic within natural populations have not been much studied so far. We use here a set of 2,025 such retrocopies in nine house mouse populations from three subspecies (Mus musculus domesticus, M. m.

Frequent lineage-specific substitution rate changes support an episodic model for protein evolution.

Since the inception of the molecular clock model for sequence evolution, the investigation of protein divergence has revolved around the question of a more or less constant change of amino acid sequences, with specific overall rates for each family. Although anomalies in clock-like divergence are well known, the assumption of a constant decay rate for a given protein family is usually taken as the null model for protein evolution. However, systematic tests of this null model at a genome-wide scale have lagged behind, despite the databases' enormous growth.

A humanized version of Foxp2 affects ultrasonic vocalization in adult female and male mice.

The transcription factor FoxP2 is involved in setting up the neuronal circuitry for vocal learning in mammals and birds and is thought to have played a special role in the evolution of human speech and language. It has been shown that an allele with a humanized version of the murine Foxp2 gene changes the ultrasonic vocalization of mouse pups compared to pups of the wild-type inbred strain. Here we tested if this humanized allele would also affect the ultrasonic vocalization of adult female and male mice.

Natural copy number variation of tandemly repeated regulatory SNORD RNAs leads to individual phenotypic differences in mice.

Genic copy number differences can have phenotypic consequences, but so far this has not been studied in detail in natural populations. Here, we analysed the natural variation of two families of tandemly repeated regulatory small nucleolar RNAs (SNORD115 and SNORD116) in the house mouse (Mus musculus). They are encoded within the Prader-Willi Syndrome gene region, known to be involved in behavioural, metabolic, and osteogenic functions in mammals.

The imprinted lncRNA regulates sexual preference and the sex-specific brain transcriptome in mice.

Mammalian genomes include many maternally and paternally imprinted genes. Most of these are also expressed in the brain, and several have been implicated in regulating specific behavioral traits. Here, we have used a knockout approach to study the function of , a gene that codes for a fast-evolving lncRNA (long noncoding RNA) and is part of a complex of imprinted genes on chromosome 15 in mice and chromosome 8 in humans.

Independent evolution toward larger body size in the distinctive Faroe Island mice.

Most phenotypic traits in nature involve the collective action of many genes. Traits that evolve repeatedly are particularly useful for understanding how selection may act on changing trait values. In mice, large body size has evolved repeatedly on islands and under artificial selection in the laboratory.

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 focused on between-species comparisons where negatively selected copies are mostly not observed, as they are quickly lost from populations. Here, we show for natural house mouse populations that the primary rate of retroposition is orders of magnitude higher than the long-term rate.

Testing Implications of the Omnigenic Model for the Genetic Analysis of Loci Identified through Genome-wide Association.

Organismal phenotypes usually have a quantitative distribution, and their genetic architecture can be studied by genome-wide association (GWA) mapping approaches. In most of such studies, it has become clear that many genes of moderate or small effects contribute to the phenotype. Hence, the attention has turned toward the loci falling below the GWA cut-off, which may contribute to the phenotype through modifier interactions with a set of core genes, as proposed in the omnigenic model.

Dedicated transcriptomics combined with power analysis lead to functional understanding of genes with weak phenotypic changes in knockout lines.

Systematic knockout studies in mice have shown that a large fraction of the gene replacements show no lethal or other overt phenotypes. This has led to the development of more refined analysis schemes, including physiological, behavioral, developmental and cytological tests. However, transcriptomic analyses have not yet been systematically evaluated for non-lethal knockouts.

Inbred lab mice are not isogenic: genetic variation within inbred strains used to infer the mutation rate per nucleotide site.

For over a century, inbred mice have been used in many areas of genetics research to gain insight into the genetic variation underlying traits of interest. The generalizability of any genetic research study in inbred mice is dependent upon all individual mice being genetically identical, which in turn is dependent on the breeding designs of companies that supply inbred mice to researchers. Here, we compare whole-genome sequences from individuals of four commonly used inbred strains that were procured from either the colony nucleus or from a production colony (which can be as many as ten generations removed from the nucleus) of a large commercial breeder, in order to investigate the extent and nature of genetic variation within and between individuals.

The amylase gene cluster in house mice (Mus musculus) was subject to repeated introgression including the rescue of a pseudogene.

Background: Amylase gene clusters have been implicated in adaptive copy number changes in response to the amount of starch in the diet of humans and mammals. However, this interpretation has been questioned for humans and for mammals there is a paucity of information from natural populations.

Results: Using optical mapping and genome read information, we show here that the amylase cluster in natural house mouse populations is indeed copy-number variable for Amy2b paralogous gene copies (called Amy2a1 - Amy2a5), but a direct connection to starch diet is not evident.

Population Genomics of the House Mouse and the Brown Rat.

Mice (Mus musculus) and rats (Rattus norvegicus) have long served as model systems for biomedical research. However, they are also excellent models for studying the evolution of populations, subspecies, and species. Within the past million years, they have spread in various waves across large parts of the globe, with the most recent spread in the wake of human civilization.