Repeat associated mechanisms of genome evolution and function revealed by the Mus caroli and Mus pahari genomes

Understanding the mechanisms driving lineage-specific evolution in both primates and rodents has been hindered by the lack of sister clades with a similar phylogenetic structure having high-quality genome assemblies. Here, we have created chromosome-level assemblies of the Mus caroli and Mus pahari genomes. Together with the Mus musculus and Rattus norvegicus genomes, this set of rodent genomes is similar in divergence times to the Hominidae (human-chimpanzee-gorilla-orangutan). By comparing the evolutionary dynamics between the Muridae and Hominidae, we identified punctate events of chromosome reshuffling that shaped the ancestral karyotype of Mus musculus and Mus caroli between 3 and 6 million yr ago, but that are absent in the Hominidae. Hominidae show between four- and sevenfold lower rates of nucleotide change and feature turnover in both neutral and functional sequences, suggesting an underlying coherence to the Muridae acceleration. Our system of matched, high-quality genome assemblies revealed how specific classes of repeats can play lineage-specific roles in related species. Recent LINE activity has remodeled protein-coding loci to a greater extent across the Muridae than the Hominidae, with functional consequences at the species level such as reproductive isolation. Furthermore, we charted a Muridae-specific retrotransposon expansion at unprecedented resolution, revealing how a single nucleotide mutation transformed a specific SINE element into an active CTCF binding site carrier specifically in Mus caroli, which resulted in thousands of novel, species-specific CTCF binding sites. Our results show that the comparison of matched phylogenetic sets of genomes will be an increasingly powerful strategy for understanding mammalian biology

Repeat associated mechanisms of genome evolution and function revealed by the Mus caroli and Mus pahari genomes.

Understanding the mechanisms driving lineage-specific evolution in both primates and rodents has been hindered by the lack of sister clades with a similar phylogenetic structure having high-quality genome assemblies. Here, we have created chromosome-level assemblies of the Mus caroli and Mus pahari genomes. Together with the Mus musculus and Rattus norvegicus genomes, this set of rodent genomes is similar in divergence times to the Hominidae (human-chimpanzee-gorilla-orangutan). By comparing the evolutionary dynamics between the Muridae and Hominidae, we identified punctate events of chromosome reshuffling that shaped the ancestral karyotype of Mus musculus and Mus caroli between 3 and 6 million yr ago, but that are absent in the Hominidae. Hominidae show between four- and sevenfold lower rates of nucleotide change and feature turnover in both neutral and functional sequences, suggesting an underlying coherence to the Muridae acceleration. Our system of matched, high-quality genome assemblies revealed how specific classes of repeats can play lineage-specific roles in related species. Recent LINE activity has remodeled protein-coding loci to a greater extent across the Muridae than the Hominidae, with functional consequences at the species level such as reproductive isolation. Furthermore, we charted a Muridae-specific retrotransposon expansion at unprecedented resolution, revealing how a single nucleotide mutation transformed a specific SINE element into an active CTCF binding site carrier specifically in Mus caroli, which resulted in thousands of novel, species-specific CTCF binding sites. Our results show that the comparison of matched phylogenetic sets of genomes will be an increasingly powerful strategy for understanding mammalian biology

Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci.

We report full-length draft de novo genome assemblies for 16 widely used inbred mouse strains and find extensive strain-specific haplotype variation. We identify and characterize 2,567 regions on the current mouse reference genome exhibiting the greatest sequence diversity. These regions are enriched for genes involved in pathogen defence and immunity and exhibit enrichment of transposable elements and signatures of recent retrotransposition events. Combinations of alleles and genes unique to an individual strain are commonly observed at these loci, reflecting distinct strain phenotypes. We used these genomes to improve the mouse reference genome, resulting in the completion of 10 new gene structures. Also, 62 new coding loci were added to the reference genome annotation. These genomes identified a large, previously unannotated, gene (Efcab3-like) encoding 5,874 amino acids. Mutant Efcab3-like mice display anomalies in multiple brain regions, suggesting a possible role for this gene in the regulation of brain development

Mouse protein coding diversity: What's left to discover?

For over a century, mice have been used to model human disease, leading to many fundamental discoveries about mammalian biology and the development of new therapies. Mouse genetics research has been further catalysed by a plethora of genomic resources developed in the last 20 years, including the genome sequence of C57BL/6J and more recently the first draft reference genomes for 16 additional laboratory strains. Collectively, the comparison of these genomes highlights the extreme diversity that exists at loci associated with the immune system, pathogen response, and key sensory functions, which form the foundation for dissecting phenotypic traits in vivo. We review the current status of the mouse genome across the diversity of the mouse lineage and discuss the value of mice to understanding human disease

Innate Resistance against Toxoplasma gondii: An Evolutionary Tale of Mice, Cats, and Men

Submitted by Nuzia Santos ([email protected]) on 2015-07-21T17:55:54Z No. of bitstreams: 1 Innate Resistance against Toxoplasma gondii- An Evolutionary Tale of Mice, Cats, and Men.pdf: 1199408 bytes, checksum: 4d1bed7034f47c642f7fd88134b3c9f6 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-07-21T17:56:02Z (GMT) No. of bitstreams: 1 Innate Resistance against Toxoplasma gondii- An Evolutionary Tale of Mice, Cats, and Men.pdf: 1199408 bytes, checksum: 4d1bed7034f47c642f7fd88134b3c9f6 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-07-21T17:59:20Z (GMT) No. of bitstreams: 1 Innate Resistance against Toxoplasma gondii- An Evolutionary Tale of Mice, Cats, and Men.pdf: 1199408 bytes, checksum: 4d1bed7034f47c642f7fd88134b3c9f6 (MD5)Made available in DSpace on 2015-07-21T17:59:20Z (GMT). No. of bitstreams: 1 Innate Resistance against Toxoplasma gondii- An Evolutionary Tale of Mice, Cats, and Men.pdf: 1199408 bytes, checksum: 4d1bed7034f47c642f7fd88134b3c9f6 (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Centro de Pesquisa Rene Rachou. Laboratorio de Imunopatologia. Belo Horizonte, MG, Brazil/Universidade Federal de Minas Gerais. Instituto de Ciencias Biologicas. Departamento de Bioquimica e Imunologia. Belo Horizonte, MG, Brazil/University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, USAUniversidade Federal de Minas Gerais. Instituto de Ciencias Biologicas. Departamento de Bioquimica e Imunologia. Belo Horizonte, MG, BrazilUniversity of Cologne. Institute for Genetics. Cologne, GermanyUniversity of Cologne. Institute for Genetics. Cologne, Germany/Instituto Gulbenkian de Ciencia. Oeiras, PortugalNational Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases. Bethesda, MD, USARecent studies have revealed remarkable species specificity of the Toll-like receptors (TLRs) TLR11 and TLR12 and the immunity-related GTPase (IRG) proteins that are essential elements for detection and immune control of Toxoplasma gondii in mice, but not in humans. The biological and evolutionary implications of these findings for the T. gondii host-pathogen relationship and for human disease are discussed

Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging

Abstract The insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme a candidate pathophysiological link between Alzheimer's disease (AD) and type 2 diabetes (T2D). These antecedents led us to address the impact of IDE absence in hippocampus and olfactory bulb. A specific induction of microgliosis was found in the hippocampus of IDE knockout (IDE-KO) mice, without any effects in neither hippocampal volume nor astrogliosis. Performance on hippocampal-dependent memory tests is influenced by IDE gene dose in 12-month-old mice. Furthermore, a comprehensive characterization of the impact of IDE haploinsufficiency and total deletion in metabolic, behavioral, and molecular parameters in the olfactory bulb, a site of high insulin receptor levels, reveals an unambiguous barcode for IDE-KO mice at that age. Using wildtype and IDE-KO primary microglial cultures, we performed a functional analysis at the cellular level. IDE absence alters microglial responses to environmental signals, resulting in impaired modulation of phenotypic states, with only transitory effects on amyloid-β management. Collectively, our results reveal previously unknown physiological functions for IDE in microglia that, due to cell-compartment topological reasons, cannot be explained by its enzymatic activity, but instead modulate their multidimensional response to various damaging conditions relevant to aging and AD conditions

Single-cell RNA sequencing and analysis of rodent blood stage Plasmodium

Summary: Bulk RNA sequencing of Plasmodium spp., the causative parasite of malaria, fails to discriminate developmental-stage-specific gene regulation. Here, we provide a protocol that uses single-cell RNA sequencing of FACS-sorted Plasmodium-chabaudi-chabaudi-AS-infected red blood cells (iRBCs) to characterize developmental-stage-specific modulation of gene expression during malaria blood stage. We describe steps for infecting mice, monitoring disease progression, preparing iRBCs, and single-cell sequencing iRBCs. We then detail procedures for analyzing scRNA-seq data.For complete details on the use and execution of this protocol, please refer to Ramos et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics

Variation in olfactory neuron repertoires is genetically controlled and environmentally modulated

The mouse olfactory sensory neuron (OSN) repertoire is composed of 10 million cells and each expresses one olfactory receptor (OR) gene from a pool of over 1000. Thus, the nose is sub-stratified into more than a thousand OSN subtypes. Here, we employ and validate an RNA-sequencing-based method to quantify the abundance of all OSN subtypes in parallel, and investigate the genetic and environmental factors that contribute to neuronal diversity. We find that the OSN subtype distribution is stereotyped in genetically identical mice, but varies extensively between different strains. Further, we identify cis-acting genetic variation as the greatest component influencing OSN composition and demonstrate independence from OR function. However, we show that olfactory stimulation with particular odorants results in modulation of dozens of OSN subtypes in a subtle but reproducible, specific and time-dependent manner. Together, these mechanisms generate a highly individualized olfactory sensory system by promoting neuronal diversity6FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP09/00473-0; 2015/50371-

A hypometabolic defense strategy against malaria

Copyright © 2022 Elsevier Inc. All rights reserved.Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Here, we report that malaria-associated hypoglycemia emerges from a non-canonical resistance mechanism, whereby the infected host reduces glycemia to starve Plasmodium. This hypometabolic response is elicited by labile heme, a byproduct of hemolysis that induces illness-induced anorexia and represses hepatic glucose production. While transient repression of hepatic glucose production prevents unfettered immune-mediated inflammation, organ damage, and anemia, when sustained over time it leads to hypoglycemia, compromising host energy expenditure and adaptive thermoregulation. The latter arrests the development of asexual stages of Plasmodium via a mechanism associated with parasite mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program associated with the reduction of virulence and sexual differentiation toward the generation of transmissible gametocytes. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic-based defense strategy that balances parasite virulence versus transmission.publishersversionepub_ahead_of_prin