RESUMEN
Most cases of human prion disease arise due to spontaneous misfolding of WT or mutant prion protein, yet recapitulating this event in animal models has proven challenging. It remains unclear whether spontaneous prion generation can occur within the mouse lifespan in the absence of protein overexpression and how disease-causing mutations affect prion strain properties. To address these issues, we generated knockin mice that express the misfolding-prone bank vole prion protein (BVPrP). While mice expressing WT BVPrP (I109 variant) remained free from neurological disease, a subset of mice expressing BVPrP with mutations (D178N or E200K) causing genetic prion disease developed progressive neurological illness. Brains from spontaneously ill knockin mice contained prion disease-specific neuropathological changes as well as atypical protease-resistant BVPrP. Moreover, brain extracts from spontaneously ill D178N- or E200K-mutant BVPrP-knockin mice exhibited prion seeding activity and transmitted disease to mice expressing WT BVPrP. Surprisingly, the properties of the D178N- and E200K-mutant prions appeared identical before and after transmission, suggesting that both mutations guide the formation of a similar atypical prion strain. These findings imply that knockin mice expressing mutant BVPrP spontaneously develop a bona fide prion disease and that mutations causing prion diseases may share a uniform initial mechanism of action.
Asunto(s)
Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Ratones Transgénicos , Enfermedades por Prión , Proteínas Priónicas , Animales , Ratones , Enfermedades por Prión/genética , Enfermedades por Prión/patología , Enfermedades por Prión/metabolismo , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Mutación Missense , Humanos , Arvicolinae/genética , Arvicolinae/metabolismo , Sustitución de Aminoácidos , Priones/genética , Priones/metabolismo , Pliegue de ProteínaRESUMEN
Genetic admixture introduces new variants at relatively high frequencies, potentially aiding rapid responses to environmental changes. Here, we evaluate its role in adaptive variation related to climatic conditions in bank voles (Clethrionomys glareolus) in Britain, using whole-genome data. Our results reveal loci showing excess ancestry from one of the two postglacial colonist populations inconsistent with overall admixture patterns. Notably, loci associated with climate adaptation exhibit disproportionate amounts of excess ancestry, highlighting the impact of admixture between colonist populations on local adaptation. The results suggest strong and localized selection on climate-adaptive loci, as indicated by steep clines and/or shifted cline centres, during population replacement. A subset, including a haemoglobin gene, is associated with oxidative stress responses, underscoring a role of oxidative stress in local adaptation. Our study highlights the important contribution of admixture during secondary contact between populations from distinct climatic refugia enriching adaptive diversity. Understanding these dynamics is crucial for predicting future adaptive capacity to anthropogenic climate change.
Asunto(s)
Arvicolinae , Cambio Climático , Animales , Arvicolinae/genética , Arvicolinae/fisiología , Adaptación Fisiológica/genética , Variación Genética , Aclimatación/genética , Reino Unido , Genética de Población , Clima , Polimorfismo de Nucleótido SimpleRESUMEN
The quality of romantic relationships can predict health consequences related to aging. DNA methylation-based biomarkers of aging accurately estimate chronological age. We developed several highly accurate epigenetic aging clocks, based on highly conserved mammalian CpGs, for the socially monogamous prairie vole (Microtus ochrogaster). In addition, our dual-species human-vole clock accurately measured relative age and illustrates high species conservation of epigenetic aging effects. Next, we assessed how pair bonding impacts epigenetic aging. We did not find evidence that pair-bonded voles exhibit accelerated or decelerated epigenetic aging effects in blood, ear, liver, or brain tissue. Our epigenome wide association study identified CpGs in five genes strongly associated with pair bonding: Foxp4, Phf2, Mms22l, Foxb1, and Eif1ad. Overall, we present accurate DNA methylation-based estimators of age for a species of great interest to researchers studying monogamy in animals. We did not find any evidence that sex-naive animals age differently from pair-bonded animals.
Asunto(s)
Envejecimiento , Arvicolinae , Metilación de ADN , Epigénesis Genética , Animales , Arvicolinae/genética , Envejecimiento/genética , Femenino , Masculino , Apareamiento , Islas de CpGRESUMEN
Island populations often experience different ecological and demographic conditions than their counterparts on the continent, resulting in divergent evolutionary forces affecting their genomes. Random genetic drift and selection both may leave their imprints on island populations, although the relative impact depends strongly on the specific conditions. Here we address their contributions to the island syndrome in a rodent with an unusually clear history of isolation. Common voles (Microtus arvalis) were introduced by humans on the Orkney archipelago north of Scotland >5000 years ago and rapidly evolved to exceptionally large size. Our analyses show that the genomes of Orkney voles were dominated by genetic drift, with extremely low diversity, variable Tajima's D, and very high divergence from continental conspecifics. Increased d N/d S ratios over a wide range of genes in Orkney voles indicated genome-wide relaxation of purifying selection. We found evidence of hard sweeps on key genes of the lipid metabolism pathway only in continental voles. The marked increase of body size in Orkney-a typical phenomenon of the island syndrome-may thus be associated to the relaxation of positive selection on genes related to this pathway. On the other hand, a hard sweep on immune genes of Orkney voles likely reflects the divergent ecological conditions and possibly the history of human introduction. The long-term isolated Orkney voles show that adaptive changes may still impact the evolutionary trajectories of such populations despite the pervasive consequences of genetic drift at the genome level.
Asunto(s)
Arvicolinae , Evolución Molecular , Islas , Selección Genética , Animales , Arvicolinae/genética , Flujo Genético , Genoma , Escocia , Variación GenéticaRESUMEN
Motherhood is a costly life-history transition accompanied by behavioral and neural plasticity necessary for offspring care. Motherhood in the monogamous prairie vole is associated with decreased pair bond strength, suggesting a trade-off between parental investment and pair bond maintenance. Neural mechanisms governing pair bonds and maternal bonds overlap, creating possible competition between the two. We measured mRNA expression of genes encoding receptors for oxytocin (oxtr), dopamine (d1r and d2r), mu-opioids (oprm1a), and kappa-opioids (oprk1a) within three brain areas processing salience of sociosensory cues (anterior cingulate cortex; ACC), pair bonding (nucleus accumbens; NAc), and maternal care (medial preoptic area; MPOA). We compared gene expression differences between pair bonded prairie voles that were never pregnant, pregnant (~day 16 of pregnancy), and recent mothers (day 3 of lactation). We found greater gene expression in the NAc (oxtr, d2r, oprm1a, and oprk1a) and MPOA (oxtr, d1r, d2r, oprm1a, and oprk1a) following the transition to motherhood. Expression for all five genes in the ACC was greatest for females that had been bonded for longer. Gene expression within each region was highly correlated, indicating that oxytocin, dopamine, and opioids comprise a complimentary gene network for social signaling. ACC-NAc gene expression correlations indicated that being a mother (oxtr and d1r) or maintaining long-term pair bonds (oprm1a) relies on the coordination of different signaling systems within the same circuit. Our study suggests the maternal brain undergoes changes that prepare females to face the trade-off associated with increased emotional investment in offspring, while also maintaining a pair bond.
Asunto(s)
Arvicolinae , Conducta Materna , Núcleo Accumbens , Apareamiento , Receptores Opioides mu , Animales , Femenino , Arvicolinae/genética , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Conducta Materna/fisiología , Núcleo Accumbens/metabolismo , Embarazo , Receptores de Oxitocina/genética , Receptores de Oxitocina/metabolismo , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Giro del Cíngulo/metabolismo , Área Preóptica/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismoRESUMEN
This study aims to explore the relationship between altered vitamin D (VitD3) status and ovarian steroidogenesis in muskrats during the breeding and non-breeding seasons. During the breeding season, the ovaries of muskrats were observably enlarged and increased in weight, accompanied by elevated serum and ovarian VitD3 status. Vitamin D receptor (VDR), VitD3 metabolic molecules (CYP2R1, CYP27B1, and CYP24A1), and steroidogenic enzymes were immunolocalized in the ovarian cells of muskrats. The mRNA levels of VDR, CYP2R1, CYP27B1, and steroidogenic enzymes were considerably higher during the breeding season compared to the non-breeding season. RNA-seq analysis revealed a prominent enrichment of vitamin-related and ovarian steroidogenesis pathways. Furthermore, the addition of 1,25(OH)2D3 to the muskrat granulosa cells in vitro increased VDR and steroidogenic enzymes mRNA levels and enhanced the 17ß-estradiol level. Overall, these findings supported that VitD3 promotes the secretion of steroid hormones, thereby affecting seasonal changes in ovarian function in the muskrats.
Asunto(s)
Ovario , Vitamina D , Animales , Femenino , Vitamina D/metabolismo , Ovario/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Arvicolinae/genética , Arvicolinae/metabolismo , Vitaminas , Células de la Granulosa/metabolismo , ARN Mensajero/genéticaRESUMEN
Tannic acid (TA), a significant plant secondary metabolite, is contained in the daily food of Brandt's voles. Its adverse effect on gut function has been shown in earlier research, but the underlying molecular mechanisms remain uncertain. In this study, male Brandt's vole (13 weeks old) were divided into two groups and given 0 (control) or 1,200 (TA-treated) mgâ¢kg-1 TA for 18 days. Then RNA sequencing was used to conduct a thorough transcriptome analysis on the duodenum, jejunum, and ileum of Brandt's voles. Results showed that TA significantly increased serum total cholesterol concentration (P < 0.05) and decreased the nutrient digestibility (P < 0.05) of Brandt's voles. Furthermore, there were 174 differentially expressed genes (DEGs) in the duodenum, 96 DEGs in the jejunum, and 88 DEGs in the ileum between the control and TA-treated groups. Enrichment analysis revealed that many genes associated with bile secretion, fat digestion and absorption, innate immune response, and tight junction such as ABCG2, ABCG8, PEAK1, and IFR2, etc. were altered after TA treatment, which were verified by quantitative real-time PCR. These findings suggested that TA can change the expression of intestinal genes, thereby, altering nutrition metabolism and immunological function, eventually hindering the growth of Brandt's voles. The results of this study provide a theoretical basis for explaining how TA affects the gut function of Brandt's voles at the molecular level.
Asunto(s)
Arvicolinae , Perfilación de la Expresión Génica , Polifenoles , Animales , RNA-Seq , Análisis de Secuencia de ARN , Arvicolinae/genéticaRESUMEN
BACKGROUND: Ellobius talpinus is a subterranean rodent representing an attractive model in population ecology studies due to its highly special lifestyle and sociality. In such studies, mitochondrial DNA (mtDNA) is widely used. However, if nuclear copies of mtDNA, aka NUMTs, are present, they may co-amplify with the target mtDNA fragment, generating misleading results. The aim of this study was to determine whether NUMTs are present in E. talpinus. METHODS AND RESULTS: PCR amplification of the putative mtDNA CytB-D-loop fragment using 'universal' primers from 56 E. talpinus samples produced multiple double peaks in 90% of the sequencing chromatograms. To reveal NUMTs, molecular cloning and sequencing of PCR products of three specimens was conducted, followed by phylogenetic analysis. The pseudogene nature of three out of the seven detected haplotypes was confirmed by their basal positions in relation to other Ellobius haplotypes in the phylogenetic tree. Additionally, 'haplotype B' was basal in relation to other E. talpinus haplotypes and found present in very distant sampling sites. BLASTN search revealed 195 NUMTs in the E. talpinus nuclear genome, including fragments of all four PCR amplified pseudogenes. Although the majority of the NUMTs studied were short, the entire mtDNA had copies in the nuclear genome. The most numerous NUMTs were found for rrnL, COXI, and D-loop. CONCLUSIONS: Numerous NUMTs are present in E. talpinus and can be difficult to discriminate against mtDNA sequences. Thus, in future population or phylogenetic studies in E. talpinus, the possibility of cryptic NUMTs amplification should always be taken into account.
Asunto(s)
ADN Mitocondrial , Genoma Mitocondrial , Animales , ADN Mitocondrial/genética , Filogenia , Genoma , Mitocondrias/genética , Arvicolinae/genética , Análisis de Secuencia de ADN , Genoma Mitocondrial/genéticaRESUMEN
In this survey, we inventoried the helminths of heteromyid and cricetid rodents captured in the Yucatan Peninsula from 2017 to 2019. Helminths were identified using morphological techniques (clearing, staining, and scanning electron microscopy). Also, the 28S rRNA gene of individuals from several helminth taxa was successfully amplified and sequenced. To confirm the identification at the generic level, and in some cases at the specific level, and the genealogical relationships of the parasites, phylogenetic analyses were performed with the new 28S sequences. We identified 22 species of helminths including three trematodes (Brachylaimidae, Dicrocoeliidae, and Microphallidae), five cestodes (Davaineidae, Hymenolepididae, and Taeniidae), and 14 nematodes (Trichuridae, Ancylostomatidae, Ornithostrongylidae, Heligmonellidae, and Oxyuridae) from Heteromys gaumeri (Heteromyidae), Ototylomys phyllotis, Oligoryzomys fulvescens, Peromyscus yucatanicus, Sigmodon toltecus, and Reithrodontomys gracilis (Cricetidae). The overall frequency of infection in small rodents was 84.1% (143/170); all specimens of H. gaumeri, S. toltecus and Ol. fulvescens were infected with helminths. In total, we provided 46 new sequences of the 28S gene from 17 species of helminths. Seven species are likely undescribed species, six are reported for the first time in rodents from Mexico, and 12 are new host records in the Americas. Before this study, 87 taxa of helminths had been reported from 35 cricetid and 12 heteromyid species in 21 Mexican states. Our findings increase to 93 the helminth taxa in these rodents, and to 36 the cricetid species parasitized by helminths. This large scale-survey is the first to use an integrative approach to inventory the helminths of wild small rodents in Mexico.
Asunto(s)
Helmintos , Roedores , Animales , Roedores/parasitología , Arvicolinae/genética , Arvicolinae/parasitología , México , Filogenia , Helmintos/genética , Sigmodontinae , PeromyscusRESUMEN
We present the revalidation of the sigmodontinae rodent species R. emiliae, as well as the description of a new species for the genus Rhipidomys. The maximum likelihood analysis recovers R. emiliae as sister species of the clade with Rhipidomys sp. nov. and R. ipukensis, with high bootstrap values. Comparisons between these species based on the external, cranial, and dental morphology identified several unique characters in Rhipidomys sp. nov., including more grayish brown color of the dorsal coat, subsquamosal fenestra wide and long, angular process ends in the same position of the end of condyloid process, conspicuous protostyle and enterostyle. We describe a new karyotype (2n = 44 and FN = 64) for the genus and, based on an integrative analysis together with morphology and molecular phylogeny, assign it to R. emiliae, and assign the karyotype with 2n = 44 and FN = 52 to Rhipidomys sp. nov.. The analysis integrating data indicated that R. emiliae has a geographic distribution restricted to the lowlands of eastern Amazonia, whereas Rhipidomys sp. nov. occurs in the central Amazonia and Cerrado. The data showed that some Rhipidomys species have its distribution currently limited by rivers, as Rhipidomys sp. nov. occurring west of the Araguaia-Tocantins interfluve, R. emiliae east of the Tocantins River, and R. ipukensis between the Tocantins and Araguaia rivers. This work, in addition to revealing a still unknown biodiversity describing a species, brings a new understanding to the genus, and shows how integrating different markers helps in the correct association between the nominal form and the karyotype.
Asunto(s)
Arvicolinae , Roedores , Animales , Arvicolinae/genética , Brasil , Sigmodontinae/genética , Cariotipificación , FilogeniaRESUMEN
Estudos experimentais têm falhado em reproduzir a patologia humana da infecção esquistossomótica mansônica, justificando a procura de modelos alternativos. O objetivo deste trabalho foi estudar parâmetros parasitológicos e histopatológicos em Cc infectado com Sm usando Swiss Webster (SW) (infectado com Sm) como padrão. Número igual de Cc e SW, pareados em idade, foram percutaneamente infectados com 70 cercárias de Sm e sacrificados diariamente do 20°. ao 41°. dia (três animais/grupo/dia) e nos dias 42,45,50,55 (fase aguda), 80,90 (transicional) e 160 (fase crônica) após a infecção (10 animais/grupo/pontos). Amostras de figado, intestino, pâncreas, mesentério, omento e pulmões foram fixadas em Fonnalina-Millonig de Carson, processadas e incluídas em parafina. Secções de tecido foram coradas com HE e outras colorações especiais para exame em microscopia de campo claro, polarização e de varredura confocal a laser. Imunohistologia para matriz extracelular, citoesqueleto, vasos sangüíneos, enzimas teciduais (gelatinase e lisil-oxidase) foi feita em cortes de criostato, e/ou parafina. Intestino foi examinado em TEM e SEM. O colágeno do figado foi avalido por método colorimétrico em secções de parafina. O tamanho dos granulomas hepáticos e sua densidade de superfície de colágeno foram medidos por análise de imagem em computador. Parâmetros biológicos e quantitativos foram investigados por técnicas histológicas em fígado, intestino, pâncreas e pulmões. Recuperação de vennes adultos, contagem de ovos no fígado, intestino e pulmões por digestão cáustica (KOH a 4%), oograma qualitativo e contagem de ovos nas fezes (Kato-Katz) foram também realizados. Os seguintes eventos (dias de infecção) foram registrados em C. callosus: acasalamento de vennes adultos (26°.); ovos no fígado, intestino (imaturos=31°.; maduros com miracídios=34°.) e pâncreas (imaturos=32°.; maduros com miracídio=37°.); recuperação de vennes adultos: 14-39% (45°.), 16-20% (90°.), 4-20% (160°.); proporção de machos> fêmeas (45°. & 90°.),1:1 (160°.); pico de número de ovos (tecidos) (90°.); número de ovos retidos em tecido/fêmea/dia=160; início da eliminação de ovos nas fezes (35°.); e retenção de ovos em intestino> fígado. Os principais achados histopatológicos em C. callosus foram: resposta periovular diferente, confonne o local anatômico, com granulomas menores e menos fibróticos que os encontrados em camundongos, compostos principalmente por macrófagos, mesmo na fase aguda inicial, sem evidências de modulação marcante; dois padrões de reação intestinal: nodular (com fibrogênese e angiogêne) e nãonodular; pancreatite granulomatosa freqüente, com graus variáveis; mobilização mastocitária em intestino (intra-epitelial), mesentério, omento, pâncreas, quase ausente em fígado; e grande ativação de manchas lácteas ("mi1ky spots") omentais e mesentéricas. Os aspectos parasitológicos foram semelhantes em C. callosus e camundongos. Embora os granulomas de Cc fossem menores, menos fibróticos, sem sinais histopato1ógicos de hipersensibilidade, eles foram efetivos em circunscrever os ovos de S. mansoni, evitando necrose hepática parenquimatosa. Os nódulos intestinais podem ser usados como um modelo de fibrogênese e angiogênese concomitantes em esquistossomose mansônica experimental.
Asunto(s)
Animales , Arvicolinae/genética , Parasitología , Schistosoma mansoni/parasitologíaRESUMEN
O cariótipo da espécie Oryzomys capito oniscus é descrito (2n=52, FN = 62), incluindo os dados referentes aos padröes de bandas G e C e as regiöes organizadoras do nucléolo, marcadas pela prata. Estes dados contribuem para o estudo das relaçöes cromossômicas dentro do complexo capito
Asunto(s)
Masculino , Femenino , Arvicolinae/genética , Cariotipificación , Región Organizadora del NucléoloRESUMEN
Con el propósito de obtener información sobre el grado de contacto entre poblaciones de C. musculinus, se analizaron las frecuencias alélicas en tres loci polimórficos en muestras de seis diferentes localidades de la provincia de Córdoba ubicadas en el área endémica de fiebre hemorrágica argentina (FHA) y en regiones marginales, libres de virus Junín. Dichas localidades están situadas sobre una línea sur-noreste (250km de longitud) y otra sur-noreste (50km) que siguen el sentido en el cual progresó la endemia desde su aparición en Córdoba, hace más de veinte años. En el locus Aat-1 la frecuencia del alelo b osciló entre 0,95 y 0,99 en las diferentes localidades analizadas. En cinco de las seis muestras, las frecuencias génicas fueron muy similares en el locus Es-4 y en el Es-6. En la sexta localidad, los alelos a de ambos loci presentaron menor frecuencia. Esta población mostraba una característica particular: era la única con predominio de individuos de peso mayor a 16g, los cuales corresponderían a ejemplares adultos y viejos. Si se comparan las frecuencias alélicas de las diferentes muestras agrupando los ejemplares con menos de 16g (¿jóvenes?) y los adultos más los viejos, se observa una notable homogeneidad geográfica. Algunas características ecológicas conocidas para C. musculinus, tales como su gran capacidad de adaptación a ambientes inestables, su alta actividad ambulatoria y la ausencia de barreras naturales en el área estudiada, apoyarían la presunción de que existe un importante flujo génico entre poblaciones contiguas. Por otro lado, la observación de que los alelos a en los loci Es-4 y Es-6 se presentan con mayor frecuencia entre los individuos de menor peso, sugiere que los portadores del alelo b deben poseer mayor tasa de supervivencia, lo cual estaría determinado por fuerzas selectivas similares en toda el área analizada. La FHA se ha expandido lenta pero sostenidamente desde la aparición de los primeros casos humanos. Tal progresión es consecuencia de la transmisión del virus de Calomys infectados de la zona endémica a los de las zonas marginales. La ...