Non-Mendelian inheritance of DNA methylation patterns in mice

Nature Genetics · 2026-05-20

Epigenetic mechanisms such as genomic imprinting demonstrate that molecular inheritance can deviate from typical Mendelian patterns. Despite this, the intergenerational inheritance of DNA methylation remains poorly understood. Here we developed a genome-wide approach to study epigenetic inheritance in mice using long-read nanopore sequencing. Using this approach in both liver and muscle, we found that ~93% of autosomal epigenetic inheritance patterns followed Mendel's laws, primarily driven by cis-acting methylation quantitative trait loci. However, we also identified extensive non-Mendelian inheritance, including emergent epigenetic inheritance patterns, widespread sex-specific DNA methylation patterns localized to the liver, and five seemingly new autosomal and X-linked imprinted genes. Notably, we also report an example of naturally occurring intergenerational paramutation, confirmed over strain-specific transposable elements within Capn11 and highly likely at Vps37c. Overall, an unexpectedly high ~7% of autosomal epigenetic inheritance patterns identified were non-Mendelian, highlighting the importance of epigenetic information in the analysis of inherited traits and disorders.

ERBB2 deficiency enhances colorectal cancer progression through EGFR-dependent compensatory mechanisms

Research Square · 2026-04-02

Snrnp25 is a candidate for the peri-implantation lethal phenotype of the Hba deletions

Mammalian Genome · 2025-05-21

Abstract Mutations in adult hemoglobin alpha genes in humans lead to blood disorders commonly known as α-thalassemia. In search of a mouse model for this disease, mutagenesis screens have identified several deletions that resemble these phenotypes. The Hba b2(th) deletion, in particular, replicates the characteristics of alpha-thalassemia minor in heterozygous mice but presents a homozygous embryonic lethal phenotype. Previous analyses of Hba b2(th) mice suggested that the deletion affects both Hba genes ( Hba-a1 and Hba-a2 ) and considered epidermal growth factor receptor ( Egfr ) or rhomboid 5 homolog 1 ( Rhbdf1 ) to be responsible for the embryonic lethality. Molecular analysis of Hba b2(th) revealed a deletion spanning a 1 cM region of mouse chromosome 11. Importantly, the Hba b2(th) deletion does not extend to Egfr , indicating that the observed lethality of homozygous embryos is not due to the loss of Egfr . Sequence analysis of the Hba b2(th) deletion showed that the Hba-a2 gene is not deleted, but the lack of expression is likely due to the disruption of upstream regulatory regions. Furthermore, we identify Snrnp2 5, which codes for the small nuclear ribonucleoprotein 25 (U11/U12), as the candidate gene most likely responsible for the peri-implantation lethality of Hba b2(th) homozygous mice. These findings enhance the understanding of the genetic mechanisms underlying α-thalassemia and provide insights into novel genes essential for early mammalian development.

Noninvasive Optical Sensing of Aging and Diet Preferences Using Raman Spectroscopy

Analytical Chemistry · 2025-01-01 · 1 citations

Effective dietary strategies and interventions for monitoring dietary exposures require accurate and noninvasive methods to understand how diet modulates health and risk of obesity; advances in technology are transforming the landscape and enabling more specific tailored approaches to nutritional guidance. This study explores the use of Raman spectroscopy (RS), a noninvasive and nondestructive analytical technique, to identify changes in the mice skin in response to constant dietary exposures. We found that RS is highly accurate to determine body composition as a result of habitual dietary patterns, specifically Vegan, Typical American, and Ketogenic diets, all very common in the US context. RS is based on major differences in the intensities of vibrational bands that originate from collagen. Moreover, RS could be used to predict folate deficiency and identify the sex of the animals. Finally, we found that RS could be used to track the chronological age of the mice. Considering the hand-held nature of the utilized spectrometer, one can expect that RS could be used to monitor and, consequently, personalize effects of diet on the body composition.

The association between virus-induced spinal cord pathology and the genetic background of the host

Journal of Neuropathology & Experimental Neurology · 2025-10-17

Theiler's murine encephalomyelitis virus (TMEV) infection in mice has been used to study diverse neurological diseases, including multiple sclerosis and epilepsy. In this investigation, 5 strains of collaborative cross (CC) mice were infected with TMEV and examined clinically and histologically at days 4, 14, and 90 post-infection (dpi). All CC strains tested exhibited lumbar spinal cord and/or ventral peripheral nerve lesions by 14 dpi; CC027, CC023, and CC078 strains exhibited lesions at 4 dpi. At 90 dpi, lesions were remnants of the inflammatory responses associated with earlier infection; there was skeletal muscle atrophy in the CC023 strain. Increased microglial/macrophage reactivity was observed in all strains at 4 and 14 dpi, but not at 90 dpi. TMEV mRNA expression was greatest in the CC023 and CC078 strains at the acute timepoints; TMEV was completely cleared in all mice at 90 dpi. The neuropathological and clinical profiles in CC023 mice, mainly at 14 dpi, share some clinical and histologic features with those in amyotrophic lateral sclerosis patients. This work demonstrates how viral infection might interact with the genetic background of a susceptible individual to contribute to the onset, clinical presentation and persistence of lesions despite viral clearance.

Derivation of ultrasound and electrocardiogram cardiac reference ranges for Mus musculus using the collaborative cross and identification of new cardiac models

BMC Cardiovascular Disorders · 2025-09-26 · 2 citations

BACKGROUND: Contemporary approaches for developing interventions and assessing pre-clinical cardiovascular risk frequently utilize animal and in vitro models. However, these models currently lack normal species-specific reference ranges similar to what exists for humans. The genetically diverse Collaborative Cross (CC) population that models human genetic heterogenetiety was characterized to develop mouse-specific cardiac reference ranges for Mus musculus, the most commonly used pre-clincial model. METHODS: Heart function was analyzed in males and females from 58 CC strains and C57BL/6J using high-frequency ultrasound under both conscious and anesthetized conditions, as well as conscious electrocardiography to develop two standard deviation-based reference ranges. The sources and magnitude of measurement variability were identified, and inter-laboratory comparisons determined to quantify phenotypic robustness and heritability. RESULTS: Strain was the largest source of variability, while laboratory where data were collected was also significant but sex was not. Additionally, strains were identified that have characteristics of disease-associated phenotypes in cardiac function and electrophysiology similar to human cases including dilated cardiomyopathy, cancer therapy-related cardiac dysfunction, and long QT. CONCLUSIONS: These new models allow a more natural, and therefore more translatable progression to a cardiac disease state, supporting development of strain-specific models for cardiac pathologies, ultimately allowing more accurate diagnoses and informative human relevant assessments.

Derivation of cardiac reference ranges for <i>Mus musculus</i> using the Collaborative Cross and identification of new cardiac models

bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-10 · 1 citations

Abstract Contemporary approaches for developing interventions and assessing pre-clinical cardiovascular risk frequently utilize animal and in vitro models. However, these models currently lack normal species-specific reference ranges similar to what exists for humans. The genetically diverse Collaborative Cross (CC) population that models human genetic heterogenetiety was characterized to develop mouse-specific cardiac reference ranges for Mus muscuslus , the most commonly used pre-clincial model. Heart function was analyzed in males and females from 58 CC strains and C57BL/6J using high-frequency ultrasound under both conscious and anesthetized conditions, as well as conscious electrocardiography to develop two standard deviation-based reference ranges. The sources and magnitude of measurement variability were identified, and inter-laboratory comparisons determined to quantify phenotypic robustness and heritability. Strain was the largest source of variability, while laboratory where data were collected was also significant but sex was not. Additionally, strains were identified that have characteristics of disease-associated phenotypes in cardiac function and electrophysiology similar to human cases including dilated cardiomyopathy, systolic cardiomyopathy, cancer therapy-related cardiac dysfunction, and long QT. These new models allow a more natural, and therefore more translatable progession to a cardiac disease state, supporting development of strain-specific models for cardiac pathologies, ultimately allowing more accurate diagnoses and informative safety assessments in humans. Article Summary The Collaborative Cross (CC) mouse reference population, modeling human genetic diversity, was utilized to derive cardiac reference values for Mus musculus . Strain was the primary source of variability, with the laboratory also playing a significant role, while sex had no impact. Despite inter-laboratory reproducibility challenges, the study identified strains resembling disease-associated phenotypes that offer a more natural progression to cardiac disease and provide crucial data for early disease identification and accurate safety assessments in humans.

Examining risk assessment implications of genetic and dose-dependent dynamics of lead exposure in breastfeeding using the collaborative cross mouse population

Toxicological Sciences · 2025-01-30

Breastfeeding offers well-documented advantages but may inadvertently introduce lead (Pb) exposure to infants. Scarce data exist on the risks of Pb exposure for breastfed infants, and strategies for risk mitigation are needed, particularly considering the heightened susceptibility of children to adverse effects from Pb exposure. To investigate the potential influence of breastfeeding on blood Pb levels (BLL) in offspring, population variation in BLL between nonparous and parous mouse dams was quantified, as well as in dams exposed to low and high dose while breastfeeding, and their offspring. Female mice from 14 distinct collaborative cross (CC) mouse strains were mated with sires from different CC strains to produce 14 F1 hybrids. Subsequently, dams were administered either low- (100 ppm) or high- (1,000 ppm) dose Pb through ad libitum access drinking water starting the day of delivery for a duration of 4 wk, leading to the subsequent exposure of the offspring via lactation. Genetic background emerged as a predominant factor contributing to variation, with substantial interstrain variability observed in both CC dams and F1 hybrids exposed to low and high doses of Pb. Crucially, the degree of variation in BLL among CC dams exceeded the default variability estimate (geometric SD = 1.6) utilized in regulatory standard settings. These findings underscore the importance of integrating population variability in risk assessment. Ultimately, this study provides critical insights to guide public health decision-making processes concerning Pb exposure through breastfeeding and its potential implications for infants' health.

Snrnp25 is a candidate for the peri-implantation lethal phenotype of the Hba deletions

Research Square · 2025-04-22

Collaborative Cross mice have diverse phenotypic responses to infection with Methicillin-resistant Staphylococcus aureus USA300

PLoS Genetics · 2024-05-02 · 10 citations

Staphylococcus aureus (S. aureus) is an opportunistic pathogen causing diseases ranging from mild skin infections to life threatening conditions, including endocarditis, pneumonia, and sepsis. To identify host genes modulating this host-pathogen interaction, we infected 25 Collaborative Cross (CC) mouse strains with methicillin-resistant S. aureus (MRSA) and monitored disease progression for seven days using a surgically implanted telemetry system. CC strains varied widely in their response to intravenous MRSA infection. We identified eight 'susceptible' CC strains with high bacterial load, tissue damage, and reduced survival. Among the surviving strains, six with minimal colonization were classified as 'resistant', while the remaining six tolerated higher organ colonization ('tolerant'). The kidney was the most heavily colonized organ, but liver, spleen and lung colonization were better correlated with reduced survival. Resistant strains had higher pre-infection circulating neutrophils and lower post-infection tissue damage compared to susceptible and tolerant strains. We identified four CC strains with sexual dimorphism: all females survived the study period while all males met our euthanasia criteria earlier. In these CC strains, males had more baseline circulating monocytes and red blood cells. We identified several CC strains that may be useful as new models for endocarditis, myocarditis, pneumonia, and resistance to MRSA infection. Quantitative Trait Locus (QTL) analysis identified two significant loci, on Chromosomes 18 and 3, involved in early susceptibility and late survival after infection. We prioritized Npc1 and Ifi44l genes as the strongest candidates influencing survival using variant analysis and mRNA expression data from kidneys within these intervals.