Mouse minisatellite mutations induced by ionizing radiation.

The detection of changes in germline mutation rate in human populations remains extremely difficult. Estimating the genetic hazards of radiation and other mutagens in humans therefore depends on extrapolation from experimental systems. Because of the very low frequency of spontaneous mutation at most loci, enormous samples are required to detect increases of mutation rate. A very high rate of spontaneous germline mutation altering the length of minisatellite loci has been found in human populations and therefore this system might be useful for detecting induced mutations in relatively small samples. Here we present evidence that minisatellite mutation rate in mice is increased by low doses of ionizing radiation.

Genetic mapping of ecotropic murine leukemia virus-inducing loci in six inbred strains.

Mendelian segregation analysis was used to map chromosomal genes for the induction of endogenous N- and B-tropic ecotropic retroviruses (V loci) in high and low leukemic mouse strains. Patterns of virus expression were determined for mice of various inbred strains, congenic lines carrying single V loci, and the linkage testing stocks used in mapping studies. Segregation analysis resulted in the genetic mapping of V loci from six inbred strains to five mouse chromosomes. The V locus of A/J was mapped to chromosome 5 and shown to be allelic with that of BALB/cJ and C3H/HeJ (Cv); this suggests that Cv-represents a stable ancestral V locus present in Bagg albino stocks before the separation of inbred lines. The single, poorly inducible V locus of C57BL/10J and one of the four high virus loci of C58/Lw were mapped to the same region of chromosome 8 and may represent an allelic pair with different patterns of expression. An N-tropic V locus of the SEA/GnJ mouse was mapped to chromosome 9, and one of the three V loci of C3H/FgLw was mapped to chromosome 7. The endogenous B-tropic virus of B10.BR/SgLi was mapped to chromosome 11. These studies provide further evidence that endogenous ecotropic V loci are present at different chromosomal sites in unrelated mouse strains and emphasize the role of germ line reinfections in the generation of this diversity.

Molecular characterization of the C3HfB/HeN H-2Kkm2 mutation. Implications for the molecular basis of alloreactivity.

The C3HfB/HeN (C3Hf) mouse strain expresses an H-2Kk molecule, previously denoted H-2Kkv1, that is structurally and functionally distinct from H-2Kk of the parental C3H strain. By molecular genetic analysis, we demonstrate that the C3Hf H-2K gene carries a homozygous coding region mutation relative to the C3H allele, revealing that C3Hf meets the requirements for assignment of a mutant haplotype, H-2km2. C3Hf H-2Kkm2 bears a single clustered substitution of four nucleotides within 14 contiguous nucleotides in exon 3. Since this sequence also is present intact at the homologous position in H-2Dk of both C3H and C3Hf, the origin of the H-2Kkm2 mutation is consistent with a nonreciprocal sequence transfer from the H-2Dk donor gene, analogous to the mechanism proposed for generation of the H-2Kb mutations. The H-2Kkm2 mutation encodes three clustered amino acid substitutions, at positions 95, 98, and 99, that map to one of the large beta strands at the bottom of the peptide antigen binding cleft of the H-2Kkm2 molecule. The nature and location of these amino acid substitutions are unique relative to any other known H-2 mutant or HLA variant, and underscore the importance of the beta-pleated sheet in influencing CTL recognition. These results indicate that H-2Kkm2 alloantigenicity may derive largely from altered presentation of self cellular peptides.

Elevated myc expression and c-myc amplification in spontaneously occurring B lymphoid cell lines.

Recently, a minor subpopulation of murine B lymphocytes, Ly-1+ B cells, has been distinguished by its unique ontogeny, tissue distribution, and prominence in certain autoimmune and neoplastic B cell diseases. We have previously described a simple murine spleen culture system that results in the spontaneous and exclusive outgrowth of long-term Ly-1+ B cell lines (B Ly-1 cells). Here, we report that the immortal growth property of B Ly-1 cells correlates with a 10-45-fold elevation of steady-state myc RNA and 2-10-fold amplification of the c-myc locus. While c-myc amplification has been observed in malignant cell lines derived from several tissues of origin, its occurrence in lymphoid cells has not been previously reported. The consistent c-myc amplification in B Ly-1 cells may reflect a unique state of this locus in the Ly-1+ B lymphocyte lineage, and contribute to the spontaneous immortalization of this B cell population in vitro, and its apparent predilection for malignant transformation in vivo.

Comparative phenotypic assessment of cardiac pathology, physiology, and gene expression in C3H/HeJ, C57BL/6J, and B6C3F1/J mice.

Human cardiomyopathies often lead to heart failure, a major cause of morbidity and mortality in industrialized nations. Described here is a phenotypic characterization of cardiac function and genome-wide expression from C3H/HeJ, C57BL/6J, and B6C3F1/J male mice. Histopathologic analysis identified a low-grade background cardiomyopathy (murine progressive cardiomyopathy) in eight of nine male C3H/HeJ mice (age nine to ten weeks), but not in male C57BL/6J and in only of ten male B6C3F1/J mice. The C3H/HeJ mouse had an increased heart rate and a shorter RR interval compared to the B6C3F1/J and C57BL/6J mice. Cardiac genomic studies indicated the B6C3F1/J mice exhibited an intermediate gene expression phenotype relative to the 2 parental strains. Disease-centric enrichment analysis indicated a number of cardiomyopathy-associated genes were induced in B6C3F1/J and C3H/HeJ mice, including Myh7, My14, and Lmna and also indicated differential expression of genes associated with metabolic (e.g., Pdk2) and hypoxic stress (e.g. Hif1a). A novel coexpression and integrated pathway network analysis indicated Prkaa2, Pdk2, Rhoj, and Sgcb are likely to play a central role in the pathophysiology of murine progressive cardiomyopathy in C3H/HeJ mice. Our studies indicate that genetically determined baseline differences in cardiac phenotype have the potential to influence the results of cardiotoxicity studies.

Inter-Strain Epigenomic Profiling Reveals a Candidate IAP Master Copy in C3H Mice.

Insertions of endogenous retroviruses cause a significant fraction of mutations in inbred mice but not all strains are equally susceptible. Notably, most new Intracisternal A particle (IAP) ERV mutagenic insertions have occurred in C3H mice. We show here that strain-specific insertional polymorphic IAPs accumulate faster in C3H/HeJ mice, relative to other sequenced strains, and that IAP transcript levels are higher in C3H/HeJ embryonic stem (ES) cells compared to other ES cells. To investigate the mechanism for high IAP activity in C3H mice, we identified 61 IAP copies in C3H/HeJ ES cells enriched with H3K4me3 (a mark of active promoters) and, among those tested, all are unmethylated in C3H/HeJ ES cells. Notably, 13 of the 61 are specific to C3H/HeJ and are members of the non-autonomous 1Δ1 IAP subfamily that is responsible for nearly all new insertions in C3H. One copy is full length with intact open reading frames and hence potentially capable of providing proteins in trans to other 1Δ1 elements. This potential "master copy" is present in other strains, including 129, but its 5' long terminal repeat (LTR) is methylated in 129 ES cells. Thus, the unusual IAP activity in C3H may be due to reduced epigenetic repression coupled with the presence of a master copy.

Mouse Genetic Background Affects Transfer of an Antibiotic Resistance Plasmid in the Gastrointestinal Tract.

Dissemination of antibiotic resistance (AR) genes, often on plasmids, leads to antibiotic-resistant bacterial infections, which is a major problem for animal and public health. Bacterial conjugation is the primary route of AR gene transfer in the mammalian gastrointestinal tract. Significant gaps in knowledge about which gastrointestinal communities and host factors promote plasmid transfer remain. Here, we used Salmonella enterica serovar Kentucky strain CVM29188 carrying plasmid pCVM29188_146 (harboring streptomycin and tetracycline resistance genes) to assess plasmid transfer to Escherichia coli under in vitro conditions and in various mouse strains with a conventional or defined microbiota. As an initial test, the transfer of pCVM29188_146 to the E. coli strains was confirmed in vitro Colonization resistance and, therefore, a lack of plasmid transfer were found in wild-type mice harboring a conventional microbiota. Thus, mice harboring the altered Schaedler flora (ASF), or ASF mice, were used to probe for host factors in the context of a defined microbiota. To assess the influence of inflammation on plasmid transfer, we compared interleukin-10 gene-deficient 129S6/SvEv ASF mice (proinflammatory environment) to wild-type 129S6/SvEv ASF mice and found no difference in transconjugant yields. In contrast, the mouse strain influenced plasmid transfer, as C3H/HeN ASF mice had significantly lower levels of transconjugants than 129S6/SvEv ASF mice. Although gastrointestinal members were identical between the ASF mouse strains, a few differences from C3H/HeN ASF mice were detected, with C3H/HeN ASF mice having significantly lower abundances of ASF members 356 (Clostridium sp.), 492 (Eubacterium plexicaudatum), and 502 (Clostridium sp.) than 129S6/SvEv ASF mice. Overall, we demonstrate that microbiota complexity and mouse genetic background influence in vivo plasmid transfer.IMPORTANCE Antibiotic resistance is a threat to public health. Many clinically relevant antibiotic resistance genes are carried on plasmids that can be transferred to other bacterial members in the gastrointestinal tract. The current study used a murine model to study the transfer of a large antibiotic resistance plasmid from a foodborne Salmonella strain to a gut commensal E. coli strain in the gastrointestinal tract. We found that different mouse genetic backgrounds and a different diversity of microbial communities influenced the level of Escherichia coli that acquired the plasmid in the gastrointestinal tract. This study suggests that the complexity of the microbial community and host genetics influence plasmid transfer from donor to recipient bacteria.

Altered laryngeal morphology in Period1 deficient mice.

BACKGROUND: Ultrasonic vocalizations (USV) of mice are produced in and emitted by the larynx. However, which anatomical elements of the mouse larynx are involved and to which aspects of USV they contribute is not clear. Frequency and amplitude parameters of mice, deficient in the clock gene Period1 (mPer1-/- mice) are distinguishably different compared to C3H wildtype (WT) controls. Because structural differences in the larynx may be a reason for the different USV observed, we analyzed laryngeal anatomy of mPer1-/- mice and WT control animals using micro-computed-tomography and stereology. RESULTS: In mPer1-/- mice, we found laryngeal cartilages to be normally arranged, and the thyroid, arytenoid and epiglottal cartilages were similar in diameter and volume measurements, compared to WT mice. However, in the cricoid cartilage, a significant difference in the dorso-ventral diameter and volume was evident. CONCLUSION: Our findings imply that laryngeal morphology is affected by inactivation of the clock gene Period1 in mice, which may contribute to their abnormal USV.

Quantitative trait locus analysis of carotid atherosclerosis in an intercross between C57BL/6 and C3H apolipoprotein E-deficient mice.

BACKGROUND AND PURPOSE: Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in atherosclerotic lesion formation in the carotid arteries on the apolipoprotein E-deficient (apoE(-/-)) background when fed a Western diet. Quantitative trait locus analysis was performed on an intercross between B6.apoE(-/-) and C3H.apoE(-/-) mice to determine genetic factors contributing to variation in the phenotype. METHODS: Female B6.apoE(-/-) mice were crossed with male C3H.apoE(-/-) mice to generate F(1) hybrids, which were intercrossed to generate 241 female F(2) progeny. At 6 weeks of age, F(2) mice were started on a Western diet. After being fed the diet for 12 weeks, F(2) mice were analyzed for phenotypes such as lesion size in the left carotid arteries and plasma lipid levels and typed for 154 genetic markers spanning the mouse genome. RESULTS: One significant quantitative trait locus, named CAth1 (25 cM, log of the odds score: 4.5), on chromosome 12 and 4 suggestive quantitative trait loci, on chromosomes 1, 5, 6, and 11, respectively, were identified to influence carotid lesion size. One significant quantitative trait locus on distal chromosome 1 accounted for major variations in plasma low-density lipoprotein/very-low-density lipoprotein, high-density lipoprotein cholesterol, and triglyceride levels. Carotid lesion size was not significantly correlated with plasma low-density lipoprotein/very-low-density lipoprotein or high-density lipoprotein cholesterol levels. CONCLUSIONS: These data indicate that the loci for carotid lesions do not overlap with those for aortic lesions as identified in a previous cross derived from the same parental strains, and carotid atherosclerosis and plasma lipids are controlled by separate genetic factors in the B6 and C3H mouse model.

Mapping, genetic isolation, and characterization of genetic loci that determine resistance to atherosclerosis in C3H mice.

OBJECTIVE: C3H/HeJ (C3H) mice are extremely resistant to atherosclerosis. To identify the genetic factors involved in lesion initiation, we studied a cross between C3H and the susceptible strain C57BL/6J (B6) on a hyperlipidemic (apolipoprotein E-null) background. METHODS AND RESULTS: Whereas a previous cross in mice fed a Western diet for 16 weeks revealed a very complex inheritance pattern with many significant lesion QTLs, the present cross, on a chow diet, revealed a single major locus on chromosome 9 (lod=5.0, Ath29*), and a suggestive locus on chromosome 4 (lod=2.6, Ath8). QTLs for plasma HDL, total cholesterol, and triglyceride levels were found on chromosome 1 over the ApoA2 gene. Neither of the lesion QTLs were associated with differences in plasma lipid levels or other systemic risk factors, consistent with the concept that genetic factors affecting cellular functions of the vessel wall are important determinants of atherosclerosis susceptibility. We generated a congenic strain for Ath29 and confirmed its contribution to lesion development. Toll-like receptor 4 (Tlr4), the lipopolysaccharide (LPS) receptor, is located in the Ath8 region and is known to be defective in C3H/HeJ mice. We constructed a congenic strain carrying a normal Tlr4 gene on the C3H Apoe-null background and found that the defective Tlr4 does not contribute significantly to lesion resistance during early lesion development. CONCLUSIONS: We identified one major QTL on chromosome 9, Ath29, for early lesion development in the BXH ApoE(-/-) cross fed on a chow diet and confirmed its contribution in congenic mice. We have also determined that Tlr4 on the C3H ApoE(-/-) background does not contribute to early lesion development. *Ath29 is referred to as Ath22 in Su et al 2006.

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.

Involvement of the tyrosinase gene in the deposition of cardiac lipofuscin in mice. Association with aortic fatty streak development.

Lipofuscin pigment, a terminal oxidation product, accumulates within cells during the normal aging process and under certain pathological conditions. We have analyzed a genetic cross between two inbred mouse strains, BALB/cJ and a subline of C57BL/6J, which differ in lipofuscin deposition. A comparison of the segregation pattern of cardiac lipofuscin with the albino locus (c) on mouse chromosome 7 revealed complete concordance. Analysis of spontaneous mutants of the tyrosinase gene, encoded by the albino locus, confirmed that the tyrosinase gene itself controls lipofuscin formation. Genetic analysis of other strains indicated that one or more additional genes cab contribute to the inheritance of lipofuscin. We also present evidence for an association between cardiac lipofuscin deposition and aortic fatty streak development in the mouse.

Cloned mouse DNA fragments can replicate in a simian virus 40 T antigen-dependent system in vivo and in vitro.

Mouse liver DNA was cut out with BamHI and cloned into YIp5, which contained the URA3 gene of Saccharomyces cerevisiae in pBR322. Of the several plasmids isolated, two plasmids, pMU65 and pMU111, could transform S. cerevisiae from the URA- to the URA+ phenotype and could replicate autonomously within the transformant, indicating that mouse DNA fragments present in pMU65 or pMU111 contain autonomously replicating sequences (ARS) for replication in S. cerevisiae. Furthermore, to determine the correlation between ARS function in yeast cells and that in much higher organisms, we tried to challenge these plasmids with the simian virus 40 (SV40) DNA replication system. Of the two plasmids tested, the EcoRI-BglII region of pMU65 could be hybridized with a chemically synthesized 13-nucleotide fragment corresponding to the origin region of SV40 DNA. Both pMU65 (the EcoRI-BglII region cloned in pBR322) and its subclone pMU65EB could replicate semiconservatively, and initiation of DNA replication started from the EcoRI-BglII region when the replicating activity of these plasmids was tested in the in vitro SV40 DNA replication system we have established before. Furthermore, pMU65 and pMU65EB could replicate autonomously within monkey Cos cells which produce SV40 T antigen constitutively. These results show that a 2.5-kilobase fragment of the EcoRI-BglII region in pMU65 contains the ARS needed for replication in the SV40 DNA replication system.

Mapping of jog locus to the region between D6Mit104 and D6Mit336 on mouse chromosome 6.

The joggle mouse is a recessive ataxic mutant carrying an unknown mutation in a C3H/He (C3H)-derived chromosomal segment. Taking advantage of the mouse genome database, we selected 127 DNA microsatellite markers showing heterozygosity between C3H and C57BL/6J (B6) and a first round of screening for the joggle mutation was performed on B6-jog/+ partial congenic mice (N4). We identified 4 chromosomal regions in which 13 microsatellite markers show heterozygosity between C3H and B6. Then, we analyzed the genotype of these 4 chromosomal regions in mice that showed the joggle phenotype and mapped the jog locus between markers D6Mit104 (111.4 Mb) and D6Mit336 (125.1 Mb) (an interval of 13.7 Mb) on chromosome 6. By using a partial congenic strain together with the mouse genome database, we successfully mapped the chromosomal localization of the jog locus much more efficiently than by conventional linkage analysis.

Mouse strain-specific differences in vascular wall gene expression and their relationship to vascular disease.

OBJECTIVE: Different strains of inbred mice exhibit different susceptibility to the development of atherosclerosis. The C3H/HeJ and C57Bl/6 mice have been used in several studies aimed at understanding the genetic basis of atherosclerosis. Under controlled environmental conditions, variations in susceptibility to atherosclerosis reflect differences in genetic makeup, and these differences must be reflected in gene expression patterns that are temporally related to the development of disease. In this study, we sought to identify the genetic pathways that are differentially activated in the aortas of these mice. METHODS AND RESULTS: We performed genome-wide transcriptional profiling of aortas from C3H/HeJ and C57Bl/6 mice. Differences in gene expression were identified at baseline as well as during normal aging and longitudinal exposure to high-fat diet. The significance of these genes to the development of atherosclerosis was evaluated by observing their temporal pattern of expression in the well-studied apolipoprotein E model of atherosclerosis. CONCLUSIONS: Gene expression differences between the 2 strains suggest that aortas of C57Bl/6 mice have a higher genetic propensity to develop inflammation in response to appropriate atherogenic stimuli. This study expands the repertoire of factors in known disease-related signaling pathways and identifies novel candidate genes for future study. To gain insights into the molecular pathways that are differentially activated in strains of mice with varied susceptibility to atherosclerosis, we performed comprehensive transcriptional profiling of their vascular wall. Genes identified through these studies expand the repertoire of factors in disease-related signaling pathways and identify novel candidate genes in atherosclerosis.

Mammary tumors, hepatocellular carcinomas, and pancreatic islet changes in C3H-Avy Mice.

Studies of tumor incidence and assorted lesions found in 187 C3H-Avy mice throughout their natural life-spans revealed the following: Hepatocellular carcinomas occurred in 54.3% of males, mammary carcinomas in 95% of females, pancreatic islet cell adenomas in 9.4% of males and in no females, and pancreatic islet cell hyperplasia in 41% of males and 23% of fefemales. Islet cell hyperplasia and adenomas appeared to consist predominantly of alpha and delta cells. Multiple tumors, or hyperplasia, or both, of a single site or of multiple sites occurred as frequently in males as they did in females--49.6% and 51.7% respectively. The most frequent neoplasms were hepatocellular carcinomas and islet cell tumors or hyperplasia in males (45.7%) and multiple mammary tumors in females (30%). Heretofore unreported tumors found in this strain of mouse were 12 islet cell adenomas, 2 spindle cell tumors of the meninges and olfactory lobes, a squamous cell carcinoma of the nasal turbinates, and a schwannoma of the spermatic cord.

Malignant transformation of a cloned, nontumorigenic mouse epidermal keratinocyte cell line, MSK-C3H-NU, by 7,12-dimethylbenz(a)anthracene.

MSK-C3H-NU, a cloned mouse epidermal keratinocyte cell line, was established from the epidermis of C3H/HeN mammary tumor virus-positive nude mice. Although it has lost its diploid chromosome number, the cell line is nontumorigenic, has been stable during serial subcultivations for over 2 years, and has retained some differentiated biological characteristics of normal keratinocytes. MSK-C3H-NU cells were cultured in growth medium containing 7,12-dimethylbenz(a)anthracene. After 2 months, colonies exhibited marked changes in cell morphology, cell arrangement, and keratinization pattern that appeared. The transformation frequency per 10(5) survivors in 7,12-dimethylbenz(a)anthracene-treated (10, 100, and 500 ng/ml) subgroups was 0, 119, and 1370 for Experiment I and 3.9, 238, and 2500 for Experiment II, respectively. Most of these transformed cells became malignant and formed tumors in nude mice. Histologically, the tumors were well-differentiated, keratinizing, squamous cell carcinomas showing papillary growths. In 7,12-dimethylbenz(a)anthracene-treated subgroups, cells from colonies that retained the original morphological characteristics did not form tumors in animals, and in control groups, no cell population showed tumorigenicity. In the MSK-C3H-NU cell system, the morphological alterations seem to be strongly associated with malignant conversion.

Genetic knockout of the α7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation in a background strain-dependent manner.

Reduced α7 nicotinic acetylcholine receptor (nAChR) function is linked to impaired hippocampal-dependent sensory processing and learning and memory in schizophrenia. While knockout of the Chrna7 gene encoding the α7nAChR on a C57/Bl6 background results in changes in cognitive measures, prior studies found little impact on hippocampal synaptic plasticity in these mice. However, schizophrenia is a multi-genic disorder where complex interactions between specific genetic mutations and overall genetic background may play a prominent role in determining phenotypic penetrance. Thus, we compared the consequences of knocking out the α7nAChR on synaptic plasticity in C57/Bl6 and C3H mice, which differ in their basal α7nAChR expression levels. Homozygous α7 deletion in C3H mice, which normally express higher α7nAChR levels, resulted in impaired long-term potentiation (LTP) at hippocampal CA1 synapses, while C3H α7 heterozygous mice maintained robust LTP. In contrast, homozygous α7 deletion in C57 mice, which normally express lower α7nAChR levels, did not alter LTP, as had been previously reported for this strain. Thus, the threshold of Chrna7 expression required for LTP may be different in the two strains. Measurements of auditory gating, a hippocampal-dependent behavioral paradigm used to identify schizophrenia-associated sensory processing deficits, was abnormal in C3H α7 knockout mice confirming that auditory gating also requires α7nAChR expression. Our studies highlight the importance of genetic background on the regulation of synaptic plasticity and could be relevant for understanding genetic and cognitive heterogeneity in human studies of α7nAChR dysfunction in mental disorders.

Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis.

Liver disease progression is modulated by genetic modifiers in mouse strains and across human races and ethnicities. We hypothesized that hepatocyte culture duration and genetic background regulate hepatocyte susceptibility to apoptosis. Hepatocytes were isolated from FVB/N, C57BL/6, and C3H/He mice and cultured or treated with Fas ligand or acetaminophen after different culture times. Protein and mRNA expressions of Fas receptor, caspases-3/7/8, and Bak/Bax/Bid proteins were determined. FVB/N hepatocytes manifested rapid decreases of caspases-3/7 but not caspase-8 as culture time increased, which paralleled decreased susceptibility to apoptosis. Some changes were also found in Fas-receptor and Bak, Bax, and Bid proteins; caspase mRNA decreases were also noted. Caspase protein degradation was partially reversed by lysosomal protease but not proteasome or autophagy inhibitors. C57BL/6 and FVB/N hepatocytes behaved similarly in their limited susceptibility to apoptosis, whereas C3H/He hepatocytes show limited alterations in caspases, with consequent increased susceptibility to apoptosis. Similarly, C3H/He mice were more susceptible than C57BL/6 and FVB/N mice to Fas-mediated liver injury. Therefore there are significant mouse strain-dependent differences in susceptibility to apoptosis and selective loss of caspases upon short-term hepatocyte culture, with consequent decrease in susceptibility to apoptosis. These differences likely reflect genetic modifiers that provide resistance or predisposition to hepatocyte death.

Genetic control of pathogenesis of diabetes in C3H mice. Influence of the major histocompatibility complex.

Inbred strains of genetically diabetic (db/db) male mice with H-2b haplotype were heretofore found resistant to the diabetogenic action of the db mutation, whereas C3HeB/FeJ-db/db males with H-2k haplotype were susceptible. To determine whether the major histocompatibility complex was linked to diabetes predisposition, we mated C3H.SW/SnJ females (H-2b haplotype) with C3HeB/FeJ- +/db males, identified the +/db heterozygotes in the F1 generation (all H-2b/H-2k), and intercrossed these to produce F2 db/db male offspring that were classed and studied according to the three segregating H-2 genotypes. We found an accelerated diabetes pathogenesis in terms of early onset of severe hyperglycemia, destruction of pancreatic beta cells, and mortality that was not linked to H-2. Of 9 F2 male diabetics with H-2b/H-2b genotype, 14 with H-2b/H-2k genotype, and 5 with H-2k/H-2k genotype, all showed a more severe syndrome than did the grandparental-type C3HeB/FeJ-db/db males. We conclude that on the C3H inbred background, the major histocompatibility complex is not a major background modifier of the diabetes syndrome. The complexity of the results suggests residual non-H-2-related genetic variance between the two grandparental C3H stocks, with C3H.SW/SnJ females possessing diabetes susceptibility factors apparently lacking in C3HeB/FeJ (a stock bred to be free of the milk-borne mouse mammary tumor virus). Since C3H.SW/SnJ females transmitted to F2 males unknown diabetogenic factor(s) that did not appear to segregate, inheritance of a virus was suggested.(ABSTRACT TRUNCATED AT 250 WORDS)