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PubMed2006

Mapping cis-acting regulatory variation in recombinant congenic strains.

We present an integrated approach for the enriched detection of genes subject to cis-acting variation in the mouse genome. Gene expression profiling was performed with lung tissue from a panel of recombinant congenic strains (RCS) derived from A/J and C57BL/6J inbred mouse strains. A multiple-regression model measuring the association between gene expression level, donor strain of origin (DSO), and predominant strain background identified over 1,500 genes (P < 0.05) whose expression profiles differed according to the DSO. This model also identified over 1,200 genes whose expression showed dependence on background (P < 0.05), indicating the influence of background genetic context on transcription levels. Sequences obtained from 1-kb segments of 3'-untranslated regions identified single nucleotide polymorphisms in 64% of genes whose expression levels correlated with DSO status, compared with 29% of genes that displayed no association (P < 0.01, Fisher exact test). Allelic imbalance was identified in 50% of genes positive for expression-DSO association, compared with 22% of negative genes (P < 0.05, Fisher exact test). Together, these results demonstrate the utility of RCS mice for identifying the roles of proximal genetic determinants and background genetic context in determining gene expression levels. We propose the use of this integrated experimental approach in multiple tissues from this and other RCS panels as a means for genome-wide cataloging of genetic regulatory mechanisms in laboratory strains of mice.

Allelic Imbalance↗
PubMed2004

Host genetics and tumour metastasis.

Metastasis, the spread and growth of tumours at secondary sites, is an extremely important clinical event, since a majority of cancer mortality is associated with the metastatic tumours, rather than the primary tumour. In spite of the importance of metastasis in the clinical setting, the actual process is extremely inefficient. Millions of tumour cells can be shed into the vasculature daily; yet, few secondary tumours are formed. The classical hypothesis explaining the inefficiency was a series of secondary events occurring in the tumour, resulting in a small subpopulation of cells capable of completing all of the steps required to successfully colonise a distant site. However, recent discoveries demonstrating the ability to predict metastatic propensity from gene expression profiles in bulk tumour tissue are not consistent with only a small subpopulation of cells in the primary tumour acquiring metastatic ability, suggesting that metastatic ability might be pre-programmed in tumours by the initiating oncogenic mutations. Data supporting both of these seemingly incompatible theories exist. Therefore, to reconcile the observed results, additional variables need to be added to the model of metastatic inefficiency. One possible variable that might explain the discrepancies is genetic background effects. Studies have demonstrated that the genetic background on which a tumour arises on can have significant affects on the ability of the tumour to metastasise and on gene expression profiles. Thus, the observations could be reconciled by combining the theories, with genetic background influencing both metastatic efficiency and predictive gene expression profiles, upon which, subsequently, metastasis-promoting mutational and epigenetic events occur. If the genetic background is an important determinant of metastatic efficiency, it would have significant implications for the clinical prediction and treatment of metastatic disease, as well as for the design of potential prevention strategies.

Animals↗
PubMedDate not supplied

Perspectives on the role of viruses in insulin-dependent diabetes.

Insulin-dependent diabetes mellitus (IDDM) results from the destruction of pancreatic beta cells. Viruses have been suggested as one of the possible causes. The evidence for viruses comes largely from experiments in animals, but several studies in humans also point to viruses as a trigger of this disease in some cases. Encephalomyocarditis (EMC) virus, Mengovirus (2T), and Coxsackie B4 virus infect and destroy pancreatic beta cells when inoculated into mice. This results in hypoinsulinemia and hyperglycemia. The development of EMC virus-induced diabetes is dependent on the genetic background of the host and genetic makeup of the virus. Animals with diabetes for several months show some long-term complications, including glomerulosclerosis, ocular changes, and decreased bone formation and mineralization in addition to acute metabolic changes. EMC virus-induced diabetes can be prevented by a live-attenuated vaccine. The capacity of Coxsackie B4 virus to induce diabetes is also influenced by the genetic background of the host. However, Mengovirus-induced diabetes is not dependent on the genetic background of the host. In contrast to the EMC, Mengo, and Coxsackie B4 viruses, reovirus type 1 seems to be somehow associated with an autoimmune response producing a diabetes-like syndrome in suckling mice. This virus produces an autoimmune polyendocrinopathy that results in very mild and transient glucose intolerance. Several common human viruses including mumps, Coxsackie B3 and B4 viruses, and reovirus type 3 can infect human beta cells in culture and destroy them. A variant of Coxsackie B4 virus has been isolated from the pancreas of a child who died of acute-onset IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Resistance and susceptibility to pulmonary metastasis of Lewis lung carcinoma in different mouse strains.

The ability of the highly metastatic 3LL tumor of C57Bl/6 (H-2b) origin to form pulmonary metastases after an intramuscular transplantation was investigated in various allogeneic mouse strains. Metastatic proliferation was observed in all tested strains of B10 genetic background. In mice of A genetic background, metastases formation was reduced and a strong resistance to metastatic progression seemed to require the association of the A genetic background with the H-2f haplotype (A.CA strain). Determination of 3H-TdR uptake in the lungs of C57Bl/6 and A.CA mice bearing large local tumors confirmed these results. The development of lung tumor nodules following an intravenous injection of 3LL tumor cells was also different in these two strains. Thus, A.CA strain appears as a useful model system for studies of mechanisms involved in metastases formation.

Animals↗
PubMed2005

MHC odours are not required or sufficient for recognition of individual scent owners.

To provide information about specific depositors, scent marks need to encode a stable signal of individual ownership. The highly polymorphic major histocompatibility complex (MHC) influences scents and contributes to the recognition of close kin and avoidance of inbreeding when MHC haplotypes are shared. MHC diversity between individuals has also been proposed as a primary source of scents used in individual recognition. We tested this in the context of scent owner recognition among male mice, which scent mark their territories and countermark scents from other males. We examined responses towards urine scent according to the scent owner's genetic difference to the territory owner (MHC, genetic background, both and neither) or genetic match to a familiar neighbour. While urine of a different genetic background from the subject always stimulated greater scent marking than own, regardless of familiarity, MHC-associated odours were neither necessary nor sufficient for scent owner recognition and failed to stimulate countermarking. Urine of a different MHC type to the subject stimulated increased investigation only when this matched both the MHC and genetic background of a familiar neighbour. We propose an associative model of scent owner recognition in which volatile scent profiles, contributed by both fixed genetic and varying non-genetic factors, are learnt in association with a stable involatile ownership signal provided by other highly polymorphic urine components.

Animals↗
PubMed1999

Analysis of background-dependent genetic interactions without inbred strains.

Experimental analysis of background dependent effects of genetic interactions can be designed using strains generated by introgression of small genetic regions containing identical genotypes at loci in question into different inbred strains. We use a novel multilocus paradigm, denoted conditional intergenic functional association (CIFA), to simulate this procedure, with the trade-off of power for convenience that is affordable when sufficiently strong effects are present. We analyze nine enzyme loci at three chromosomes in groups of D. melanogaster with different developmental rates that showed similar allelic frequencies at individual loci. Results obtained suggest the presence of adaptive interaction between particular alleles at two loci when genetic variation at seven background loci is eliminated. Biochemical considerations show that, in the resulting developmental context, strong interaction between these genes may emerge from shifted control of the pentose phosphate pathway, with cascading effects on the glycolysis, TCA cycle, and biosynthetic pathways: one gene may assume control of the irreversible rate-limiting step in the pentose phosphate pathway, whereas the other gene may assume control of the NADP+ level that regulates the same rate-limiting step as an electron acceptor. The newly developing functional genomics research and the absence of inbreeding make CIFA directly applicable to complex human traits in large samples.

Animals↗
PubMed1998

Instability at the k2 Mdh1-n y20 chromosomal region in soybean.

Ten mutants have been reported at the k2 (tan saddle seed coat) Mdh1-n (mitochondrial malate dehydrogenase 1 null) y20 (yellow foliage) chromosomal region in soybean [Glycine max (L.) Merr.]. The precise genetic mechanism(s) responsible for generating these mutants is (are) not known. The objective of this study was to determine whether chromosomal instability exists at this region. We introduced the w4-m and Y18-m mutable systems into the three independent sources of tan saddle seed coat mutants, T239 (k2), T261 (k2 Mdh1-n), and L67-3483 (k2). A total of 12 bright yellow mutants were isolated with tan saddle seed coat, malate dehydrogenase 1 null phenotypes. Of these, 11 were found in 11 F2 mutant families out of a total of 977 derived by crossing T239 (k2), T261 (k2 Mdh1-n), and L67-3483 (k2) with six lines suspected to contain active transposable elements. One was found in the F3 generation derived from the cross A1937 x T239 (k2). Of the 11 F2 mutant families, 10 (out of a total of 381 F2 families) were associated with the T239 (k2) genetic background, and one out of 323 was associated with the T261 (k2 Mdh1-n) genetic background. But no mutation events were found among the 273 families with the L67-3483 (k2) genetic background. Allelism and inheritance studies indicated that these 12 bright yellow mutants were new mutants in the k2 Mdh1-n y20 chromosomal region. Thus, on introducing the w4-m and Y18-m mutable systems into T239 (k2) and T261 (k2 Mdh1-n) genetic backgrounds, chromosomal instability was induced in this region. In addition, 21 greenish yellow mutants were identified in the total of 977 F2 families. All 21 greenish yellow mutants were associated with the T239 (k2) genetic background. The mutations for greenish yellow foliage affected foliage color only at the seedling stage. Cosegregation of the tan saddle seed coat character with greenish yellow foliage were observed for these 21 greenish yellow mutants, suggesting that the greenish yellow phenotype may be due to a pleiotropic effect of the k2 allele in T239 or to chromosomal rearrangements at or near the k2 allele in T239. Finally, we believe that the genetic mechanism responsible for this high frequency of instability at the k2 Mdh1-n y20 chromosomal region involves receptor element activities present at this chromosomal region, which may contain complex chromosomal rearrangements in T239 and T261.

Chromosome Breakage↗
PubMed2005

Modifier genes play a significant role in the phenotypic expression of PKD1.

BACKGROUND: Polycystic kidney disease type 1 (PKD1) is characterized by extreme variation in the severity and progression of renal and extrarenal phenotypes. There are significant familial phenotype differences; but it is not clear if this is due to differences in PKD1 mutations, differences in genetic background, or both. METHODS: A total of 315 affected relatives (83 PKD1 families) without end-stage renal disease (ESRD) were evaluated for disease markers, including renal volume, creatinine clearance, proteinuria, liver cysts, and hypertension. Of these patients, 19% progressed to ESRD within 1 to 10 years after the initial examination. Nested analysis of variance was used to investigate interfamilial and intrafamilial differences in these phenotypes. Heritability analyses were used to estimate the effect of the genetic background on phenotypic variability. The age of onset of ESRD was also analyzed with an additional 389 family members from the same PKD1 families without clinical evaluation but with data on age of onset of ESRD (or age without ESRD). RESULTS: There were significant phenotype differences between patients with the same mutation and different genetic backgrounds. The phenotypic variation between patients with different mutations and different genetic backgrounds was not significantly greater than the variation between patients with the same mutation and different genetic backgrounds. However, when the 389 family members were included, both the mutation and modifier genes had significant effects on the age of onset of ESRD. Inherited differences in genetic background were estimated to account for 18% to 59% of the phenotypic variability in PKD1 disease markers in patients prior to ESRD and in the subsequent progression to ESRD (43% heritability) in the 315 patients who were clinically evaluated. CONCLUSION: Modifier loci in the genetic background are important factors in inter- and intrafamilial variability in the phenotypic expression of PKD1. The extreme intrafamilial phenotype differences are consistent with the hypothesis that one or a few modifier genes have a major effect on the progression and severity of PKD1.

Adult↗
PubMed2003

Genetic aspects of susceptibility to air pollution.

Inter-individual variation in human responses to air pollutants suggests that some subpopulations are at increased risk, and it is increasingly clear that genetic background is an important susceptibility factor. Genetically standardised animal models provide useful investigative tools. Linkage analyses using inbred mice identified chromosomal segments (quantitative trait loci (QTL)), with genes controlling susceptibility to the lung inflammatory (chromosome 17), injury (chromosome 11), and hyperpermeability (chromosome 4) responses to ozone (O3) exposure. An immune dysfunction response induced by exposure to sulphate-associated particles is linked to the identical chromosome 17 and 11 QTLs described for O3 susceptibility, thus similar genetic mechanisms may be controlling pulmonary responses to these pollutants. Candidate genes within the QTLs on chromosomes 4 and 17 include the toll-like receptor 4 and the pro-inflammatory cytokine, tumour necrosis factor-alpha, respectively. Functional analyses strongly support a role for these candidate genes in determining susceptibility to O3 and particulates. Because striking linkage homology exists between the human and mouse genomes, candidate susceptibility genes identified in the mouse are likely to aid research aimed at understanding human genetic factors that contribute to differential susceptibility. To date, no studies have examined the interaction between age and genetic background in the development of air pollution-induced lung disease. However, investigations have suggested an influence of age on genetic susceptibility to lung cancer and other diseases, which indicate that an interaction between age and genetic background may be important in air pollution disease pathogenesis.

Age Factors↗
PubMed2005

Age-specific changes in epistatic effects on mortality rate in Drosophila melanogaster.

Models for the evolution of senescence assume that genes with age-specific effects act independently of one another. Although recent empirical data show that longevity is influenced in part by interactions between genes, there are currently few data on whether epistasis influences age-specific components of mortality. To gauge if and how interactions affect age-specific traits, we incorporated the Drosophila visible marker mutations ebony, forked, and purple into seven wild-caught strains of D. melanogaster to examine gene x genetic background interactions. We found significant natural genetic variation for longevity and baseline mortality rates. Gene x genetic background interactions were prevalent not only for longevity but also for baseline mortality rates and age-specific mortality rates. We conclude that gene x genetic background epistasis is prevalent for aging-related traits and could play a significant role in the evolution of aging. These results suggest that future genetic models for the evolution of aging should incorporate the effects of epistasis.

Age Factors↗
PubMed2006

Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure.

Although the identification of specific genes that regulate apoptosis has been a topic of intense study, little is known of the role that background genetic variance plays in modulating cell death. Using germ cells from inbred mouse strains, we found that apoptosis in mature (metaphase II) oocytes is affected by genetic background through at least two different mechanisms. The first, manifested in AKR/J mice, results in genomic instability. This is reflected by numerous DNA double-strand breaks in freshly isolated oocytes, causing a high apoptosis susceptibility and impaired embryonic development following fertilization. Microinjection of Rad51 reduces DNA damage, suppresses apoptosis and improves embryonic development. The second, manifested in FVB mice, results in dramatic dimorphisms in mitochondrial ultrastructure. This is correlated with cytochrome c release and a high apoptosis susceptibility, the latter of which is suppressed by pyruvate treatment, Smac/DIABLO deficiency, or microinjection of 'normal' mitochondria. Therefore, background genetic variance can profoundly affect apoptosis in female germ cells by disrupting both genomic DNA and mitochondrial integrity.

Animals↗
PubMed2004

A rational treatment of Mendelian genetics.

BACKGROUND: The key to a rational treatment of elementary Mendelian genetics, specifically to an understanding of the origin of dominant and recessive traits, lies in the facts that: (1) alleles of genes encode polypeptides; (2) most polypeptides are catalysts, i.e. enzymes or translocators; (3) the molecular components of all traits in all cells are the products of systems of enzymes, i.e. of fluxing metabolic pathways; (4) any flux to the molecular components of a trait responds non-linearly (non-additively) to graded mutations in the activity of any one of the enzymes at a catalytic locus in a metabolic system; (5) as the flux responds to graded changes in the activity of an enzyme, the concentrations of the molecular components of a trait also change. CONCLUSIONS: It is then possible to account rationally, and without misrepresenting Mendel, for: the origin of dominant and recessive traits; the occurrence of Mendel's 3(dominant):1(recessive) trait ratio; deviations from this ratio; the absence of dominant and recessive traits in some circumstances, the occurrence of a blending of traits in others; the frequent occurrence of pleiotropy and epistasis.

Genes, Dominant↗
PubMed1996

MHC-associated and MHC-independent urinary chemosignals in mice.

The chemosensory identity of mice, rats, and humans is determined partly by polymorphic genes of the major histocompatibility complex (MHC). In inbred strains of mice as well as in seminatural populations MHC-associated mating preferences selectively influence reproductive success. To explore MHC-associated chemosignals in relation to otherwise genetically determined chemosignals a first study was conducted on seven trained rats' responses to the odors of inbred strains of mice. Results of the first study confirmed that neither the MHC nor genes in the genetic background dominate in determining urine odor specificity of mice and that specific olfactory cues associated with either the MHC or the genetic background can be identified by olfaction. In a second study, these specific olfactory cues were analyzed by means of gas chromatography. The results indicate that specific volatile components associated with either the MHC or the genetic background can be found in mouse urine odor, and that profiles of ubiquitous volatile components show some association with either the MHC or the genetic background. Furthermore, results show that a small number of specific compounds as well as a profile of some few ubiquitous volatiles constitute MHC-associated odor cues and that influences of the MHC and genes in the genetic background interact in constituting urine odor specificity in mice.

Animals↗
PubMed2004

[Applications of congenic strains in the mouse].

The sequencing of the human and the mouse genomes has shown that the chromosomes of these two species contain approximately 30,000 genes. The biological systems that can be studied in an individual or in a tissue result from complex interactions within this multitude of genes. Before describing these interactions, it is necessary to understand the function of each gene. In the mouse, congenic strains are developed to introduce a chromosomal segment in a given inbred genetic background. One can then compare the biological effects of different alleles at the same locus in the same genetic background or the effect of a given allele in different genetic backgrounds. One can also introduce into different congenic strains with the same genetic background genes which control a complex genetic trait, then combine these genes by appropriate crosses to study their interactions. Although the chromosomal segment transferred into a congenic strain usually contains up to several hundreds of genes, molecular markers can be used to reduce this number as well as the number of crosses required for the development of congenic strains.

Animals↗
PubMed2004

Background matters: the effects of estrogen receptor alpha gene disruption on male sexual behavior are modified by background strain.

One approach to study interactions between behavior and genetics is to use inbred mice with different genetic backgrounds. To examine the effect of background on a specific gene, we conducted a series of experiments with a well-characterized knockout (KO) mouse, the estrogen receptor alpha KO (ERalphaKO). The ERalphaKO mouse has so far been examined in one inbred line, C57BL/6J. Here, we examined the behavior of ERalphaKO mice within three different backgrounds mixed with C57BL/6J; DBA/2J, BALB/c, and A/J. First, we assessed masculine sexual behavior in both intact male and testosterone-treated female offspring. More ERalphaKO males in the DBA/2J (5/12) and BALB/c (5/13) backcrosses displayed intromissions and many ejaculated as compared with males in a C57BL/6J and A/J mixed background. Many fewer ERalphaKO females than males displayed masculine sexual behavior in any of the three hybrid crosses. We assessed fertility in males from the C57BL/6J by DBA/2J cross and found that one of 12 ERalphaKO males sired a litter. Several other characteristics of sexual behavior and physiology were unaffected by genetic background in ERalphaKO mice. Our data suggest that genetic background has dramatic effects on male sexual behavior and its dependence on the ERalpha gene.

Analysis of Variance↗
PubMedDate not supplied

Factors affecting cellular mosaicism in the expression of a lacZ transgene in two-cell stage mouse embryos.

In the present study, we have analysed the expression pattern of a lacZ transgene (CMZ12) in preimplantation stage mouse embryos. The transgene is expressed at the two-cell stage, where it shows cellular mosaicism due to variable expressivity. The variable gene expression indicates a partial penetrance of the transgene. The extent of variation in expression is influenced by the genetic background of the oocyte. DBA/2 and CFLP genetic backgrounds promote high expression of the transgene, while Balb/c, C57BL/6, DDK, and F1 (C57BL/6 x CBA) genetic backgrounds give none or very little lacZ activity. In vitro culture of one-cell embryos to the two-cell stage induces the expression of lacZ in all strain backgrounds tested. The variation in CMZ12 expression is a transient phenomenon and does not affect later stage activity of the transgene. Nuclear transfer experiments and DNA methylation analysis suggests that a heritable modification of the transgene locus has not occurred.

Animals↗
PubMed2006

Style-by-style analysis of two sporadic self-compatible Solanum chacoense lines supports a primary role for S-RNases in determining pollen rejection thresholds.

A method for the quantification of S-RNase levels in single styles of self-incompatible Solanum chacoense was developed and applied toward an experimental determination of the S-RNase threshold required for pollen rejection. It was found that, when single style values are averaged, accumulated levels of the S(11)- and S(12)-RNases can differ up to 10-fold within a genotype, while accumulated levels of the S(12)-RNase can differ by over 3-fold when different genotypes are compared. Surprisingly, the amount of S(12)-RNase accumulated in different styles of the same plant can differ by over 20-fold. A low level of 160 ng S-RNase in individual styles of fully incompatible plants, and a high value of 68 ng in a sporadic self-compatible (SSC) line during a bout of complete compatibility was measured, suggesting that these values bracket the threshold level of S-RNase needed for pollen rejection. Remarkably, correlations of S-RNase values to average fruit sets in different plant lines displaying sporadic self-compatibility (SSC) to different extents as well as to fruit set in immature flowers, are all consistent with a threshold value of 80 ng S(12)-RNase. Taken together, these results suggest that S-RNase levels alone are the principal determinant of the incompatibility phenotype. Interestingly, while the S-RNase threshold required for rejection of S(12)-pollen from a given genetic background is the same in styles of different genetic backgrounds, it is different when pollen donors of different genetic backgrounds are used. These results reveal a previously unsuspected level of complexity in the incompatibility reaction.

Flowers↗
PubMed1982

Expression of beta-glucuronidase haplotypes in prototype and congenic mouse strains.

A gene complex consists of a structural gene with its associated regulatory information; together they behave as the functional and evolutionary unit of mammalian chromosomes. The use of congenic lines, in which alternate forms, or haplotypes, of a gene complex are transferred into a common genetic background by repeated backcrossing, provides a means of comparing the regulatory properties of different haplotypes of a gene complex without the complications introduced by extraneous genetic differences. We have now carried out such a study of the A, B, and H haplotypes of the beta-glucuronidase gene complex, [Gus], in mice. These haplotypes were derived from strains A/J, C57BL/6J, and C3H/HeJ and were compared against the C57BL/6J genetic background. Enzyme structure was compared in terms of charge (isoelectric point), stability (rate of thermal denaturation), substrate affinity (for 4 MU glucuronide), and antigenicity (reactivity with a standard antibody). Compared to the B form, the enzyme coded by the A haplotype has a lower isoelectric point, and that coded by the H haplotype is less stable. The decreased stability is the result of a lower activation energy for the thermal denaturation reaction. These differences were maintained in the congenic strains. All three enzyme forms showed identical substrate affinities. Antigenicity per enzyme unit was also identical for all three, indicating that none lacks an antigenic site possessed by the others and that they all possess the same catalytic activity per molecule. The expression of alleles of the Gus-t temporal locus within the gene complex was not affected by transfer into the C57BL/6 genetic background. The same developmental switches in enzyme activity were seen in each case. Transfer into the C57Bl/6 background also did not affect expression of the Gus-r regulator determining androgen inducibility of beta-glucuronidase synthesis in kidney epithelial cells. However, enzyme accumulation in induced cells was altered when the haplotypes were transferred into the C57BL/6 genetic background. Since the rate of synthesis was not affected, it suggests that the genetic differences between strains that are not linked to the [Gus] complex affect the rate of enzyme loss by degradation or secretion. Beta-Glucuronidase in liver is present in both lysosomes and endoplasmic reticulum (microsomes). The relative amount of enzyme at each site depended on both the indentity of the structural allele and the function of unlinked genetic modifiers. Within the C57BL/6 background the percentage of total enzyme present in the microsome fraction was the order A greater than B greater than H. For the H form of the enzyme the percentage was appreciably greater in the C3H genetic background compared to C57BL/6. As expected, then, the [Gus] complex contains all of the genetic determinants of enzyme structure detected by thermal stability and isoelectric point measurements...

Animals↗