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PubMed2006

Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder.

The genetics of schizophrenia has been approached utilizing a variety of methods. One emerging strategy is the use of endophenotypes in order to understand and identify the functional importance of genetically transmitted, brain-based deficits across schizophrenia kindreds. The endophenotype strategy is a topic of this issue of Schizophrenia Bulletin. Endophenotypes are quantitative, heritable, trait-related deficits typically assessed by laboratory-based methods rather than clinical observation. Endophenotypes are seen as closer to genetic variation than are clinical symptoms of schizophrenia, and are therefore closely linked to heritable risk factors. There has been a broad expansion of opportunities available to psychiatric neuroscientists who use the endophenotype strategy to understand the genetic basis of schizophrenia. In this context, genetic variation such as single nucleotide polymorphisms (SNPs) induces abnormalities in endophenotypic domains such as neurocognition, neurodevelopment, metabolism, and neurophysiology. This article discusses the challenges that abound in genetic research of schizophrenia, including issues in ascertainment, epistasis, ethnic diversity, and the potentially normalizing effects of second-generation antipsychotic medications on neurocognitive and neurophysiological measures. Robust strategies for meeting these challenges are discussed in this review and the subsequent articles in this issue. This article summarizes conceptual advances and progress in the measurement and use of endophenotypes in schizophrenia that form the basis of the multisite National Institute of Mental Health Consortium on the Genetics of Schizophrenia. The endophenotype strategy offers powerful and exciting opportunities to understand the genetically conferred neurobiological vulnerabilities and possible new strong inference and molecularly based treatments for schizophrenia.

Antipsychotic Agents↗

PubMed2005

Genetic variation in epigenetic inheritance of ribosomal RNA gene methylation in Arabidopsis.

We investigated the fidelity of epigenetic inheritance in crosses between three accessions of the flowering plant Arabidopsis thaliana (Canary Islands, Cape Verde Islands, and Columbia). Specifically, we examined the cytosine methylation content of the ribosomal RNA genes at the two nucleolus organizer regions (NOR2 and NOR4) in F1 and F2 hybrid individuals derived from reciprocal crosses between the high NOR methylation strain, Columbia, and the two other accessions, both of which have less NOR methylation. In crosses between the Columbia and Cape Verde Islands strains, the cytosine methylation content segregated as an additive Mendelian trait: the high NOR methylation state was tightly associated with the inheritance of the two Columbia-derived NOR loci. First-generation hybrid individuals between the Canary Islands and Columbia strains also showed a cytosine methylation content at the NORs intermediate between the parental values, consistent with the epigenetic inheritance of parental methylation patterns. Interestingly, mapping data from F2 individuals derived from a Canary Islands x Columbia cross revealed that NOR2 accounted for nearly all of the NOR methylation variation segregating in the population. NOR4 retains a significant effect on total NOR methylation content only through a complex epistatic interaction with NOR2. Our results indicate that the inheritance of differential cytosine methylation states at NOR loci can be modified by their genetic context, opening up the possibility of genetic dissection of epigenetic inheritance.

Arabidopsis↗

PubMed1999

Genetic testing in families with hereditary nonpolyposis colon cancer.

CONTEXT: Genetic testing for hereditary nonpolyposis colon cancer (HNPCC) is available, but the rates of acceptance of testing or barriers to participation are not known. OBJECTIVE: To investigate rates and predictors of utilization of genetic testing for HNPCC. DESIGN: Cohort study conducted between July 1996 and July 1998. SETTING: Hereditary nonpolyposis colon cancer family registry. PARTICIPANTS: Adult male and female members (n = 208) of 4 extended HNPCC families contacted for a baseline telephone interview. INTERVENTIONS: Family education and individual genetic counseling. MAIN OUTCOME MEASURE: Participant acceptance of HNPCC test results. RESULTS: Of the 208 family members, 90 (43%) received test results and 118 (57%) declined. Of 139 subjects (67%) who completed a baseline telephone interview, 84 (60%) received test results and 55 (40%) declined. Of the 84 subjects who received test results, 35 (42%) received information indicating that they had HNPCC-associated mutations and 49 (58%) that they did not. Test acceptors had higher education levels (odds ratio [OR], 3.74; 95% confidence interval [CI], 2.49-5.61) and were more likely to have participated in a previous genetic linkage study (OR, 4.30; 95% CI, 1.84-10.10). The presence of depression symptoms significantly reduced rates of HNPCC test use (OR, 0.34; 95% CI, 0.17-0.66). Although rates of test use were identical among men and women, the presence of depression symptoms resulted in a 4-fold decrease in test use among women (OR, 0.25; 95% CI, 0.08-0.80) and a smaller, nonsignificant reduction among men (OR, 0.49; 95% CI, 0.19-1.27). CONCLUSIONS: Despite having significantly elevated risks of developing colon cancer, a relatively small proportion of HNPCC family members are likely to use genetic testing. Barriers to test acceptance may include less formal education and the presence of depression symptoms, especially among women. Additional research is needed to generalize these findings to different clinical settings and racially diverse populations.

Adult↗

PubMedDate not supplied

Analytical resources for assessment of clinical genetics services in public health: current status and future prospects.

CONTEXT: Genetics services are not well integrated into the public health programs of most states, nor has there been effective use of clinical and program databases in the design, evaluation, and monitoring of public health genetics services at the state level. OBJECTIVE: To evaluate the availability and current use of population-based clinical genetics databases, including birth defects surveillance programs, in state-level public health genetics programs. DESIGN: Mail survey to state genetics coordinators in 50 states and 3 territories during 1996 with an update in 1997. RESULTS: Thirty states had birth defects surveillance programs; data from these resources were used in public health genetics program planning and management in only 15 states. Thirty states or territories had clinical genetics services databases. Most states had newborn screening program databases; few linked these records to vital statistics for programmatic purposes. Only 24 states had individual record databases for the Children with Special Health Care Needs program; 8 states had databases for maternal serum alpha-fetoprotein screening, and 7 had statewide cytogenetics registries. CONCLUSION: Population-based databases concerning aspects of public health genetics are largely unavailable at the state level. Where these databases exist, they are poorly integrated into state public health genetics program activities. More attention should be paid to the development and use of clinical data programs for the assessment, monitoring, and assurance of genetics issues with relevance to population health.

Child↗

PubMed1998

Development of a comparative genetic linkage map for Armigeres subalbatus using Aedes aegypti RFLP markers.

One of the causative agents of lympahtic filariasis is the nematode parasite Brugia malayi that requires a competent mosquito vector for its development and transmission. Armigeres subalbatus mosquitoes rapidly destroy invading B. malayi microfilariae via a defense response known as melanotic encapsulation. We have constructed a genetic linkage map for this mosquito species using RFLP markers from Aedes aegypti. This heterologous approach was possible because of the conserved nature of the coding sequences used as markers and provided an experimental framework to evaluate the hypothesis that linkage and gene order are conserved between these mosquito species. Of the 56 Ae. aegypti markers tested, 77% hybridize to genomic DNA digests of Ar. subalbatus under stringent conditions, with 53% of these demonstrating strain-specific polymorphisms. Twenty-six Ae. aegypti markers have been mapped using an F2- segregating Ar. subalbatus population derived from a cross of strains originating in Japan and Malaysia. Linear order of these marker loci is highly conserved between the two species. Only 1 of these markers, LF92, was not linked in the manner predicted by the Ae. aegypti map. In addition, the autosomal sex-determination locus that occurs in linkage group 1 in Ae. aegypti resides in group 3 in Ar. subalbatus. The Ar. subalbatus map provides a basic genetic context that can be utilized in further genetic studies to clarify the genetic basis of parasite resistance in this mosquito and is a necessary precursor to the identification of genome regions that carry genes that determine the encapsulation phenotype. [The composite map and sequence database information for Ae. aegypti markers can be retrieved directly from the Ae. aegypti Genome Database through the World Wide Web: http://klab.agsci.colostate.edu.]

Aedes↗

PubMed2003

Pharmacogenomics of primary hypertension--the lessons from the past to look toward the future.

A number of recent reviews have addressed the issue of the pharmacogenomics of primary hypertension and related complications by considering the data on the genotype-drug response relationship. Here we mainly discuss the methodological aspects of this issue, trying to integrate 'traditional' clinical and experimental pathophysiology and therapy-pharmacology with the 'new' genetics. Such integration is indispensable to: a). define the appropriate 'context' (genetic background, environment, age, gender, phase of hypertension, previous therapy etc.) in which a given genotype-drug response relationship should be tested (it is indeed likely that many discrepancies among published data originate from context's interference); b). assign the correct clinical meaning to the results obtained by statistics and functional genetics methodologies; c). define a novel clinical entity caused by a disease favoring allele, alone or in combination with other alleles, with a consistent clinical picture, prognosis and responsiveness to the appropriate drug; d). estimate the size of the population target amenable to benefit from a therapeutic intervention developed according to the pharmacogenomics' principles; e). develop a novel drug that selectively interferes with the sequence of events triggered by the genetic mechanism(s) underlying the clinical entity. Peculiar to this strategy is to look for consistency among findings gathered from different 'contexts' after having properly accounted for the context's dependency of the results.

Animals↗

PubMed1994

An exact test for neutrality based on the Ewens sampling distribution.

Using the Ewens sampling distribution of selectively neutral alleles in a finite population, it is possible to develop an exact test of neutrality by finding the probability of each configuration with the same sample size and observed number of allelic classes. The exact test provides the probability of obtaining a configuration with the same or smaller probability as the observed configuration under the null hypothesis. The results from the exact test may be quite different from those from the Ewens-Watterson test based on the homozygosity in the sample. The advantages and disadvantages of using an exact test in this and other population genetic contexts are discussed.

Alleles↗

PubMed2006

Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression.

CONTEXT: Genetic moderation of the depression-inducing effects of stressful life events (SLEs) has been reported, but findings suggest that genes may not moderate the effects of SLEs per se but instead may moderate the risk of depression associated with the stable tendency to develop negative emotions in response to minor environmental experiences. OBJECTIVE: To examine whether a functional polymorphism of the serotonin transporter gene (5-HTTLPR) moderates the association between negative affectivity (neuroticism) and depression and to what degree this can explain previous findings involving SLEs. DESIGN: A prospective cohort study involving 1 baseline and 4 follow-up measurements in 15 months analyzing change in self-reported depressive symptoms across time as a function of negatively attributed SLEs, neuroticism, 5-HTTLPR, and their interactions. SETTING: General community. PARTICIPANTS: A population-based sample of 374 ethnically homogeneous young adult female twins. MAIN OUTCOME MEASURE: A continuous score of self-reported depressive symptoms. RESULTS: The depressogenic effect of SLEs in the 3 months before interview was significantly greater in women with 2 short (S) alleles compared with women with 1 or none. However, this effect disappeared after accounting for the effect of SLEs conditional on neuroticism. Similarly, the depressogenic effect of neuroticism was progressively greater with number of S alleles, and this was unchanged after accounting for the effect of neuroticism conditional on SLEs. CONCLUSIONS: Genotype x environment interactions in depression may be more productively interpreted by involving mechanisms more proximal to psychological experience itself. The probability that stress-related cognitive vulnerabilities for depression result in symptom formation may be moderated by a neurobiologic phenotype characterized by altered processing of negative emotions associated with variation in 5-HTTLPR.

Adolescent↗

PubMed1999

Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing.

CONTEXT: Genetic testing for cancer predisposition is evolving from purely research applications to affecting clinical management. OBJECTIVE: To determine how often genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) can be definitively interpreted and used to guide clinical management. DESIGN: Case-series study conducted in 1996 to 1998 in which a complete sequence analysis of hMSH2 and hMLH1 coding sequence and flanking intronic regions was performed. Mutations were categorized as protein truncating and missense. In the case of missense alterations, additional analyses were performed in an effort to assess pathogenicity. SETTING AND PARTICIPANTS: Families were identified by self-referral or health care provider referral to a cancer genetics program. Participants and kindreds were classified into 1 of 4 categories: (1) Amsterdam criteria for HNPCC, (2) modified Amsterdam criteria for HNPCC, (3) young age at onset, or (4) HNPCC-variant. In addition, each proband was classified according to the Bethesda guidelines for identification of individuals with HNPCC. MAIN OUTCOME MEASURE: Alterations of hMSH2 and hMLH1 genes. RESULTS: Twenty-seven alterations of hMSH2 and hMLH1 were found in 24 of 70 families (34.3%). Of these, deleterious mutations that could be used with confidence in clinical management were identified in 25.7% (18/70) of families. The rates of definitive results for families fulfilling Amsterdam criteria, modified Amsterdam criteria, young age at onset, HNPCC-variant, and Bethesda guidelines were 27 (39.3%), 13 (18.2%), 12 (16.7%), 11 (15.8%), and 21 (30.4%), respectively. The prevalence of missense mutations, genetic heterogeneity of the syndrome, and limited availability of validated functional assays present a challenge in the interpretation of genetic test results of HNPCC families. CONCLUSIONS: The identification of pathogenic mutations in a significant subset of families for whom the results may have marked clinical importance makes genetic testing an important option for HNPCC and HNPCC-like kindreds. However, for the majority of individuals in whom sequence analysis of hMSH2 and hMLH1 does not give a definitive result, intensive follow-up is still warranted.

Adaptor Proteins, Signal Transducing↗

PubMed1999

A Btk transgene restores the antiviral TI-2 antibody responses of xid mice in a dose-dependent fashion.

X-linked agammaglobulinemia in humans and X-linked immunodeficiency (xid) in mice are both caused by mutations in Bruton's tyrosine kinase (Btk). Xid mice lack the early T cell-independent type 2 (TI-2) antibody response to polio virus and to a recombinant vaccinia virus (Vacc-IND-G) expressing the neutralizing determinant of vesicular stomatitis virus (VSV). This response could be restored by introduction of one or two copies of a murine Btk cDNA transgene driven by the Ig heavy chain promoter plus enhancer and depended crucially on a sufficient Btk expression level. Introduction of the same transgene into wild-type mice had little to no negative effect. The TI-1 antibody response to VSV and the T cell-dependent response to lymphocytic choriomeningitis virus were comparable in all mice tested. All mice analyzed eventually reached similar primary and memory antibody titers against all viruses independent of the mouse Btk genotype. These studies show that the xid mutation in mice has no dominant negative effect and that a transgene - even when not provided in the natural genetic context - may be able to restore functional defects resulting from genetic mutation.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2003

Behavior of the hobo transposable element with regard to TPE repeats in transgenic lines of Drosophila melanogaster.

The hobo transposable element of Drosophila melanogaster is known to induce a hybrid dysgenesis syndrome. Moreover it displays a polymorphism of a microsatellite in its coding region: TPE repeats. In European populations, surveys of the distribution of hobo elements with regard to TPE repeats revealed that the 5TPE element is distributed along a frequency gradient, and it is even more frequent than the 3TPE element in Western populations. This suggests that the invasive ability of the hobo elements could be related to the number of TPE repeats they contain. To test this hypothesis we monitored the evolution of 16 lines derived from five initial independent transgenic lines bearing the 3TPE element and/or the 5TPE element. Four lines bearing 5TPE elements and four bearing 3TPE elements were used as a noncompetitive genetic background to compare the evolution of the 5TPE element to that of the 3TPE element. Eight lines bearing both elements provided a competitive genetic context to study potential interactions between these two elements. We studied genetic and molecular aspects of the first 20 generations. At the molecular level, we showed that the 5TPE element is able to spread within the genome at least as efficiently as the 3TPE element. Surprisingly, at the genetic level we found that the 5TPE element is less active than the 3TPE element, and moreover may be able to regulate the activity of the 3TPE element. Our findings suggest that the invasive potential of the 5TPE element could be due not only to its intrinsic transposition capacity but also to a regulatory potential.

Animals↗

PubMed1999

Kinetics of the secretion of Bacillus subtilis levanase overproduced during the exponential phase of growth.

The Bacillus subtilis levanase structural gene sacC was expressed under the regulated control of sacR, the inducible levansucrase leader region, in a degU32(Hy) strain. In this genetic context, exocellular levanase is overproduced (0.5% of total protein) during the exponential phase of growth upon induction by sucrose at 37 degrees C and pH 7. No precursor form that comprised a signal peptide was detected in pulse-chase experiments. The subsequent release of the cell-associated processed protein is a slow event (t(1,2) = 80+/-10 s). The unfolding-folding transition of pure levanase monitored in vitro by the resistance to proteolysis was achieved within the same time range (t(1/2) = 50 s) under the same conditions of pH and temperature. Calcium ions, which modulate the rate and the yield of refolding, have a low affinity for the protein. Comparison of these results with those obtained previously with levansucrase and alpha-amylase overproduced in the same genetic and physiological context suggests that the precursor processing is more efficient in levanase and alpha-amylase than in levansucrase. This discrepancy could lie in information borne by the signal peptide sequence of these exoproteins. However, the rate of the ultimate stage of release of these three proteins, which includes the passage through the cell wall, is correlated with the rate of folding and appears to be independent of their molecular size.

Bacillus subtilis↗

PubMed2001

[Individual genetic counseling and collective screening strategies in particular at-risk populations].

Carrier screening for recessive disorders together with prenatal diagnosis offered in at risk pregnancies can achieve efficient prevention of genetic diseases occurring with particularly high frequencies in specific populations. In this context, genetic counseling, which should be available to each at risk couple, must be integrated into a more elaborate framework geared towards informing the target population. Dramatically different outcomes of carrier screening programmes implemented in the past illustrate the conditions for success or failure. The need to target selected ethnic groups accounts for most of the problems encountered: underpriviledged minorities, risk of discrimination and, most importantly, cultural gaps leading to refusal of prenatal diagnosis and/or of selective abortion. In order to achieve prevention through screening programmes, the tests should therefore be preceded by dissemination of adequate information into the target population, followed by genetic counseling for at risk couples, addressing cultural differences. Prenatal diagnosis should always be proposed, but never imposed on these couples. Finally, these screening programmes must be underpinned by comprehensive subsidies covering not only the tests but also education and counseling that should always be provided with the tests. In terms of public health, this is the price for a cost-effective genetic screening programme.

Abortion, Therapeutic↗

PubMed2002

The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism.

As our knowledge of the molecular mechanisms underlying idiopathic hypogonadotropic hypogonadism (IHH) expands, it becomes increasingly important to define the phenotypic spectrum of IHH. In this study we examined historical, clinical, biochemical, histological, and genetic features in 78 men with IHH to gain further insight into the phenotypic heterogeneity of the syndrome. We hypothesized that at least some of the spectrum of phenotypes could be explained by placing the disorder into a developmental and genetic context. Thirty-eight percent of the population had Kallmann syndrome (KS; IHH with anosmia), 54% had normosmic IHH, and 8% had acquired IHH after completion of puberty. Phenotypically, KS represented the most severe subtype (87% with complete absence of any history or signs of spontaneous pubertal development), normosmic IHH displayed the most heterogeneity (41% with some evidence of spontaneous puberty), and acquired IHH after completion of puberty clustered at the mildest end (all had complete puberty). Classification based on historical or clinical evidence of prior pubertal development, rather than the presence or absence of sense of smell, served to distinguish the population more clearly with respect to other clinical and biochemical features. Comparing IHH patients according to the absence (68%) or presence (24%) of some prior pubertal development revealed significant differences in testicular size (3.3 +/- 0.2 vs. 11.8 +/- 1.2 ml; P < 0.001), incidence of cryptorchidism (40% vs. 5%; P < 0.05), microphallus (21% vs. 0%; P < 0.05), inhibin B levels (45 +/- 4 vs. 144 +/- 20 pg/ml; P < 0.0001), and Mullerian inhibitory substance levels (9.8 +/- 1.4 vs. 2 +/- 0.5 ng/ml). Most familial cases had no pubertal development (95% vs. 5%; P < 0.001); males with mutations in the KAL gene displayed the most severe phenotype. Mean gonadotropins levels (LH, 1.8 +/- 0.1 vs. 2.9 +/- 0.4 IU/liter; FSH, 2.2 +/- 0.2 vs. 3.3 +/- 0.3 IU/liter; P < 0.05) and the finding of apulsatile LH secretion based on frequent sampling (80% vs. 55%; P < 0.05) were statistically different between patients lacking and those exhibiting partial pubertal development, but the overlap was extensive. The use of clinical parameters (presence or absence of some evidence of prior pubertal development, cryptorchidism, and microphallus), biochemical markers of testicular growth and differentiation (inhibin B and Mullerian inhibitory substance), and genetic evidence provides insight into the time of onset and the severity of GnRH deficiency. Viewing IHH in the full context of its developmental, genetic, and biochemical complexity permits greatest insight into its phenotypic variability.

Adult↗

PubMed2005

Genetic studies in rat models: insights into cardiovascular disease.

PURPOSE OF REVIEW: Limited to 2003-2004 publications, this review focuses on 'big picture' concepts learned from rat genetic studies of cardiovascular disease. RECENT DEVELOPMENTS: Analysis reveals insights into pathogenic paradigms, as well as experimental perspectives into rat-based systems of analyses of complex cardiovascular disease. Key concepts are forwarded. Multiple susceptibility genes underlie several quantitative trait loci for blood pressure suggesting a 'quantitative trait loci cluster' concept; hypertension end-organ disease quantitative trait loci are distinct from blood pressure quantitative trait loci indicating differential susceptibility paradigms for hypertension and each complication (stroke, renal disease, cardiac hypertrophy); distinct blood pressure quantitative trait loci are found in males and females indicating gender-specific susceptibility; and genetic subtypes comprise polygenic hypertension in rat models suggesting a genetic basis for clinical heterogeneity of human essential hypertension. Gender specific genetic susceptibility plays a key role in coronary artery disease susceptibility; multiple distinct quantitative trait loci underlie hyperlipidemia and type-2 diabetes, indicating multiple susceptibilities in risk factors for cardiovascular disease. Studies in transgenic inbred rat-strain models demonstrate value for serial, complex, cardiovascular pathophysiological analyses within a genetic context. SUMMARY: Cognizant of the limitations of animal model studies, observations from rat genetic studies provide insight into respective modeled human cardiovascular diseases and risk factor susceptibility, as well as systematically dissect the multifaceted complexities apparent in human complex cardiovascular disease. Given the recapitulation of many features of human cardiovascular disease, the value of rat model-based genetic studies for complex cardiovascular disease is unequivocal, thus mandating the expansion of resources for maximization of rat-based genetic studies.

Animals↗

PubMed2025

Computational modeling of human genetic variants in mice.

Mouse models represent a powerful platform to study genes and variants associated with human diseases. While genome editing technologies have increased the rate and precision of model development, predicting and installing specific types of mutations in mice that mimic the native human genetic context is complicated. Computational tools can identify and align orthologous wild-type genetic sequences from different species; however, predictive modeling and engineering of equivalent mouse variants that mirror the nucleotide and/or polypeptide change effects of human variants remains challenging. Here, we present H2M (human-to-mouse), a computational pipeline to analyze human genetic variation data to systematically model and predict the functional consequences of equivalent mouse variants. We show that H2M can integrate mouse-to-human and paralog-to-paralog variant mapping analyses with precision genome editing pipelines to devise strategies tailored to model specific variants in mice. We leveraged these analyses to establish a database containing > 3 million human-mouse equivalent mutation pairs, as well as in silico-designed base and prime editing libraries to engineer 4,944 recurrent variant pairs. Using H2M, we also found that predicted pathogenicity and immunogenicity scores were highly correlated between human-mouse variant pairs, suggesting that variants with similar sequence change effects may also exhibit broad interspecies functional conservation. Overall, H2M fills a gap in the field by establishing a robust and versatile computational framework to identify and model homologous variants across species while providing key experimental resources to augment functional genetics and precision medicine applications. The H2M database (including software package and documentation) can be accessed at https://human2mouse.com.

Journal Article↗

PubMed2004

Pervasive joint influence of epistasis and plasticity on mutational effects in Escherichia coli.

The effects of mutations on phenotype and fitness may depend on the environment (phenotypic plasticity), other mutations (genetic epistasis) or both. Here we examine the fitness effects of 18 random insertion mutations in E. coli in two resource environments and five genetic backgrounds. We tested each mutation for plasticity and epistasis by comparing its fitness effects across these ecological and genetic contexts. Some mutations had no measurable effect in any of these contexts. None of the mutations had effects on phenotypic plasticity that were independent of genetic background. However, half the mutations had epistatic interactions such that their effects differed among genetic backgrounds, usually in an environment-dependent manner. Also, the pattern of mutational effects across backgrounds indicated that epistasis had been shaped primarily by unique events in the evolutionary history of a population rather than by repeatable events associated with shared environmental history.

Epistasis, Genetic↗

PubMedDate not supplied

Evidence for a histocompatibility locus probably linked to but distinct from Mls and H-25.

BALB/c (Mlsb) and BALB.D2-Mlsa strains of mice, both H-2d, are congenic and differ for the Mls locus (and linked genes) located on chromosome 1. The BALB.D2-Mlsa strain was obtained by introducing the Mlsa allele of DBA/2 mice into BALB/c mice. In previous studies we showed that BALB.D2-Mlsa recipients reject, relatively rapidly, all skin grafts from BALB/c donors. We and other groups have questioned whether the rejections observed were indeed due to the incompatibility for Mlsb products or for products of a histocompatibility (non-H-2) locus linked to, but distinct from, Mlsb. To answer this question, several hybrids carrying either Mlsa or Mlsb in various genetic contexts were grafted with skin from Mls-compatible BALB/c or BALB.D2-Mlsa donors; in the genetic combinations selected, any rejection which might occur would reflect the effects of a non-Mls incompatibility between BALB/c and BALB.D2-Mlsa strains. In certain of the donor-recipient combinations studied, the skin grafts were tolerated for greater than 200 days, but a relatively rapid rejection of BALB/c skin grafts was observed in (B10.D2 x BALB.D2-Mlsa)F1 and (B10.BR x BALB. D2-Mlsa)F1 hybrid recipients. These results indicated that in addition to Mls, the BALB/c and BALB.D2-Mlsa strains differ for at least one other non-H-2 histocompatibility locus. The possible involvement of H-25 was then investigated. Indeed, disparity for H-25, which maps on chromosome 1 close to Mls, can induce relatively rapid skin graft rejection. The H-25 allele of the DBA/2 strain has not been defined: we considered, therefore, that BALB/c and DBA/2 could be disparate at the H-25 locus, and that H-25 (transmitted by DBA/2 to the BALB.D2-Mlsa strain, together with the Mlsa allele) could be responsible for the skin graft rejection we observed. Our results showed, however, that DBA/2, BALB/c and BALB.D2-Mlsa strains of mice all share the H-25c allele; they therefore ruled out a role for H-25 incompatibility in the skin graft rejections we observed, and indicated that these rejections are due to the effects of a yet undefined histocompatibility locus (locus 'x'), probably linked to, but distinct from, the Mls locus. Further experiments showed that the histocompatibility effect of locus 'x' cumulates with that exhibited by Mlsb (or by a putative histocompatibility locus linked to Mlsb).

Animals↗