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PubMed2002

The dual AngII/AVP receptor gene N119S/C163R variant exhibits sodium-induced dysfunction and cosegregates with salt-sensitive hypertension in the Dahl salt-sensitive hypertensive rat model.

BACKGROUND: Essential hypertension is a prevalent complex polygenic disease and a major risk factor for cardiovascular disease, the leading cause of death in developed countries. Because of its complex and multifactorial nature, its genetic determinants still remain largely unknown. The Dahl salt-sensitive hypertensive rat model exhibits impaired sodium handling, which is hypothesized to play a key role in the pathophysiology of polygenic hypertension. Thus, genes associated with renal regulation of salt and water balance are a priori likely candidates for a causative role in hypertension pathogenesis. The functional properties and renal-specific expression of the recently characterized AngII/AVP receptor suggest a putative modulator role in tubular sodium and fluid reabsorption. Based on these observations, we investigated the potential involvement of the AngII/AVP receptor in salt-sensitive hypertension. MATERIALS AND METHODS: We performed cosegregation analysis of the AngII/AVP receptor locus with salt-sensitive hypertension in an F2 (Dahl S X Dahl salt-resistant [R]) hybrid male cohort characterized for blood pressure by radiotelemetry after 8 weeks of high salt challenge. Further molecular analysis was done to identify putative AngII/AVP receptor molecular variants that could account for the AngII/ AVP receptor involvement in salt-sensitive hypertension pathogenesis. RESULTS: The AngII/AVP receptor was mapped to rat chromosome 1, 1.7 cM centromeric to the D1Rat188 marker by radiation hybrid mapping analysis. Quantitative trait locus (QTL) analysis detected a highly significant linkage of the AngII/AVP receptor locus with high blood pressure (LRS = 13.8, p= 0.0002). Molecular characterization of the Dahl S and Dahl R AngII/AVP receptor cDNAs revealed two amino acid substitutions in the Dahl S AngII/AVP receptor (N119S, C163R) when compared to the Dahl R AngII/AVP receptor. These mutations are associated with an increased receptor affinity for both ligands (AVP and AngII) and an enhanced G(s)-coupling by the receptor resulting in increased activation of adenylate cyclase with concomitant increase in cAMP production. CONCLUSIONS: The observed molecular dysfunction in the Dahl S AngII/AVP receptor is consistent with increased tubular sodium and fluid reabsorption observed in Dahl S rats. Interestingly, the AngII/AVPr locus is within the narrowed chromosome 1 QTL region for blood pressure detected in different rat intercross linkage analyses. Altogether, the data strongly suggest that the AngII/AVP receptor is a hypertension susceptibility gene in the Dahl S rat model, as well as raises the hypothesis that it too underlies the chromosome 1 blood pressure QTL identified in other hypertension rat models.

Allosteric Regulation↗

PubMed2003

Genetic architecture of the mouse hippocampus: identification of gene loci with selective regional effects.

We recently mapped two quantitative trait loci that have widespread effects on hippocampal architecture in mouse: Hipp1a and Hipp5a. We also noted remarkable strain differences in the relative sizes of different hippocampal regions. Estimated heritable variation for these differences was 42% in hippocampus proper, 40% in dentate gyrus, 31% in granule cell layer and 18% in pyramidal cell layer. Region size varied at least 50% from largest to smallest measurement. Here we have utilized these differences to identify loci with effects on the dentate gyrus, granule cell layer, hippocampus proper and pyramidal cell layer. Our sample consists of C57BL/6J and DBA/2J and 32 BXD recombinant inbred strains. Volumetric data were corrected for shrinkage and for differences in brain weight. We identified significant loci on chromosomes (Chr) 6, 13 and 15, and a significant interaction locus on proximal Chr 11. A suggestive distal Chr 1 locus overlaps with Hipp1a. HipV13a (Chr 13, 42-78Mb) has an additive effect of 0.56 mm3 (12.1%) on dentate gyrus volume, while GrV6a (Chr 6, 29-65 Mb) has additive effects of 0.14 mm3 (16.0%) on the volume of the granule cell layer. HipV13a also interacts with DGVi11a, a locus on proximal Chr 11 that operates exclusively through its epistatic effect on HipV13a and has no independent main effect HipV15a (Chr 15, 0-51 Mb) has an additive effect of 1.76 mm3 (9.0%) on the volume of the hippocampus proper. We used WebOTL, a recently described web-based tool, to examine genetic correlation of gene expression with hippocampal volume. We identified a number of genes that map within the OTL intervals and have highly correlated expression patterns. Using WebQTL's extensive database of published BXD phenotypes, we also detected a strong and potentially biologically meaningful correlation between hippocampal volume and the acoustic startle response.

Age Factors↗

PubMed1994

Chromosomal assignment of 11 loci in the rat by mouse-rat somatic hybrids and linkage.

Eleven rat genes have been assigned to rat chromosomes by use of mouse x rat somatic hybrids and/or use of linkage to known chromosome markers. Among them, the genes for the inducible nitric oxide synthase (Nos2) and for a vasoactive intestinal peptide receptor (Vipr) are potential candidates for genetic regulation of blood pressure and were localized to rat Chromosomes (Chrs) 10 and 8 respectively. Genes for gastric H,K-ATPase alpha subunit (Atp4a), Class I alcohol dehydrogenase (Adh), and aldolase C (Aldoc) were localized to Chrs 1, 2, and 10 respectively, and thus provide more DNA markers for genetic mapping of quantitative trait loci for blood pressure on those chromosomes. Genes for alkaline phosphatase (Alp1) and cardiac AE-3 Cl-/HCO3- exchanger (Ae3) were both localized to Chr 9. Genes for glutamate dehydrogenase (Glud) and gastric H,K-ATPase beta subunit (Atp4b) were localized to Chr 16. The ornithine decarboxylase (Odc) gene and ornithine decarboxylase pseudogene (Odcp) were localized to Chrs 6 and 11 respectively.

Animals↗

PubMed2000

Construction of a high-throughput rat genetic mapping system with 466 arbitrarily primed-representational difference analysis markers.

Linkage mapping of quantitative trait loci (QTLs) requires genetic markers that can be efficiently genotyped for a large number of individuals. To isolate genetic markers suitable for this purpose, we previously established the arbitrarily primed RDA (AP-RDA) method. Dot-blotting AP-PCR products (AP-amplicons) onto filters at a high density and hybridization of the filters with the AP-RDA markers made it possible to genotype a large number of individuals simultaneously for multiple loci. In this study, by using 25 primers or primer combinations, we isolated a total of 419 AP-RDA markers by subtracting the AP-amplicon of BUF rats from that of ACI rats, and vice versa. By combining 47 previously isolated markers, a rat genetic map was drawn with 466 AP-RDA markers. Between two given strains of rats other than ACI and BUF, the average informativeness of the markers was 38%. As for the intercross of ACI and BUF rats, 12 selected primers served to genotype 259 loci. In addition, the amounts and quality of genomic DNA to be used for AP-PCR were examined to guarantee reliable genotyping. Now, initial genome scanning of the rat for linkage analysis can be performed efficiently using this mapping system with AP-RDA markers.

Animals↗

PubMed2001

Modulation of retinal cell populations and eye size in retinoic acid receptor knockout mice.

PURPOSE: The retinoic acid receptors are expressed from early stages of development in the diverse tissues that make up the vertebrate eye. Their loss has subtle effects on eye development. We adapted sensitive quantitative trait locus (QTL) mapping methods to assess consequences of inactivating alleles of the alpha and beta receptors, Rara and Rarb, on eye and retinal development. Rara is of particular interest because this gene is a candidate for Nnc1, a QTL that controls retinal ganglion cell proliferation. METHODS: We studied lines of mice in which expression of the a1 isoform of Rara or all isoforms of Rarb had been disrupted by gene targeting. We measured eye weight, lens weight, retinal area, and retinal ganglion cell number in each of six genotypes (Rara and Rarb -/-, +/-, +/+; 10-25 cases/genotype). RESULTS: Loss of either protein is associated with a small but significant loss of eye weight and retinal area. However, only the Rarb knockout has a significant effect on the ganglion cell population and the loss of both wildtype alleles leads to an 8,000 cell deficit. Surprisingly, loss of the Rara a1 isoform that is expressed in this cell population from early stages has no effect on number. Null alleles of both genes have little if any effect on lens growth. CONCLUSIONS: Despite its expression in embryonic retina, Rara is unlikely to be the Nnc1 QTL. In contrast, Rarb, a gene that maps to Chr 14 and which is not an Nnc1 candidate gene, has a significant effect on cell number and is therefore a QTL controlling this key population. This raises the intriguing possibility that normal allelic variants of Rarb modulate the ganglion cell population in other vertebrates, including humans.

Animals↗

PubMed2006

Quantitative trait loci for panicle size, heading date and plant height co-segregating in trait-performance derived near-isogenic lines of rice (Oryza sativa).

Near-isogenic lines (NILs) are ideal materials for precise estimation of quantitative trait loci (QTL) effects and map-based gene isolation. With the completion of the rice genome sequence, QTL isolation based on NILs is becoming a routine. In this study, a trait-performance derived NIL strategy was adopted to develop NILs. Two plants were identified within one inbred line of recombinant inbred lines (RILs, F(7) generation), exhibiting a significant difference in panicle size. By marker screening of the whole genome the genetic background of the two plants was estimated to be 98.7% identical. These two plants were selected as parents to produce a near-isogenic F(2) (NIL-F(2)) population, consisting of 125 individuals, in which spikelets per panicle (SPP), grains per panicle (GPP), heading date (HD) and plant height (PH) were recorded. These four traits expressed discontinuous or bimodal distribution in the NIL-F(2) population and followed the expected segregation ratios for a single Mendelian factor by progeny tests. A partial dominant QTL for the four traits was mapped to the same interval flanked by RM310 and RM126 on chromosome 8. The QTL region explained 83.0, 80.2, 94.9 and 93.8% of trait variation of SPP, GPP, HD and PH in the progenies, respectively. Progeny tests also confirmed co-segregation of QTL for the four traits, tall plants consistently flowering late and carrying large panicles. Different NILs development strategies are discussed.

Genes, Plant↗

PubMed2000

Comparative organization of cattle chromosome 5 revealed by comparative mapping by annotation and sequence similarity and radiation hybrid mapping.

A whole genome cattle-hamster radiation hybrid cell panel was used to construct a map of 54 markers located on bovine chromosome 5 (BTA5). Of the 54 markers, 34 are microsatellites selected from the cattle linkage map and 20 are genes. Among the 20 mapped genes, 10 are new assignments that were made by using the comparative mapping by annotation and sequence similarity strategy. A LOD-3 radiation hybrid framework map consisting of 21 markers was constructed. The relatively low retention frequency of markers on this chromosome (19%) prevented unambiguous ordering of the other 33 markers. The length of the map is 398.7 cR, corresponding to a ratio of approximately 2.8 cR(5,000)/cM. Type I genes were binned for comparison of gene order among cattle, humans, and mice. Multiple internal rearrangements within conserved syntenic groups were apparent upon comparison of gene order on BTA5 and HSA12 and HSA22. A similarly high number of rearrangements were observed between BTA5 and MMU6, MMU10, and MMU15. The detailed comparative map of BTA5 should facilitate identification of genes affecting economically important traits that have been mapped to this chromosome and should contribute to our understanding of mammalian chromosome evolution.

Animals↗

PubMed2005

Familiality of temperament in bipolar disorder: support for a genetic spectrum.

BACKGROUND: The array of different diagnoses and clinical presentations seen in the family members of bipolar probands suggests a quantitative or spectrum phenotype. Consistent with this idea, it has been proposed that an underlying quantitative variation in temperament may be the primary phenotype that is genetically transmitted and that it in turn predisposes to bipolar disorder (BP). Choosing the appropriate phenotypic model for BP is crucial for success in genetic mapping studies. To test this theory, various measures of temperament were examined in the family members of bipolar probands. We predicted that a gradient of scores would be observed from those with BP to those with major depression to unaffected relatives to controls. METHODS: Members of 85 bipolar families and 63 control subjects were administered clinical interviews for diagnosis (SCID) and two temperament assessments, the TEMPS-A and TCI-125. Subjects with BP, major depressive disorder, unaffected relatives, and controls were compared on each temperament scale and on eight factors extracted from a joint factor analysis of the TEMPS-A and TCI-125. RESULTS: The four groups were found to be significantly different and with the expected order of average group scores for four of the TEMPS-A scales, three of the TCI-125 scales, and one of the extracted factors. On the fifth TEMPS-A scale, hyperthymic, controls scored higher than the other three subject groups contrary to expectations. Significant differences were seen between unaffected relatives and controls on the hyperthymic scale and on the first extracted factor, anxious/reactive. LIMITATIONS: Controls were mainly recruited through advertisements, which may have introduced an ascertainment bias. It is also possible that mood state at the time of completing the questionnaire influenced subject's rating of their temperament. Additionally, bipolar I and bipolar II subjects were placed in the same group even though they had some differing clinical features. CONCLUSIONS: Our data support the theory that some dimensions of temperament are transmitted in families as quantitative traits that are part of a broader bipolar spectrum. In particular, the hyperthymic scale of the TEMPS-A and the anxious/reactive extracted factor distinguished unaffected relatives from controls. The hyperthymic scale yielded results opposite to expectation with controls higher than any family group. This may be an artifact of the self-rated form of the questionnaire, a consequence of our grouping bipolar I and II subjects together, or the result of a "protective" factor and bears further study. Nevertheless, both of these scales may be useful quantitative traits for genetic mapping studies.

Bipolar Disorder↗

PubMed1994

Genetic animal models of alcohol and drug abuse.

Behavioral and pharmacological responses of selectively bred and inbred rodent lines have been analyzed to elucidate many features of drug sensitivity and the adverse effects of drugs, the underlying mechanisms of drug tolerance and dependence, and the motivational states underlying drug reward and aversion. Genetic mapping of quantitative trait loci (QTLs) has been used to identify provisional chromosomal locations of genes influencing such pharmacological responses. Recent advances in transgenic technology, representational difference analysis, and other molecular methods now make feasible the positional cloning of QTLs that influence sensitivity to drugs of abuse. This marks a new period of synthesis in pharmacogenetic research, in which networks of drug-related behaviors, their underlying pharmacological, physiological, and biochemical mechanisms, and particular genomic regions of interest are being identified.

Alcoholism↗

PubMed2006

Murine weight loss exhibits significant genetic variation during dietary restriction.

We present genetic analyses of murine weight loss during dietary restriction (DR) for females eating 60% ad libitum (AL). We examined 5 cohorts across 81 different strains (22 strains tested twice) that included the LXS and LSXSS recombinant inbred strains, the LXS parental strains ILS and ISS, and the classical inbreds 129S6, A, BALB/c, C57BL/6, C3H, and DBA. Weight loss exhibited highly significant genetic variation, with DR body weights ranging from approximately 60 to approximately 85% of AL body weight. This variation was not explained by the strain differences in absolute food intake, feces calorie content, motor activity, or AL body fat. Heritability was 40-50%, and several provisional quantitative trait loci were mapped. This variation can be used to test whether weight loss correlates with the health benefits of DR, independently of the reduction in calories. The genetic variation also implies the existence of genes that would be novel therapeutic targets, distinct from genes affecting AL body weight or body fat, for enhancing (or mitigating) weight loss during food restriction.

Adipose Tissue↗

PubMed2026

Identification and fine mapping of a locus controlling multi-main-stem trait in Brassica napus.

BACKGROUND: The main stem is a crucial component determining individual plant yield in rapeseed (Brassica napus). However, the genetic and developmental basis underlying the multi-main-stem trait remains largely unclear. RESULTS: In this study, we identified a multi-main-stem mutant, mms1, which exhibited a significantly increased silique number per plant and abnormal shoot apical meristem (SAM) development. Genetic analysis demonstrated that the multi-main-stem trait was controlled by a recessive gene. Using bulked segregant analysis combined with a Brassica napus 50 K SNP array and map-based cloning, the locus was mapped to a 340-kb interval on chromosome A09 of the ZS11 reference genome and was designated BnaA09.MMS1. Candidate gene analysis revealed that BnaA09G0254500ZS, which harbors sequence variations in both the promoter and coding regions and shows significantly increased expression in the mutant, was the most likely candidate gene. In addition, phytohormone analysis revealed reduced auxin accumulation in mutant SAMs, together with transcriptomic changes in genes associated with the CLAVATA3 (CLV3)-WUSCHEL (WUS) feedback loop. CONCLUSIONS: These findings provide an important foundation for elucidating the genetic basis of the multi-main-stem trait and offer a valuable genetic resource for rapeseed improvement.

Brassica napus↗

PubMed2005

Type 2 diabetes mouse model TallyHo carries an obesity gene on chromosome 6 that exaggerates dietary obesity.

The TallyHo (TH) mouse strain is a polygenic model for Type 2 diabetes with obesity. Genetic analysis in backcross progeny from a cross between F1 [C57BL/6J (B6) x TH] and TH mice mapped a quantitative trait locus (QTL) named TH-associated body weight 2 (tabw2) to chromosome 6. The TH-derived allele is associated with increased body weight. As a first step to identify the molecular basis of this obesity QTL, we constructed a congenic line of mice on the B6 genetic background that carries a genomic region from TH mice containing tabw2. Congenic mice homozygous for tabw2 (B6.TH-tabw2/tabw2) fed a chow diet exhibited slightly, but significantly, higher body weight and body fat and plasma leptin levels compared with controls (B6.TH-+/+). This difference was exacerbated when the animals were maintained on a high-fat and high-sucrose (HFS) diet. The diet-induced obesity in tabw2 congenic mice is accompanied by hyperleptinemia, mild hyperinsulinemia, impaired glucose tolerance, and reduced glucose uptake in adipose tissue in response to insulin administration. Using F2 progeny fed a HFS diet from an intercross of B6.TH-tabw2/+ mice, we were able to refine the map position of the tabw2 obesity susceptibility locus to a 15-cM region (95% confidence interval) extending distally from the marker D6Mit102. In summary, tabw2 congenic mice are a new animal model for diet-induced obesity that will be valuable for the study of gene-diet interactions.

Alleles↗

PubMed2026

Integrating Genetics and Environment to Find Causal Mechanisms for Multiple Sclerosis.

Genome-wide association studies (GWAS) have identified hundreds of risk loci for multiple sclerosis (MS), but we have limited knowledge of the mechanisms through which genetic variants mediate risk. Similarly, epidemiological studies implicate numerous environmental risk factors in MS risk, but these cannot identify specific causal mechanisms. We review our current knowledge of genetic mechanisms in MS, including the critical role of expression quantitative trait locus (eQTL) mapping in translating genetic risk loci into causal mechanisms. Molecular and functional context has emerged as an important missing component of these studies, and we discuss how environmental risk factors can be modelled in a quantitative genetic context to identify disease mechanisms. In parallel, we highlight recent advances in which quantitative genetic methods establish a causal role for low vitamin D and obesity in MS, and to dissect the mechanisms through which these operate. As genetic, transcriptional, and epigenetic studies continue to expand, further mechanistic insights for MS are likely to come from the integration of genetic and environmental data.

Humans↗

PubMed1995

Genetics in arterial hypertension--clinical and experimental aspects.

Genetic approaches provide a new insight into the understanding of biological mechanisms underlying blood pressure regulation and hypertension. Some progress has been made in elucidating the molecular mechanisms of rare forms of hypertension. Common forms of hypertension are likely to be due to combinations of DNA variants of several genes involved in blood pressure regulation. Only little progress has been made in the identification of the underlying genetic factors, due to the complex nature of this disease. Experimental crosses of hypertensive rats offer an ideal setting for the genetic dissection of mammalian physiology. With the opportunity to study inbred rat strains the problem of genetic heterogeneity becomes irrelevant. Cosegregation studies investigating candidate genes for hypertension have been carried out for a number of genes. Moreover, systematic mapping of quantitative trait loci involved in blood pressure regulation has recently become possible in genetically hypertensive rat models. In contrast, genetic studies involving hypertensive individuals are currently limited to the investigation of candidate genes in association and sib-pair analysis. So far, the angiotensinogen gene is the only locus that has been implicated in the pathogenesis of human hypertension in association as well as sib-pair analysis. Considering the complexities of genetic hypertension, animal models will play an important role in the genetic dissection of this disease. A critical prerequisite for the study of human hypertension is the availability of large patient and family cohorts.

Animals↗

PubMed2005

Epistasis and genotype-environment interaction for quantitative trait loci affecting flowering time in Arabidopsis thaliana.

A major goal of evolutionary biology is to understand the genetic architecture of the complex quantitative traits that may lead to adaptations in natural populations. Of particular relevance is the evaluation of the frequency and magnitude of epistasis (gene-gene and gene-environment interaction) as it plays a controversial role in models of adaptation within and among populations. Here, we explore the genetic basis of flowering time in Arabidopsis thaliana using a series of quantitative trait loci (QTL) mapping experiments with two recombinant inbred line (RIL) mapping populations [Columbia (Col) x Landsberg erecta (Ler), Ler x Cape Verde Islands (Cvi)]. We focus on the response of RILs to a series of environmental conditions including drought stress, leaf damage, and apical damage. These data were explicitly evaluated for the presence of epistasis using Bayesian based multiple-QTL genome scans. Overall, we mapped fourteen QTL affecting flowering time. We detected two significant QTL-QTL interactions and several QTL-environment interactions for flowering time in the Ler x Cvi population. QTL-environment interactions were due to environmentally induced changes in the magnitude of QTL effects and their interactions across environments--we did not detect antagonistic pleiotropy. We found no evidence for QTL interactions in the Ler x Col population. We evaluate these results in the context of several other studies of flowering time in Arabidopsis thaliana and adaptive evolution in natural populations.

Arabidopsis↗

PubMed2002

Resolving the composite trait of hypertension into its pharmacogenetic determinants by acute pharmacological modulation of blood pressure regulatory systems.

Acute pharmacogenetic analysis was carried out in an intercross F2 population derived from Prague hypertensive-hypertriglyceridemic and Lewis rats. Quantitative trait loci (QTL) mapping was performed for baseline blood pressure (BP) and for BP after blockade of the renin-angiotensin system by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide system by N(G)-nitro- L-arginine methyl ester. Two significant loci for baseline BP were found on chromosome (Chr) 3 (logarithm of likelihood, LOD, 3.8) and Chr 5 (LOD 3.6), and one suggestive locus on Chr 1 (LOD 2.7). The QTL on Chr 3 persisted after treatment with the three agents while the QTL on Chr 5 and Chr 1 disappeared after pentolinium administration. This suggests independence of the locus on Chr 3 from each acute BP regulatory system examined, whereas the loci on Chr 5 and Chr 1 appeared to be controlled mainly by the SNS. Although not apparent at baseline, a significant locus appeared on Chr 8 (LOD 7.0) after blockade of the SNS, and NO system blockade led to the appearance of a new QTL on Chr 1 (LOD 3.6), indicating the contribution of the inhibited systems to these loci. Pharmacogenetic dissection of the BP trait is a powerful tool to unravel the underlying physiological mechanisms of QTL affecting baseline BP and to identify specific QTL for the response to drugs. This pharmocogenetic approach enabled us to determine the main causative acute BP regulatory systems and should lead to better selection of suitable antihypertensive drugs for individual patients.

Animals↗

PubMed1998

Measured haplotype analysis of the angiotensin-I converting enzyme gene.

Linkage and segregation analysis have shown that circulating angiotensin-I converting enzyme (ACE) levels are influenced by a major quantitative trait locus that maps within or close to the ACE gene. The D variant of a 287 bp insertion/deletion (I/D) polymorphism in intron 16 of the gene is associated with high ACE levels and may also be related to increased risk of cardiovascular disease. Multiple variants that are in linkage disequilibrium with the I/D polymorphism have been described, but it is unknown if any of these are directly implicated, alone or in combination with as yet undiscovered variants, in the determination of ACE levels. An analysis of 10 polymorphisms spanning 26 kb of the ACE gene revealed a limited number of haplotypes in Caucasian British families due to strong linkage disequilibrium operating over this small chromosomal region. A haplotype tree (cladogram) was constructed with three main branches (clades A-C) which account for 90% of the observed haplotypes. Clade C is most likely derived from clades A and B following an ancestral recombination event. This evolutionary information was then used to direct a series of nested, measured haplotype analyses that excluded upstream sequences, including the ACE promoter, from harbouring the major ACE-linked variant that explains 36% of the total trait variability. Residual familial correlations were highly significant, suggesting the influence of additional unlinked genes. Our results demonstrate that a combined cladistic/measured haplotype analysis of polymorphisms within a gene provides a powerful means to localize variants that directly influence a quantitative trait.

England↗

PubMed1999

Genes influencing resistance to Coccidioides immitis and the interleukin-10 response map to chromosomes 4 and 6 in mice.

Coccidioidomycosis is a fungal infection that is endemic in the southwestern United States. Infection is more severe in blacks and Filipinos, which suggests that there is a genetic basis for susceptibility to this infection in humans. We found that there is also a difference in resistance to Coccidioides immitis infection among inbred mouse strains: B6 mice are susceptible, while DBA/2 mice are resistant (T. N. Kirkland and J. Fierer, Infect. Immun. 40:912-916, 1983). In this paper we report the results of our efforts to map the genes responsible for resistance to this infection in mice. Mice were infected by intraperitoneal inoculation, and 15 days later the numbers of viable fungi in their lungs and spleens were enumerated. We also determined the amounts of interleukin-10 mRNA made in the infected lungs. These three phenotypes were mapped as quantitative traits by using the 26 available lines of recombinant inbred mice derived from a cross between B6 and DBA/2 mice. The best associations were those between the regions near the Lv locus on chromosome 4 and the Tnfr1 locus on chromosome 6. We then infected backcross mice [(B6 x DBA/2) x B6] and confirmed these associations; 14 of 16 (87%) mice that were heterozygous at both Lv and Tnfr1 were resistant to infection, whereas only 4 of 16 (25%) mice that were homozygous B6 at both loci were resistant. These are the first genetic loci to be associated with susceptibility to C. immitis, but there may be additional genes involved in murine resistance to this infection.

Animals↗