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PubMed2000

A recombination hotspot delimits a wild-species quantitative trait locus for tomato sugar content to 484 bp within an invertase gene.

In nature, genetic variation usually takes the form of a continuous phenotypic range rather than discrete classes. The genetic variation underlying quantitative traits results from the segregation of numerous interacting quantitative trait loci (QTLs), whose expression is modified by the environment. To uncover the molecular basis of this variation, we characterized a QTL (Brix9-2-5) derived from the green-fruited tomato species Lycopersicon pennellii. The wild-species allele increased glucose and fructose contents in cultivated tomato fruits in various genetic backgrounds and environments. Using nearly isogenic lines for the QTL, high-resolution mapping analysis delimited Brix9-2-5 to a single nucleotide polymorphism-defined recombination hotspot of 484 bp spanning an exon and intron of a fruit-specific apoplastic invertase. We suggest that the differences between the Brix9-2-5 alleles of the two species are associated with a polymorphic intronic element that modulates sink strength of tomato fruits. Our results demonstrate a link between naturally occurring DNA variation and a Mendelian determinant of a complex phenotype for a yield-associated trait.

Alleles↗
PubMed2000

Mapping of quantitative trait loci (QTL) of differential stress gene expression in rat recombinant inbred strains.

OBJECTIVE: Stress has been shown to be a major environmental contributor to cardiovascular diseases through its effects on blood pressure variability and cardiac function. The cellular stress response is characterized by the expression of specific heat stress genes (hsps), under the transcriptional control of heat shock transcription factors (HSTFs). The levels of hsp mRNA depend on the severity of the stress, with hstf1 acting as a stress sensor. The aim of this work was to evaluate the genetic contribution of the variability in hsp expression, and to identify its putative quantitative trait loci (QTL). METHODS: Twenty recombinant inbred rat strains (RIS) were studied. The animals underwent a standardized, identical 1 h immobilization stress in restraint cages, followed by 1 h of rest before sacrifice. Total RNA was extracted from the heart kidneys and adrenals, and the mRNA levels of hsp27, hsp70, hsp84, hsp86 and hsp105 were measured. The strain distribution pattern (SDP) of hsp expression was correlated with that of 475 polymorphic markers distributed throughout the RIS genome. A polymorphism of rat hstf1 in RIS was used for its mapping in RIS. RESULTS: Despite an identical stress being applied to all strains, hsp expression showed up to a 1 2-fold gradient with little intra-strain variability, indicative of a strong genetic contribution to the trait Heritability ranged from 50 to 77% for most hsp genes in the three target organs. The continuous SDP of stress gene expression indicated the polygenic nature of the trait A common locus on chromosome 7 (at D7Cebrp187s3 marker) was consistently associated with all hsp expression in most of the organs [with a likelihood of odds (LOD) score of 3.0 for hsp27 expression]. We have mapped rat hstf1 on chromosome 7 at the same locus. Finally, the D4Mit19 marker was significantly associated with hsp84 expression in the heart (LOD score of 3.1). CONCLUSION: Two loci were linked with the differential expression of HSPs in response to immobilization stress in target organs of RIS. The chromosome 7 locus unveiled for all HSPs could explain up to 42% of the observed inter-strain variability of hsp levels in response to stress. We propose hstf1 as a positional candidate at this locus.

Adrenal Glands↗
PubMed2004

A major suppressor of cell death, slm1, modifies the expression of the maize (Zea mays L.) lesion mimic mutation les23.

Disease lesion mimics provide an excellent biological system to study the genetic basis of cell death in plants. Many lesion mimics show variation in phenotype expression in different genetic backgrounds. Our goal was to identify quantitative trait loci (QTL) modifying lesion mimic expression thereby identifying genetic modifiers of cell death. A recessive lesion mimic, les23, in a severe-expressing line was crossed to the maize inbred line Mo20W, a lesion-suppressing line, and an F(2) population was developed for QTL analysis. In addition to locating les23 to the short arm of chromosome 2, this analysis detected significant loci for modification of lesion expression. One highly significant locus was found on the long arm of chromosome 2. The Mo20W allele at this QTL significantly delayed initiation of the lesion phenotype and decreased the final lesion severity. Other QTL with lesser effect affected severity of lesion expression without affecting lesion initiation date. Our results demonstrate that dramatic change in lesion phenotype can be controlled by a single major QTL. The presumed function of this QTL in normal plants is to regulate some aspect of the cell death pathway underlying the les23 phenotype.

Alleles↗
PubMed2006

Of flies and man: Drosophila as a model for human complex traits.

Understanding the genetic and environmental factors affecting human complex genetic traits and diseases is a major challenge because of many interacting genes with individually small effects, whose expression is sensitive to the environment. Dissection of complex traits using the powerful genetic approaches available with Drosophila melanogaster has provided important lessons that should be considered when studying human complex traits. In Drosophila, large numbers of pleiotropic genes affect complex traits; quantitative trait locus alleles often have sex-, environment-, and genetic background-specific effects, and variants associated with different phenotypic are in noncoding as well as coding regions of candidate genes. Such insights, in conjunction with the strong evolutionary conservation of key genes and pathways between flies and humans, make Drosophila an excellent model system for elucidating the genetic mechanisms that affect clinically relevant human complex traits, such as alcohol dependence, sleep, and neurodegenerative diseases.

Animals↗
PubMed2004

Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment.

Specific language impairment (SLI) is defined as an unexplained failure to acquire normal language skills despite adequate intelligence and opportunity. We have reported elsewhere a full-genome scan in 98 nuclear families affected by this disorder, with the use of three quantitative traits of language ability (the expressive and receptive tests of the Clinical Evaluation of Language Fundamentals and a test of nonsense word repetition). This screen implicated two quantitative trait loci, one on chromosome 16q (SLI1) and a second on chromosome 19q (SLI2). However, a second independent genome screen performed by another group, with the use of parametric linkage analyses in extended pedigrees, found little evidence for the involvement of either of these regions in SLI. To investigate these loci further, we have collected a second sample, consisting of 86 families (367 individuals, 174 independent sib pairs), all with probands whose language skills are >/=1.5 SD below the mean for their age. Haseman-Elston linkage analysis resulted in a maximum LOD score (MLS) of 2.84 on chromosome 16 and an MLS of 2.31 on chromosome 19, both of which represent significant linkage at the 2% level. Amalgamation of the wave 2 sample with the cohort used for the genome screen generated a total of 184 families (840 individuals, 393 independent sib pairs). Analysis of linkage within this pooled group strengthened the evidence for linkage at SLI1 and yielded a highly significant LOD score (MLS = 7.46, interval empirical P<.0004). Furthermore, linkage at the same locus was also demonstrated to three reading-related measures (basic reading [MLS = 1.49], spelling [MLS = 2.67], and reading comprehension [MLS = 1.99] subtests of the Wechsler Objectives Reading Dimensions).

Adaptor Proteins, Signal Transducing↗
PubMed2003

FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice.

BACKGROUND & AIMS: Cholesterol gallstone formation is a complex genetic trait. To identify additional cholesterol gallstone susceptibility loci, we performed a quantitative trait locus analysis using an intercross of PERA/Ei and I/LnJ inbred strains of mice. METHODS: Mice of both sexes were examined for gallstone weight and evaluated according to a scoring system for the physical chemistry of cholelithiasis during feeding of a lithogenic diet. Intercross offspring were genotyped, and linkage analysis was performed by interval mapping. Differences in messenger RNA expression of positional candidate genes were determined using reverse-transcription and real-time polymerase chain reaction. RESULTS: We identified significant loci associated with gallstone weight on chromosomes 10 and 4, named Lith7 and Lith8, respectively (both susceptibility alleles conferred by strain I/LnJ). Positional candidate genes with higher expression in I/LnJ mice are Fxr (official symbol, Nr1h4), encoding the nuclear bile salt receptor, on chromosome 10 and Shp1 (official symbol, Nr0b2), encoding the small heterodimer partner 1, on chromosome 4. A significant locus associated with gallstone score on chromosome 17, named Lith9 (susceptibility allele conferred by strain PERA/Ei), colocalizes with the genes Abcg5 and Abcg8 that encode the canalicular cholesterol transporter. Higher hepatic messenger RNA expression of Abcg5 and Abcg8 in strain PERA/Ei correlates positively with higher biliary cholesterol levels. CONCLUSIONS: Our findings suggest a primary role of the nuclear bile salt receptor FXR and the canalicular cholesterol transporter ABCG5/ABCG8 in the genetic susceptibility and pathogenesis of cholesterol cholelithiasis in these strains of inbred mice.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2005

Genetic interactions between polymorphisms that affect gene expression in yeast.

Interactions between polymorphisms at different quantitative trait loci (QTLs) are thought to contribute to the genetics of many traits, and can markedly affect the power of genetic studies to detect QTLs. Interacting loci have been identified in many organisms. However, the prevalence of interactions, and the nucleotide changes underlying them, are largely unknown. Here we search for naturally occurring genetic interactions in a large set of quantitative phenotypes--the levels of all transcripts in a cross between two strains of Saccharomyces cerevisiae. For each transcript, we searched for secondary loci interacting with primary QTLs detected by their individual effects. Such locus pairs were estimated to be involved in the inheritance of 57% of transcripts; statistically significant pairs were identified for 225 transcripts. Among these, 67% of secondary loci had individual effects too small to be significant in a genome-wide scan. Engineered polymorphisms in isogenic strains confirmed an interaction between the mating-type locus MAT and the pheromone response gene GPA1. Our results indicate that genetic interactions are widespread in the genetics of transcript levels, and that many QTLs will be missed by single-locus tests but can be detected by two-stage tests that allow for interactions.

Crosses, Genetic↗
PubMed2005

Sucrose-specific induction of anthocyanin biosynthesis in Arabidopsis requires the MYB75/PAP1 gene.

Sugar-induced anthocyanin accumulation has been observed in many plant species. We observed that sucrose (Suc) is the most effective inducer of anthocyanin biosynthesis in Arabidopsis (Arabidopsis thaliana) seedlings. Other sugars and osmotic controls are either less effective or ineffective. Analysis of Suc-induced anthocyanin accumulation in 43 Arabidopsis accessions shows that considerable natural variation exists for this trait. The Cape Verde Islands (Cvi) accession essentially does not respond to Suc, whereas Landsberg erecta is an intermediate responder. The existing Landsberg erecta/Cvi recombinant inbred line population was used in a quantitative trait loci analysis for Suc-induced anthocyanin accumulation (SIAA). A total of four quantitative trait loci for SIAA were identified in this way. The locus with the largest contribution to the trait, SIAA1, was fine mapped and using a candidate gene approach, it was shown that the MYB75/PAP1 gene encodes SIAA1. Genetic complementation studies and analysis of a laboratory-generated knockout mutation in this gene confirmed this conclusion. Suc, in a concentration-dependent way, induces MYB75/PAP1 mRNA accumulation. Moreover, MYB75/PAP1 is essential for the Suc-mediated expression of the dihydroflavonol reductase gene. The SIAA1 locus in Cvi probably is a weak or loss-of-function MYB75/PAP1 allele. The C24 accession similarly shows a very weak response to Suc-induced anthocyanin accumulation encoded by the same locus. Sequence analysis showed that the Cvi and C24 accessions harbor mutations both inside and downstream of the DNA-binding domain of the MYB75/PAP1 protein, which most likely result in loss of activity.

Alleles↗
PubMed2003

Up-regulation of cyr61 in vascular smooth muscle cells of spontaneously hypertensive rats.

In the present study, we applied a fluorescent differential display method to mRNAs from aortae of spontaneously hypertensive rats (SHRs), stroke-prone spontaneously hypertensive rats (SPSHRs), and their parental strain, Wistar Kyoto rats (WKYRs), to identify the genes involved in the development of hypertension. Through this screen we came across a gene that is consistently up-regulated in hypertensive rats. Nucleotide sequence determination of the corresponding cDNA revealed that the gene is the rat orthologue of cyr61. Northern blot analysis showed that cyr61 expression increases in SHR and SPSHR before the onset of hypertension and is sustained thereafter at higher levels than in age-matched WKYRs. In situ hybridization analysis demonstrated that cyr61 is expressed strongly in smooth muscle cells (SMCs) in media of SHR and SPSHR but not WKYR aorta. Fluorescent in situ hybridization mapped the cyr61 gene to rat chromosome 1p12-13, which is located in close proximity to a recently defined quantitative trait locus including NHE3 Na(+)/H(+) exchanger. Overexpression of the cyr61 gene in stably transfected rat SMC line A7r5 caused rather inhibitory effects on the proliferation and DNA and protein synthesis. Our results thus demonstrate for the first time that cyr61 can also act as a growth inhibitor in SMC of genetically hypertensive rats. This may reveal a new route for investigation of the pathogenesis of hypertension.

Amino Acid Sequence↗
PubMed1995

Cold-Specific Induction of a Dehydrin Gene Family Member in Barley.

An interval on barley (Hordeum vulgare L.) chromosome 7 accounting for significant quantitative trait locus effects for winter hardiness were detected in a winter (Dicktoo) x spring (Morex) barley population (P.M. Hayes, T. Blake, T.H.H. Chen, S. Tragoonrung, F. Chen, A. Pan, and B. Liu [1993] Genome 36: 66-71). Two members of the barley dehydrin gene family, Dhn1 and Dhn2, were located within the region defining the winter hardiness quantitative trait locus effect (A. Pan, P.M. Hayes, F. Chen, T. Blake, T.H.H. Chen, T.T.S. Wright, I. Karsai, Z. Bedo [1994] Theor Appl Genet 89: 900-910). To investigate the possible role of Dhn1 and Dhn2 in winter hardiness, we examined the expression pattern of six barley dehydrin gene family members in shoot tissue in response to cold temperature. Incubation of 3-week-old barley plants at 2[deg]C resulted in a rapid induction of a single 86-kD polypeptide that was recognized by an antiserum against a peptide conserved in the dehydrin gene family. Northern blot analysis confirmed the induction of an mRNA corresponding to Dhn5. The expression patterns of cold-induced dehydrins in shoot tissue for Dicktoo and Morex were identical under the conditions studied, in spite of the known phenotypic differences in their winter hardiness. These results, together with the allelic structure of selected high- and low-survival lines, suggest that the Dicktoo alleles at the Dhn1 and Dhn2 may not be the primary determinants of winter hardiness in barley.

Journal Article↗
PubMed2004

Regulatory polymorphisms underlying complex disease traits.

There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to complex disease traits. In contrast to coding sequence polymorphisms, where the consequences of non-synonymous variation may be resolved at the level of the protein phenotype, defining specific functional regulatory polymorphisms has proved problematic. This has arisen for a number of reasons, including difficulties with fine mapping due to linkage disequilibrium, together with a paucity of experimental tools to resolve the effects of non-coding sequence variation on gene expression. Recent studies have shown that variation in gene expression is heritable and can be mapped as a quantitative trait. Allele-specific effects on gene expression appear relatively common, typically of modest magnitude and context specific. The role of regulatory polymorphisms in determining susceptibility to a number of complex disease traits is discussed, including variation at the VNTR of INS, encoding insulin, in type 1 diabetes and polymorphism of CTLA4, encoding cytotoxic T lymphocyte antigen, in autoimmune disease. Examples where regulatory polymorphisms have been found to play a role in mongenic traits such as factor VII deficiency are discussed, and contrasted with those polymorphisms associated with ischaemic heart disease at the same gene locus. Molecular mechanisms operating in an allele-specific manner at the level of transcription are illustrated, with examples including the role of Duffy binding protein in malaria. The difficulty of resolving specific functional regulatory variants arising from linkage disequilibrium is demonstrated using a number of examples including polymorphism of CCR5, encoding CC chemokine receptor 5, and HIV-1 infection. The importance of understanding haplotypic structure to the design and interpretation of functional assays of putative regulatory variation is highlighted, together with discussion of the strategic use of experimental tools to resolve regulatory polymorphisms at a transcriptional level. A number of examples are discussed including work on the TNF locus which demonstrate biological and experimental context specificity. Regulatory variation may also operate at other levels of control of gene expression and the modulation of splicing at PTPRC, encoding protein tyrosine phosphatase receptor-type C, and of translational efficiency at F12, encoding factor XII, are discussed.

Autoimmune Diseases↗
PubMed2005

Identification of candidate genes in the type 2 diabetes modifier locus using expression QTL.

To identify new genetic determinants relevant to type 2 diabetes (T2D), diabetic F2 progeny were generated by intercrossing F1 mice obtained from a cross of BKS.Cg-Lepr(db)+/+m and DBA/2, and T2D-related phenotypes were measured. In the F2 population, increased susceptibility to diabetes and obesity was observed. We also detected the major quantitative trait loci (QTL) modifying the severity of diabetes on chromosome 9, where peaks of logarithm of odds (LOD) overlapped for three traits. To identify candidate genes in the QTL intervals, we combined "expression QTL" (eQTL), taking mRNA levels as quantitative traits, and "interstrain sequence variations, including cSNPs." As a result, four genes were identified from cosegregation of clinical QTL with eQTL and 13 genes were found from interstrain cSNPs as candidates in the T2D modifier QTL. Our combined approach shows the acceleration of the discovery of candidate genes in the QTL of interest, spanning several megabases.

Animals↗
PubMed2001

Improving the comparative map of SSC2p-q13 by sample sequencing of BAC clones.

To improve the comparative map for pig chromosome 2 and increase the gene density on this chromosome, a porcine bacterial artificial chromosome (BAC) library was screened with 17 microsatellite markers and 18 genes previously assigned to pig chromosome 2. Fifty-one BAC clones located in the region of a maternally imprinted quantitative trait locus for backfat thickness (BFT) were identified. From these BACs 372 kb were sample sequenced. The average read length of a subclone was 442 basepair (bp). Contig assembly analysis showed that every bp was sequenced 1.28 times. Subsequently, sequences were compared with sequences in the nucleotide databases to identify homology with other mammalian sequences. Sequence identity was observed with sequences derived from 35 BACs. The average percentage identity with human sequences was 87.6%, with an average length of 143 bp. In total, sample sequencing of all BACs resulted in sequence identity with 29 human genes, 13 human expressed sequence tags (ESTs), 17 human genomic clones, one rat gene, one porcine gene and nine porcine ESTs. Eighteen genes located on human chromosome 11 and 19, and seven genes from other human locations, one rat gene and one porcine gene were assigned to pig chromosome 2 for the first time. The new genes were added to the radiation hybrid map at the same position as the locus from which the BAC that was sequenced was derived. In total 57 genes were placed on the radiation hybrid map of SSC2p-q13.

Animals↗
PubMed2002

Genetic determinants of the stress response in cardiovascular disease.

Originating from Hans Selye's general concept, the biological notion of the stress response implicates neuroendocrine and endocrine pathways as well as their cellular mediators as components of the general adaptation syndrome and its consequences. A highly variable degree of response to psychological and physical stresses has been noted in experimental animals and in human populations. Some stressors, such as the "cold pressor test," have been developed as tools for disease prediction. They apply to variable conditions, from hypertension to insulin resistance, but mostly in relation to cardiovascular outcomes. Other environmental factors, including the degree of salt intake, potentiate the stress response in animals and humans. Our group has undertaken to explore the genetic determinants of the stress response in inbred strains, recombinant congenic and congenic strains, as well as founder human populations. We have succeeded, initially, in linking increased body temperature, a major phenotypic response to stress, to the quantitative trait loci (QTL), one at myh3 on chromosome (Chr) 10, one at hsp27 on Chr 12, and one on Chr Y in the rat. The expression of several stress proteins is under the dominant influence of hstf1 at the rat Chr 7 locus (Mit3). The high prevalence of cardiovascular diseases with traits of enhanced stress responsiveness is discussed here in the context of a paradigm, such as hypertension, in the general population.

Animals↗
PubMed1990

The inheritance of metabolic flux: expressions for the within-sibship mean and variance given the parental genotypes.

Recent developments have related quantitative trait expression to metabolic flux. The present paper investigates some implications of this for statistical aspects of polygenic inheritance. Expressions are derived for the within-sibship genetic mean and genetic variance of metabolic flux given a pair of parental, diploid, n-locus genotypes. These are exact and hold for arbitrary numbers of gene loci, arbitrary allelic values at each locus, and for arbitrary recombination fractions between adjacent gene loci. The within-sibship, genetic variance is seen to be simply a measure of parental heterozygosity plus a measure of the degree of linkage coupling within the parental genotypes. Approximations are given for the within-sibship phenotypic mean and variance of metabolic flux. These results are applied to the problem of attaining adequate statistical power in a test of association between allozymic variation and inter-individual variation in metabolic flux. Simulations indicate that statistical power can be greatly increased by augmenting the data with predictions and observations on progeny statistics in relation to parental allozyme genotypes. Adequate power may thus be attainable at small sample sizes, and when allozymic variation is scored at a only small fraction of the total set of loci whose catalytic products determine the flux.

Animals↗
PubMed2006

QTL analysis of cadmium and zinc accumulation in the heavy metal hyperaccumulator Thlaspi caerulescens.

Thlaspi caerulescens (Tc; 2n = 14) is a natural Zn, Cd and Ni hyperaccumulator species belonging to the Brassicaceae family. It shares 88% DNA identity in the coding regions with Arabidopsis thaliana (At) (Rigola et al. 2006). Although the physiology of heavy metal (hyper)accumulation has been intensively studied, the molecular genetics are still largely unexplored. We address this topic by constructing a genetic map based on AFLP markers and expressed sequence tags (ESTs). To establish a genetic map, an F(2) population of 129 individuals was generated from a cross between a plant from a Pb/Cd/Zn-contaminated site near La Calamine, Belgium, and a plant from a comparable site near Ganges (GA), France. These two accessions show different degrees of Zn and, particularly, Cd accumulation. We analyzed 181 AFLP markers (of which 4 co-dominant) and 13 co-dominant EST sequences-based markers and mapped them to seven linkage groups (LGs), presumably corresponding to the seven chromosomes of T. caerulescens. The total length of the genetic map is 496 cM with an average density of one marker every 2.5 cM. This map was used for Quantitative Trait Locus (QTL) mapping in the F(2). For Zn as well as Cd concentration in root we mapped two QTLs. Three QTLs and one QTL were mapped for Zn and Cd concentration in shoot, respectively. These QTLs explain 23.8-60.4% of the total variance of the traits measured. We found only one common locus (LG6) for Zn and Cd (concentration in root) and one common locus for shoot and root concentrations of Zn (LG1) and of Cd (LG3). For all QTLs, the GA allele increased the trait value except for two QTLs for Zn accumulation in shoot (LG1 and LG4) and one for Zn concentration in root (LG1).

Cadmium↗
PubMed2005

Quantitative analysis of activated microglia, ramified and damage of processes in the frontal and temporal lobes of chronic schizophrenics.

Under pathological conditions, microglial cells undergo activation, which is manifested by the expression of histocompatibility locus antigens class II (HLA II) on their surface as well as by proliferation and varied morphological forms. In schizophrenia, characterised by an essential role played by immunological mechanisms, quantitative analysis of activated microglia -- with well-developed ramification (RM), degenerative traits and damaged processes (from their shortening to their complete lack) (DM) -- may contribute to better understanding of schizophrenia etiopathogenesis. Quantitative analysis was performed on slices derived from the frontal and temporal lobes of 9 brains of schizophrenics and 6 control brains. The nonparametric Mann-Whitney U test was used to assess quantitative differences in the distribution of microglia in these regions of the brain. Statistical analyses were performed with STATISTICA 6.5 Programme. In both structures of the brain, the number of activated microglial cells was higher in schizophrenic brains than in control brains. Except for the first layer of the cerebral cortex with the same amounts of RM and DM, the number of DM cells in the remaining regions was several-fold higher than that of RM cells. It is most likely that disturbances in calcium metabolism and energetic balance as well as antibodies produced in the course of schizophrenia are the agents able to trigger a cascade transforming RM into DM. Quantitative differences in RM and DM, observed between the studied structures and cortical regions, could depend not only on functioning of inter-neuronal and inter-structural links. Our study suggests a pivotal role of microglial cells in repair processes and/or etiopathogenesis of schizophrenia and indicates that they undergo substantial damage in the course of chronic schizophrenia.

Adult↗
PubMed1997

Genetic analysis of a quantitative trait in a mouse model of polycystic kidney disease.

The development of a variety of powerful tools for genome analysis has facilitated the ability to genetically map loci which contribute to the variation of a quantitative trait. However, the fact that these traits are often determined as a result of complex genetic interactions has made their analysis considerably more difficult then the molecular characterization of qualitative traits that are monogenic in origin. We have described the use of a novel method of chromosomal exclusion to map the recessive mutation juvenile cystic kidney (jck) to mouse chromosome 11 using an intercross between (C57BL/6J x DBA/2J) F1 jck/+ mice. The severity of polycystic kidney disease (PKD) in the intercross progeny, which could be quantitated as a function of kidney size, was significantly more variable than that found in the parental C57BL/6J strain, suggesting that a modifier locus or loci introduced from DBA/2J affects expression of jck. Two regions (one from DBA/2J on chromosome 10 and a second from C57BL/6J on chromosome 1) were found to be associated with inheritance of a more severe PKD phenotype. The finding of a highly significant association of inheritance of a C57BL/6J-related locus with disease severity was unexpected since the PKD phenotype in this inbred background is mild. This result suggests that inheritance in the affected F2 mice of loci from the two different parental backgrounds results in the more severe phenotype, presumably as a consequence of a direct or indirect interaction between their protein products. This type of effect, which is an example of genetic epistasis, will make the molecular characterization of loci that contribute to complex traits markedly more difficult than the analysis of monogenic disorders.

Animals↗