The cardiac actin locus (Actc-1) is not on mouse chromosome 17 but is linked to beta 2-microglobulin on chromosome 2

A restriction fragment variant and recombinant inbred strains were used to show that the cardiac actin locus (Actc-1) is closely linked to beta 2-microglobulin (B2m) and several other loci on chromosome 2 of the mouse. Close linkage of Actc-1 and B2m in both man and mouse provides another example of a chromosomal segment that has been conserved since the divergence of the lineages leading to these two species.     

The locus for apolipoprotein CII is closely linked to the apolipoprotein E locus on chromosome 19 in man

Summary We have demonstrated close linkage between the genes for apolipoprotein E (apoE) and apolipoprotein CII (apoCII). Families segregating for apoE protein variants were screened for a DNA restriction fragment length polymorphism close to the apoCII gene by using an apoCII cDNA clone. The maximum lod score is 4.52 (sexes combined) at a recombination frequency of zero. Given linkage, it may be assumed that no recombinations have happened in altogether 33 observed meioses. It is therefore evident that the apoCII gene is situated on chromosome 19, close to the apoE gene.     

Differential inspiratory timing is genetically linked to mouse chromosome 3

Genetic control ofdifferential inspiratory timing(TI) at baseline has beenpreviously demonstrated among inbred mouse strains. The inheritancepattern for TI between C3H/HeJ(C3; 188 ± 3 ms) and C57BL/6J (B6; 111 ± 2 ms) progenitors wasconsistent with a two-gene model. By using the strain distributionpattern for recombinant inbred strains derived from C3 and B6progenitors, 100% concordance was established betweenTI phenotypes and DNA markers onmouse chromosome 3. This genotype-phenotype hypothesis was tested bytyping 52 B6C3F₂(F₂) progeny by using simplesequence repeat DNA markers (n = 21)polymorphic between C3 and B6 strains on mouse chromosome 3. Linkageanalysis compared marker genotypes to baseline ventilatory phenotypesby computing log-likelihood values. A putative quantitative trait locuslocated in proximity to D3Mit119 wassignificantly associated with baselineTI phenotypes. At the peak(log-likelihood = 3.3), the putative quantitative trait locusdetermined 25% of the phenotypic variance inTI among F₂ progeny. In conclusion, thisgenetic model of ventilatory characteristics demonstrated an importantlinkage between differential baseline TI and a candidate genomicregion on mouse chromosome 3.

     

The achondroplasia gene is not linked to the locus for neurofibromatosis 1 on chromosome 17

Summary We have investigated genetic linkage of von Recklinghausen neurofibromatosis (NF1) and achondroplasia (ACH) using chromosome-17 markers that are known to be linked to NF1. Physical proximity of the two loci was suggested by the report of a patient with mental retardation and the de novo occurrence of both NF1 and ACH. Since the chance of de novo occurrence of these two disorders in one individual is 1 in 600 million, this suggested a chromosomal deletion as a single unifying molecular event and also that the ACH and NF1 loci might be physically close. To test this, we performed linkage analysis on a three-generation family with ACH. We used seven DNA probes that are tightly linked to the NF1 locus, including DNA sequences that are known to flank the NF1 locus on the centromeric and telomeric side. We detected two recombinants between the ACH trait and markers flanking the NF1 locus. In one recombinant, the flanking markers themselves were nonrecombinant. Multi-point linkage analysis excluded the ACH locus from a region surrounding the NF1 locus that spans more than 15cM (lod score < -2). Therefore, analysis of this ACH pedigree suggests that the ACH locus is not linked to the NF1 locus on chromosome 17.     

Susceptibility to streptozotocin-induced diabetes is mapped to mouse chromosome 11

To study the contribution of beta-cell vulnerability to susceptibility to diabetes, we studied beta-cell vulnerability to a single high dose of streptozotocin (STZ) in an animal model of type 2 diabetes, the NSY mouse, a sister strain of the STZ-sensitive NOD mouse, in comparison with the STZ-resistant C3H mouse. NSY mice were found to be extremely sensitive to STZ. Introgression of a single Chr 11, where STZ-sensitivity was mapped in the NOD mouse, from NSY mice converted STZ-resistant C3H mice to STZ-sensitive. Two nucleotide substitutions were identified in the nucleoredoxin gene, a positional and functional candidate gene for STZ-induced diabetes on Chr 11. These data, together with the co-localization of type 1 (Idd4) and type 2 (Nidd1n) susceptibility genes on Chr 11, suggest that the intrinsic vulnerability of pancreatic beta cells is determined by a gene or genes on Chr 11, which may also contribute to susceptibility to spontaneous diabetes.     

A family of type I keratin genes and the homeobox-2 gene complex are closely linked to the rex locus on mouse chromosome 11

Type I and type II keratins are major constituents of intermediate filaments that play a fundamental role in the cytoskeletal network. By using both somatic cell hybrids and conventional and interspecific linkage crosses, several genes encoding type I keratins, including the epidermal keratin K10, were shown to be closely linked to the homeobox-2 complex and the rex locus on mouse chromosome 11. The absence of crossovers between type I keratin-encoding genes and rex (N = 239), a locus affecting hair development, raises the possibility that mutations at rex and neighboring loci affecting skin and hair development involve type I keratin genes.     

Mapping of the azh locus to mouse chromosome 4.

The azh (abnormal spermatozoon headshape) mutation in the mouse, which results in abnormal sperm head formation, was demonstrated to display an autosomal recessive pattern of inheritance. The azh locus was mapped by crossing mice with the mutation on a relatively pure C57BL/6J(B6) background with C3H/HeKam and backcrossing the F1 mice to B6-azh/azh mice. Up to 60 backcross progeny were typed for azh, by microscopic examination of sperm heads, and for other markers. Eleven loci on chromosomes other than 4 showed no significant linkage with azh. Glucose 6-phosphate dehydrogenase-1 (Gpd-1), located on the distal part of chromosome 4, showed 26% recombination frequency with azh, indicating significant linkage (P less than .001). Linkage with an anonymous DNA probe for the D4Rp1 locus in the central region of chromosome 4 was then analyzed, and only a 5% recombination frequency was observed. The map location indicates that azh is distinct from other known mutations that also result in abnormal sperm heads.     

The genes for interleukins 3 and 5 map to the same locus on mouse chromosome 11

The cytokines, IL-3, IL-4, IL-5, and GM-CSF (encoded by murine genes Il-3, Il-4, Il-5, and Csfgm) belong to a family of secreted glycoprotein hormones that regulate the haemopoietic and immune systems. We demonstrate here using in situ hybridization that Il-3 and Il-5 are both probably located in the segment comprising band A5 and the proximal half of band B1 on mouse chromosome 11 with a possible location point in band B1 near its proximal interface with band A5. In studies reported elsewhere we have shown close physical linkage between Il-3 and Csfgm and also between Il-4 and Il-5. The in situ hybridization results therefore indicate that all four cytokine genes are clustered on chromosome 11 raising the possibility that they arose by ancient gene duplication.     

Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11

We have established that there is a considerable amount of common genetic influence on physiological dependence and associated withdrawal from sedative-hypnotic drugs including alcohol, benzodiazepines, barbiturates and inhalants. We previously mapped two loci responsible for 12 and 9% of the genetic variance in acute alcohol and pentobarbital withdrawal convulsion liability in mice, respectively, to an approximately 28-cM interval of proximal chromosome 11. Here, we narrow the position of these two loci to a 3-cM interval (8.8 Mb, containing 34 known and predicted genes) using haplotype analysis. These include genes encoding four subunits of the GABA(A) receptor, which is implicated as a pivotal component in sedative-hypnotic dependence and withdrawal. We report that the DBA/2J mouse strain, which exhibits severe withdrawal from sedative-hypnotic drugs, encodes a unique GABA(A) receptor gamma2 subunit variant compared with other standard inbred strains including the genetically similar DBA/1J strain. We also demonstrate that withdrawal from zolpidem, a benzodiazepine receptor agonist selective for alpha1 subunit containing GABA(A) receptors, is influenced by a chromosome 11 locus, suggesting that the same locus (gene) influences risk of alcohol, benzodiazepine and barbiturate withdrawal. Our results, together with recent knockout studies, point to the GABA(A) receptor gamma2 subunit gene (Gabrg2) as a promising candidate gene to underlie phenotypic differences in sedative-hypnotic physiological dependence and associated withdrawal episodes.     

The autosomal dominant familial exudative vitreoretinopathy locus maps on 11q and is closely linked to D11S533.

Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is a hereditary disorder characterized by the incomplete vascularization of the peripheral retina. The primary biochemical defect in adFEVR is unknown. The adFEVR locus has tentatively been assigned to 11q by linkage studies. We report the results of an extended multipoint linkage analysis of two families with adFEVR by using five markers (INT2, D11S533, D11S527, D11S35, and CD3D) from 11q13-q23. Pairwise linkage data obtained in the two families were rather similar and hence have not provided evidence for genetic heterogeneity. The highest complied two-point lod score (3.67, at a recombination fraction of .07) was obtained for the disease locus versus D11S533. Multipoint analyses showed that the adFEVR locus maps most likely, with a maximum location score of over 20, between D11S533/D11S527 and D11S35, at recombination rates of .147 and .104, respectively. Close linkage without recombination (maximum lod score 11.26) has been found between D11S533 and D11S527.     

Tightly linked flanking microsatellite markers for the Usher syndrome type I locus on the short arm of chromosome 11.

Usher syndrome type I is an autosomal recessive disease characterized by profound congenital hearing impairment and vestibular dysfunction followed by the onset of progressive pigmentary retinopathy in childhood or early adolescence. A locus (USH1C) for one form of this disease was previously assigned to the short arm of chromosome 11 through linkage studies in the Acadian population of southwestern Louisiana. Linkage analyses of a set of microsatellite markers in 27 Acadian families provide evidence that USH1C lies between D11S861 and D11S928. Three markers (D11S419, D11S921, and D11S899) that lie between the flanking markers show no recombination with USH1C, and all 54 chromosomes with the abnormal allele at the disease locus have identical alleles for D11S419 and D11S921. This haplotype was found on only 10 of 50 chromosomes with the normal allele at the disease locus, suggesting a strong founder effect. Of the 54 chromosomes with the abnormal allele, 12 had a divergent allele at D11S899. These results suggest that USH1C is in the 2-3-cM interval between D11S861 and D11S899.     

Linkage of the cadmium resistance locus to loci on mouse chromosome 12.

The autosomal recessive gene cdm that confers resistance to cadmium-induced testicular necrosis in certain inbred strains of mice has been mapped on Chromosome 12 near varitint-waddler (Va). A 3-point cross involving Va, cdm, and amylase-1 (Amy-1) indicated the following gene order and approximate distances: Va-8-cdm-17-Amy-1. The cdm locus is the first polymorphic locus to be placed on Chromosome 12.     

Mapping the Flv locus controlling resistance to flaviviruses on mouse chromosome 5.

Genetically determined resistance to flaviviruses in mice is a dominant trait conferred by alleles at a single autosomal locus designated Flv, but no gene products have been associated with this locus and the mechanism of resistance is not well understood. To further characterize this model of genetic resistance, we conducted mapping studies to determine the chromosomal location of Flv. Because of evidence suggesting that the Flv locus is on chromosome 5, three-point backcross linkage analyses were used to define the location of Flv relative to previously assigned chromosome 5 markers. The results confirm the chromosome 5 location of Flv and indicate a map position between the anchor loci rd and Gus-s. The chromosomal localization of Flv is the first step in the production of a detailed linkage map of the Flv region, which may open approaches to positional cloning of the resistance gene.     

The IgG2a antibody response to thyroglobulin is linked to the Igh locus in mouse

The IgG-subclass usage by several strains of mice in the response to immunization with mouse thyroglobulin (mTg) was examined in the experimental autoimmune thyroiditis model. While the subclass usage by most mouse strains was similar, the Igh^b allotype-bearing mice consistently produced lower IgG2a levels to mTg. Using CBA-Igh ^b congenic and recombinant inbred strains of mice, the lower level of IgG2a in the Igh^b mouse was mapped to the Igh locus. The regulation of IgG2a appeared to be cis controlled, as the CBA x C57BL/6F₁ mouse also produced reduced IgG2a of the Igh^b (B6) allotype but not Igh^j (CBA) allotype.