Proximal Part Of Chromosome Research Articles

A Novel Growth Retardation and Abnormal Gonad Morphology Locus on Mouse Chromosome 4

Mutant mice exhibiting a growth retardation phenotype arose spontaneously in the inbred NC/Sgn mouse strain. The mode of inheritance of this mutation was autosomal recessive, and I named this mutation growth deficit (gd). The gd locus was mapped to the proximal part of chromosome 4, between microsatellite markers D4Mit139 and D4Mit178. Histologic abnormalities were detected in the mutant testis and ovary. Degeneration and/or necrosis were found in the seminiferous epithelium, particularly in the spermatocytes; therefore, mutant males were thought to be sterile owing to defective spermatogenesis. Mutant ovaries were generally atrophied. Necrosis of granulosa cells and increased number of atretic follicles were remarkable. The gd locus is suggested to be syntenic to human chromosome segment 9q32-q34, to which no similar mutations had been mapped. Although the molecular nature of this mutation is unclear, gd promises to make future contribution to relevant diseases in human beings.

Mapping genetic modulators of amyloid plaque deposition in TgCRND8 transgenic mice

Alzheimer's disease (AD) is a complex disorder for which various in vivo models exist. The TgCRND8 mouse, transgenic for the human amyloid precursor protein, is an aggressive early onset model of brain amyloid deposition. Preliminary studies revealed that when the transgene is expressed on an A/J genetic background, these mice not only survive longer but also deposit less parenchymal amyloid-beta (Abeta) peptides as compared to those on a C57BL/6 background. We performed a genome-wide study of an F2 intercross between TgCRND8 on an A/J background and C57BL/6 mice, to identify genetic modulators of amyloid accumulation and deposition. We identified four highly significant QTLs that together account for 55% of the phenotypic variance in the number of plaques (Thioflavin S). QTLs were found on the distal part of chromosome 4 with an LOD score of 8.1 at D4Mit251, on chromosome 11 with an LOD score of 5.5 at D11Mit242, on chromosome 9 with an LOD score of 5.0 at D9Mit336 and on the proximal part of chromosome 8 with an LOD score of 4.5 at D8Mit223. A/J alleles at these loci are protective and all decreased the amount of Abeta deposition. Interestingly, the QTL on chromosome 11 is also significantly linked to the levels of brain Abeta(42) and Abeta(40). Although these QTLs do not control the levels of plasmatic Abeta, other regions on chromosomes 1 and 6 show significant linkage. Further characterization of these QTL regions may lead to the identification of genes involved in the pathogenesis of AD.

Oncogene amplification in the proximal part of chromosome 6 in rat endometrial adenocarcinoma as revealed by combined BAC/PAC FISH, chromosome painting, zoo‐FISH, and allelotyping

The inbred BDII rat is a valuable experimental model for the genetic analysis of endometrial adenocarcinoma (EAC). One common aberration detected by comparative genomic hybridization in rat EAC was gain/amplification affecting the proximal part of rat chromosome 6 (RNO6). We applied rat and mouse chromosome painting probes onto tumor cell metaphase preparations in order to detect and characterize gross RNO6 aberrations. In addition, the RNO6q11-q16 segment was analyzed by fluorescence in situ hybridization with probes representing 12 cancer-related genes in the region. The analysis revealed that seven tumors contained large RNO6-derived homogeneously staining regions (HSRs) in addition to several normal or near-normal RNO6 chromosomes. Five tumors (two of which also had HSRs) exhibited a selective increase of the RNO6q11-q16 segment, sometimes in conjunction with moderate amplification of one or a few genes. Most commonly, the amplification affected the region centered around band 6q16 and included the Mycn, Ddx1, and Rrm2 genes. A second region, centering around Slc8a1 and Xdh, also was affected by gene amplification but to a lesser extent. The aberrations in the proximal part of RNO6 were further analyzed using allelotyping of microsatellite markers in all tumors from animals that were heterozygous in the proximal RNO6 region. We could detect allelic imbalance (AI) in 12 of 20 informative tumors, 6 of which were in addition to those already analyzed by molecular cytogenetic methods as described. Our findings suggest that increase/amplification of genes in this chromosome region contribute to the development of this hormone-dependent tumor.

Mapping of genes controlling quantitative antibody production in Biozzi mice.

An extensive search for in vivo immunomodulatory genes (Im genes) was made, using highly polymorphic DNA markers (microsatellites), in F2 hybrids between the two lines of mice selected for high (H) or low (L) Ab production (Biozzi mice). H and L mice have extreme phenotypes resulting from the accumulation, during selective breeding, of genes endowed with, respectively, upward or downward additive effects on Ab production. A total genome screening with 90 microsatellite markers (polymorphic between H and L mice) was conducted in 60 F2 hybrids sorted out for their extreme phenotypes from an immunized population of 240 individuals. A difference in parental marker frequency between these two groups (measured by a chi2 test) reveals the presence of an Im gene close to the marker. Significant chi2 scores were indeed found in two regions corresponding to the MHC and Igh loci, already identified as partly contributing to the H/L phenotypic difference. A notable finding was the demonstration that a gene(s), located on the proximal part of chromosome 6, was linked with Ab responsiveness. Other markers at distinct chromosomal regions also give increased chi2 scores, the two regions most clearly pointed out being on chromosomes 4 and 8.

Chromosomal assignment of three novel mouse genes expressed in testicular cells.

The chromosomal positions of three genes that are selectively expressed in mouse testis cells have been identified. These genes include (i) TAZ83, which codes for an early- to mid-pachytene germ cell stage-expressed, cysteine-rich transmembrane protein (cyritestin) with homologies to various snake toxins and guinea pig sperm-egg fusion proteins; (ii) TNZ1, which is expressed in neonatal Leydig cells; and (iii) TAZ4, a testis-specific gene isolated by immunoscreening with antiserum raised against Sertoli cell membranes. Our experimental data, derived from chromosomal in situ hybridizations and RFLP studies of genetic backcrosses, indicate that (i) the TAZ83 (cyritestin) gene maps to chromosome 8, band A2, near the Plat locus; (ii) TNZ1 is located in the proximal region of chromosome 11; and (iii) TAZ4 is located at band D in the distal portion of chromosome 11, near the Hlr1 locus, with a related sequence, TAZ4-rs1, in the proximal part of chromosome 1.

Assignment of four sequence-tagged sites to three subregions of 13q12 using a somatic cell hybrid mapping panel.

To define the position of a 13q12 breakpoint from a patient with ganglioneuroblastoma, a series of somatic cell hybrids carrying human chromosome translocations with breakpoints in the proximal part of chromosome 13 has been compiled. Sequence-tagged sites (STS) have been generated from a series of Alu-PCR probes previously shown to be in the 13q12 region. Together with an STS for the oncogene FLT1, these have been used to define the relative positions of the translocation breakpoints in the hybrids. In this way, four markers have been ordered in three subregions of 13q12 and reference breakpoints established. The refined physical map of 13q12 provides a series of reference markers with known locations and will be invaluable in the further characterization of breakpoints in this region.

Fine genetic mapping of the proximal part of mouse chromosome 2 excludes Pax-8 as a candidate gene for Danforth's short tail (Sd).

Danforth's short tail (Sd) is a semidominant mutation of the mouse with effects on the skeleton and the urogenital system. In view of its phenotype and its position in the proximal part of Chromosome (Chr) 2, three genes qualified as possible candidates: Pax-8, a paired box-containing gene; Midkine (Mdk), a retinoic acid-responsive gene; and a new locus (Etl-4) identified by enhancer trapping with a lacZ reporter gene which showed expression in the notochord, the mesonephric mesenchyme, and the apical ectodermal ridge. Three different backcrosses involving all three genes in different combinations were set up and analyzed. From our results we conclude that Sd, Etl-4, Pax-8, and Mdk are independent loci, with Etl-4 being the closest genetic marker (1.1 +/- 1.4 cM) to the Danforth's short tail (Sd) gene.

A new Pax gene, Pax-9, maps to mouse chromosome 12.

Members of the Pax gene family have recently been shown to play important roles in mouse embryogenesis. Of eight so far characterized Pax genes, three have been associated with mouse developmental mutants. Here we report the cloning of a new Pax gene, Pax-9. Most of the DNA sequence encoding the highly conserved paired domain has been determined and compared with previously known paired domains. This comparison classifies Pax-9 as a member of the same subgroup as Pax-1/undulated. By analysis of the segregation of a Pax-9 restriction fragment length polymorphism and a large number of simple sequence length polymorphisms in an interspecific C57BL/6 x Mus musculus mollosinus backcross, Pax-9 was mapped close to the D12Nds1 locus on the proximal part of Chromosome (Chr) 12.

Deletion of mouse t-complex distorter-1 produces an effect like that of the t-form of the distorter.

An allele of the mouse brachyury locus, T22H, had been shown previously to involve a deletion of several markers in the proximal part of chromosome 17, and almost certainly includes deletion of the t-complex distorter gene Tcd-1. The effects of T22H on transmission ratio distortion and male sterility caused by the t-complex were compared with those of a partial t-haplotype th51, which carries the t-form of the distorter Tcd-1t. In combination with the complete haplotype tw32, T22H caused severe impairment of male fertility, but males of genotype T22H/t6 or T22H/th51 were normally fertile. These results were very similar to those obtained when th51 was in combination with the same haplotypes. In effect on transmission ratio T22H was again similar to th51, in that it produced a marked increase in the transmission of the haplotype t6. To test whether the effects of T22H were due to deletion of elements other than Tcd-1, the effect of T22H on transmission of the partial haplotype th2 was compared with that of the deletion Thp. Again T22H markedly increased transmission of the t-haplotype and the effect was significantly greater than the small effect produced by Thp. It is concluded that deletion of the distorter Tcd-1 has an effect like that of the t-form of this distorter, Tcd-1t, and hence that Tcd-1t must be an amorph or hypomorph. It is speculated that other t-complex distorters, Tcd-2t and Tcd-3t, may also be amorphs or hypomorphs.(ABSTRACT TRUNCATED AT 250 WORDS)

T(16: 17)43H translocation as a tool in analysis of the proximal part of chromosome 17 (including T-t gene complex) of the mouse.

SUMMARYLinkage relationships of three gene markers of chromosome 17, namely Brachyury (T), tufted (tf), and Histocompatibility-2 (H-2), to the break-point of T(16; 17)43H male sterile translocation were established. The following order was found: T−tf−T43H−H-2. In all cases the translocation break was found in cis to H-2k, haplotype, no recombinant being found among 218 backcross individuals examined. More than 60 viable and fertile animals trisomic for the proximal part of chromosome 17 (including T-t genetic complex) have been recovered among progeny of T43H/+ female translocation heterozygotes as a result of adjacent −2 disjunction at first meiotic division. Mutation tf has been assigned to band 17B in chromosome 17 by comparing the location of T190Ca and T43H genetic and cytological breakpoints. Recombination between centromere 17 and T43H break was reduced almost to zero in the presence of Rb(16.17)7Bnr translocation. The unexpected restoration of male fertility was observed in T43H/Rb7Bnr hybrids (T43H/+ males being completely sterile) which made it possible to prepare the first homozygotes for T43H male–sterile translocation. Direct estimation of chiasma frequencies in centromere 17−T43H region indicated an 11 cM distance between the centromere 17 and the proximal end of t12 haplotype. The significance of centromere −t (or H-2) distance on the predictable restrictions of the possible haploid manifestation of T-t or H-2 gene products on sperm membrane is discussed.

Gene for a serum protein on chromosome 9 in the mouse.

SUMMARYAn electrophoretic variation in a mouse serum protein moving closely to the vitamin D binding protein is described. The variation is determined by two codominant alleles at one locus with the allele in DBA causing fast mobility and that in C57BL causing slow mobility. This locus is located in the proximal part of chromosome 9, 14·3 cM from thedlocus and 31·9 cM from theBgslocus. The protein has not yet been identified but possible candidates among the serum proteins are discussed.