Comparative map between chicken Chromosome 15 and human chromosomal region 12q24 and 22q11-q12

The physical and comparative map of GGA15 was improved by the construction of 9 BAC contigs around loci previously mapped on GGA15 by linkage analysis. In total, 240 BAC clones were isolated, covering 30–35% of GGA15, and 120 STS were developed (104 STS derived from BAC end sequences and 18 STS derived within genes). Seventeen chicken orthologues of human genes located on human Chr 22q11-q12 were directly mapped within BAC contigs of GGA15. Furthermore, the partial sequences of the chicken BAC clones were compared with sequences present in the EMBL/GenBank databases and revealed matches to 26 genes, ESTs, and genomic clones located on HSA22q11-q12 and HSA12q24. These results provide a better alignment of GGA15 with the corresponding regions in human and mouse, and improve our knowledge of the evolution and dynamics of the vertebrate genome. GenBank Accession Numbers: The nucleotide sequence data reported in this paper have been submitted to GenBank and have been assigned the accession numbers BZ592394-BZ592544.     

Angelman's syndrome and 15q11-q13 deletion

We discuss the results of cytogenetic reinvestigation in 10 patients with Angelman's syndrome reexamined during the last year. A deletion with 15q11-13 could be demonstrated in 6 of them, confirming that with the available cytogenetic techniques a 15q11-13 deletion is visible and detectable in at least half of the patients with this MCA/MR syndrome. On the other hand, the deletion could not be seen in two affected siblings. This indicates that de novo visible 15q11-13 deletions with low recurrence risk and autosomal recessively inherited cases combine to give an overall sib recurrence risk of less than 25%.     

A new susceptibility locus for migraine with aura in the 15q11-q13 genomic region containing three GABA-A receptor genes

Migraine is the most common type of chronic episodic headache. Several population-based family studies have suggested a strong genetic predisposition to migraine, especially migraine with aura (MA). Although several susceptibility loci have been identified, none of the numerous studies performed to date have led to the identification of a gene responsible for the more common forms of migraine. GABA-A receptors and their modulator sites seem to be involved in the pathophysiological events that underlie migraine. We report on clinical and molecular data from a total of 10 families with MA, in which MA segregates as an autosomal dominant trait and presents with homogeneous clinical features. After excluding linkage with the known candidate loci, we used a functional candidate approach and genotyped these families with markers from the 15q11-q13 genomic region, which contains the genes encoding GABA-A receptor subunits. Evidence of linkage was obtained with a parametric two-point linkage analysis (maximum LOD score of 5.56 at a recombination fraction of 0.001 for marker GABRB3) and was supported by multipoint analysis (maximum LOD score of 6.54 between markers D15S113 and D15S1019). The critical region spanned 3.6 Mb. These results provide the basis for further investigation of the hypothesized relationship between a GABA-A receptor dysfunction and migraine.     

Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in Autism Spectrum Disorder Brazilian Individuals with and without Epilepsy

Copy number variations (CNVs) are an important cause of ASD and those located at 15q11-q13, 16p11.2 and 22q13 have been reported as the most frequent. These CNVs exhibit variable clinical expressivity and those at 15q11-q13 and 16p11.2 also show incomplete penetrance. In the present work, through multiplex ligation-dependent probe amplification (MLPA) analysis of 531 ethnically admixed ASD-affected Brazilian individuals, we found that the combined prevalence of the 15q11-q13, 16p11.2 and 22q13 CNVs is 2.1% (11/531). Parental origin could be determined in 8 of the affected individuals, and revealed that 4 of the CNVs represent de novo events. Based on CNV prediction analysis from genome-wide SNP arrays, the size of those CNVs ranged from 206 kb to 2.27 Mb and those at 15q11-q13 were limited to the 15q13.3 region. In addition, this analysis also revealed 6 additional CNVs in 5 out of 11 affected individuals. Finally, we observed that the combined prevalence of CNVs at 15q13.3 and 22q13 in ASD-affected individuals with epilepsy (6.4%) was higher than that in ASD-affected individuals without epilepsy (1.3%; p<0.014). Therefore, our data show that the prevalence of CNVs at 15q13.3, 16p11.2 and 22q13 in Brazilian ASD-affected individuals is comparable to that estimated for ASD-affected individuals of pure or predominant European ancestry. Also, it suggests that the likelihood of a greater number of positive MLPA results might be found for the 15q13.3 and 22q13 regions by prioritizing ASD-affected individuals with epilepsy.     

Seven polymorphic loci mapping to human chromosomal region 11q22-qter

Seven polymorphic loci that map to human chromosomal region 11q22-qter are revealed by DNA probes isolated from a chromosome-specific phage library constructed from a human X mouse somatic cell hybrid that has retained an 11q;16q translocation as the only human DNA. Three probes, each of which reveals a two-allele polymorphism, and four probes, each of which detects two linked RFLPs, have been characterized. Using a somatic cell hybrid mapping panel that divides 11q into four discrete sections, the seven clones have been localized to specific chromosomal regions. Localization of one of the clones has been confirmed and refined by in situ hybridization.     

A primary linkage map of the human chromosome 11q22-23 region

We have constructed a genetic map of the human chromosomal region 11q22-23 by multipoint linkage analysis of 13 DNA polymorphisms that we have condensed into eight loci. An analysis for linkage disequilibrium between tightly linked probe/enzyme systems allows us to make specific recommendations for future DNA typing at these loci. The resulting sex-averaged multipoint map spans approximately 80 cM and differs considerably from previously reported genetic maps of this region. Our mathematically derived "most likely order" of the markers is compatible with physical mapping data using somatic cell hybrids. The known localizations of at least 14 functional genes and several disease loci to 11q22-23, including ataxia telangiectasia, make the mapping of this region especially relevant to studies of disease pathogenesis.     

Comparative mapping of human Chromosome 14q11.2-q13 genes with mouse homologous gene regions

An examination of the synteny blocks between mouse and human chromosomes aids in understanding the evolution of chromosome divergence between these two species. We comparatively mapped the human (HSA) Chromosome (Chr) 14q11.2-q13 cytogenetic region with the intervals of orthologous genes on mouse (MMU) chromosomes. A lack of conserved gene order was identified between the human cytogenetic region and the interval of orthologs on MMU 12. The evolutionary breakpoint junction was defined within 2.5 Mb, where the conserved synteny of genes on HSA 14 changes from MMU 12 to MMU 14. At the evolutionary breakpoint junction, a human EST (GI: 1114654) with identity to the human and mouse BCL2 interacting gene, BNIP3, was mapped to mouse Chr 3. New gene homologs of LAMB1, MEOX2, NRCAM, and NZTF1 were identified on HSA 7 and on the proximal cytogenetic region of HSA 14 by mapping mouse genes recently reported to be genetically linked within the relevant MMU 12 interval. This study contributes to the identification of homology relationships between the genes of HSA 14q11.2-q13 and mouse Chr 3, 12, and 14. Received: 16 March 2000 / Accepted: 16 June 2000     

Regional mapping of genes encoding human steroidogenic enzymes: P450scc to 15q23-q24, adrenodoxin to 11q22; adrenodoxin reductase to 17q24-q25; and P450c17 to 10q24-q25

Steroid hormones are synthesized by a complex array of 10 enzymes. The genes for each of these have now been cloned, and previous work has determined the regional chromosomal assignments of six of these. We used in situ hybridization to determine the regional chromosomal assignments of the four remaining enzymes. The CYP11A1 gene encodes mitochondrial P450scc, which converts cholesterol to pregnenolone, and is located on 15q23-q24. The gene for adrenodoxin, which receives electrons from adrenodoxin reductase and transfers them to P450scc, is on 11q22 while its pseudogenes are on 20q11-q12. The gene for adrenodoxin reductase is on 17q24-q25. The CYP17 gene encodes P450c17, which has both 17 alpha-hydroxylase and 17,20-lyase activities, and is located on 10q24-q25. None of the 10 genes involved in human steroidogenesis is closely linked to another gene for a steroidogenic enzyme.     

Genomic organization of the human folate receptor genes on chromosome 11q13.

There has been interest in the high affinity folate receptor (FOLR) recently because of its high expression in the majority of ovarian tumors. The FOLR genes are part of a family that includes an adult gene, a fetal gene, and one or more pseudogenes, which have been localized to chromosome 11. As a step toward understanding why the adult FOLR gene product is expressed on tumors, we have determined the organization of all the human FOLR-related genes. YAC clones were isolated using the adult FOLR probe. The organization of the locus was determined by PFGE of YAC DNA and by YAC fragmentation. Four FOLR-related genes were found within 140 kb. The adult and fetal genes are not more than 23 kb apart, with the 3' end of the adult gene facing the 5' of the fetal gene. A physical map of over 900 kb of the surrounding region was also constructed. The chromosomal assignment of the FOLR locus was refined to 11q13.3-q13.5 telomeric of the FGF3 locus using fluorescence in situ hybridization.     

A progressive autosomal recessive cataract locus maps to chromosome 9q13-q22

Cataracts are the leading cause of blindness in most countries. Although most hereditary cases appear to follow an autosomal dominant pattern of inheritance, autosomal recessive inheritance has been clearly documented and is probably underrecognized. We studied a large family-from a relatively isolated geographic region-whose members were affected by autosomal recessive adult-onset pulverulent cataracts. We mapped the disease locus to a 14-cM interval at a novel disease locus, 9q13-q22 (between markers D9S1123 and D9S257), with a LOD score of 4.7. The study of this progressive and age-related cataract phenotype may provide insight into the cause of the more common sporadic form of age-related cataracts.     

Genetic mapping of nine DNA markers in the q11----q22 region of the human X chromosome

We have ordered nine polymorphic DNA markers within detailed map of the proximal part of the human X chromosome long arm, extending from band q11 to q22, by use of both physical mapping with a panel of rodent-human somatic hybrids and multipoint linkage analysis. Analysis of 44 families (including 17 families from the Centre d'Etude du Polymorphisme Humain) provided highly significant linkage data for both order and estimation of map distances between loci. We have obtained the following order: DXS1-DXS159-DXYS1-DXYS12-DXS3-(DXS94 , DXS178)-DXYS17. The most probable location of DXYS2 is between DXS159 and DXS3, close to DXYS1 and DXYS12. The high density of markers (nine loci within 30 recombination units) and the improvement in the estimation of recombination frequencies should be very useful for multipoint mapping of disease loci in this region and for diagnostic applications.     

A refined radiation hybrid map of the telomeric region of bovine chromosome 18q25-q26 compared with human chromosome 19q13

Genome-wide scans have mapped economically important quantitative trait loci (QTL) for mastitis susceptibility in dairy cattle at the telomeric end of bovine chromosome 18 (BTA18). In order to increase the density of markers in this chromosomal region and to improve breakpoint resolution in the human-bovine comparative map, this study describes the chromosomal assignment of seven newly developed gene-associated markers and five microsatellites and eight previously mapped sequence tagged site markers near these QTL. The orientation of KCNJ14, BAX, CD37, NKG7, LIM2, PRKCG, TNNT1, MGC2705, RPL28, EPN1, ZNF582, ZIM2, STK13, ZNF132 and SLC27A5 on the 3000-rad radiation hybrid (RH) map of BTA18 is homologous to the organization found on the corresponding 10 Mbp of human chromosome 19q (HSA19q). The resulting bovine RH map with a length of 20.9 cR spans over about 11 cM on the bovine linkage map. The location of KCNJ14 and SLC27A5 flanking the RH map on BTA18q25-26 has been confirmed by fluorescence in situ hybridization. The data of this refined human-bovine comparative map should improve selection of candidate genes for mastitis susceptibility in dairy cattle.