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Physical map of a conditionally dispensable chromosome in Nectria haematococca mating population VI and location of chromosome breakpoints.

Certain isolates of the plant pathogenic fungus Nectria haematococca mating population (MP) VI contain a 1.6-Mb conditionally dispensable (CD) chromosome carrying the phytoalexin detoxification genes MAK1 and PDA6-1. This chromosome is structurally unstable during sexual reproduction. As a first step in our analysis of the mechanisms underlying this chromosomal instability, hybridization between overlapping cosmid clones was used to construct a map of the MAK1 PDA6-1 chromosome. The map consists of 33 probes that are linked by 199 cosmid clones. The polymerase chain reaction and Southern analysis of N. haematococca MP VI DNA digested with infrequently cutting restriction enzymes were used to close gaps and order the hybridization-derived contigs. Hybridization to a probe extended from telomeric repeats was used to anchor the ends of the map to the actual chromosome ends. The resulting map is estimated to cover 95% of the MAK1 PDA6-1 chromosome and is composed of two ordered contigs. Thirty-eight percent of the clones in the minimal map are known to contain repeated DNA sequences. Three dispersed repeats were cloned during map construction; each is present in five to seven copies on the chromosome. The cosmid clones representing the map were probed with deleted forms of the CD chromosome and the results were integrated into the map. This allowed the identification of chromosome breakpoints and deletions.

Ascomycota↗

The gene for autosomal dominant cerebellar ataxia type II is located in a 5-cM region in 3p12-p13: genetic and physical mapping of the SCA7 locus.

Two families with autosomal dominant cerebellar ataxia with pigmentary macular dystrophy (ADCA type II) were investigated. Analysis of 23 parent-child couples demonstrated the existence of marked anticipation, greater in paternal than in maternal transmissions, with earlier age at onset and a more rapid clinical course in successive generations. Clinical analysis revealed the presence of a great variability in age at onset, initial symptom, and associated signs, confirming the characteristic clinical heterogeneity of ADCA type II. The gene for ADCA type II previously was mapped to the spinocerebellar ataxia 7 (SCA7) locus on chromosome 3p12-p21.1. Linkage analysis of the two new families of different geographic origin confirmed the characteristic genetic homogeneity of ADCA type II, distinguishing it from ADCA type I. Haplotype analysis permitted refinement of the SCA7 region to the 5-cM interval between markers D3S1312 and D3S1600 on chromosome 3p12-p13. Eighteen sequence-tagged sites were used for the construction of an integrated map of the candidate region, based on a YACs contig. The entire candidate region is contained in a single nonchimeric YAC of 660 kb. The probable involvement of a CAG trinucleotide expansion, suggested by previous studies, should greatly facilitate the identification of the gene for ADCA type II.

Adolescent↗

An integrated gene and SSLP BAC map framework of mouse chromosome 11.

Physical maps are important resources both in sequencing and in functional analyses of large genomes. Global contig-building approaches are regarded to be more efficient relative to the cumulative outcome of scattered and more localized physical mapping studies accompanying positional cloning. This work is part of an effort to assemble a complete physical map of mouse chromosome 11 in which selection of clones containing specific genetic markers from genomic libraries is the first step in the process. Using a previously developed strategy, we identified 361 bacterial artificial chromosomes (BACs) containing 88 gene markers. Since the linkage positions of markers chosen for these studies are known, the BAC framework obtained is anchored to the genetic map and represents about 13% of the length of the entire chromosome. Together with similar assignments of BACs generated previously using D11Mit markers (Cai et al., 1988, Genomics, 54: 387-397), 36-40% of the chromosome 11 is now assembled into contigs, and these contigs correlate through 51 clones carrying both gene and simple sequence length polymorphism markers.

Animals↗

Construction of a BAC library of Rosa rugosaThunb. and assembly of a contig spanning Rdr1, a gene that confers resistance to blackspot.

A BAC library to serve as a general tool for the physical mapping and positional cloning of rose genes has been constructed from Rosa rugosa DNA. With 27,264 clones the library contains 5.2 genome equivalents. The library was used to assemble a contig of BAC clones spanning Rdr1, a locus that confers resistance to blackspot. For this purpose fine-scale mapping of the target locus was achieved by bulked segregant analysis using 816 AFLP primer combinations. The target region around Rdr1 comprises about 400 kb and is covered by a minimum of six BAC clones. Furthermore, the detection of at least five resistance gene analogs of the TIR-NBS-LRR family on the contig indicates the presence of a cluster of resistance genes around Rdr1. These results will not only allow the isolation and identification of Rdr1 in the near future, but also provide the tools for the physical mapping and positional cloning of other horticulturally interesting genes in roses.

Base Sequence↗

A first-generation porcine whole-genome radiation hybrid map.

A whole-genome radiation hybrid (WG-RH) panel was used to generate a first-generation radiation map of the porcine (Sus scrofa) genome. Over 900 Type I and II markers were used to amplify the INRA-University of Minnesota porcine Radiation Hybrid panel (IMpRH) comprised of 118 hybrid clones. Average marker retention frequency of 29.3% was calculated with 757 scorable markers. The RHMAP program established 128 linkage groups covering each chromosome (n = 19) at a lod >/= 4.8. Fewer than 10% of the markers (59) could not be placed within any linkage group at a lod score >/=4.8. Linkage group order for each chromosome was determined by incorporating linkage data from the swine genetic map as well as physical assignments. The current map has an estimated ratio of approximately 70 kb/cR and a maximum theoretical resolution of 145 kb. This initial map forms a template for establishing accurate YAC and BAC contigs and eventual positional cloning of genes associated with complex traits.

Animals↗

A physical map encompassing GP2B, EPB3, D17S183, D17S78, D17S1183, and D17S1184.

The q21 region of chromosome 17 contains the gene BRCA1, which is involved in familial early-onset breast and ovarian cancers. A physical map of a region that extends from a distal boundary of the BRCA1 region, D17S78, to GP2B has been constructed. The map consists of 30 STSs, including 2 new short tandem repeat polymorphic markers. The contig is composed of a mixture of 7 YACs, 5 P1 plasmids, and 14 cosmids and was ordered by STS-content mapping.

BRCA1 Protein↗

Establishment of bovine chromosome region specific high resolution maps using microdissection.

An alternative approach for the direct analysis of chromosome regions corresponding to economical traits on the basis of chromosome microdissection is described. Large fragment clones isolated with primer pairs designed from chromosome fragment-specific DNA sequences were localized by FISH to the scraped chromosome region of interest. The chromosome fragment-specific clones are a useful tool for the generation of region specific high density marker and gene maps and represent the source material for the development of a DNA contig including the economical trait.

Animals↗

Molecular mapping of chromosome 2 deletions in murine radiation-induced AML localizes a putative tumor suppressor gene to a 1.0 cM region homologous to human chromosome segment 11p11-12.

Radiation-induced acute myeloid leukemias (AMLs) in the mouse are characterized by chromosome 2 deletions. Previous studies showed that a minimal deleted region (mdr) of approximately 6.5 cM is lost from one homologue in chromosome 2-deleted AMLs. An AML tumor suppressor gene is proposed to map within this mdr. In this study, we refine the mdr to a I cM interval between markers D2Mit126 and D2Mit185 by microsatellite analysis of 21 primary radiation-induced F I AMLs. The construction of a partial yeast artificial chromosome (YAC) contig spanning the mdr and the location of six known genes indicated that the 1 cM mdr is homologous to human 11p11-12, a region implicated in some human AMLs. Screening of five cell lines derived from primary radiation-induced AMLs for homozygous loss of microsatellites and genes mapping within the mdr revealed loss of both copies of the hemopoietic tissue-specific transcription factor Sfpi1(PU.1/Spi1) in one cell line. Studies of primary and F1 AMLs failed to implicate Sfpi1 as the AML tumor suppressor gene. YAC contig construction, together with data suggesting that the critical gene flanks Sfpi1, represents significant progress toward identifying an AML tumor suppressor gene.

Animals↗

Refined genetic mapping of the darier locus to a <1-cM region of chromosome 12q24.1, and construction of a complete, high-resolution P1 artificial chromosome/bacterial artificial chromosome contig of the critical region.

Darier disease (DD) (MIM 124200) is an autosomal dominant skin disorder characterized by loss of adhesion between epidermal cells and by abnormal keratinization. We present linkage analysis showing, in four families, key recombination events that refine the location of the DD locus on chromosome 12q23-24.1 to a region of <1 cM. We have constructed a YAC/P1 artificial chromosome (PAC)/bacterial artificial chromosome (BAC)-based physical map that encompasses this refined DD region. The map consists of 35 YAC, 69 PAC, 16 BAC, and 2 cosmid clones that were ordered by mapping 54 anonymous sequence-tagged sites. The critical region is estimated to be 2.4 Mb in size, with an average marker resolution of 37.5 kb. The refinement of the critical interval excludes the ALDH2, RPL6, PTPN11, and OAS genes, as well as seven expressed sequence tags (ESTs) previously mapped in the DD region. The three known genes (ATP2A2, PPP1CC, and SCA2) and the 10 ESTs mapped within the critical region are not obvious candidates for the DD gene. Therefore, this detailed integrated physical, genetic, and partial transcript map provides an important resource for the isolation of the DD gene and, possibly, other disease genes.

Chromosome Mapping↗

A 100-kb physical and transcriptional map around the EDH17B2 gene: identification of three novel genes and a pseudogene of a human homologue of the rat PRL-1 tyrosine phosphatase.

In this paper, we describe the physical map and transcriptional organisation of a 100-kb region with the BRCA1 locus at 17q12-21. Using the cDNA of the EDH17B2 gene as a probe, we screened a human genomic cosmid library. Positive cosmid clones were aligned and a contig around the EDH17B2 gene was established, expanding the previously reported map. In order to identify genes located in this region, we used the cosmid inserts to select cDNAs from a human ovarian cDNA library. Among the clones identified, cDNA OV-1 corresponds to a human homologue of a rat PRL-1 tyrosine phosphatase gene that shows enhanced expression during hepatic regeneration and in some tumour cell lines. Neither the OV-1 nor the PRL-1 protein shares strong homology with any previously characterised phosphotyrosine phosphatase, suggesting that they probably belong to a new phosphatase family. In an attempt to characterise the OV-1 gene, we found that the genomic sequence present on chromosome 17 probably corresponds to a nonfunctional copy of the gene, as it contains several sequence changes that disrupt the potential coding information of the gene. Three other cDNAs, corresponding to unrelated genes, were also identified and characterised. They did not reveal striking homologies in database sequence comparison and therefore represent new genes localised on chromosome 17q, in a region that frequently shows loss of heterozigosity in sporadic breast and ovarian cancers.

Amino Acid Sequence↗

A YAC contig across the fragile X site defines the region of fragility.

The fragile X syndrome is a common cause of mental retardation and is associated with a fragile site at Xq27.3 (FRAXA). Recently, evidence has been presented for the role of methylation and genomic imprinting in the expression of the disease. We have identified a site of methylation in patients by long range restriction mapping of the region. In this paper we present a YAC contig of this area, localise the CpG sequences which are methylated, and show by in situ hybridisation that the site of fragility lies within this region.

Base Sequence↗

Delineation of a minimal region of deletion at 6q16.3 in follicular lymphoma and construction of a bacterial artificial chromosome contig spanning a 6-megabase region of 6q16-q21.

Regional deletions of 6q are frequent karyotypic alterations in malignant lymphoma and are associated with an adverse clinical outcome. One such region of recurrent deletion is 6q16-q21; however, the specific genes affected have not been identified. Our objective in this study was to identify cases with deletion of 6q16-q21 in follicular lymphoma and to define a minimal region of deletion. A physical map of 6q16.2-q21 was constructed using map information from both sequence-based and bacterial artificial chromosome (BAC) fingerprint-based maps. Forty-three BAC clones spanning a 6-Mb region of 6q16.2-q21 were identified and obtained from the RP-11 library. Selected BACs were fluorescence-labeled and hybridized to a series of 34 follicular lymphomas with a regional 6q deletion detected by G banding. Twenty-four cases with deletion of the 6q16.3 region were detected. A minimal deletion of 2.3 Mb was defined. Our study has identified a limited region of deletion of 6q16.3 that may implicate four known genes in follicular lymphoma and possibly in other cancers. A BAC contig spanning a 6-Mb region has been anchored to the 6q16.2-q21 region. This map represents a useful resource for gene identification in this region, not only in lymphoma but also in other neoplasms with 6q alterations.

Chromosome Deletion↗

Transcription map of Xq27: candidates for several X-linked diseases.

Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found.

Chromosome Mapping↗

Constructing chromosome- and region-specific cosmid maps of the human genome.

A chromosome-specific ordered set of cosmids would be a significant contribution toward understanding human chromosome structure and function. We are developing two parallel approaches for creating an ordered cosmid library of human chromosome 19 and other selected subregions of the human genome. The "bottom up" approach is used to establish sets of overlapping cosmids as islands or "contigs" along the chromosome, while the "top down" approach, using pulsed-field gel electrophoresis and yeast cloning, will establish a large-fragment map and close the inevitable gaps remaining from the "bottom up" approach. Source DNA consists of a single homolog of chromosome 19 from a hamster--human hybrid cell and human fragments cloned in yeast artificial chromosomes. We have constructed cosmid libraries in a vector that facilitates cloning small amounts of DNA, allows transcription of the insert termini, and contains unique sites for partial-digest mapping. Computer simulations of cosmid contig building suggest that near-optimal efficiency can be achieved with high-density restriction fragment digest schemes that can detect 20-30% overlap between cosmids. We developed the chemistry and data analysis tools to compare the ordering efficiencies of several cosmid restriction digest fingerprinting strategies. Restriction fragments from a four-cutter digest are labeled with a fluorochrome, separated by polyacrylamide gel electrophoresis, and detected after laser excitation as they traverse a fixed point in the gel. We have also developed the software to rapidly process the output signal to define and analyze the fragment peaks. Up to three cosmids (or three different digests of the same cosmid) plus a size standard are analyzed simultaneously in a single gel lane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

YAC/STS map across 12 Mb of Xq27 at 25-kb resolution, merging Xq26-qter.

A 12-Mb YAC contig has been assembled spanning the Xq27 cytogenetic band with 203 YACs, 121 STSs, and >300 hybridization probes to a resolution of 25 kb. At its centromeric end, the contig is merged with a 9-Mb contig covering Xq26.1-q26.3 at a point 1 Mb telomeric to the factor IX gene; at its telomeric end, it is merged to 7.5 Mb of contigs from the IDS gene to the Xq28 telomere. Thus, the distal 29 Mb of the Xq arm is available cloned in long-range contiguity. The physical map has been integrated with current genetic data by the localization of 18 markers that detect polymorphism. Apparent recombination levels reach >4.5 cM/Mb near the centromeric border of Xq27. The ratio of cM/Mb correspondingly delimits the location of several disease genes-including, for example, X-linked hypoparathyroidism in 3 Mb (6 cM) telomeric to Factor IX.

Base Sequence↗

Characterization of two chromosome 12 cosmid libraries and development of STSs from cosmids mapped by FISH.

We have constructed and characterized two related human chromosome 12-specific cosmid libraries. DNA from flow-sorted chromosomes from a somatic cell hybrid was cloned into a cosmid vector. Approximately 61% of the cosmids in the nearly 26,200 member arrayed libraries (LL12NC01 and LL12NC02) contain human DNA inserts, and 31% of the cosmids derived from human DNA contain CA repeats. One hundred and fifty-two cosmids isolated from the libraries have been mapped by fluorescence in situ hybridization (FISH). Cosmids containing human DNA inserts were localized by FISH exclusively to chromosome 12, confirming the chromosomal specificity of the libraries. The cosmids have been localized to all parts of this chromosome, although some regions are more highly represented than others. Partial sequence information was obtained from 44 mapped cosmids, and oligonucleotide primer pairs were synthesized that define unique sequence tagged sites (STSs). These mapped cosmids, and unique STSs derived from them, provide a set of useful clones and primer pairs for screening YAC libraries and developing contigs centered on regions of interest within chromosome 12. In addition, 120 of the mapped cosmids contain CA repeats, and thus they also provide a useful resource for defining highly polymorphic simple tandem repeat elements that serve as genetic markers for linkage analysis and disease gene localization.

Base Sequence↗

A first generation bovine BAC-based physical map.

A first generation clone-based physical map for the bovine genome was constructed combining, fluorescent double digestion fingerprinting and sequence tagged site (STS) marker screening. The BAC clones were selected from an Inra BAC library (105,984 clones) and a part of the CHORI-240 BAC library (26,500 clones). The contigs were anchored using the screening information for a total of 1303 markers (451 microsatellites, 471 genes, 127 EST, and 254 BAC ends). The final map, which consists of 6615 contigs assembled from 100,923 clones, will be a valuable tool for genomic research in ruminants, including targeted marker production, positional cloning or targeted sequencing of regions of specific interest.

Animals↗

Identification and characterization of the multiple endocrine neoplasia type 1 (MEN1) gene.

For nearly a decade since the mapping of the multiple endocrine neoplasia type 1 (MEN1) locus to 11q13 and the suggestion that it is a tumour suppressor gene, efforts have been made to identify the gene responsible for this familial cancer syndrome. Recently, we have identified the MEN1 gene by the positional cloning approach. This effort involved construction of a 2.8-Mb physical map (D11S480-D11S913) based primarily on a bacterial clone contig. Using these resources, 20 new polymorphic markers were isolated which helped to reduce the interval for candidate genes by haplotype analysis in families and by loss of heterozygosity (LOH) studies in approximately 200 tumours, utilizing laser-assisted microdissection to obtain tumour cells with minimal or no admixture by normal cells. The interval was narrowed by LOH to only 300 kb, and nearly 20 new transcripts that map to this region of 11q13 were isolated and characterized. One of the transcripts was found by dideoxyfingerprinting and cycle sequencing to harbour deleterious germline mutations in affected individuals from MEN-1 kindreds and therefore identified as the MEN1 gene. The type of germline mutations and the identification of mutations in sporadic tumours support the Knudson's two-hit model of tumorigenesis for MEN-1. Efforts are being made to identify the function of the MEN1 gene-encoded protein, menin, and to study its role in tumorigenesis.

Amino Acid Sequence↗