Genomic Mapping of Chromosomal Region 2p15–p21 (D2S378–D2S391): Integration of Genemap'98 within a Framework of Yeast and Bacterial Artificial Chromosomes

doi:10.1006/geno.1999.5957

Genomics

Volume 62, Issue 1, 15 November 1999, Pages 21-33

https://doi.org/10.1006/geno.1999.5957 Get rights and content

Abstract

The region of chromosome 2 encompassed by the polymorphic markers D2S378 (centromeric) and D2S391 (telomeric) spans an approximately 10-cM distance in cytogenetic bands 2p15–p21. This area is frequently involved in cytogenetic alterations in human cancers. It also harbors the genes for several genetic disorders, including Type I hereditary nonpolyposis colorectal cancer (HNPCC), familial male precocious puberty (FMPP), Carney complex (CNC), Doyne's honeycomb retinal dystrophy (DHRD), and one form of familial dyslexia (DYX-3). Only a handful of known genes have been mapped to 2p16. These include MSH2, which is responsible for HNPCC, FSHR, the gene responsible for FMPP, EFEMP-1, the gene mutated in DHRD, GTBP, a DNA repair gene, and SPTBN1, nonerythryocytic β-spectrin. The genes for CNC and DYX-3 remain unknown, due to lack of a contig of this region and its underrepresentation in the existing maps. This report presents a yeast- and bacterial-artificial chromosome (YAC and BAC, respectively) resource for the construction of a sequence-ready map of 2p15–p21 between the markers D2S378 and D2S391 at the centromeric and telomeric ends, respectively. The recently published Genemap'98 lists 146 expressed sequence tags (ESTs) in this region; we have used our YAC–BAC map to place each of these ESTs within a framework of 40 known and 3 newly cloned polymorphic markers and 37 new sequence-tagged sites. This map provides an integration of genetic, radiation hybrid, and physical mapping information for the region corresponding to cytogenetic bands 2p15–p21 and is expected to facilitate the identification of disease genes from the area.

References (52)

K. Akiyama et al.
Structure, promoter analysis and chromosomal assignment of the human APEX gene
Biochim. Biophys. Acta
(1994)
G. Bepler et al.
A 1.4-Mb high-resolution physical map and contig of chromosome segment 11p15.5 and genes in the LOH11A metastasis suppressor region
Genomics
(1999)
K.M. Boycott et al.
Construction of a 1.5-Mb bacterial artificial chromosome contig in Xp11.23, a region of high gene content
Genomics
(1998)
A.R. Brothman
Cytogenetic studies in prostate cancer: Are we making progress
Cancer Genet. Cytogenet.
(1997)
X. Chen et al.
From amplification to gene in thyroid cancer: A high-resolution mapped bacterial-artificial-chromosome resource for cancer chromosome aberrations guides gene discovery after comparative genome hybridization
Am. J. Hum. Genet.
(1998)
R.W. DeBry et al.
Human/mouse homology relationships
Genomics
(1996)
A.O. Edwards et al.
Malattia leventinese: Refinement of the genetic locus and phenotypic variability in autosomal dominant macular drusen
Am. J. Opthalmol.
(1998)
M. Feder et al.
Clinical relevance of chromosome abnormalities in non-small cell lung cancer
Cancer Genet. Cytogenet.
(1998)
R. Fishel et al.
The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer
Cell
(1993)
F.S. Leach et al.
Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer
Cell
(1993)

S.E. Taymans et al.

Radiation hybrid mapping of chromosomal region 2p15–p16: Integration of expressed and polymorphic sequences maps at the Carney complex (CNC) and Doyne's honeycomb retinal dystrophy (DHRD) loci

Genomics

(1999)

A.M. Bjorkqvist et al.

Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung

Br. J. Cancer

(1998)

J.A. Carney et al.

The complex of myxomas, spotty pigmentation, and endocrine overactivity

Medicine

(1985)

A.G. Comuzzie et al.

A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2

Nat. Genet.

(1997)

P. Deloukas et al.

A physical map of 30,000 human genes

Science

(1998)

T. Fagerheim et al.

A new gene (DYX3) for dyslexia is located on chromosome 2

Am. J. Hum. Genet.

(1998)

C.Y. Gregory et al.

The gene responsible for autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) maps to chromosome 2p16

Hum. Mol. Genet.

(1996)

G. Gyapay et al.

A radiation hybrid map of the human genome

Hum. Mol. Genet.

(1996)

T. Haaf et al.

High resolution ordering of YAC contigs using extended chromatin and chromosomes

Hum. Mol. Genet.

(1994)

J. Hager et al.

A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10

Nat. Genet.

(1998)

E. Heon et al.

Linkage of autosomal dominant radial drusen (malattia leventinese) to chromosome 2p16–21

Arch. Ophthalmol.

(1996)

M. Hirai et al.

A method for simultaneous detection of fluorescent G-bands and in situ hybridization signals

Cytogenet. Cell Genet.

(1994)

S. Kermani et al.

Refined genetic and physical positioning of the gene for Doyne honeycomb retinal dystrophy (DHRD)

Hum. Genet.

(1999)

L.S. Kirschner et al.

Large scale preparation of sequence-ready BAC DNA using Qiagen columns

BioTechniques

(1999)

M. Kjellman et al.

Genotyping of adrenocortical tumors: Very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16

J. Clin. Endocrinol. Metab.

(1999)

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^☆: This work was (in part) presented in an abstract form at the 80th Annual Meeting of the Endocrine Society, New Orleans, Louisiana June 24–27, 1998.

¹: To whom correspondence should be addressed at Unit on Genetics and Endocrinology, DEB, NICHD, NIH, Building 10, Room 10N262, 10 Center Drive MSC1862, Bethesda, MD 20892-1862. Telephone: (301) 496-4686 or 402-1998. Fax: (301) 402-0574. E-mail: [email protected].

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Regular ArticleGenomic Mapping of Chromosomal Region 2p15–p21 (D2S378–D2S391): Integration of Genemap'98 within a Framework of Yeast and Bacterial Artificial Chromosomes☆

Abstract

Biochim. Biophys. Acta

Genomics

Genomics

Cancer Genet. Cytogenet.

Am. J. Hum. Genet.

Genomics

Am. J. Opthalmol.

Cancer Genet. Cytogenet.

Cell

Cell

Genomics

Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung

Br. J. Cancer

The complex of myxomas, spotty pigmentation, and endocrine overactivity

Medicine

A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2

Nat. Genet.

A physical map of 30,000 human genes

Science

A new gene (DYX3) for dyslexia is located on chromosome 2

Am. J. Hum. Genet.

The gene responsible for autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) maps to chromosome 2p16

Hum. Mol. Genet.

A radiation hybrid map of the human genome

Hum. Mol. Genet.

High resolution ordering of YAC contigs using extended chromatin and chromosomes

Hum. Mol. Genet.

A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10

Nat. Genet.

Linkage of autosomal dominant radial drusen (malattia leventinese) to chromosome 2p16–21

Arch. Ophthalmol.

A method for simultaneous detection of fluorescent G-bands and in situ hybridization signals

Cytogenet. Cell Genet.

Refined genetic and physical positioning of the gene for Doyne honeycomb retinal dystrophy (DHRD)

Hum. Genet.

Large scale preparation of sequence-ready BAC DNA using Qiagen columns

BioTechniques

Genotyping of adrenocortical tumors: Very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16

J. Clin. Endocrinol. Metab.

Regular Article
Genomic Mapping of Chromosomal Region 2p15–p21 (D2S378–D2S391): Integration of Genemap'98 within a Framework of Yeast and Bacterial Artificial Chromosomes☆