Physical and meiotic mapping of the region of human chromosome 4q11-q13 encompassing the vitamin D binding protein DBP/Gc-globulin and albumin multigene cluster

Abstract

The vitamin D binding protein/Gc-globulin (DBP) gene is a member of a multigene cluster that includes albumin (ALB), alpha-fetoprotein (AFP), and alpha-albumin/afamin (AFM). All four genes have structural and functional similarities and map to the same chromosomal regions in humans (4q11-q13), mice, and rats. An accurate physical map of the region encompassing these genes is a prerequisite for study of their respective transcriptional regulation and identification of potential shared regulatory elements. By refining the physical and meiotic maps of the 4q11-q13 region and creating a local PAC contig, the order and transcriptional orientations of these four genes were determined to be centromere-3'-DBP-5'-5'-ALB-3'-5'-AFP-3'-5'-AFM3'-telomere. The ancestral DBP gene was separated from the ALB gene by >1.5 Mb. This organization and spacing establishes a foundation for ongoing functional studies in this region.

Figure 1

Genetic and physical maps of the subcentromeric region of chromosome 4. (A) Genetic map (Fan et al. 1994); (B) physical map of 4q11–q21 (The Genome Database; Stanford Human Genome Center; Karrman et al. 1997). Lack of redundancy in this YAC contig suggested the possibility of an inversion of the interval enclosed in brackets. (C) Order of loci derived from the genotyping of CEPH families. The three markers tested in this study are boxed. Markers are underlined to indicate that there were no recombinants between them. (D) Crossover map of 4q11–q21. DNA samples of seven individuals from CEPH families known to have a recombination between (D4S392/D4S2969/D4S1543) and (D4S2958/D4S2990/D4S1558/D4S3042) were genotyped for markers D4S2641, D4S1517, and D4S2403, resulting in the deduced ordering shown in C.

Figure 2

Schematic diagram of the human chromosome 4q11–q21 region deduced from P1/PAC and YAC contigs. (A) The order of markers determined from previous (Stanford Human Genome Center; Karrman et al. 1997) and present data are shown. The distances between the markers are not drawn to scale, and the orders of STS markers enclosed by parentheses were not determined. Markers are indicated without the D4S designation. The angled arrows indicate the transcriptional directions of the genes. (B) Contigs of bacteriophage P1/PAC clones in the DBP gene region and in region of the ALB/AFP/AFM gene cluster isolated for this study. (C) YAC contig linking the DBP gene with the ALB/AFP/AFM gene cluster from previous (Stanford Human Genome Center; Karrman et al. 1997) and present data. The sizes of each YAC clone are indicated in parentheses. All the markers shown were tested for each YAC. A solid circle indicates the presence of the STS or the gene shown in A. An open circle indicates that the presence of that marker could not be confirmed in our experiments. An asterisk (*) indicates that our results were discrepant with the literature.