Physical maps on chromosome 1p
Genetic Localisation
The position of 27 chromosome 1p genes have either been refined or established in the period following the last chromosome workshop (Table 1). Approximately half of the localizations were within 1p35-1pter, the region of 1p believed to contain genes responsible for various neoplasias. A few genetic localizations of note are discussed below.
DFFA, believed to involved in cellular apoptosis by chromatin cleavage, has been localized by FISH to 1p36.2-p36.3 by Leek and colleagues. Human DR3, which encodes a tumor necrosis factor and is also believed to be involved in apoptosis, is reported to be tandemly duplicated in 1p36.2-p36.3 and deleted or translocated in neuroblastoma cell lines. CD137, another member of the tumor necrosis family, has been localized by PCR and Southern blot analysis to 1p36 by Schwarz and colleagues. In an attempt to identify putative tumor suppressors in 1p36, Onyango and co-workers have identified two new genes, C1orf1 and XBX1; two new members of known gene families, PTPRZ2 and FRAP2; and ENO1L1, which shares coding sequence with ENO1 and MBP-1, differing only in its 5’ UTR. The previously reported human cDNA, B120, has been localized to 1p35-p36, and is believed to have a role in lipid metabolism and a possible association with Schnyder crystalline corneal dystrophy. Van Camp and colleagues have established linkage of DFNA2, one of thirteen genes thought to be responsible for autosomal dominant hearing loss, to 1p34 between D1S432 and MYCL1. Hereditary isolated congenital ptosis, an autosomal dominant disorder characterized by dropping of the upper eyelids, has been positioned in 1p32-p34 by Engle and co-workers using FISH. SSCP, mutation analysis and physical mapping by Van Hul and colleagues has excluded CSF-1 as the gene responsible for causing Albers-Schonberg disease in 1p21.
Physical Mapping
Significant progress has been made towards the generation of a sequence ready bacterial clone map of 1p since the last workshop. Contributions towards this target have been made by 10 localized projects (Table 2), six of which were reported at this workshop, and by the whole chromosome mapping project.
Three new physical maps have been generated within 1p36, a region of the chromosome prone to deletion or rearrangements in several human malignancies. White and colleagues have mapped CA6 and ENO1 to a 1.3 Mb contig and have reassigned SLC2A5 from 1p31 to 1p36.2 by somatic hybrid and RH typing. Tao and co-workers have provided anecdotal evidence to confirm the difficulty of obtaining faithful YAC coverage in telomeric regions of the chromosome. In their attempt to identify the CMT2A gene they have reported that all but 1 of 45 YACs isolated for the region to be chimeric. Contigs from the Sanger Centre are now being amalgamated with PAC clones isolated using markers chosen from RH and genetic maps. A YAC contig covering the GLC3A critical region is being used as an anchor by Stoilov and colleagues to establish bacterial clone coverage. Bacterial clones, which map within the critical region, are currently being used to identify candidate genes.
In an attempt to isolate the gene responsible for Choreoathetosis/Spasticity, episodic (CSE) Hofele and colleagues have constructed an 8 cM YAC contig comprising 50 YACs covering a region of 1p33. Previously identified loci as well as 15 new STSs, generated from YAC ends, and 13 ESTs have been assigned to the contig.
Loss of heterozygosity in breast cancer is frequent in 1p31. Two contigs have been generated in the period following the last workshop. Brintnell and colleagues have constructed a 7 Mb contig comprising CEPH and Zeneca YACs and BACs. Two overlapping BACs spanning the region of loss have been sequenced and are being used for gene detection. Baptista and co-workers are using YACs across a 10 Mb interval as probes to generate a cosmid pocket map and to identify additional PACs from the region. Roberts and colleagues are characterizing a neuroblastoma breakpoint in 1p22 by constructing a 6 Mb YAC contig. The contig contains 6 STSs and 3 newly assigned ESTs.
A 2 Mb YAC contig in 1p13.3 is being constructed by Flomen and co-workers. YACs from this gene rich region, defined by the genes MCSF (distal) and YKL39 (proximal), are being used in conjunction with STSs/ESTs and YAC ends to isolate PAC clones. Overlaps between bacterial clones will be identified by EcoRI fingerprinting. Two physical maps of the GSTM cluster have been constructed. The partial map of the 4 GSTM genes generated by Xu and colleagues has been used to localise the end points of a polymorphic GSTM1 deletion. Mayau and co-workers have constructed a YAC map across the same region of 1p13 and were able to determine the order of 12 genes, whilst reassigning AMPD2 from 1p21-p34 to 1p13.
In the past 18 months substantial progress has been made by the Sanger Centre’s chromosome 1 mapping and sequencing project. The short arm has been the initial focus of large scale PAC isolation and fingerprinting. The current RH map of 1p contains 2819 STSs, 2329 of which have been used to screen gridded bacterial clone arrays. Restriction fingerprinting (Gregory et al., 1997) of a proportion of the positive clones, and parallel assignment of individual STSs, has yielded 25 Mb of contigs with established STS content. Another 110 Mb of bacterial clone contigs are awaiting individual STS assignment. (For more details see below).
Gene Structures
The genomic structures of 11 genes have been resolved in the period following the last workshop (Table 3). Of note is the characterisation of mutations within ABCR, the gene associated with autosomal recessive Stargardt disease (STGD), retinitis pigmentosa (RP19), and cone rod dystrophy (CRD).