Comparative architectural aspects of regions of conserved synteny on human chromosome 11p15.3 and mouse chromosome 7 (including genes WEE1 and LMO1)

Abstract

Human chromosome 11p15.3 is associated with chromosome aberrations in the Beckwith Wiedemann Syndrome and implicated in the pathogenesis of different tumor types including lung cancer and leukemias. To date, only single tumor-relevant genes with linkage to this region (e.g. LMO1) have been found suggesting that this region may harbor additional potential disease associated genes. Although this genomic area has been studied for years, the exact order of genes/chromosome markers between D11S572 and the WEE1 gene locus remained unclear. Using the FISH technique and PAC clones of the flanking markers we determined the order of the genomic markers. Based on these clones we established a PAC contig of the respective region. To analyse the chromosome area in detail the synteny of the orthologous region on distal mouse chromosome 7 was determined and a corresponding mouse clone contig established, proving the conserved order of the genes and markers in both species: “cen–WEE1–D11S2043–ZNF143–RANBP7–CEGF1– ST5–D11S932–LMO1–D11S572–TUB–tel”, with inverted order of the murine genes with respect to the telomere/centromere orientation. The region covered by these contigs comprises roughly 1.6 MB in human as well as in mouse. The genomic sequence of the two subregions (around WEE1 and LMO1) in both species was determined using a shotgun sequencing strategy. Comparative sequence analysis techniques demonstrate that the content of repetitive elements seems to decline from centromere to telomere (52.6% to 34.5%) in human and in the corresponding murine region from telomere to centromere (41.87% to 27.82%). Genomic organisation of the regions around WEE1 and LMO1 was conserved, although the length of gene regions varied between the species in an unpredictable ratio. CpG islands were found conserved in putative promoter regions of the known genes but also in regions which so far have not been described as harboring expressed sequences.

Comparative genomic sequencing reveals a strikingly similar architecture of a conserved syntenic region on human chromosome 11p15.3 (including gene ST5) and mouse chromosome 7

“…45 % (both human and mouse) in the major part of the region under study. A similar, but shorter AT-rich subregion has been detected in the adjacent contig containing genes LMO1/TUBBY (Cichutek et al, 2001). Earlier studies using density gradient centrifugation have shown that DNA of mammalian genomes indeed can be separated into classes of distinct GC content.…”

“…We therefore isolated a contiguous set of genomic clones from both human and mouse (ca. 1.6 and 1.4 Mb, respectively), which provided the basis for accurately determining the nucleotide sequence of almost the entire region (Cichutek et al, 2001; and this paper). Here we present the large-scale comparative genomic analysis of roughly 730 kb of human and 620 kb of mouse sequence, centered around the ST5 gene.…”

“…Dot plots were constructed using MEGALIGN (DNAstar Lasergene, USA). Anchor genes, the relative locations of which have been verified by chromosome in situ hybridization (Cichutek et al, 2001), are represented by big empty circles. Filled circles denote other (putative) genes, some of which are novel.…”

The serine/threonine kinase 33 is present and expressed in palaeognath birds but has become a unitary pseudogene in neognaths about 100 million years ago

“…Serine/threonine kinase 33 ( stk33 ) was first discovered in the course of comparative genome analyses of human chromosome 11p15.3 and its orthologous region in the mouse [ 1 – 3 ]. This region is highly syntenic (see Additional file 1 : Figure S1) and known to be associated with several diseases including different types of cancer [ 4 – 8 ].…”