Gene Identification and Study of Paralogy on the Human X Chromosome

Gene identification and study of paralogy on the Human X chromosome Ian P. Barrett and Mark T. Ross The Human X Chromosome group, Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. Email: ipb@sanger.ac.uk The availability of human genomic sequence has enabled the systematic search for genes and the study of their genomic context. In addition, the rapid rate of sequence data production from other organisms allows comparative analysis to identify conserved regions and provide information about the evolution of loci in different species. We have used the genomic sequence to identify genes and pseudogenes in a 15 Mb region of the human X chromosome, Xq22-q23, using a combination of bioinformatics and experimental verification. Selected features from the region will be presented, including evidence of an almost complete insertion of the mitochondrial genome into the nuclear genome and evidence of an apparent gene-fusion involving the NXF2 gene and its subsequent inverted duplication. In order to study the syntenic region of the mouse genome, a sequence-ready BAC tile-path of the region was constructed and is being sequenced. Preliminary comparative analysis of the COL4A5 and COL4A6 genes will be presented. During the course of the gene-mapping on Xq22-q23, extensive paralogy in the region became apparent. Work now in progress to evaluate the tissue expression patterns of these genes and to analyse the syntenic region in mouse should shed further light on the evolution of the region. The gene-map of the region also provided evidence for a large-scale duplication involving genes in the Xq22-q23 region, and genes on Xp. To date there appear to be at least 14 pairs of paralogs involved. Work is now underway to locate the orthologs of these genes in a marsupial genome. Evidence for the duplication will be presented and discussed. The ability to study genes in their context in a large region has illuminated some interesting examples of gene architecture and evidence of paralogy. Availability of large regions of annotated, contiguous genomic sequence from human, and the syntenic region in mouse, will be useful for refining comparative analysis tools and will aid the assignment of orthologs in a complex region.