Databases compiling comparative mapping data between species are rapidly expanding, with the most comprehensive data sets currently between mouse and human. Chromosome-specific lists detailing orthologous genes in mouse and human can be found at a variety of web sites including the NCBI and the Mouse Genome Database. Human chromosome 1 shares extensive homologies to regions of mouse chromosomes 1, 3 and 4, with smaller regions represented on mouse 5, 8 and 13 (http://www.ncbi.nlm.nih.gov/Omim/Homology/human1.html) and ftp://ftp.informatics.jax.org/pub/informatics/reports/HMD_Human1.sql.rpt). Although the density of comparative gene maps has been steadily increasing, they are likely to be greatly enriched in the near future through analysis and mapping of ESTs. UniGene represents a database of both mouse and human genes and ESTs that are refined into clusters, each representing the transcription product of a distinct gene. Many of the clusters have been given chromosomal assignments by RH mapping. Currently, 90,000 human clusters (release #100) have been identified, with 1980 clusters assigned to chromosome 1. Similar databases are available for the mouse and rat but are not yet as advanced as the human equivalent, with 49,000 and 28,000 clusters identifed for mouse and rat, respectively. Although it is a straightforward matter to make cross-species comparisons to well-annotated mapped ESTs or known genes, it is more problematic to make the same comparison with anonymous genes of unknown function. One way in which this can be achieved at the DNA level is to choose human ESTs mapped to a region of interest and to use BLAST searching against mouse or rat EST sequences to identify an ortholog. The mapping location can then be identified in mouse/rat UniGene if available, or can be used for RH mapping.

Doudney and colleagues (this report) report such an approach to enrich the transcript map around the loop-tail (Lp) locus on distal mouse chromosome 1. This region has previously been shown to be highly conserved with human 1q21-q23 (Kingsmore et al., 1989). Human EST clusters mapping to this region were used to BLAST search mouse gene/EST databases to identify homologous sequences. The potential mouse orthologs were then mapped against a 3 Mb YAC/PAC contig surrounding the Lp locus (Eddleston et al., 1999). A total of 31 genes were comparatively mapped in this way, confirming them as true orthologs on the basis of conserved mapping location as well as sequence similarity. Detailed physical mapping of the human sequences showed conservation of the gene order as well as gene content of this region in the two species, also providing a number of novel candidate genes for Lp.

One drawback to this approach is the potential confusion caused by the misidentification of a closely related gene family member rather than the direct ortholog. Chromosome 1q21-q25 has been duplicated several times during the evolution of mammalian chromosomes, resulting in similar clusters of paralogous genes in several distinct chromosomal locations. These genes frequently retain a high degree of similarity at the DNA level and care must be taken to design locus-specific primers. In the human, regions paralogous to 1q21-q25 include chromosomes 6p21.3, 9q33-q34 and 19q13 (Shiina et al., this report), as well as 1p13, 11q and 12p12-p13 (Lundin, 1993). These paralogous regions have also been identified in the mouse and are equivalent to chromosomes 17, 2, 7, 3, 9, and 6 respectively (Katsanis et al., 1996; Lundin, 1993; Stanier et al., 1998). It therefore follows that novel genes identified in any of these regions will allow prediction of paralogous sequences in the other respective regions (Katsanis et al., 1996), although these will not necessarily be active due to gene silencing (Li, 1982).

Although the most detailed comparative human mapping data is with the mouse, there is now a considerable amount of information available for many other species. Recent reports include assignment of regions of human chromosome 1 to chromosomes 2, 5 and 13 in the rat (Gauguier et al., 1999), linkage groups 2, 6, 16, 19 and 22 in zebrafish (Gates et al., 1999), and chromosomes 2, 3 and 16 in goat (Schibler et al., 1998). Comparative mapping is becoming an increasingly powerful aid to gene discovery, while a knowledge of orthologous genes in mouse and other species will be essential to the study of gene expression and function.