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Families of related genes are thought to be generated mainly by gene duplication (Clark, 1994; Doolittle, 1995). Duplicated genes may diverge both at the level of protein sequence and mode of expression to assume overlapping but distinct functions. Besides duplication of genes, outof-register-recombination of related genes in germline or somatic cells may at times also eliminate one gene, leaving a chimeric gene behind which might be compromised in its function. Indeed, such gene chimeras between related gene family members are readily seen in non-oncogenic genes; for example, hemoglobin Lepore (Seward et al., 1993) results from an out-of-register recombination between g and b globin (Hardison and Miller, 1993), and red-green blindness from a recombination of rhodopsin genes (Bao and Yang, 1991). In marked contrast, a typical way of generating an oncogene is by chromosome translocation in somatic cells, whereby a proto-oncogene is either brought under the influence of a strong regulatory region, notably an enhancer, or its protein coding region is directly fused to that of another gene (Magrath 1992; Barr, 1998). Oncogenic translocations typically involve, at the DNA sequence level, the joining of unrelated DNA. We hypothesize that chimeras between differently regulated members of the same proto-oncogene family would threaten proper control of cell growth (see also Matsuo et al., 1994). While such events in germ cells may well be incompatible with embryonic development, and hence selected against at an early stage, increased expression and/or improper regulation may be particularly undesirable in somatic cells, since they may cause cancer. Even in plants, a family of transcription factor genes was found to be dispersed in the genome (Fischer et al., 1995). Consequently, we assume that there is a strong selection pressure against gene chimeras as a result of out-of-register-recombination, and that such related control genes are separated in the genome to minimize recombination between them. For genes other than those involved in growth control, distorted gene function as a result of homologous out-ofregister recombination should not have such dire consequences and lead, at most, to death of individual cells. To test this hypothesis, we examined gene families whose members include proto-oncogenes as well as gene families whose members are considered ‘harmless’ from the point of view of growth control. According to the hypothesis, one would expect a clear difference in the localization Fig.1 Chromosomal Position of Members of a Proto-Oncogene and a ‘Harmless’ Gene Family. Two pronounced examples are shown, ras-related genes (A) and metallothionein genes (B; Stennard et al., 1994) which are completely dispersed and linked, respectively. The Rap1A and N-Ras genes map to different chromosomal bands; processed metallothionein pseudogenes (MT2BP and another one not mapped on the genome) are not considered for linkage assignment, as outlined in the text. Filled circles, genes that are accurately mapped (assigned to one chromosome band); filled vertical bars, genes that are not yet precisely mapped (several bands by FISH); open circles and open vertical bars, pseudogenes of precise or imprecise map position, respectively.

Proto-Oncogenes, Unlike Harmless Genes, Tend to Be Dispersed in the Human Genome: Selection Against Out-of-Register Recombination?