Chromosomal organization of the human dihydrofolate reductase genes: dispersion, selective amplification, and a novel form of polymorphism.

Publisher Website
Google Scholar
Abstract
The human dihydrofolate reductase (DHFR; tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 1.5.1.3) gene family includes a functional gene (hDHFR) and at least 4 intronless genes. Three intronless genes (hDHFR-.psi.2, hDHFR-.psi.3 and hDHFR-.psi.4) are identifiable as pseudogenes because of DNA sequence divergence from the functional gene with introns, while one intronless gene (hDHFR-.psi.1) is completely homologous to the coding sequences of the functional gene. Analysis of genomic DNA from 2 panels of somatic human-rodent cell hybrids with specific molecular probes provide insight into the chromosomal organization and assignment of these genes. The 5 genes are dispersed in that each one is found on a different chromosome. The functional gene hDHFR was assigned to chromosomes 5, and 1 pseudogene (hDHFR-.psi.4), to chromosome 3. In a human cell line (HeLa) that was selected for methotrexate resistance, the functional locus became amplified, while there was no amplification of the 4 intronless pseudogenes. hDHFR-.psi.1 was found to be present in DNA of some individuals and absent from DNA of others, consistent with a recent evolutionary origin of this gene originally suggested by its sequence identity to the coding portions of the functional gene. The presence or absence of this intronless pseudogene represents a previously unreported form of DNA polymorphism.