Chromosomal Organization of the Human Dihydrofolate Reductase Genes: Dispersion, Selective Amplification, and a Novel Form of Polymorphism
Proceedings of the National Academy of Sciences of the United States of America
Gene mapping, Methotrexate resistance, Intronless pseudogenes, Gene amplification
The human dihydrofolate reductase (DHFR; tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 220.127.116.11) gene family includes a functional gene (hDHFR) and at least four intronless genes. Three intronless genes (hDHFR-ψ2, hDHFR-ψ3, and hDHFR-ψ4) are identifiable as pseudogenes because of DNA sequence divergence from the functional gene with introns, while one intronless gene (hDHFR-ψ1) is completely homologous to the coding sequences of the functional gene. Analysis of genomic DNA from two panels of somatic human-rodent cell hybrids with specific molecular probes provide insight into the chromosomal organization and assignment of these genes. The five genes are dispersed in that each one is found on a different chromosome. The functional gene hDHFR has been assigned to chromosome 5, and one pseudogene (hDHFR-ψ4), 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 four intronless pseudogenes. hDHFR-ψ1 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.
Anagnou, Nicholas P.; Stephen J. O'Brien; Takashi Shimada; William G. Nash; Mann-Jy Chen; and Arthur W. Nienhuis. 1984. "Chromosomal Organization of the Human Dihydrofolate Reductase Genes: Dispersion, Selective Amplification, and a Novel Form of Polymorphism." Proceedings of the National Academy of Sciences of the United States of America 81, (16): 5170-5174. http://nsuworks.nova.edu/cnso_bio_facarticles/246