Gene amplification in Leishmania.

INTRODUCTION ..................................................................................... 417 A Leishmania Primer ............................................................................ 418 The Leishmania Genome and Circular DNAs ............................................... 419 MULTIPLE MECHANISMS OF DRUG RESISTANCE ...................................... 420 GENES AMPLIFIED IN RESPONSE TO DRUG PRESSURE ............................. 421 Dihydrofolate Reductase-Thymidylate Synthase ............................................. 421 The H Region: a Complex Multiple Drug-Resistance Element .......................... 422 Tunicamycin and Glycosyltransferase ......................................................... 425 ODC, IMPDH, and Classic MDR ............................................................. 425 MISCELLANEOUS AMPLIFIED GENES ....................................................... 426 T and D DNAs .................................................................................... 426 Miniexon ............................................................................................ 427 Subchromosomal Amplifications ................................................................ 427 What Leads to the Emergence of Apparently Nonfunctional Amplified DNAs? ................................................................................. 428 FREQUENCY OF GENE AMPLIFICATION ................................................... 429 STRUCTURE OF EXTRACHROMOSOMAL AMPLIFIED DNAs ........................ 429 Simple, Time-lnvariant Direct and Inverted Amplifications .............................. 430 Unstable and Stable Amplification ............................................................ 430 Recurrence of Rearrangements Involving Repetitive DNA Sequences .................. 431 Functional Genetic Elements Within Amplified DNAs ..................................... 431 Comparisons with Amplified DNAs in Cultured Mammalian Cells ..................... 432 Three Chromosomal Types of Amplification ................................................. 432 MECHANISM OF GENE AMPLIFICATION ................................................... 433 ROLE OF GENE AMPLIFICATION IN LEISHMANIA BIOLOGY AND EVOLUTION ..................................................................... 436 Clinical Drug Resistance ........................................................................ 436 Amplified Genes in Leishmania: a Bridge Between Prokaryotic Resistance Factors and Mammalian Gene Amplifications ................................. 437 Role of Amplification in Shaping the Parasite Genome ................................... 438 PROSPECTUS ......................................................................................... 439