Amplification of histone genes by circular chromosome formation in Saccharomyces cerevisiae

Abstract

A previously unknown mechanism for gene amplification has been discovered in the yeast Saccharomyces cerevisiae, involving recombination between transposons that flank a region of the genome that contains histone genes, a centromere, and origins of DNA replication. The transposon sequences physically cross over and recombine as a stable circular chromosome containing the amplified genes. This specific recombination event is enhanced in cells with reduced levels of histones H2A and H2B. Similar mechanisms may be relevant to humans, where 45% of the genome consists of transposons. Proper histone levels are critical for transcription, chromosome segregation, and other chromatin-mediated processes1–7. In Saccharomyces cerevisiae, the histones H2A and H2B are encoded by two gene pairs, named HTA1-HTB1 and HTA2-HTB2 (ref. 8). Previous studies have demonstrated that when HTA2-HTB2 is deleted, HTA1-HTB1 dosage compensates at the transcriptional level4,9. Here we show that a different mechanism of dosage compensation, at the level of gene copy number, can occur when HTA1-HTB1 is deleted. In this case, HTA2-HTB2 amplifies via creation of a new, small, circular chromosome. This duplication, which contains 39 kb of chromosome II, includes HTA2-HTB2, the histone H3-H4 locus HHT1-HHF1, a centromere and origins of replication. Formation of the new chromosome occurs by recombination between two Ty1 retrotransposon elements that flank this region. Following meiosis, recombination between these two particular Ty1 elements occurs at a greatly elevated level in hta1-htb1Δ mutants, suggesting that a decreased level of histones H2A and H2B specifically stimulates this amplification of histone genes. Our results demonstrate another mechanism by which histone gene dosage is controlled to maintain genomic integrity.