Abstract
Copy number variation of chromosomal segments is now recognized as a major source of genetic polymorphism within natural populations of eukaryotes, as well as a possible cause of genetic diseases in humans, including cancer, but its molecular bases remain incompletely understood. In the baker’s yeast Saccharomyces cerevisiae, a variety of low-order amplifications (segmental duplications) were observed after adaptation to limiting environmental conditions or recovery from gene dosage imbalance, and interpreted in terms of replication-based mechanisms associated or not with homologous recombination. Here we show the emergence of novel high-order amplification structures, with corresponding overexpression of embedded genes, during evolution under favourable growth conditions of severely unfit yeast cells bearing genetically disabled genomes. Such events form massively extended chromosomes, which we propose to call macrotene, whose characteristics suggest the products of intrachromosomal rolling-circle type of replication structures, probably initiated by increased accidental template switches under important cellular stress conditions.
Highlights
Copy number variation of chromosomal segments is recognized as a major source of genetic polymorphism within natural populations of eukaryotes, as well as a possible cause of genetic diseases in humans, including cancer, but its molecular bases remain incompletely understood
Segmental duplications are prone to play a prominent role in modelling genomes over large evolutionary timescales[19], and traces of intraand interchromosomal segmental duplications are observed in natural genomes of a variety of eukaryotic organisms, including human where they may occasionally have pathogenic consequences[20]
Several mechanisms have been invoked at the origin of these temporary low-order amplification structures, including non-allelic homologous recombination between dispersed repeated sequences made of transposable elements or their remnants[10,15,25], micro-homologymediated repair of accidentally broken replication forks[14] and interference between adjacent replication origins[26]
Summary
Copy number variation of chromosomal segments is recognized as a major source of genetic polymorphism within natural populations of eukaryotes, as well as a possible cause of genetic diseases in humans, including cancer, but its molecular bases remain incompletely understood. Evolutionary experiments aimed at studying adaptation to controlled selective pressures[7,8,9,10,11,12] or the recovery from artificial gene dosage imbalance[13,14,15] revealed the frequent formation in this genome of low-order segmental amplifications (mostly two times, rarely up to four or five times), in addition to the more classical point mutations in genes or their regulatory elements. Very little is known so far on the evolutionary trajectories followed by severely altered eukaryotic genomes, resulting from accidental mutations, when cells are allowed to proliferate under optimal conditions, as is the case in some cancers To examine this question, we built permanently disabled S. cerevisiae genomes by replacing key essential genes by their orthologues from another yeast species, taking advantage of the large evolutionary spectrum offered by presently sequenced Saccharomycotina genomes[21]. During prolonged cultures of these strains in rich medium, a variety of faster growing mutants spontaneously appeared, among which we observed novel high-order amplification structures extending chromosome sizes by over 1.5 times (macrotene chromosomes)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
