复制数变异（CNVs) 是基因组序列的重复和缺失，既有助于进化适应，也可能造成有害效应和疾病。尽管对于个别基因或整个染色体（即异染）的扩增效应进行了广泛研究，但对于不同大小和结构的CNVs的遗传和功能效应了解甚少。在这里，我们研究了在谷氨酸限制的连续培养中通过实验进化获得特异结构和拷贝数的Saccharomyces cerevisiae（酵母）菌株的CNVs。尽管在选择环境中有益，但与富含培养基的祖先比较，CNVs会导致适应度降低。我们使用转座子突变来研究CNV菌株中的突变耐受性和全基因组遗传相互作用。我们发现CNVs增加了突变靶位大小，在扩增的必需基因中提供了更高的突变耐受性，并导致与非连锁基因的新型遗传相互作用。我们验证了不同CNVs和BMH1之间的新型遗传相互作用是多个菌株共有的。我们还分析了全局基因表达，并发现转录剂量补偿对大部分被CNVs扩增的基因没有影响，尽管约12%的扩增基因发生了基因特异性的转录剂量补偿。此外，我们发现CNV菌株没有显示先前描述的异染的转录表征。我们的研究揭示了CNVs如何修改局部和全局的突变耐受性，这对基因组进化和与CNVs相关的疾病，比如癌症，具有重要意义。© 2023 Avecilla et al.; Published by Cold Spring Harbor Laboratory Press.

Copy number variants (CNVs), duplications and deletions of genomic sequences, contribute to evolutionary adaptation but can also confer deleterious effects and cause disease. Whereas the effects of amplifying individual genes or whole chromosomes (i.e., aneuploidy) have been studied extensively, much less is known about the genetic and functional effects of CNVs of differing sizes and structures. Here, we investigated Saccharomyces cerevisiae (yeast) strains that acquired adaptive CNVs of variable structures and copy numbers following experimental evolution in glutamine-limited chemostats. Although beneficial in the selective environment, CNVs result in decreased fitness compared with the euploid ancestor in rich media. We used transposon mutagenesis to investigate mutational tolerance and genome-wide genetic interactions in CNV strains. We find that CNVs increase mutational target size, confer increased mutational tolerance in amplified essential genes, and result in novel genetic interactions with unlinked genes. We validated a novel genetic interaction between different CNVs and BMH1 that was common to multiple strains. We also analyzed global gene expression and found that transcriptional dosage compensation does not affect most genes amplified by CNVs, although gene-specific transcriptional dosage compensation does occur for ∼12% of amplified genes. Furthermore, we find that CNV strains do not show previously described transcriptional signatures of aneuploidy. Our study reveals the extent to which local and global mutational tolerance is modified by CNVs with implications for genome evolution and CNV-associated diseases, such as cancer.© 2023 Avecilla et al.; Published by Cold Spring Harbor Laboratory Press.