Copy number variation alters local and global mutational tolerance.
Copy number variation alters local and global mutational tolerance.
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拷贝数变化改变了本地和全球突变耐受性。
DOI：
10.1101/gr.277625.122
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发表时间：
2023-08
期刊：
影响因子：
7
通讯作者：
Gresham, David
中科院分区：
文献类型：
--
作者：
Avecilla, Grace;Spealman, Pieter;Matthews, Julia;Caudal, Elodie;Schacherer, Joseph;Gresham, David
拷贝数变异(CNV)，即基因组序列的复制和缺失，有助于进化适应，但也可能带来有害影响和疾病。虽然扩增单个基因或整个染色体(即非整倍体)的影响已被广泛研究，但对不同大小和结构的CNV的遗传和功能影响知之甚少。在这里，我们研究了酿酒酵母(酵母)菌株，这些菌株在谷氨酰胺限制的化学物质中经过实验进化获得了可变结构和拷贝数的适应性CNV。虽然CNV在选择性环境中是有益的，但在富媒体中，与整倍体祖先相比，CNV导致适合度降低。我们使用转座子突变来研究CNV毒株的突变耐受性和全基因组的遗传相互作用。我们发现，CNV增加了突变靶点的大小，提高了扩增的必需基因的突变耐受性，并导致了与未连锁基因的新的遗传相互作用。我们验证了不同CNV和BMH1之间的一种新的遗传相互作用，这种相互作用在多个菌株中是共同的。我们还分析了整体基因的表达，发现转录剂量补偿并不影响大多数由∼扩增的基因，尽管有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毒株没有表现出先前描述的非整倍体的转录特征。我们的研究揭示了CNV改变局部和全球突变耐受性的程度，这对基因组进化和CNV相关疾病，如癌症，具有重要意义。
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.
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