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Copy number variation alters local and global mutational tolerance

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, muc...

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Autores principales: Avecilla, Grace, Spealman, Pieter, Matthews, Julia, Caudal, Elodie, Schacherer, Joseph, Gresham, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547251/
https://www.ncbi.nlm.nih.gov/pubmed/37652668
http://dx.doi.org/10.1101/gr.277625.122
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author Avecilla, Grace
Spealman, Pieter
Matthews, Julia
Caudal, Elodie
Schacherer, Joseph
Gresham, David
author_facet Avecilla, Grace
Spealman, Pieter
Matthews, Julia
Caudal, Elodie
Schacherer, Joseph
Gresham, David
author_sort Avecilla, Grace
collection PubMed
description 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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spelling pubmed-105472512023-10-04 Copy number variation alters local and global mutational tolerance Avecilla, Grace Spealman, Pieter Matthews, Julia Caudal, Elodie Schacherer, Joseph Gresham, David Genome Res Research 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. Cold Spring Harbor Laboratory Press 2023-08 /pmc/articles/PMC10547251/ /pubmed/37652668 http://dx.doi.org/10.1101/gr.277625.122 Text en © 2023 Avecilla et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Research
Avecilla, Grace
Spealman, Pieter
Matthews, Julia
Caudal, Elodie
Schacherer, Joseph
Gresham, David
Copy number variation alters local and global mutational tolerance
title Copy number variation alters local and global mutational tolerance
title_full Copy number variation alters local and global mutational tolerance
title_fullStr Copy number variation alters local and global mutational tolerance
title_full_unstemmed Copy number variation alters local and global mutational tolerance
title_short Copy number variation alters local and global mutational tolerance
title_sort copy number variation alters local and global mutational tolerance
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547251/
https://www.ncbi.nlm.nih.gov/pubmed/37652668
http://dx.doi.org/10.1101/gr.277625.122
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