Template switching during DNA replication is a prevalent source of adaptive gene amplification
Copy number variants (CNVs) are an important source of genetic variation underlying rapid adaptation and genome evolution. Whereas point mutation rates vary with genomic location and local DNA features, the role of genome architecture in the formation and evolutionary dynamics of CNVs is poorly unde...
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eLife Sciences Publications Ltd
2025-02-01
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| Online Access: | https://elifesciences.org/articles/98934 |
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| author | Julie N Chuong Nadav Ben Nun Ina Suresh Julia Cano Matthews Titir De Grace Avecilla Farah Abdul-Rahman Nathan Brandt Yoav Ram David Gresham |
| author_facet | Julie N Chuong Nadav Ben Nun Ina Suresh Julia Cano Matthews Titir De Grace Avecilla Farah Abdul-Rahman Nathan Brandt Yoav Ram David Gresham |
| author_sort | Julie N Chuong |
| collection | DOAJ |
| description | Copy number variants (CNVs) are an important source of genetic variation underlying rapid adaptation and genome evolution. Whereas point mutation rates vary with genomic location and local DNA features, the role of genome architecture in the formation and evolutionary dynamics of CNVs is poorly understood. Previously, we found the GAP1 gene in Saccharomyces cerevisiae undergoes frequent amplification and selection in glutamine-limitation. The gene is flanked by two long terminal repeats (LTRs) and proximate to an origin of DNA replication (autonomously replicating sequence, ARS), which likely promote rapid GAP1 CNV formation. To test the role of these genomic elements on CNV-mediated adaptive evolution, we evolved engineered strains lacking either the adjacent LTRs, ARS, or all elements in glutamine-limited chemostats. Using a CNV reporter system and neural network simulation-based inference (nnSBI) we quantified the formation rate and fitness effect of CNVs for each strain. Removal of local DNA elements significantly impacts the fitness effect of GAP1 CNVs and the rate of adaptation. In 177 CNV lineages, across all four strains, between 26% and 80% of all GAP1 CNVs are mediated by Origin Dependent Inverted Repeat Amplification (ODIRA) which results from template switching between the leading and lagging strand during DNA synthesis. In the absence of the local ARS, distal ones mediate CNV formation via ODIRA. In the absence of local LTRs, homologous recombination can mediate gene amplification following de novo retrotransposon events. Our study reveals that template switching during DNA replication is a prevalent source of adaptive CNVs. |
| format | Article |
| id | doaj-art-102635e2d8d54c6ab285c08f3db4caad |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-102635e2d8d54c6ab285c08f3db4caad2025-02-03T16:05:24ZengeLife Sciences Publications LtdeLife2050-084X2025-02-011310.7554/eLife.98934Template switching during DNA replication is a prevalent source of adaptive gene amplificationJulie N Chuong0https://orcid.org/0000-0002-4388-9458Nadav Ben Nun1https://orcid.org/0009-0003-3228-7720Ina Suresh2Julia Cano Matthews3Titir De4Grace Avecilla5Farah Abdul-Rahman6Nathan Brandt7Yoav Ram8https://orcid.org/0000-0002-9653-4458David Gresham9https://orcid.org/0000-0002-4028-0364Department of Biology, Center for Genomics and Systems Biology, New York University, New York, United StatesSchool of Zoology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Edmond J. Safra Center for Bioinformatics, Tel Aviv University, Tel Aviv, IsraelDepartment of Biology, Center for Genomics and Systems Biology, New York University, New York, United StatesDepartment of Biology, Center for Genomics and Systems Biology, New York University, New York, United StatesDepartment of Biology, Center for Genomics and Systems Biology, New York University, New York, United StatesDepartment of Natural Sciences, Baruch College CUNY, New York, United StatesDepartment of Ecology and Evolutionary Biology, Yale University, New Haven, United States; Microbial Sciences Institute, Yale University, New Haven, United StatesDepartment of Biological Sciences, North Carolina State University, Raleigh, United StatesSchool of Zoology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Edmond J. Safra Center for Bioinformatics, Tel Aviv University, Tel Aviv, IsraelDepartment of Biology, Center for Genomics and Systems Biology, New York University, New York, United StatesCopy number variants (CNVs) are an important source of genetic variation underlying rapid adaptation and genome evolution. Whereas point mutation rates vary with genomic location and local DNA features, the role of genome architecture in the formation and evolutionary dynamics of CNVs is poorly understood. Previously, we found the GAP1 gene in Saccharomyces cerevisiae undergoes frequent amplification and selection in glutamine-limitation. The gene is flanked by two long terminal repeats (LTRs) and proximate to an origin of DNA replication (autonomously replicating sequence, ARS), which likely promote rapid GAP1 CNV formation. To test the role of these genomic elements on CNV-mediated adaptive evolution, we evolved engineered strains lacking either the adjacent LTRs, ARS, or all elements in glutamine-limited chemostats. Using a CNV reporter system and neural network simulation-based inference (nnSBI) we quantified the formation rate and fitness effect of CNVs for each strain. Removal of local DNA elements significantly impacts the fitness effect of GAP1 CNVs and the rate of adaptation. In 177 CNV lineages, across all four strains, between 26% and 80% of all GAP1 CNVs are mediated by Origin Dependent Inverted Repeat Amplification (ODIRA) which results from template switching between the leading and lagging strand during DNA synthesis. In the absence of the local ARS, distal ones mediate CNV formation via ODIRA. In the absence of local LTRs, homologous recombination can mediate gene amplification following de novo retrotransposon events. Our study reveals that template switching during DNA replication is a prevalent source of adaptive CNVs.https://elifesciences.org/articles/98934experimental evolutioncopy number variationGAP1simulation-based inference |
| spellingShingle | Julie N Chuong Nadav Ben Nun Ina Suresh Julia Cano Matthews Titir De Grace Avecilla Farah Abdul-Rahman Nathan Brandt Yoav Ram David Gresham Template switching during DNA replication is a prevalent source of adaptive gene amplification eLife experimental evolution copy number variation GAP1 simulation-based inference |
| title | Template switching during DNA replication is a prevalent source of adaptive gene amplification |
| title_full | Template switching during DNA replication is a prevalent source of adaptive gene amplification |
| title_fullStr | Template switching during DNA replication is a prevalent source of adaptive gene amplification |
| title_full_unstemmed | Template switching during DNA replication is a prevalent source of adaptive gene amplification |
| title_short | Template switching during DNA replication is a prevalent source of adaptive gene amplification |
| title_sort | template switching during dna replication is a prevalent source of adaptive gene amplification |
| topic | experimental evolution copy number variation GAP1 simulation-based inference |
| url | https://elifesciences.org/articles/98934 |
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