Template switching during DNA replication is a prevalent source of adaptive gene amplification DOI Open Access
Julie N. Chuong,

Nadav Ben Nun,

Ina Suresh

et al.

Published: Dec. 13, 2024

Copy number variants (CNVs)—gains and losses of genomic sequences—are an important source genetic variation underlying rapid adaptation genome evolution. However, despite their central role in evolution little is known about the factors that contribute to structure, size, formation rate, fitness effects adaptive CNVs. Local sequences are likely be determinant these properties. Whereas it point mutation rates vary with location local DNA sequence features, architecture formation, selection, resulting evolutionary dynamics CNVs poorly understood. Previously, we have found GAP1 gene Saccharomyces cerevisiae undergoes frequent repeated amplification selection under long-term experimental glutamine-limiting conditions. The has a unique consisting two flanking long terminal repeats (LTRs) proximate origin replication (autonomously replicating sequence, ARS), which promote CNV formation. To test elements on CNV-mediated evolution, performed glutamine-limited chemostats using engineered strains lacking either adjacent LTRs, ARS, or all elements. Using reporter system neural network simulation-based inference (nnSBI) quantified rate effect for each strain. We find although repeatedly form sweep high frequency modified architecture, removal significantly impacts adaptation. analysis define molecular mechanisms 177 lineages. across four strain backgrounds, between 26% 80% mediated by Origin Dependent Inverted Repeat Amplification (ODIRA) results from template switching leading lagging strand during synthesis. In absence distal ARS can mediate via ODIRA. homologous recombination still following de novo insertion retrotransposon at locus. Our study demonstrates remarkable plasticity reveals

Language: Английский

Template switching between the leading and lagging strands at replication forks generates inverted copy number variants through hairpin-capped extrachromosomal DNA DOI Creative Commons
Rebecca L. Martin, Claudia Y. Espinoza, Christopher R. L. Large

et al.

PLoS Genetics, Journal Year: 2024, Volume and Issue: 20(1), P. e1010850 - e1010850

Published: Jan. 4, 2024

Inherited and germ-line de novo copy number variants (CNVs) are increasingly found to be correlated with human developmental cancerous phenotypes. Several models for template switching during replication have been proposed explain the generation of these gross chromosomal rearrangements. We a model (ODIRA—origin dependent inverted repeat amplification) in which simultaneous ligation leading lagging strands at diverging forks could generate segmental triplications through an extrachromosomal circular intermediate. Here, we created genetic assay using split- ura3 cassettes trap However, instead recovering intermediates, linear fragments ending native telomeres—suggesting that switch had occurred centromere-proximal fork bubble. As telomeric hairpin can also double strand breaks tested whether errors or repair stranded DNA were most likely initiating event. The results from CRISPR/Cas9 cleavage experiments growth inhibitor hydroxyurea indicate it is error, not break creates junctions. Since amplicons SUL1 gene occur long-term sulfate-limited chemostats, sequenced evolved populations look evidence intermediates formed by error replication. All data compatible two-step version ODIRA sequential short repeats between fork, followed integration via homologous recombination, generates interstitial triplications.

Language: Английский

Citations

13
Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci DOI Creative Commons
Christopher M. Grochowski,

Jesse D. Bengtsson,

Haowei Du

et al.

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(7), P. 100590 - 100590

Published: June 21, 2024

Highlights•Inverted triplications cause genomic disorders through alterations in gene dosage•Pairs of homologous inverted repeats generate varying structural haplotypes•Breakpoint junction mapping reveals template switches within repeats•Combining methodologies enhance the analysis complex aberrationsSummaryThe duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature and cancer genomes, its architecture remains unresolved. Here, we studied DUP-TRP/INV-DUP by investigating 24 patients array comparative hybridization (aCGH) on whom found evidence for existence 4 out predicted variant (SV) haplotypes. Using combination short-read genome sequencing (GS), long-read GS, optical mapping, single-cell strand (strand-seq), haplotype was resolved 18 samples. The point switching samples shown to be segment ∼2.2–5.5 kb 100% nucleotide similarity repeat pairs. These data provide experimental that low-copy act recombinant substrates. This type CGR can result multiple conformers generating diverse SV haplotypes susceptible dosage-sensitive loci.Graphical abstract

Language: Английский

Citations

8
Copy Number Variation in Asthma: An Integrative Review DOI

Fernanda Mariano Garcia,

Valdemir Pereira de Sousa,

Priscila Pinto e Silva-dos-Santos

et al.

Clinical Reviews in Allergy & Immunology, Journal Year: 2025, Volume and Issue: 68(1)

Published: Jan. 4, 2025

Language: Английский

Citations

0
Template switching during DNA replication is a prevalent source of adaptive gene amplification DOI Creative Commons
Julie N. Chuong,

Nadav Ben Nun,

Ina Suresh

et al.

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 3, 2025

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 local DNA features, the role architecture in formation evolutionary dynamics CNVs is poorly understood. Previously, we found GAP1 gene Saccharomyces cerevisiae undergoes frequent amplification selection glutamine-limitation. The flanked by two long terminal repeats (LTRs) proximate to origin replication (autonomously replicating sequence, ARS), which likely promote CNV formation. To test these elements on CNV-mediated adaptive evolution, evolved engineered strains lacking either adjacent LTRs, ARS, or all glutamine-limited chemostats. Using a reporter system neural network simulation-based inference (nnSBI) quantified rate fitness effect for each strain. Removal significantly impacts adaptation. In 177 lineages, across four strains, between 26% 80% mediated Origin Dependent Inverted Repeat Amplification (ODIRA) results from template switching leading lagging strand during synthesis. absence distal ones mediate via ODIRA. homologous recombination can following de novo retrotransposon events. Our study reveals that prevalent CNVs.

Language: Английский

Citations

0
DNA replication errors are a major source of adaptive gene amplification DOI Creative Commons
Julie N. Chuong,

Nadav Ben Nun,

Ina Suresh

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 6, 2024

Abstract Copy number variants (CNVs)—gains and losses of genomic sequences—are an important source genetic variation underlying rapid adaptation genome evolution. However, despite their central role in evolution little is known about the factors that contribute to structure, size, formation rate, fitness effects adaptive CNVs. Local sequences are likely be determinant these properties. Whereas it point mutation rates vary with location local DNA sequence features, architecture formation, selection, resulting evolutionary dynamics CNVs poorly understood. Previously, we have found GAP1 gene Saccharomyces cerevisiae undergoes frequent repeated amplification selection under long-term experimental glutamine-limiting conditions. The has a unique consisting two flanking long terminal repeats (LTRs) proximate origin replication (autonomously replicating sequence, ARS), which promote CNV formation. To test elements on CNV-mediated evolution, performed glutamine-limited chemostats using engineered strains lacking either adjacent LTRs, ARS, or all elements. Using reporter system neural network simulation-based inference (nnSBI) quantified rate effect for each strain. We find although repeatedly form sweep high frequency modified architecture, removal significantly impacts adaptation. analysis define molecular mechanisms 177 lineages. across four strain backgrounds, between 26% 80% mediated by Origin Dependent Inverted Repeat Amplification (ODIRA) results from template switching leading lagging strand during synthesis. In absence distal ARS can mediate via ODIRA. homologous recombination still following de novo insertion retrotransposon at locus. Our study demonstrates remarkable plasticity reveals

Language: Английский

Citations

0
DNA replication errors are a major source of adaptive gene amplification DOI Creative Commons
Julie N. Chuong,

Nadav Ben Nun,

Ina Suresh

et al.

eLife, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 2, 2024

Copy number variants (CNVs)—gains and losses of genomic sequences—are an important source genetic variation underlying rapid adaptation genome evolution. However, despite their central role in evolution little is known about the factors that contribute to structure, size, formation rate, fitness effects adaptive CNVs. Local sequences are likely be determinant these properties. Whereas it point mutation rates vary with location local DNA sequence features, architecture formation, selection, resulting evolutionary dynamics CNVs poorly understood. Previously, we have found GAP1 gene Saccharomyces cerevisiae undergoes frequent repeated amplification selection under long-term experimental glutamine-limiting conditions. The has a unique consisting two flanking long terminal repeats (LTRs) proximate origin replication (autonomously replicating sequence, ARS), which promote CNV formation. To test elements on CNV-mediated evolution, performed glutamine-limited chemostats using engineered strains lacking either adjacent LTRs, ARS, or all elements. Using reporter system neural network simulation-based inference (nnSBI) quantified rate effect for each strain. We find although repeatedly form sweep high frequency modified architecture, removal significantly impacts adaptation. analysis define molecular mechanisms 177 lineages. across four strain backgrounds, between 26% 80% mediated by Origin Dependent Inverted Repeat Amplification (ODIRA) results from template switching leading lagging strand during synthesis. In absence distal ARS can mediate via ODIRA. homologous recombination still following de novo insertion retrotransposon at locus. Our study demonstrates remarkable plasticity reveals

Language: Английский

Citations

0
Template switching during DNA replication is a prevalent source of adaptive gene amplification DOI Open Access
Julie N. Chuong,

Nadav Ben Nun,

Ina Suresh

et al.

Published: Dec. 13, 2024

Copy number variants (CNVs)—gains and losses of genomic sequences—are an important source genetic variation underlying rapid adaptation genome evolution. However, despite their central role in evolution little is known about the factors that contribute to structure, size, formation rate, fitness effects adaptive CNVs. Local sequences are likely be determinant these properties. Whereas it point mutation rates vary with location local DNA sequence features, architecture formation, selection, resulting evolutionary dynamics CNVs poorly understood. Previously, we have found GAP1 gene Saccharomyces cerevisiae undergoes frequent repeated amplification selection under long-term experimental glutamine-limiting conditions. The has a unique consisting two flanking long terminal repeats (LTRs) proximate origin replication (autonomously replicating sequence, ARS), which promote CNV formation. To test elements on CNV-mediated evolution, performed glutamine-limited chemostats using engineered strains lacking either adjacent LTRs, ARS, or all elements. Using reporter system neural network simulation-based inference (nnSBI) quantified rate effect for each strain. We find although repeatedly form sweep high frequency modified architecture, removal significantly impacts adaptation. analysis define molecular mechanisms 177 lineages. across four strain backgrounds, between 26% 80% mediated by Origin Dependent Inverted Repeat Amplification (ODIRA) results from template switching leading lagging strand during synthesis. In absence distal ARS can mediate via ODIRA. homologous recombination still following de novo insertion retrotransposon at locus. Our study demonstrates remarkable plasticity reveals

Language: Английский

Citations

0