통찰 - Computational Biology - # Mechanisms of Adaptive Copy Number Variation Formation

DNA Replication Errors Facilitate Rapid Adaptive Gene Amplification in Yeast

Q: How do transcription-replication collisions at the highly expressed GAP1 gene contribute to the formation of adaptive CNVs through ODIRA?

Transcription-replication collisions at the highly expressed GAP1 gene can contribute to the formation of adaptive CNVs through ODIRA by inducing DNA replication errors. When the transcription machinery encounters the replication fork, it can lead to replication stress and fork stalling. This stalling can trigger DNA replication errors, such as template switching, which is a key mechanism in ODIRA. In ODIRA, short inverted repeats near an origin of DNA replication enable template switching of the leading strand to the lagging strand, resulting in the formation of CNVs with an inverted middle copy. The high transcriptional activity at the GAP1 gene increases the likelihood of transcription-replication collisions, leading to an increased rate of DNA replication errors and subsequent CNV formation through ODIRA. Therefore, the transcription-replication collisions at the highly expressed GAP1 gene can be a driving force behind the generation of adaptive CNVs through ODIRA.

Q: What are the potential fitness costs associated with different CNV mechanisms, such as aneuploidy versus focal amplifications, and how do these shape the evolutionary trajectories?

Different CNV mechanisms, such as aneuploidy and focal amplifications, can have varying fitness costs that shape evolutionary trajectories. Aneuploidy, which involves whole chromosome duplications or deletions, can incur significant fitness costs due to imbalances in gene dosage and disrupted cellular processes. The presence of extra or missing chromosomes can lead to changes in gene expression, protein levels, and cellular functions, resulting in decreased fitness. In contrast, focal amplifications, which involve duplications or deletions of specific genomic regions, may have lower fitness costs as they only affect a subset of genes. Focal amplifications can provide adaptive benefits by increasing the dosage of specific genes that confer a selective advantage without the detrimental effects of aneuploidy. The fitness costs associated with aneuploidy versus focal amplifications can influence the evolutionary trajectories of populations. Aneuploidy may be less favored in the long term due to its higher fitness costs and potential destabilizing effects on cellular processes. In contrast, focal amplifications that provide adaptive benefits with minimal fitness costs are more likely to be maintained in populations over time. The balance between the fitness costs and benefits of different CNV mechanisms determines their prevalence and persistence in evolving populations, shaping the evolutionary trajectories towards adaptation or extinction.

Q: Could the insights from this yeast system be leveraged to understand the role of DNA replication errors in generating copy number variations that drive adaptation and disease progression in other organisms, including humans?

The insights gained from studying DNA replication errors and CNV formation in yeast can be valuable for understanding the role of these mechanisms in generating CNVs that drive adaptation and disease progression in other organisms, including humans. DNA replication errors, such as those leading to CNVs, are known to play a significant role in evolutionary processes and disease development. By studying these processes in a model organism like yeast, we can uncover fundamental principles that may be applicable to more complex organisms. The mechanisms identified in yeast, such as ODIRA, transcription-replication collisions, and the impact of genomic architecture on CNV formation, can provide insights into how DNA replication errors contribute to CNV diversity and evolution. These findings can be extrapolated to human systems to understand the molecular basis of CNV-related diseases, such as cancer and genetic disorders. Understanding how DNA replication errors lead to CNVs in yeast can inform research on human diseases driven by CNVs, potentially leading to the development of new diagnostic and therapeutic strategies. Overall, leveraging the insights from yeast studies on DNA replication errors and CNV formation can enhance our understanding of the genetic mechanisms underlying adaptation and disease progression in diverse organisms, offering new avenues for research and clinical applications.

핵심 개념

DNA replication errors, particularly Origin-Dependent Inverted Repeat Amplification (ODIRA), are a predominant source of adaptive copy number variations that enable rapid adaptation in yeast under nutrient-limiting conditions.

초록

The study investigates the role of local genomic architecture in the formation, selection, and evolutionary dynamics of copy number variants (CNVs) in the yeast Saccharomyces cerevisiae. The authors engineered strains lacking specific genomic elements near the GAP1 gene, which undergoes frequent amplification under glutamine-limiting conditions, and performed experimental evolution to quantify the impact on CNV dynamics.

Key insights:

Removal of the local autonomously replicating sequence (ARS) significantly reduced the CNV formation rate and delayed the appearance of CNVs, suggesting the ARS is a major determinant of GAP1 CNV-mediated adaptation.
Sequence analysis of 177 CNV lineages revealed that 49% are mediated by the DNA replication-based mechanism ODIRA, which can utilize distal ARS sites in the absence of the local ARS.
In the absence of the flanking long terminal repeats (LTRs), homologous recombination mechanisms still mediate gene amplification, often initiated by de novo insertion of retrotransposon elements at the locus.
The study demonstrates the remarkable plasticity of the genome in generating diverse CNV alleles and reveals that DNA replication errors are a predominant source of adaptive CNVs.

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biorxiv.org

통계

Strain has a significant effect on CNV appearance (Kruskal-Wallis, p =0.001384).
Strain has a significant effect on the per generation increase in proportion of cells with CNV (ANOVA, p = 0.00318).
Strain has a significant effect on time to CNV equilibrium phase (ANOVA, p = 0.00833).

인용구

"Surprisingly, we find that the proximate DNA elements are not required for GAP1 CNV formation as GAP1 CNVs were identified in all evolving populations."
"Our study reveals the remarkable plasticity of the genome and that DNA replication errors are a predominant source of adaptive CNVs."

핵심 통찰 요약

DNA replication errors are a major source of adaptive gene amplification

by Chuong,J., B... 게시일 www.biorxiv.org 05-06-2024

https://www.biorxiv.org/content/10.1101/2024.05.03.589936v1

더 깊은 질문

How do transcription-replication collisions at the highly expressed GAP1 gene contribute to the formation of adaptive CNVs through ODIRA?

Transcription-replication collisions at the highly expressed GAP1 gene can contribute to the formation of adaptive CNVs through ODIRA by inducing DNA replication errors. When the transcription machinery encounters the replication fork, it can lead to replication stress and fork stalling. This stalling can trigger DNA replication errors, such as template switching, which is a key mechanism in ODIRA. In ODIRA, short inverted repeats near an origin of DNA replication enable template switching of the leading strand to the lagging strand, resulting in the formation of CNVs with an inverted middle copy. The high transcriptional activity at the GAP1 gene increases the likelihood of transcription-replication collisions, leading to an increased rate of DNA replication errors and subsequent CNV formation through ODIRA. Therefore, the transcription-replication collisions at the highly expressed GAP1 gene can be a driving force behind the generation of adaptive CNVs through ODIRA.

What are the potential fitness costs associated with different CNV mechanisms, such as aneuploidy versus focal amplifications, and how do these shape the evolutionary trajectories?

Different CNV mechanisms, such as aneuploidy and focal amplifications, can have varying fitness costs that shape evolutionary trajectories. Aneuploidy, which involves whole chromosome duplications or deletions, can incur significant fitness costs due to imbalances in gene dosage and disrupted cellular processes. The presence of extra or missing chromosomes can lead to changes in gene expression, protein levels, and cellular functions, resulting in decreased fitness. In contrast, focal amplifications, which involve duplications or deletions of specific genomic regions, may have lower fitness costs as they only affect a subset of genes. Focal amplifications can provide adaptive benefits by increasing the dosage of specific genes that confer a selective advantage without the detrimental effects of aneuploidy.
The fitness costs associated with aneuploidy versus focal amplifications can influence the evolutionary trajectories of populations. Aneuploidy may be less favored in the long term due to its higher fitness costs and potential destabilizing effects on cellular processes. In contrast, focal amplifications that provide adaptive benefits with minimal fitness costs are more likely to be maintained in populations over time. The balance between the fitness costs and benefits of different CNV mechanisms determines their prevalence and persistence in evolving populations, shaping the evolutionary trajectories towards adaptation or extinction.

Could the insights from this yeast system be leveraged to understand the role of DNA replication errors in generating copy number variations that drive adaptation and disease progression in other organisms, including humans?

The insights gained from studying DNA replication errors and CNV formation in yeast can be valuable for understanding the role of these mechanisms in generating CNVs that drive adaptation and disease progression in other organisms, including humans. DNA replication errors, such as those leading to CNVs, are known to play a significant role in evolutionary processes and disease development. By studying these processes in a model organism like yeast, we can uncover fundamental principles that may be applicable to more complex organisms.
The mechanisms identified in yeast, such as ODIRA, transcription-replication collisions, and the impact of genomic architecture on CNV formation, can provide insights into how DNA replication errors contribute to CNV diversity and evolution. These findings can be extrapolated to human systems to understand the molecular basis of CNV-related diseases, such as cancer and genetic disorders. Understanding how DNA replication errors lead to CNVs in yeast can inform research on human diseases driven by CNVs, potentially leading to the development of new diagnostic and therapeutic strategies.
Overall, leveraging the insights from yeast studies on DNA replication errors and CNV formation can enhance our understanding of the genetic mechanisms underlying adaptation and disease progression in diverse organisms, offering new avenues for research and clinical applications.