The impact of whole genome duplications on the human gene regulatory networks

Mottes, Francesco; Villa, Chiara; Osella, Matteo; Caselle, Michele

doi:10.1101/2021.07.16.452729

Cited by 3 publications

(1 citation statement)

References 70 publications

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“…Genes that originate from whole-genome duplication and small-scale duplication events follow different patterns of retention [4,[20][21][22][23][24]. These different patterns occur because of their initial effect on the genome and cell function.…”

Section: Discussionmentioning

confidence: 99%

Dosage balance acts as a time-dependent selective barrier to subfunctionalization

Wilson

Liberles

2022

Preprint

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Background Gene duplication is an important process for genome expansion, sometimes allowing for new functionalities to develop. Duplicate genes can be retained through multiple processes, either for intermediate periods of time through processes such as dosage balance, or over extended periods of time through processes such as subfunctionalization and neofunctionalization. Results Here, we built upon an existing Markov model and created a new Markov model describing the interplay between subfunctionalization and dosage balance to explore selective pressures on duplicate copies when both subfunctionalization and dosage balance occur. Our model incorporates dosage balance using a biophysical framework that penalizes the fitness of genetic states with stoichiometrically imbalanced proteins. These imbalanced states cause increased concentrations of exposed hydrophobic surface areas, which cause deleterious misinteractions. We draw comparison between our Subfunctionalization + Dosage-Balance Model (Sub + Dos) and the previous Subfunctionalization-Only (Sub-Only) Model. This comparison includes how the retention probabilities change over time, dependent upon the effective population size and the selective cost associated with spurious interaction of dosage-imbalanced partners. We show comparison between Sub-Only and Sub + Dos models for both whole-genome duplication and small-scale duplication events. Conclusion These comparisons show that following whole-genome duplication, dosage balance serves as a time-dependent selective barrier to the subfunctionalization process, by causing an overall delay but ultimately leading to increased retention rates through subfunctionalization. This is because the competing nonfunctionalization process is also selectively blocked to a greater extent. In small-scale duplication, the reverse pattern is seen, where dosage balance drives faster rates of subfunctionalization, but ultimately leads to lower rates of retained duplicates. This is because the dosage balance of interacting gene products is negatively affected immediately after duplication and loss of a duplicate restores stoichiometric balance. Contrary to previous understanding of subfunctionalization, our findings show subfunctionalization of genes that are susceptible to dosage balance effects, such as proteins involved in complexes is not a purely neutral process. With stronger selection against stoichiometrically imbalanced gene partners, the rates of subfunctionalization and nonfunctionalization slow; however, this ultimately led to a greater proportion of subfunctionalized gene pairs.

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Section: Discussionmentioning

confidence: 99%

Dosage balance acts as a time-dependent selective barrier to subfunctionalization

Wilson

Liberles

2022

Preprint

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Chromosomal Instability in Genome Evolution: From Cancer to Macroevolution

Comaills

Castellano‐Pozo

2023

Biology

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The integrity of the genome is crucial for the survival of all living organisms. However, genomes need to adapt to survive certain pressures, and for this purpose use several mechanisms to diversify. Chromosomal instability (CIN) is one of the main mechanisms leading to the creation of genomic heterogeneity by altering the number of chromosomes and changing their structures. In this review, we will discuss the different chromosomal patterns and changes observed in speciation, in evolutional biology as well as during tumor progression. By nature, the human genome shows an induction of diversity during gametogenesis but as well during tumorigenesis that can conclude in drastic changes such as the whole genome doubling to more discrete changes as the complex chromosomal rearrangement chromothripsis. More importantly, changes observed during speciation are strikingly similar to the genomic evolution observed during tumor progression and resistance to therapy. The different origins of CIN will be treated as the importance of double-strand breaks (DSBs) or the consequences of micronuclei. We will also explain the mechanisms behind the controlled DSBs, and recombination of homologous chromosomes observed during meiosis, to explain how errors lead to similar patterns observed during tumorigenesis. Then, we will also list several diseases associated with CIN, resulting in fertility issues, miscarriage, rare genetic diseases, and cancer. Understanding better chromosomal instability as a whole is primordial for the understanding of mechanisms leading to tumor progression.

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Inverse and Proportional Trans Modulation of Gene Expression in Human Aneuploidies

Zhang,

Wang,

Zhang

et al. 2024

Genes

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Genomic imbalance in aneuploidy is often detrimental to organisms. To gain insight into the molecular basis of aneuploidies in humans, we analyzed transcriptome data from several autosomal and sex chromosome aneuploidies. The results showed that in human aneuploid cells, genes located on unvaried chromosomes are inversely or proportionally trans-modulated, while a subset of genes on the varied chromosomes are compensated. Less genome-wide modulation is found for sex chromosome aneuploidy compared with autosomal aneuploidy due to X inactivation and the retention of dosage sensitive regulators on both sex chromosomes to limit the effective dosage change. We also found that lncRNA and mRNA can have different responses to aneuploidy. Furthermore, we analyzed the relationship between dosage-sensitive transcription factors and their targets, which illustrated the modulations and indicates genomic imbalance is related to stoichiometric changes in components of gene regulatory complexes.In summary, this study demonstrates the existence of trans-acting effects and compensation mechanisms in human aneuploidies and contributes to our understanding of gene expression regulation in unbalanced genomes and disease states.

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The impact of whole genome duplications on the human gene regulatory networks

Cited by 3 publications

References 70 publications

Dosage balance acts as a time-dependent selective barrier to subfunctionalization

Dosage balance acts as a time-dependent selective barrier to subfunctionalization

Chromosomal Instability in Genome Evolution: From Cancer to Macroevolution

Inverse and Proportional Trans Modulation of Gene Expression in Human Aneuploidies

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