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. 2021 Feb 11:9:618113.
doi: 10.3389/fcell.2021.618113. eCollection 2021.

A Mechanism Leading to Changes in Copy Number Variations Affected by Transcriptional Level Might Be Involved in Evolution, Embryonic Development, Senescence, and Oncogenesis Mediated by Retrotransposons

Yunpeng Sui  1 , Shuanghong Peng  2
Affiliations

A Mechanism Leading to Changes in Copy Number Variations Affected by Transcriptional Level Might Be Involved in Evolution, Embryonic Development, Senescence, and Oncogenesis Mediated by Retrotransposons

Yunpeng Sui et al. Front Cell Dev Biol. .

Abstract

In recent years, more and more evidence has emerged showing that changes in copy number variations (CNVs) correlated with the transcriptional level can be found during evolution, embryonic development, and oncogenesis. However, the underlying mechanisms remain largely unknown. The success of the induced pluripotent stem cell suggests that genome changes could bring about transformations in protein expression and cell status; conversely, genome alterations generated during embryonic development and senescence might also be the result of genome changes. With rapid developments in science and technology, evidence of changes in the genome affected by transcriptional level has gradually been revealed, and a rational and concrete explanation is needed. Given the preference of the HIV-1 genome to insert into transposons of genes with high transcriptional levels, we propose a mechanism based on retrotransposons facilitated by specific pre-mRNA splicing style and homologous recombination (HR) to explain changes in CNVs in the genome. This mechanism is similar to that of the group II intron that originated much earlier. Under this proposed mechanism, CNVs on genome are dynamically and spontaneously extended in a manner that is positively correlated with transcriptional level or contract as the cell divides during evolution, embryonic development, senescence, and oncogenesis, propelling alterations in them. Besides, this mechanism explains several critical puzzles in these processes. From evidence collected to date, it can be deduced that the message contained in genome is not just three-dimensional but will become four-dimensional, carrying more genetic information.

Keywords: copy number variation; embryonic development; evolution; homologous recombination; oncogenesis; retrotransposons; senescence; transcription.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagram of the generation of partially overlapping lariats. The branch points and donor sites are distributed on the genome. The branch points close to the exon are much more potent than those closest to or on the exon ordinarily, which leads to the excision of the exon, whereas if they are not potent enough, the exon will be excised as alternative splicing. Because the exon-containing lariat also has part of an intron within it, mRNA with the exon sequence only is not able to be spliced because of the loss of the intron.
Figure 2
Figure 2
The possible mechanism of insertion of the HIV-1 genome into the right monomer of the Alu element. A lariat containing the left monomer of the Alu element, part of the right monomer, and the 5′ sequence of the HIV-1 genome would be produced and connected to the right monomer of Alu transcribed and spliced nearby. Then the 5′ region of the HIV-1 genome would be inserted into the right part of another Alu element nearby with the assistance of the lariat-Alu complex. The remaining HIV-1 genome downstream would be gradually inserted at the new insertion site within another Alu element.
Figure 3
Figure 3
The detailed process of the CNV extension mechanism. Partially overlapping lariats would be produced during pre-mRNA processing with exons excised of high probability by overdrive suppression. With the pre-mRNA spliced and connected, the right monomer of the Alu element could be spliced and connected to the lariats produced at the same time. With the help of ORF2p on the right monomer of the Alu element, the lariat-Alu ssRNA could be converted into dsDNA at the specific insertion site, with part A on the left and the right monomer of Alu on the right. Then part B would be inserted into the genome facilitated by HR with the two nicks produced by ORF2p. Part C would be inserted further by lariats containing parts B and C at the specific insertion site between part B and the right monomer of the Alu element. CNVs would be extended continuously and spontaneously through this mechanism.
Figure 4
Figure 4
A comparison of the group II intron and the CNV extension mechanism. Given the existence of spliceosomes in complex organisms, the various lariats would be produced without the help of the specific secondary structure, and thus CNV extension brought about by continuous insertion would be possible.
Figure 5
Figure 5
The CNV extension mechanism in evolution. The nuclear membrane of eukaryotes reduces interference from outside the nucleus, creating the environment required for stable and precise CNV extension under control while introns provide various CNVs with different lengths under regulation. The CNVs of different individuals in the same group could be oscillatory, and natural selection would pick out those individuals with CNVs fit to the environment.
Figure 6
Figure 6
The methylation status of different kinds of cells. Demethylation under regulation can be seen in the germ line cell and embryonic cell leading to the deletion of specific regions on the genome, whereas in the somatic cell after birth, methylation is sustained at a high level and is strictly irreversible. Methylation is decreased in the tumor cell, which might bring about unpredictable HR among Alu elements and at the same time, the insertion would also occur more frequently with increased expression of corresponding genes.
Figure 7
Figure 7
The process of embryonic development with the CNV extension mechanism. After fertilization, the CNV extension of genes related to demethylation could be initiated by LINE-1 inserting the 5′ flanking regions of these genes through 3′ transduction. Then continuous extension would be mediated by the Alu element. When the demethylation effect is sufficient to suppress the methylation effect, the Alu element would be thoroughly demethylated and HR could occur among them, leading to the deletion of inserted DNA on the genome, thus initializing cells in ICM. Then the CNVs of different genes would be extended according to the original copies of the corresponding genes. The different styles of CNVs extension in different genes would be developed next, resulting in various types of differentiation. Specifically, protein expression could influence changes in CNVs, which would irreversibly decide the differentiation, and then the differentiation could affect protein expression and lead to further differentiation. This gradual differentiation would ultimately construct an entire individual.
Figure 8
Figure 8
Cell division could bring about gradual genome change and thus differentiation during embryogenesis. The genome of the cell would be changed slightly with every division. The occurrence of division and the direction of differentiation are affected by adjacent cells or other external effects. The gene expression of cells could be influenced by adjacent cells, resulting in changes in CNVs extension style and therefore an altered direction of differentiation. Finally, as the cell divides, detailed and intricate differentiation would be achieved.
Figure 9
Figure 9
A proposed mechanism of senescence under the CNV extension mechanism. The entirely differentiated cell could be differentiated from the stem cell, perform certain functions, and protect the stem cell lying inside. The CNVs of inhibitory genes would be extended as the cell divides and gradually lead to senescence in the stem cell. The stem cell could continuously divide with sufficient telomerase activity and ultimately lead to senescence as the cell divides. Because of a lack of telomerase, the somatic cells would be forced to apoptosis and then substituted by older cells differentiated from stem cells. Moreover, methylation would have critical effects in terms of stabilizing the genome from embryogenesis to senescence.
Figure 10
Figure 10
A possible pattern in which cell proliferation could be strictly regulated. According to tumor stem cells and their proliferation pattern, tissue could be divided into lots of units that would consist of stem cells and somatic cells. The central stem cells would be surrounded by other stem cells, and they would not differentiate and could only divide into stem cells; the stem cells near the somatic cells would receive stimulation from stem cells and gradually differentiate to somatic cells. The proliferation of cells at the border between the two units might fluctuate. When the cell density of one side decreases, the cells below the border and those on the other side of the border will migrate toward it, resulting in increased cell density on this side of the border and decreased cell density on the other side of the border and thus stimulating the cells below the border of the same side and on the other side of the border to proliferate. As the cells on the other side of the border are on the verge of the division limit, further division will lead to apoptosis and decreased cell density. This cycle will ensure that all cells divide periodically.
Figure 11
Figure 11
A possible mechanism explaining expansion of the repeat sequence in HD and FXS affected by transcriptional level. As the abnormally expanded repeat is too long to jump across to produce a normal lariat, the 5′ end of the lariat could fall into the repeat sequence, which would ordinarily not happen. The repeat sequence could obscure recognition of the left foot of Ω, making its complementary combination to the repeat downstream, which would create an insertion site that should not exist. This would lead to the insertion of the repeat sequence, and thus the repeat could be expanded.
Figure 12
Figure 12
The entire genome might be compared to a car. The frame (the fundamental genes) cannot be altered. A modified engine (increased CNVs of stimulating genes) results in increased speed (oncogenesis). The brakes (inhibitory genes) slow the car down (cause the organism to become senile). The genes of differentiated functions can also be modified.
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