Simple Repeats as Building Blocks for Genetic Computers

Herbert, Alan

doi:10.1016/j.tig.2020.06.012

Cited by 27 publications

(30 citation statements)

References 110 publications

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“…It is possible that there is a mathematical threshold required for the abundance of STRs in various species. This is in line with the hypothesis that STRs function as scaffolds for biological computers 23 . In mouse, the overall number of dinucleotide STRs never declined to the numbers observed in the ve primates.…”

Section: Discussionsupporting

confidence: 90%

Primate Speciation Links to Massive and Directional Shrinkage of the Dinucleotide Short Tandem Repeat Compartment.

Arabfard

Salesi

Arabipour

et al. 2021

Preprint

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The evolutionary trend of short tandem repeats (STRs) at the crossroads of speciation remains largely elusive and attributed to random evolution for the most part. Here we investigated the dinucleotide STR compartment in primate speciation. We selected six species, which shared sequential chronological ancestors, including mouse, macaque, gorilla, chimpanzee, bonobo, and human, and collected three sets of data on the abundance of all classes of dinucleotide STRs (≥6-repeats) for three regions of every chromosome, each region spanning 10 Mb of DNA. In all three datasets, we found consistent directional shrinkage of the dinucleotide STR compartment in all the primate species selected vs. mouse, as follows: mouse>macaque>great apes. The >20-repeat STRs were the most significantly affected as a result of this shrinkage. We propose that massive and directional shrinkage of the dinucleotide STR compartment had a decisive link with primate speciation. This is a prime instane of massive directional STR trend in multiple speciation.

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Section: Discussionsupporting

confidence: 90%

Primate Speciation Links to Massive and Directional Shrinkage of the Dinucleotide Short Tandem Repeat Compartment.

Arabfard

Salesi

Arabipour

et al. 2021

Preprint

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“…Other helicases also have the potential to moderate formation of alternative structures like Z-RNA, Z-DNA, and quadruplexes with different outcomes than those produced by MDA5. The repeat sequences involved and the events leading to the flip may differ [ 7 ]. For helicases like MOV10, the recognition of self-transcripts likely depends on the unmasking of specific host sequences by unwinding dsRNA structures that hide them.…”

Section: Discussionmentioning

confidence: 99%

“…This class of enzymes is likely to play a much broader role than currently appreciated in dynamically shaping host responses to a constantly changing environment [ 5 ]. The alternative nucleic acid conformations they modulate, based mostly on low complexity repeats [ 7 ], likely increase transcript diversity by changing the parsing of genomic information, creating phenotypic variability for natural selection to act upon. The co-option of Alu retrotransposons to mark self is a remarkable example of how genomes evolve existential threats into something essential for their survival.…”

Section: Discussionmentioning

confidence: 99%

“…The work lead to the concept of flipons, which are genomically encoded sequences capable of flipping under physiological condition from a lower energy right-handed double helix to a higher energy alternative conformer such as Z-DNA [6]. Flipons act as switches to change the fate of transcripts, allowing compilation of different genetic programs from an initial set of RNAs [5][6][7].…”

Section: The Backgroundmentioning

confidence: 99%

“…What causes these outcomes? One possibility is that Z-formation by the DNA:RNA hybrid (DRH) and subsequent editing by p150 alters how transcripts are processed [ 7 ]. In this scenario, DHX9 tethers the 5′ end of the hybrid, delaying release of the transcript until the appropriate complexes assemble to process the nascent RNA ( Fig 3B ).…”

Section: The Backgroundmentioning

confidence: 99%

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To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

Herbert

2021

PLoS Genet

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Double-stranded RNA (dsRNA) is produced both by virus and host. Its recognition by the melanoma differentiation–associated gene 5 (MDA5) initiates type I interferon responses. How can a host distinguish self-transcripts from nonself to ensure that responses are targeted correctly? Here, I discuss a role for MDA5 helicase in inducing Z-RNA formation by Alu inverted repeat (AIR) elements. These retroelements have highly conserved sequences that favor Z-formation, creating a site for the dsRNA-specific deaminase enzyme ADAR1 to dock. The subsequent editing destabilizes the dsRNA, ending further interaction with MDA5 and terminating innate immune responses directed against self. By enabling self-recognition, Alu retrotransposons, once invaders, now are genetic elements that keep immune responses in check. I also discuss the possible but less characterized roles of the other helicases in modulating innate immune responses, focusing on DExH-box helicase 9 (DHX9) and Mov10 RISC complex RNA helicase (MOV10). DHX9 and MOV10 function differently from MDA5, but still use nucleic acid structure, rather than nucleotide sequence, to define self. Those genetic elements encoding the alternative conformations involved, referred to as flipons, enable helicases to dynamically shape a cell’s repertoire of responses. In the case of MDA5, Alu flipons switch off the dsRNA-dependent responses against self. I suggest a number of genetic systems in which to study interactions between flipons and helicases further.

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Nucleosomes and flipons exchange energy to alter chromatin conformation, the readout of genomic information, and cell fate

Herbert

2022

BioEssays

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Alternative non‐B‐DNA conformations formed under physiological conditions by sequences called flipons include left‐handed Z‐DNA, three‐stranded triplexes, and four‐stranded i‐motifs and quadruplexes. These conformations accumulate and release energy to enable the local assembly of cellular machines in a context specific manner. In these transactions, nucleosomes store power, serving like rechargeable batteries, while flipons smooth energy flows from source to sink by acting as capacitors or resistors. Here, I review the known biological roles for flipons. I present recent and unequivocal findings showing how innate immune responses are regulated by Z‐flipons that identify endogenous RNAs as self. Evidence is also presented supporting important roles for other flipon classes. In these examples, the dynamic exchange of energy between flipons and nucleosomes enables rapid switching of genetic programs without altering flipon sequence. The increased phenotypic diversity enabled by flipons drives their natural selection, with adaptations evolving faster than is possible by codon mutation alone.

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Simple Repeats as Building Blocks for Genetic Computers

Cited by 27 publications

References 110 publications

Primate Speciation Links to Massive and Directional Shrinkage of the Dinucleotide Short Tandem Repeat Compartment.

Primate Speciation Links to Massive and Directional Shrinkage of the Dinucleotide Short Tandem Repeat Compartment.

To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

Nucleosomes and flipons exchange energy to alter chromatin conformation, the readout of genomic information, and cell fate

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