Introns First

Forsdyke, Donald R.

doi:10.1007/s13752-013-0090-6

Cited by 10 publications

(9 citation statements)

References 43 publications

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“…However, with a pipeline between the various programs that were offered by the Wisconsin Genetics Computer Group, the base composition and base order-dependent components were separated and individually assessed (“folding of randomized sequence difference” analysis; FORS-D analysis). Departing from Le and Maizel, FORS-D values (see below) were not divided to yield Z-scores, but were simply plotted with statistical error bars [2, 3, 7, 23, 24]. The limits of the latter were generally close to the corresponding FORS-D values and, for clarity, are omitted here.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to assisting the study of infectious viruses and protozoa [32], FORS-D analysis proved fruitful when applied to topics such as speciation [3, 19, 33], the origin of introns [23, 24, 34], relating structure to recombination breakpoints and deletions [35, 36], and relying on a single sequence (rather than alignments) for the determination of positive Darwinian selection [37]. However, for a given sequence window, output can follow only from the base order in that window .…”

Section: Methodsmentioning

confidence: 99%

Section: Validation Of Four Base Shufflingmentioning

confidence: 99%

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Potential Achilles heels of SARS-CoV-2 are best displayed by the base order-dependent component of RNA folding energy

Zhang

Forsdyke²

2020

Preprint

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The energetics of the folding of a single-stranded nucleic acid into a stem-loop structure depend on both the composition and order of its bases. Composition tends to reflect genome-wide evolutionary pressures. Order better reflects local pressures. Base order is likely to be conserved when encoding a function critical for survival. The base order-dependent component of the folding energy has shown that a highly conserved region in HIV-1 genomes associates with an RNA structure. This corresponds to a packaging signal that is specifically recognized by the nucleocapsid domain of the Gag polyprotein. Long viewed as a potential HIV-1 "Achilles heel," the signal can be targeted by a recently described antiviral compound (NSC 260594) or by synthetic oligonucleotides. Thus, a conserved base-order-rich region of HIV-1 may facilitate therapeutic attack. Although SARS-CoV-2 differs in many respects from HIV-1, the same technology displays regions with a high base order-dependent folding energy component, which are also highly conserved. This indicates structural invariance (SI) sustained by natural selection. While the regions are often also protein-encoding (e.g. NSP3, ORF3a), we suggest that their nucleic acid level functions, such as the ribosomal frameshifting element (FSE) that facilitates differential expression of 1a and 1ab polyproteins, can be considered potential "Achilles heels" for SARS-CoV-2 that should be susceptible to therapies like those envisaged for AIDS. The region of the FSE scored well, but higher SI scores were obtained in other regions, including those encoding NSP13 and the nucleocapsid (N) protein.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Validation Of Four Base Shufflingmentioning

confidence: 99%

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Potential Achilles heels of SARS-CoV-2 are best displayed by the base order-dependent component of RNA folding energy

Zhang

Forsdyke²

2020

Preprint

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“…However, by subtracting values for shuffled sequences from those for the natural sequence, the Le-Maizel methodology permitted a distinction between the contributions of base composition (a genome-wide function) and base order (a local function). Thus, with a pipeline between the various programs that were offered by the Wisconsin Genetics Computer Group, the base composition and base order-dependent components were separated and individually assessed (“folding of randomized sequence difference” analysis; FORS-D analysis; Forsdyke 1995a , b , 2013 , 2014 ; Xu et al 2007 ; Zhang et al 2008a ).…”

Section: Nucleic Acid Structure Speciation and Chargaff's Gc Rulementioning

confidence: 99%

“…In addition to assisting the study of infectious viruses and protozoa (Xue and Forsdyke 2003 ), FORS-D analysis proved fruitful when applied to topics such as speciation (Forsdyke 1996 ; 2014 ; Zhang et al 2008b ), the origin of introns (Forsdyke 1995b , c , 2013 ), relating structure to recombination breakpoints and deletions (Zhang et al 2005a , b ), use of a single sequence (rather than alignments) for the determination of positive Darwinian selection (Forsdyke 2007b ), and showing that a highly conserved region in HIV-1 genomes associates with an RNA packaging signal (Forsdyke 1995d ). The latter is now seen as a potential "Achilles heel" (Ingemarsdotter et al 2018 ), so encouraging a similar approach to SARS-CoV-2 (Zhang and Forsdyke 2020 ).…”

Section: Nucleic Acid Structure Speciation and Chargaff's Gc Rulementioning

confidence: 99%

Neutralism versus selectionism: Chargaff's second parity rule, revisited

Forsdyke

2021

Genetica

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Of Chargaff's four "rules" on DNA base frequencies, the functional interpretation of his second parity rule (PR2) is the most contentious. Thermophile base compositions (GC%) were taken by Galtier and Lobry (1997) as favoring Sueoka's neutral PR2 hypothesis over Forsdyke's selective PR2 hypothesis, namely that mutations improving local within-species recombination efficiency had generated a genome-wide potential for the strands of duplex DNA to separate and initiate recombination through the "kissing" of the tips of stem-loops. However, following Chargaff's GC rule, base composition mainly reflects a species-specific, genome-wide, evolutionary pressure. GC% could not have consistently followed the dictates of temperature, since it plays fundamental roles in both sustaining species integrity and, through primarily neutral genome-wide mutation, fostering speciation. Evidence for a local within-species recombination-initiating role of base order was obtained with a novel technology that masked the contribution of base composition to nucleic acid folding energy. Forsdyke's results were consistent with his PR2 hypothesis, appeared to resolve some root problems in biology and provided a theoretical underpinning for alignment-free taxonomic analyses using relative oligonucleotide frequencies (k-mer analysis). Moreover, consistent with Chargaff's cluster rule, discovery of the thermoadaptive role of the "purine-loading" of open reading frames made less tenable the Galtier-Lobry anti-selectionist arguments. Supplementary Information The online version contains supplementary material available at 10.1007/s10709-021-00119-5.

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Functional Constraint and Molecular Evolution

Forsdyke¹

2021

Encyclopedia of Life Sciences

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While having one or more specific functions, macromolecules also have both collective functions (e.g. Donnan equilibrium and aggregation pressure) and general functions (e.g. contribution to organism weight). Successful molecular evolution requires an appropriate balance between the constraints on these functions, which arise from selective pressures acting at the levels of conventional phenotypes ( natural selection) and genome phenotypes (physiological selection). Genome‐wide constraints include fold pressure (nucleic acid stem–loop extrusion pressure) and GC pressure (the pressure for a certain base composition). When these bring about within‐genome physiological selection (hybrid sterility), there is the potential for new species to emerge (speciation). Local constraints include protein pressure (the pressure to encode a protein) and purine‐loading pressure (purine‐rich messenger ribonucleic acid (mRNA) synonymous strands), which avoids false antiviral alarms. As more pressures are identified, arguments for neutral evolution weaken. Molecules have specific, collective and general functions. Most macromolecules function by virtue of their higher ordered structure. Nucleic acids have both structural and templating functions. Each species achieves its own balance between the competing demands (constraints) of external and internal environments. The organismal phenotype comprises the classical phenotype and the genome phenotype. Natural selection operates on the classical (conventional) phenotype. Physiological selection operates on the genome phenotype. By balancing natural and physiological selection, the ‘hand of nature’ resolves conflicts between functions. Chargaff's base composition rules are fundamental to understanding nucleic acid‐level functions. Physiological selection targets oligonucleotide differences that, when in coding regions, may initially favour genes encoding intrinsically disordered proteins.

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Introns First

Cited by 10 publications

References 43 publications

Potential Achilles heels of SARS-CoV-2 are best displayed by the base order-dependent component of RNA folding energy

Potential Achilles heels of SARS-CoV-2 are best displayed by the base order-dependent component of RNA folding energy

Neutralism versus selectionism: Chargaff's second parity rule, revisited

Functional Constraint and Molecular Evolution

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