scholarly journals Ribosome Evolution and Structural Capacitance

2019 ◽  
Author(s):  
Ashley M Buckle ◽  
Malcolm Buckle
Keyword(s):  
Amino Acid ◽  
Genetic Code ◽  
Protein Evolution ◽  
Bioinformatic Analysis ◽  
Amino Acid Usage ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Acceptor Stem ◽  
Ribosome Evolution ◽  
Disordered Regions

In addition to the canonical loss-of-function mutations, mutations in proteins may additionally result in gain-of-function through the binary activation of cryptic ‘structural capacitance elements’. Our previous bioinformatic analysis allowed us to propose a new mechanism of protein evolution - structural capacitance – that arises via the generation of new elements of microstructure upon mutations that cause a disorder-to-order (DO) transition in previously disordered regions of proteins. Here we propose that the DO transition is a necessary follow-on from expected early codon-anticodon and tRNA acceptor stem-amino acid usage, via the accumulation of structural capacitance elements - reservoirs of disorder in proteins. We develop this argument further to posit that structural capacitance is an inherent consequence of the evolution of the genetic code.

scholarly journals Biological function polarity prediction of missense variants using machine learning

2020 ◽  
Author(s):  
Adhideb Ghosh ◽  
Alexander A. Navarini
Keyword(s):  
Machine Learning ◽  
Amino Acid ◽  
Roc Curve ◽  
Protein Level ◽  
Biological Function ◽  
Underlying Disease ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Missense Variants ◽  
Bioinformatics Tools

AbstractFunctional interpretation is crucial when facing on average 20,000 missense variants per human exome, as the great majority are not associated with any underlying disease. In silico bioinformatics tools can predict the deleteriousness of variants or assess their functional impact by assigning scores, but they cannot predict whether the variant in question results in gain or loss of function at the protein level. Here, we show that machine learning can effectively predict this biological function polarity of missense variants. The new method adapts weighted gradient boosting machine approach on a set of damaging variants (1,288 loss of function and 218 gain of function variants) as annotated by the tools SIFT, PolyPhen2 and CADD. Area under the ROC curve of 0.85 illustrates high discriminative power of the classifier. Predictive performance of the classifier remains consistent against an independent set of damaging variants as highlighted by the area under the ROC curve of 0.83. This new approach may help to guide biological experiments on the clinical relevance of damaging genetic variants.Author summaryMissense variant occurs when a single genetic alteration in DNA takes place and as a result a new amino acid is translated into the protein. This amino acid change can inactivate the existing protein function causing loss-of-function or produce a new function causing gain-of-function. Therefore, it is very important to interpret these functional consequences of missense variants as they often turn out to be disease causing. Each individual’s genome sequence has thousands of missense variants, out of which very few are actually associated with any underlying disease. Various computational tools have been developed to predict whether missense variants are damaging or not, but none of them can actually predict whether the damaging missense variants cause gain-of-function or loss-of-function. We have developed a new ensemble classifier to predict this biological function polarity at the protein level. The classifier combines the prediction scores of three existing bioinformatics tools and applies machine learning to make effective predictions. We have validated our classifier against an independent data set to show its high predictive power and robustness. The predictions made by our machine learning tool can be used as indicators of biological function polarity, but with further evidence on pathogenicity.

scholarly journals The reversion variant (p.Arg90Leu) at the evolutionarily adaptive p.Arg90 site in CELA3B predisposes to chronic pancreatitis

2020 ◽  
Author(s):  
Emmanuelle Masson ◽  
Vinciane Rebours ◽  
Louis Buscail ◽  
Frédérique Frete ◽  
Mael Pagenault ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Amino Acid ◽  
Human Genome ◽  
Low Frequency ◽  
Missense Variant ◽  
Loss Of Function ◽  
Ancestral Allele ◽  
Functional Effect ◽  
Gain Of Function ◽  
Missense Variants

ABSTRACTA gain-of-function missense variant in the CELA3B gene, p.Arg90Cys (c.268C>T), has recently been reported to cause pancreatitis in an extended pedigree. Herein, we sequenced the CELA3B gene in 644 genetically unexplained French chronic pancreatitis (CP) patients (all unrelated) and 566 controls. No predicted loss-of-function variants were identified. None of the six low frequency or common missense variants detected showed significant association with CP. Nor did the aggregate rare/very rare missense variants (n=14) show any significant association with CP. However, p.Arg90Leu (c.269G>T), which was found in 4 patients but no controls and affects the same amino acid as p.Arg90Cys, serves to revert p.Arg90 to the human elastase ancestral allele. Since p.Arg90Leu has previously been shown to exert a similar functional effect to p.Arg90Cys, our findings not only confirm the involvement of CELA3B in the etiology of CP but also pinpoint a new evolutionarily adaptive site in the human genome.

scholarly journals Loss of Function but No Gain of Function Caused by Amino Acid Substitutions in the Hexapeptide of Hoxa1 In Vivo

2004 ◽  
Vol 24 (19) ◽  
pp. 8567-8575 ◽  
Author(s):  
Sophie Remacle ◽  
Leïla Abbas ◽  
Olivier De Backer ◽  
Nathalie Pacico ◽  
Anthony Gavalas ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitutions ◽  
Loss Of Function ◽  
Functional Importance ◽  
Gain Of Function ◽  
Hox Proteins ◽  
Cellular Models ◽  
Critical Amino Acid ◽  
Skeletal Defects

ABSTRACT Homeodomain containing transcription factors of the Hox family play critical roles in patterning the anteroposterior embryonic body axis, as well as in controlling several steps of organogenesis. Several Hox proteins have been shown to cooperate with members of the Pbx family for the recognition and activation of identified target enhancers. Hox proteins contact Pbx via a conserved hexapeptide motif. Previous biochemical studies provided evidence that critical amino acid substitutions in the hexapeptide sequence of Hoxa1 abolish its interaction with Pbx. As a result, these substitutions also abolish Hoxa1 activity on known target enhancers in cellular models, suggesting that Hoxa1 activity relies on its capacity to interact with Pbx. Here, we show that mice with mutations in the Hoxa1 hexapeptide display hindbrain, cranial nerve, and skeletal defects highly reminiscent of those reported for the Hoxa1 loss of function. Since similar hexapeptide mutations in the mouse Hoxb8 and the Drosophila AbdA proteins result in activity modulation and gain of function, our data demonstrate that the functional importance of the hexapeptide in vivo differs according to the Hox proteins.

scholarly journals Frameshifts and wild-type protein sequences are always highly similar because the genetic code is optimal for frameshift tolerance

2016 ◽  
Author(s):  
Xiaolong Wang ◽  
Quanjiang Dong ◽  
Gang Chen ◽  
Jianye Zhang ◽  
Yongqiang Liu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Genetic Code ◽  
Protein Sequences ◽  
Loss Of Function ◽  
Wild Type ◽  
Standard Genetic Code ◽  
Type Protein ◽  
Wild Type Protein ◽  
Codon Pairs ◽  
Reading Frames

AbstractFrameshift mutation yields truncated, dysfunctional product proteins, leading to loss-of-function, genetic disorders or even death. Frameshift mutations have been considered as mostly harmful and of little importance for the molecular evolution of proteins. Frameshift protein sequences, encoded by the alternative reading frames of a coding gene, have been therefore considered as meaningless. However, existing studies had shown that frameshift genes/proteins are widely existing and sometimes functional. It is puzzling how a frameshift kept its structure and functionality while its amino-acid sequence is changed substantially. Here we demonstrate that the protein sequences of the frameshifts are highly conservative when compared with the wild-type protein sequence, and the similarities among the three protein sequences encoded in the three reading frames of a coding gene are defined mainly by the genetic code. In the standard genetic code, amino acid substitutions assigned to frameshift codon substitutions are far more conservative than those assigned to random substitutions. The frameshift tolerability of the standard genetic code ranks in the top 1.0-5.0% of all possible genetic codes, showing that the genetic code is optimal in terms of frameshift tolerance. In some higher species, the shiftability is further optimized at gene- or genome-level by a biased usage of codons and codon pairs, in which frameshift-tolerable codons/codon pairs are overrepresented in their genomes.

scholarly journals Indirect Routes to Aminoacyl-tRNA: The Diversity of Prokaryotic Cysteine Encoding Systems

2022 ◽  
Vol 12 ◽  
Author(s):  
Takahito Mukai ◽  
Kazuaki Amikura ◽  
Xian Fu ◽  
Dieter Söll ◽  
Ana Crnković
Keyword(s):  
Amino Acid ◽  
Genetic Code ◽  
Elongation Factor ◽  
Methanogenic Archaea ◽  
Bioinformatic Analysis ◽  
Trna Synthetase ◽  
Indirect Pathway ◽  
Gradual Loss ◽  
Editing Domain ◽  
Diverse Groups

Universally present aminoacyl-tRNA synthetases (aaRSs) stringently recognize their cognate tRNAs and acylate them with one of the proteinogenic amino acids. However, some organisms possess aaRSs that deviate from the accurate translation of the genetic code and exhibit relaxed specificity toward their tRNA and/or amino acid substrates. Typically, these aaRSs are part of an indirect pathway in which multiple enzymes participate in the formation of the correct aminoacyl-tRNA product. The indirect cysteine (Cys)-tRNA pathway, originally thought to be restricted to methanogenic archaea, uses the unique O-phosphoseryl-tRNA synthetase (SepRS), which acylates the non-proteinogenic amino acid O-phosphoserine (Sep) onto tRNACys. Together with Sep-tRNA:Cys-tRNA synthase (SepCysS) and the adapter protein SepCysE, SepRS forms a transsulfursome complex responsible for shuttling Sep-tRNACys to SepCysS for conversion of the tRNA-bound Sep to Cys. Here, we report a comprehensive bioinformatic analysis of the diversity of indirect Cys encoding systems. These systems are present in more diverse groups of bacteria and archaea than previously known. Given the occurrence and distribution of some genes consistently flanking SepRS, it is likely that this gene was part of an ancient operon that suffered a gradual loss of its original components. Newly identified bacterial SepRS sequences strengthen the suggestion that this lineage of enzymes may not rely on the m1G37 identity determinant in tRNA. Some bacterial SepRSs possess an N-terminal fusion resembling a threonyl-tRNA synthetase editing domain, which interestingly is frequently observed in the vicinity of archaeal SepCysS genes. We also found several highly degenerate SepRS genes that likely have altered amino acid specificity. Cross-analysis of selenocysteine (Sec)-utilizing traits confirmed the co-occurrence of SepCysE and the Sec-utilizing machinery in archaea, but also identified an unusual O-phosphoseryl-tRNASec kinase fusion with an archaeal Sec elongation factor in some lineages, where it may serve in place of SepCysE to prevent crosstalk between the two minor aminoacylation systems. These results shed new light on the variations in SepRS and SepCysS enzymes that may reflect adaptation to lifestyle and habitat, and provide new information on the evolution of the genetic code.

scholarly journals Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Gerhard Binder ◽  
Julian Ziegler ◽  
Roland Schweizer ◽  
Wisam Habhab ◽  
Tobias B. Haack ◽  
...  
Keyword(s):  
Amino Acid ◽  
Adrenal Insufficiency ◽  
Novel Mutation ◽  
Hot Spot ◽  
Missense Variant ◽  
Single Family ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Functional Region ◽  
Silver Russell Syndrome

Abstract Background Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C missense mutation (p.Arg279Leu) was identified in several members of a single family clinically diagnosed with Silver–Russell syndrome (SRS) but without adrenal insufficiency. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation. This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome. Results Here, we describe a third familial case with maternally inherited SRS due to a missense variant affecting the same amino acid position 279 but leading to a different amino acid substitution (p. (Arg279Ser)). The two affected family members (mother and son) presented with the complete SRS phenotype (both Netchine–Harbison CSS score 5 of 6) but without body asymmetry or adrenal insufficiency. Conclusions In comparison with loss-of-function genomic IGF2 mutations, CDKN1C gain-of-function mutations are a less frequent cause of SRS and seem to affect a cluster of few amino acids.

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