Characterization of Compensated Mutations in Terms of Structural and Physico-Chemical Properties

Ferrer-Costa, Carles; Orozco, Modesto; Cruz, Xavier de la

doi:10.1016/j.jmb.2006.09.053

Cited by 43 publications

(53 citation statements)

References 33 publications

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“…An inferred evolutionary trajectory was constructed based on the stability constraints [42]. Epistasis has also been revealed by studying disease-causing single mutations in humans and comparing them with compensated mutations that do not cause disease in other species [400][401][402]. One estimate indicates that 80% of pathological mutations result in protein stability changes [403].…”

Section: Epistasis and Co-evolution Of Interacting Amino Acid Residuesmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

224

207

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The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence-structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by 'hidden' conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution.

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Section: Epistasis and Co-evolution Of Interacting Amino Acid Residuesmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

224

207

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“…CPDs tend to be less severe in terms of the difference in physicochemical properties between the substituted and substituting amino acids than is normally the case for pathological mutations [Barešić et al, 2010;Ferrer-Costa et al, 2007]. In the context of human disease, Suriano et al [2007] have provided a good example of the influence of compensated and compensating mutations in the OTC gene.…”

Section: Compensated Pathogenic Deviationsmentioning

confidence: 99%

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

et al. 2010

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The number of reported germline mutations in human nuclear genes, either underlying or associated with inherited disease, has now exceeded 100,000 in more than 3,700 different genes. The availability of these data has both revolutionized the study of the morbid anatomy of the human genome and facilitated “personalized genomics.” With ∼300 new “inherited disease genes” (and ∼10,000 new mutations) being identified annually, it is pertinent to ask how many “inherited disease genes” there are in the human genome, how many mutations reside within them, and where such lesions are likely to be located? To address these questions, it is necessary not only to reconsider how we define human genes but also to explore notions of gene “essentiality” and “dispensability.” Answers to these questions are now emerging from recent novel insights into genome structure and function and through complete genome sequence information derived from multiple individual human genomes. However, a change in focus toward screening functional genomic elements as opposed to genes sensu stricto will be required if we are to capitalize fully on recent technical and conceptual advances and identify new types of disease‐associated mutation within noncoding regions remote from the genes whose function they disrupt. Hum Mutat 31:631–655, 2010. © 2010 Wiley‐Liss, Inc.

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“…From a medical point of view, the individual combination of nsSNVs may play a crucial role in clinical diagnostics regarding personalized medicine (49). Previous studies analyzed the occurrence and characteristics of compensatory mutations (8), although there might also be cumulative effects of mutations, packing single benign effects together to an observable disease phenotype. More precisely, benign-annotated nsSNVs in combination might be responsible for a pathological effect.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies analyzed the existence of compensatory mutations canceling the damaging effect of deleterious mutations (8). A compensatory mutation occurs when the loss caused by one mutation is corrected by its epistatic interaction with a second mutation at a different site in the genome.…”

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confidence: 99%

From Single Variants to Protein Cascades

Mueller

Sommer

Backes

et al. 2016

Journal of Biological Chemistry

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Understanding the role of genetics in disease has become a central part of medical research. Non-synonymous single nucleotide variants (nsSNVs) in coding regions of human genes frequently lead to pathological phenotypes. Beyond single variations, the individual combination of nsSNVs may add to pathogenic processes. We developed a multiscale pipeline to systematically analyze the existence of quantitative effects of multiple nsSNVs and gene combinations in single individuals on pathogenicity. Based on this pipeline, we detected in a data set of 842 nsSNVs discovered in 76 genes related to cardiomyopathies, associated nsSNV combinations in seven genes present in at least 70% of all 639 patient samples, but not in a control cohort of healthy humans. Structural analyses of these revealed primarily an influence on the protein stability. For amino acid substitutions located at the protein surface, we generally observed a proximity to putative binding pockets. To computationally analyze cumulative effects and their impact, pathogenicity methods are currently being developed. Our approach supports this process, as shown on the example of a cardiac phenotype but can be likewise applied to other diseases such as cancer.

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Characterization of Compensated Mutations in Terms of Structural and Physico-Chemical Properties

Cited by 43 publications

References 33 publications

Biophysics of protein evolution and evolutionary protein biophysics

Biophysics of protein evolution and evolutionary protein biophysics

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

From Single Variants to Protein Cascades

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