Predicting the functional consequences of non-synonymous single nucleotide polymorphisms: structure-based assessment of amino acid variation11Edited by F. Cohen

Chasman, Daniel I.; Adams, Rhys M.

doi:10.1006/jmbi.2001.4510

Cited by 384 publications

(329 citation statements)

References 48 publications

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“…For the multiple sequence alignments of protein families homologous to each of these proteins, Blocks9 components 3 and 8 revealed a different threshold of sequence similarity that was inferred to reveal the limits of functional similarity (Table 3). Overall, Ϸ30% of the polymorphisms [46͞134 from Cargill et al (21) and 15͞51 from Halushka et al (22)] were predicted to affect function, which is similar to the proportion found by others (19,(23)(24)(25)(26), and the following were most strongly predicted to affect function: CETP-486VM, F5-817NT, F13A1-589LQ, FSHR-524SR, GH1-105SC, GHR-495PT, NTRK1-604HY, and TFPI-292VM. The variants in NTRK1 and TFPI had Fig.…”

Section: Resultssupporting

confidence: 74%

Functional classification of proteins and protein variants

Lau¹,

Chasman²

2004

Proc. Natl. Acad. Sci. U.S.A.

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To help characterize the diversity in biological function of proteins emerging from the analysis of whole genomes, we present an operational definition of biological function that provides an explicit link between the functional classification of proteins and the effects of genetic variation or mutation on protein function. Using phylogenetic information, we establish definite criteria for functional relatedness among proteins and a companion procedure for predicting deleterious alleles or mutations. Applied to the functional classification of sequences similar to 13 human tumor suppressor proteins, our methods predict there are functional properties unique to mammals for three of them, BRCA1, BRCA2, and WT1. We examine protein variants caused by nonsynonymous single-nucleotide polymorphisms in a set of clinically important genes and estimate the magnitude of a disproportionate propensity for disruption of function among the nonsynomous singlenucleotide polymorphisms that are maintained at low frequency in the human population.A lthough the idea that structural similarity between proteins can be anticipated from their sequences alone is well established, the notion that a signature of functional similarity exists in the comparison of sequences is much less well developed. In fact, the very definition of functional similarity is more elusive than that of structural similarity, which can be quantified (1-3), and pertains to relatively subtle aspects of proteins and their sequences. In proteins inferred to share a remote common ancestor, amino acids determined to be homologous from accurately aligned sequences may not share strictly analogous roles in function and stability, even though their relationship to an overall structural fold may be the same. This observation suggests an operational criterion for what it means that a set of proteins is functionally similar: corresponding amino acids at each residue position in functionally related proteins should serve analogous roles and should likely be interchangeable. From this perspective, the separate problems of functional classification of proteins and the prediction of functional consequences of amino acid substitutions are very closely related.This study demonstrates how information in a multiple sequence alignment can provide an explicit link between protein functional classification and the tolerance of protein function to amino acid substitutions. In our analysis, we note that most multiple sequence alignments of a query and its homologues will contain too few sequences for the observed profile of amino acids at each residue position to reflect thorough sampling of all 20 amino acids by evolution. To overcome this paucity of empirical amino acid sampling, a key element of our analysis is the use of preexisting mixtures of Dirichlet prior distributions of amino acid frequencies (4) to infer which additional amino acids might be functionally consistent with the observed profiles. Using the Bayesian formalism associated with these distributions, we present a fram...

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Section: Resultssupporting

confidence: 74%

Functional classification of proteins and protein variants

Lau¹,

Chasman²

2004

Proc. Natl. Acad. Sci. U.S.A.

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“…The more buried a residue, the more likely are mutations of the site to be pathogenic [Vitkup et al, 2003]. In addition, the introduction of charged side chains into the hydrophobic core is known to destabilize protein structure [Chasman and Adams, 2001].…”

Section: Discussionmentioning

confidence: 99%

“…The probability of a mutation to be pathogenic has been shown to increase with a decrease in the solvent accessibility of the site [Vitkup et al, 2003]. In addition, the introduction of charged side chains into the hydrophobic core destabilizes protein structure [Chasman and Adams, 2001]. Of the 29 HNE trypsin homology domain mutations, four cause significant loss of hydrophobic interactions: L47P, I60T, C71S, and L206F.…”

Section: Mutations Causing Changes In Contacts Maintaining Stabilitymentioning

confidence: 99%

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Thusberg

Vihinen

2006

Hum. Mutat.

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For the Immunogenetics Special IssueCyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.

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“…First, the regions of proteins which are critical to function evolve under long-term negative selection; thus when the sequence of a human protein is aligned for comparison with its homologs from other species, these sites will display only specific patterns of amino acid residue variation or complete conservation. The analysis of phylogenetic information in the form of multiple sequence alignment is a powerful source of information about the spectrum of residues allowed at a particular position of the protein of interest (62)(63)(64). Second, most pathogenic mutations affect protein stability (65,66).…”

Section: Computational Predictionsmentioning

confidence: 99%

Inferring causality and functional significance of human coding DNA variants

Sunyaev

2012

Human Molecular Genetics

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Sequencing technology enables the complete characterization of human genetic variation. Statistical genetics studies identify numerous loci linked to or associated with phenotypes of direct medical interest. The major remaining challenge is to characterize functionally significant alleles that are causally implicated in the genetic basis of human traits. Here, I review three sources of evidence for the functional significance of human DNA variants in protein-coding genes. These include (i) statistical genetics considerations such as co-segregation with the phenotype, allele frequency in unaffected controls and recurrence; (ii) in vitro functional assays and model organism experiments; and (iii) computational methods for predicting the functional effect of amino acid substitutions. In spite of many successes of recent studies, functional characterization of human allelic variants remains problematic.

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Predicting the functional consequences of non-synonymous single nucleotide polymorphisms: structure-based assessment of amino acid variation11Edited by F. Cohen

Cited by 384 publications

References 48 publications

Functional classification of proteins and protein variants

Functional classification of proteins and protein variants

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Inferring causality and functional significance of human coding DNA variants

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