Review Article

Advances in Human Biology: Combining Genetics and Molecular Biophysics to Pave the Way for Personalized Diagnostics and Medicine

Table 1

Tools and methods for predicting effects of mutations.

PurposeNameURLDescription and advantages/disadvantages

DatabasesOMIMhttp://www.ncbi.nlm.nih.gov/omimManually curated, freely available
dbSNPhttp://www.ncbi.nlm.nih.gov/SNP/Freely available. Includes short variations in nucleotide sequences from a wide range of organisms
1000 Genomes: A Deep Catalog of Human Genetic Variationhttp://www.1000genomes.org/Freely available, provides tools for various searches as within populations, allele frequency and linkage disequilibrium structure
HGMDhttp://www.hgmd.org/Requires license, but is the most comprehensive database of human mutations and provides visualization tools and search engines

NetworkingCytoscapehttp://www.cytoscape.org/An open source software platform for visualizing molecular interaction networks and biological pathways and integrating these networks with annotations, gene expression profiles, and other state data
Network Portalhttp://networks.systemsbiology.net/Provides analysis and visualization tools for selected gene regulatory networks to aid researchers in biological discovery and hypothesis development
Network2Canvashttp://www.maayanlab.net/N2C/#.U1fP4qJWAkIAllows for generation of drug-drug similarity and functional association of gene canvases

3D structure modelingSwiss Modelhttp://swissmodel.expasy.org/Automated server allowing 3D structure of a protein to be predicted inputting the sequence of the target
I-TASSERhttp://zhanglab.ccmb.med.umich.edu/I-TASSER/Fully automated 3D structure predictor, especially useful for difficult targets (low sequence similarity to known structures)
Modellerhttp://salilab.org/modeller/Stand-alone 3D structure predictor. Can be installed locally and used for large-scale predictions

Protein stabilityFoldXhttp://foldx.crg.es/Fast assessment of the changes of the unfolding free energy caused by mutations using empirical formula
I-Mutanthttp://gpcr2.biocomp.unibo.it/%7Eemidio/I-Mutant/I-Mutant.htmVery fast and accurate prediction of the changes of the folding free energy caused by mutations. The input can be just the sequence of the protein
ERIShttp://dokhlab.unc.edu/tools/eris/Uses Medusa force field to make predictions of the change of the folding free energy caused by mutations

Protein interactionsBeAtMuSiChttp://babylone.ulb.ac.be/beatmusic/Evaluates change in binding affinity between proteins caused by single-site mutations in their sequence
ICMhttp://www.molsoft.com/gui/mutation-protein-binding.htmlComputes the change in binding free energy of a protein complex upon mutation of a single residue. Requires license
Robettahttp://robetta.bakerlab.org/alascansubmit.jspProvides estimation for the binding free energy changes caused by mutations to Alanine

Subcellular localization and pH dependenceWoLF PSORThttp://wolfpsort.org/Predicts the subcellular localization of proteins based on their amino acid sequences. The predictions are based on both known sorting signal motifs and amino acid content
PredSLhttp://aias.biol.uoa.gr/PredSL/Stand-alone code utilizing neural networks, Markov chains, and HMMs for the prediction of the subcellular localization of proteins
UniLocā€‰This is a webserver using PSI-Blast to infer homology between query sequence and already annotated proteins

Macromolecular functionSNAPhttps://www.rostlab.org/services/snap/SNAP is a neural network-based method that uses in silico derived protein information (e.g., secondary structure, conservation, solvent accessibility, etc.) in order to make predictions regarding functionality of mutated proteins
MutationAssessorhttp://mutationassessor.org/The server predicts the functional impact of amino acid substitutions in proteins
SIFThttp://sift.jcvi.org/The prediction is based on the degree of conservation of amino acid residues in sequence alignments derived from closely related sequences