Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Dec 4:14:352.
doi: 10.1186/1471-2105-14-352.

Status quo of annotation of human disease variants

Hanka Venselaar  1 , Franscesca Camilli, Shima Gholizadeh, Marlou Snelleman, Han G Brunner, Gert Vriend
Affiliations

Status quo of annotation of human disease variants

Hanka Venselaar et al. BMC Bioinformatics. .

Abstract

Background: The ever on-going technical developments in Next Generation Sequencing have led to an increase in detected disease related mutations. Many bioinformatics approaches exist to analyse these variants, and of those the methods that use 3D structure information generally outperform those that do not use this information. 3D structure information today is available for about twenty percent of the human exome, and homology modelling can double that fraction. This percentage is rapidly increasing so that we can expect to analyse the majority of all human exome variants in the near future using protein structure information.

Results: We collected a test dataset of well-described mutations in proteins for which 3D-structure information is available. This test dataset was used to analyse the possibilities and the limitations of methods based on sequence information alone, hybrid methods, machine learning based methods, and structure based methods.

Conclusions: Our analysis shows that the use of structural features improves the classification of mutations. This study suggests strategies for future analyses of disease causing mutations, and it suggests which bioinformatics approaches should be developed to make progress in this field.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Performance of the mutation analysis servers grouped by type. Shown is the average percentage of the correctly predicted pathogenic mutants and neutral SNPs. The different servers are divided in groups based on their underlying methods. G = Grantham scores only, MSA = Multiple Sequence Alignment-centred methods (PhD-SNP, Panther, and SIFT), ML = Machine Learning based methods (SNPs&GO, SNAP, MutPred), 3D = structure based methods (nsSNPanalyzer, SNP3D, PolyPhen-2, and HOPE).
Figure 2
Figure 2
Mutation W177R in opsin. The opsin molecule is shown in grey, the side chain of wildtype tryptophan and mutant arginine are shown in green and red, respectively. The picture illustrates that the tryptophan residue is located at the surface where it can make hydrophobic interactions with the membrane.
Figure 3
Figure 3
Mutation V359 in SPTC2. The SPTC2 molecule is shown in grey, the side chain of wildtype valine and mutant methionine are shown in green and red respectively. Other side chains of surrounding residues are also shown in grey and indicate that the residue is buried.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308–311. doi: 10.1093/nar/29.1.308. - DOI - PMC - PubMed
    1. Webb AJ, Thorisson GA, Brookes AJ. An informatics project and online “Knowledge Centre” supporting modern genotype-to-phenotype research. Hum Mutat. 2011;32(5):543–550. doi: 10.1002/humu.21469. - DOI - PubMed
    1. Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT. LOVD v.2.0: the next generation in gene variant databases. Hum Mutat. 2011;32(5):557–563. doi: 10.1002/humu.21438. - DOI - PubMed
    1. The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061–1073. doi: 10.1038/nature09534. - DOI - PMC - PubMed
    1. The international HapMap Consortium. Integrating ethics and science in the International HapMap Project. Nat Rev Genet. 2004;5(6):467–475. doi: 10.1038/nrg1351. - DOI - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources

-