DEFLATE Compression Algorithm Corrects for Overestimation of Phylogenetic Diversity by Grantham Approach to Single-Nucleotide Polymorphism Classification

International Journal of Molecular Sciences

Arran Schlosberg¹  Brian Y. H. Lam²  Giles S. H. Yeo² 

[1] Kolling Institute of Medical Research, Royal North Shore Hospital, Pacific Hwy, St Leonards, NSW 2065, Australia; E-Mail:;University of Cambridge Metabolic Research Laboratories, Box 289, Level 4 Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK; E-Mails:

关键词: DEFLATE;    compression;    Grantham;    variation;    sequence alignment;    nsSNP;   

DOI  :  10.3390/ijms15058491

来源: mdpi

【 摘 要 】

Improvements in speed and cost of genome sequencing are resulting in increasing numbers of novel non-synonymous single nucleotide polymorphisms (nsSNPs) in genes known to be associated with disease. The large number of nsSNPs makes laboratory-based classification infeasible and familial co-segregation with disease is not always possible. In-silico methods for classification or triage are thus utilised. A popular tool based on multiple-species sequence alignments (MSAs) and work by Grantham, Align-GVGD, has been shown to underestimate deleterious effects, particularly as sequence numbers increase. We utilised the DEFLATE compression algorithm to account for expected variation across a number of species. With the adjusted Grantham measure we derived a means of quantitatively clustering known neutral and deleterious nsSNPs from the same gene; this was then used to assign novel variants to the most appropriate cluster as a means of binary classification. Scaling of clusters allows for inter-gene comparison of variants through a single pathogenicity score. The approach improves upon the classification accuracy of Align-GVGD while correcting for sensitivity to large MSAs. Open-source code and a web server are made available at https://github.com/aschlosberg/CompressGV.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland