DEFLATE compression algorithm corrects for overestimation of phylogenetic diversity by Grantham approach to single-nucleotide polymorphism classification.
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.
Kolling Institute of Medical Research, Royal North Shore Hospital, Pacific Hwy, St Leonards, NSW 2065, Australia. asch5328@uni.sydney.edu.au.
Arran
A
Schlosberg
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. yhbl2@cam.ac.uk.
Brian Y H
BY
Lam
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. gshy2@cam.ac.uk.
Giles S H
GS
Yeo
Kolling Institute of Medical Research, Royal North Shore Hospital, Pacific Hwy, St Leonards, NSW 2065, Australia. jclifton@med.usyd.edu.au.
Roderick J
RJ
Clifton-Bligh
D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D014644:Genetic Variation; D020407:Internet; D008962:Models, Theoretical; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D014584:User-Computer Interface