QuadGT is a software package for calling single-nucleotide variants in four sequenced genomes comprising a normal-tumor pair and the two parents. Genotypes are inferred using a joint model of parental variant frequencies, de novo germline mutations, and somatic mutations. The model quantifies the descent-by-modification relationships between the unknown genotypes by using a set of parameters in a Bayesian inference setting.
Note that you can use QuadGT on any subset of the four related genomes, including parent-offspring trios, and normal-tumor pairs without parental samples.
The software package assumes a thorough probabilistic model of single-nucleotide variants with the following notable features.
- Multiple alleles. Every locus has four possible alleles (A,C,G,T). Diploid genotypes combine multi-allele frequencies with adjusted heterozygous/homozygous SNP ratios.
- DNA mutation models. Point mutations between related genomes follow standard DNA evolution models. The implemented models include the basic Jukes-Cantor model and a version of the Hasegawa-Kishino-Yano (a.k.a. Felsenstein's F84) model with purine-pyrimidine balance %(A+G)=%(C+T)=50% and four parameters that adjust sequence divergence, transition/transversion ratio and nucleotide composition (GC-content and amino/keto %(A+C)/%(T+G) content).
- Known variants. QuadGT integrates prior information on minor allele frequencies from a chosen variant database such as the NHLBI Exome Sequencing Project's Exome Variant Server.
- Inheritance. Inheritance models span autosomes, sex chromosomes, and mitochondrial DNA. De novo mutations follow a DNA substitution model.
- Basecall qualities. QuadGT's model incorporates alignment quality scores, uses them in inference, and automatically recalibrates score→probability mappings during model training.
- Tumor purity. QuadGT infers tumor purity (normal-tumor sample mixture coefficient) from basecall statistics at somatic mutations, and takes it into account during variant calls.
QuadGT is implemented in 64-bit Java, and thus works on diverse platforms including Mac OS X, Microsoft Windows, and Unix/Linux flavors. The software is packaged in a JAR file (QuadGT.jar) and can be executed in Java versions 1.6 and above.
Download the JAR file QuadGT.jar.
If you want to work with BAM input files, then you also need the
Picard/SAMTools JDK (version 1.85).
The simplest is to download QuadGT.zip
which bundles QuadGT.jar with the SAMTools library.
(Specifically, QuadGT.zip contains dist/QuadGT.jar and dist/lib/samtools-1.85.jar,
as well as the User's Guide dist/quadgt-usage.pdf.)
The User's Guide is available in PDF format as quadgt-usage.pdf. It gives detailed information about command-line options, discusses the mathematical background, and provides some advice on designing variant-calling pipelines.
There is a built-in wizard that helps you set up then proper command-line options through a graphical interface. Execute QuadGT.jar with no arguments to launch the wizard.
% java -jar QuadGT.jar &
The QuadGT software package was developed in conjunction with a study led by Daniel Sinnett at the Sainte-Justine UHC Research Centre (Montréal, QC) on pediatric acute lymphoblastic leukemia. The project has been supported by funds from the Terry Fox Research Institute and the Canadian Institutes for Health Research, the François-Karl-Viau Research Chair in Pediatric Oncogenomics, and the National Science and Engineering Research Council.
The QuadGT software package was developed by Eric Bareke and Miklós Csűrös.