Rare disorders afflict millions of families worldwide. The extremely rare genetic variants that potentially underlie disease traits can be discovered by sequencing large cohorts of patients and analyzing the genomic data with sophisticated bioinformatic tools. In this workshop, a collaborative team from Universidad Andrés Bello (Chile) and the Data Sciences Platform at the Broad Institute of MIT and Harvard (United States) will introduce you to variant discovery step-by-step, from preliminary clinical steps and hypothesis generation to the fundamentals of genomic analysis with the Genome Analysis Toolkit (GATK). Developed at the Broad Institute, GATK is the most widely-used open-source software package for variant discovery on whole genome and exome data.
Through a mix of lectures and practical exercises, you will learn the key scientific concepts and approaches for (1) formulating a hypothesis that a disease affecting a patient is controlled by a single deleterious variant, and (2) the official GATK Best Practices pipelines for variant discovery published by the Broad Institute. This includes learning how to write GATK pipelines using the Workflow Description Language (WDL) that is used in the GATK Best Practices, and execute them using the Cromwell execution engine on any platform, including FireCloud -- the Broad's open-source cloud-based analysis platform. FireCloud integrates computational resources, methods repository and data management in a secure environment. We will then guide you through the reproduction of an exome-sequencing study involving a large cohort of Tetralogy of Fallot patients (soon to be published: https://www.biorxiv.org/content/early/2018/04/13/300905) using FireCloud, simultaneously learning how to assemble a workspace containing workflows and data that recapitulates all stages of the approach, which could then be published as part of a manuscript to build a fully reproducible analysis. The session will close with a discussion of the next steps following variant discovery, from the variant validation process to in vitro and in vivo experiments to confirm the association between a candidate variant and the disease.