Geraldine A. Van der Auwera - Genomics in the Cloud: Using Docker, GATK, and WDL in Terra

by Geraldine A. Van der Auwera and Brian D. OConnor

Copyright 2020 The Broad Institute, Inc. and Brian OConnor All rights reserved.

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I migrated from mathematics into the field of genomics in 1985roughly a year before the field officially came into existence. The word genomics was coined in 1986, which also saw the first public debate, at the Cold Spring Harbor Laboratory, about the notion of mounting a Human Genome Project.

Its hard to imagine how much has changed since then. Computers hardly figured in biomedicinethe initial design for the Whitehead Institute for Biomedical Research, founded in the early 1980s, included no provision for a computer. Large amounts of data were seen as a nuisance, not an assetin a Nature article reporting on the Human Genome Project debate, the journals biology editor wrote, If the skill and ingenuity of modern biology are already stretched to interpret sequences of known importance, such as those of the DMD and CGD genes, what possible use could be made of more sequences?

Despite such doubts, biologists eventually decided to press onlaunching the Human Genome Project, their first major data gathering effort, in 1990. One of the important motivations was the prospect of deploying systematic methodsrather than guessworkto discover the genes responsible for human diseases. In 1980, a brilliant biologist, David Botstein, had conceived how to find the location of genes for rare monogenic diseases by tracing their inheritance in families relative to a genetic map of DNA variants across the human genome. Realizing the full power of the idea, though, would require mappingand eventually sequencingthe entire human genome.

The Human Genome Project was an extraordinary collaboration that spanned six countries and twenty institutions, took thirteen years, and cost $3 billion. When the dust settled, the world had the three billion nucleotide-long DNA sequence of a single human genome.

With this project completed, many biologists thought that business would return to usual. But what happened next was even more remarkable. Over the next 15 years, biology became an information sciencein which the generation of massive amounts of data reshaped the field. For example:

• Genetic mapping in families revealed the genes responsible for more than 5,000 serious rare monogenic disorders.

• New kinds of genetic mapping in populations led to the discovery of ~100,000 robust associations of specific genetic regions with common diseases and traits.

• Genetic analysis of thousands of tumors uncovered hundreds of new genes in which mutations propelled cancer.

Remarkably, the cost of sequencing a human genome fell by a factor of five millionfrom $3 billion to $600and the cost is likely to reach $100 in the coming years. More than one million genomes have been sequenced so far. Overall, genomic data of all kinds is doubling roughly every eight months.

None of this would have been possible without the development of powerful new computational methods and tools to work with the many new types of data that were being generated. A good example is the Genome Analysis Toolkit, developed by colleagues at the Broad Institute, which youll read a lot more about in this book.