The recipe for finding human genetic variation

Alice McCarthy, April 11th, 2011
  • Broad researchers provide the guide for finding DNA differences

Think of it as the Julia Child recipe for how to discover variations in the human genome. A paper published online yesterday in Nature Genetics from Broad researchers is the go-to source for investigators searching for the differences in the DNA sequences between individuals. For those who appreciate Julia’s multi-page masterpiece of how to bone a duck, this is an equivalent recipe for tackling one of the most medically informative pursuits facing today’s genomics investigators. Finding DNA variations between individuals and groups is one of the bedrock approaches for finding clues to what causes human disease.

“It is a step-by-step guide to finding high-quality variation information using next-generation sequencing technology,” explains Mark DePristo, Manager, Genetic Analysis in the Broad's Program in Medical and Population Genetics. “This paper is a compilation of all the steps needed from preparing the data and integrating it to give you a complete picture of all real differences in the genomes of individuals. It provides the intellectual organization of a very complicated problem.”

Much as a cook relies on rigorous testing and development of recipes to come up with just the right menu, scientists have been relying on the many tools developed at the Broad for working with today’s complicated sequencing data. ‘There are many, many discrete steps to finding variations in the human genome,” Mark explains. “We name every step, every tool, describing each of them.”

The paper represents years of work at the Broad, all in pursuit of solving a single, but highly complicated, problem: how to sequence the genomes of individuals and see where they differ from the accepted reference.

The question has taken years to answer correctly but researchers have been developing new tools, or ingredients, to solve the puzzle. Because the Broad’s software tools are made publicly available immediately and without fee, researchers globally have been using all of these tools for a long time. “This paper is somewhat like an archival statement of what people have been using,” adds Mark. “This is saying here is the flow between tools. There have been many publications of individual tools. But this paper explains the tools used and why they are used.”

Just as a professional cook is always looking to add just the right ingredients in their proper proportions, Broad researchers continue to develop new and improved tools within their variation discovery framework.

A Google search revealed the following reviewer’s comments about Julia’s duck deboning: “It seems intimidating in theory, but it turns out to be oddly satisfying…. [the] instructions demystify the process and reassure.” Perhaps genomics researchers taking on variation discovery will feel the same about one of the Broad’s master recipes.

And though Julia may have worked solo, this work was accomplished with the help of a team of computational biologists, mathematicians, and computer scientists. Current team members include Mark DePristo, Eric Banks, Ryan Poplin, Kiran Garimella, Jared Maguire, Christopher Hartl, Anthony Philippakis, Guillermo del Angel, Manuel Rivas, Matthew Hanna, Aaron McKenna, Timothy Fennell, Andrey Sivachenko, Kristian Cibulskis, Stacey Gabriel, David Altshuler, and Mark Daly.