The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics

TLDR

Complex traits and disease comorbidity in humans and model organisms arise from naturally occurring polymorphisms that interact with each other and with the environment. The authors established the Collaborative Cross mouse population to enable systems genetics studies of complex traits and to support future investigations of biomolecular networks. At ORNL, the Collaborative Cross is bred using a software‑assisted program that maintains traceable lineages, high genetic diversity, and a large population, while controlled conditions and high‑throughput phenotyping enable detailed mapping of recombination, allele drift, and population structure. The program has produced 650 lines, with nearly 200 beyond the seventh generation of inbreeding, demonstrating substantial progress toward a comprehensive resource for systems genetics.

Abstract

Complex traits and disease comorbidity in humans and in model organisms are the result of naturally occurring polymorphisms that interact with each other and with the environment. To ensure the availability of resources needed to investigate biomolecular networks and systems-level phenotypes underlying complex traits, we have initiated breeding of a new genetic reference population of mice, the Collaborative Cross. This population has been designed to optimally support systems genetics analysis. Its novel and important features include a high level of genetic diversity, a large population size to ensure sufficient power in high-dimensional studies, and high mapping precision through accumulation of independent recombination events. Implementation of the Collaborative Cross has been ongoing at the Oak Ridge National Laboratory (ORNL) since May 2005. Production has been systematically managed using a software-assisted breeding program with fully traceable lineages, performed in a controlled environment. Currently, there are 650 lines in production, and close to 200 lines are now beyond their seventh generation of inbreeding. Retired breeders enter a high-throughput phenotyping protocol and DNA samples are banked for analyses of recombination history, allele drift and loss, and population structure. Herein we present a progress report of the Collaborative Cross breeding program at ORNL and a description of the kinds of investigations that this resource will support.