QTL mapping in outbred populations: successes and challenges

Abstract

Solberg Woods LC. QTL mapping in outbred populations: successes and challenges. Physiol Genomics 46: 81-90, 2014. First published December 10, 2013 doi:10.1152/physiolgenomics.00127.2013.-Quantitative trait locus (QTL) mapping in animal populations has been a successful strategy for identifying genomic regions that play a role in complex diseases and traits. When conducted in an F2 intercross or backcross population, the resulting QTL is frequently large, often encompassing 30 Mb or more and containing hundreds of genes. To narrow the locus and identify candidate genes, additional strategies are needed. Congenic strains have proven useful but work less well when there are multiple tightly linked loci, frequently resulting in loss of phenotype. As an alternative, we discuss the use of highly recombinant outbred models for directly fine-mapping QTL to only a few megabases. We discuss the use of several currently available models such as the advanced intercross (AI), heterogeneous stocks (HS), the diversity outbred (DO), and commercially available outbred stocks (CO). Once a QTL has been finemapped, founder sequence and expression QTL mapping can be used to identify candidate genes. In this regard, the large number of alleles found in outbred stocks can be leveraged to identify causative genes and variants. We end this review by discussing some important statistical considerations when analyzing outbred populations. Fine-resolution mapping in outbred models, coupled with full genome sequence, has already led to the identification of several underlying causative genes for many complex traits and diseases. These resources will likely lead to additional successes in the coming years.intercross; heterogeneous stock; diversity outbred; genetic mapping; high resolution mapping QUANTITATIVE TRAIT LOCUS (QTL) mapping in rodents has been a successful strategy for identifying regions of the genome that play a role in many diseases and traits. Initial QTL studies used F2 intercross or backcrosses, in which two strains that differ phenotypically and genetically are bred for two generations (see Fig. 1). With this strategy, F2 progeny are phenotyped and genotyped, and genetic loci linked to the trait of interest are identified. Although this method works extremely well for detecting QTL, it provides only a broad localization, with identified regions tending to be very large (30 -40 Mb) and often encompassing hundreds of genes. As a result, although F2 intercrosses and backcrosses have identified thousands of QTL over the past 30 yr, they have proven less useful for identifying the underlying causative genes and variants (see Ref. 30).In an attempt to narrow the QTL regions and identify causative genes, multiple methods have been developed (see Ref. 32). One popular method is to create a congenic strain in which consecutively smaller portions of the QTL from the disease strain are bred onto the genetic background of the disease resistant strain. This strategy has successfully narrowed numerous QTL and has the potential to lead ...

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