Abstract
Abstract
Background
Advanced intercross lines (AIL) are segregating populations created using a multigeneration breeding protocol for fine mapping complex traits in mice and other organisms. Applying quantitative trait locus (QTL) mapping methods for intercross and backcross populations, often followed by na�ve permutation of individuals and phenotypes, does not account for the effect of family structure in AIL populations in which final generations have been expanded and leads to inappropriately low significance thresholds. The critical problem with a na�ve mapping approach in such AIL populations is that the individual is not an exchangeable unit given the family structure.
Methodology/Principal Findings
The effect of family structure has immediate implications for the optimal AIL creation (many crosses, few animals per cross, and population expansion before the final generation) and we discuss these and the utility of AIL populations for QTL fine mapping.
We also describe Genome Reshuffling for Advanced Intercross Permutation, (GRAIP) a method for analyzing AIL data that accounts for family structure. RAIP permutes a more interchangeable unit in the final generation crosses - the parental genome - and simulating regeneration of a permuted AIL population based on exchanged parental identities. GRAIP determines appropriate genome- ide significance thresholds and locus-specific P-values for AILs and other populations with similar family structures.
We contrast GRAIP with na�ve permutation using a large densely genotyped mouse AIL population (1333 individuals from 32 crosses). A na�ve permutation using coat color as a model phenotype demonstrates high false-positive locus identification and uncertain significance levels in our AIL population, which are corrected by use of GRAIP. We also show that GRAIP detects an established hippocampus weight locus and a new locus, Hipp9a.
Conclusions and Significance
GRAIP determines appropriate genome-wide significance thresholds and locus- specific P-values for AILs and other populations with similar family structures. The effect of family structure has immediate implications for the optimal AIL creation (many crosses, few animals per cross, and population expansion before the final generation) and we discuss these and the utility of AIL populations.