QTL fine-mapping Strategies
This page describes mapping strategies that we have devised in order to fine-map QTL using Heterogeneous Stocks whilst minimising genotyping cost.
The Inbred-Outbred Cross
The Inbred-Outbred cross is an F2 intercross between an inbred line and a heterogeneous Stock. It may be used to detect and fine-map QTL simultaneously. Full details of the method are available from Mott R and Flint J (2002) Simultaneous Detection and Fine-mapping of Quantitative Trait Loci in Mice using Heterogenous Stocks Genetics 160:1609-1618
Abstract
We describe a method to simultaneously detect and fine map quantitative trait loci (QTL) that is especially suited to the mapping of modifier loci in mouse mutant models. The method exploits the high level of historical recombination present in a heterogeneous stock (HS), an outbred population of mice derived from known founder strains. The experimental design is an F2 cross between the HS and a genetically distinct line, such as one carrying a knockout or transgene. QTL detection is performed by a standard genome scan with 100 markers and fine mapping by typing the same animals using densely spaced markers over those candidate regions detected by the scan. The analysis uses an extension of the dynamic-programming technique employed previously to fine map QTL in HS mice. We show by simulation that a QTL accounting for 5% of the total variance can be detected and fine mapped with 50% probability to within 3 cM by genotyping 1500 animals.
Recombinant Inbred Heterogeneous Stocks and In-vitro Heterogeneous Stocks
A Recombinant Inbred Heterogeneous Stock (RIHS) is a panel of recombinant inbred lines derived from an HS.
Abstract
We compare strategies to fine-map Quantitative Trait Loci (QTL) in mice using Heterogeneous Stocks (HS). We show that a panel of about 100 Recombinant Inbred Lines (RIL) derived from an HS, and which we call an RIHS, is ideally suited to fine-map QTL to very high resolution, without the cost of additional genotyping. We also investigate a strategy based on in-vitro fertilisation of large numbers of F1 offspring of HS males crossed with an inbred line (IVHS). This method requires some additional genotyping but avoids the breeding delays and costs associated with the construction of a RI panel. We show that QTL detection is higher using RIHS than with IVHS, and that it is independent of the number of RI lines, provided the total number of animals phenotyped is constant. However, fine-mapping accuracy is slightly better using IVHS. We also investigate the effects of varying the number of HS generations and using multiallelic microsatellites instead of SNPs. We find that quite modest generation times of 10-20 generations are optimal. Microsatellites are only superior to SNPs when the generation time is 30 or more and when the markers are widely spaced.
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