From QTL to QTN identification in livestock--winning by points rather than knock-out: a review.

Many quantitative trait loci (QTL) affecting economic traits in livestock have now been identified. However, the confidence interval (CI) of individual QTL as determined by linkage analysis often spans tens of map units, containing hundreds of genes. Linkage disequilibrium (LD) mapping can reduce the CI to individual map units, but this reduced interval will still contain tens of genes. Methods suitable for model animals to find and validate specific quantitative trait nucleotides (QTN) underlying the QTL cannot be easily applied to livestock species because of their long generation intervals, the cost of maintaining each animal and the difficulty of producing transgenics or 'knock-outs'. Considering these limitations, we review successful approaches for identifying QTN in livestock and outline a schematic strategy for QTN determination and verification. In addition to linkage and LD mapping, the methods include positional cloning, selection of candidate genes, DNA sequencing and statistical analyses. Concordance determination and functional assays are the critical tests for validation of a QTN; we provide a generalized formula for the probability of concordance by chance. Three genes that meet the burden of proof for QTN identification--DGAT1 in cattle, IGF2 in swine and GDF8 in sheep--are discussed in detail. The genetic and economic ramifications of identified QTN and the horizon for selection and introgression are also considered.