Identifying genomic targets of population-specific positive selection is a major goal in several areas of basic and applied biology. However, it is unclear how often such selection should act on new mutations versus standing genetic variation or recurrent mutation, and furthermore, favored alleles may either become fixed or remain variable in the population. Very few population genetic statistics are sensitive to all of these modes of selection. Here we introduce and evaluate the Comparative Haplotype Identity statistic (χMD), which assesses whether pairwise haplotype sharing at a locus in one population is unusually large compared with another population, relative to genome-wide trends. Using simulations that emulate human and Drosophila genetic variation, we find that χMD is sensitive to a wide range of selection scenarios, and for some very challenging cases (e.g. partial soft sweeps), it outperforms other two population statistics. We also find that, as with FST, our haplotype approach has the ability to detect surprisingly ancient selective sweeps. Particularly for the scenarios resembling human variation, we find that χMD outperforms other frequency and haplotype-based statistics for soft and/or partial selective sweeps. Applying χMD and other between-population statistics to published population genomic data from D. melanogaster, we find both shared and unique genes and functional categories identified by each statistic. The broad utility and computational simplicity of χMD will make it an especially valuable tool in the search for genes targeted by local adaptation.
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