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Am J Hum Genet. Jun 2004; 74(6): 1111–1120.
Published online Apr 26, 2004. doi:  10.1086/421051
PMCID: PMC1182075

Genetic Signatures of Strong Recent Positive Selection at the Lactase Gene

Abstract

In most human populations, the ability to digest lactose contained in milk usually disappears in childhood, but in European-derived populations, lactase activity frequently persists into adulthood (Scrimshaw and Murray ). It has been suggested (Cavalli-Sforza ; Hollox et al. ; Enattah et al. ; Poulter et al. ) that a selective advantage based on additional nutrition from dairy explains these genetically determined population differences (Simoons ; Kretchmer ; Scrimshaw and Murray ; Enattah et al. ), but formal population-genetics–based evidence of selection has not yet been provided. To assess the population-genetics evidence for selection, we typed 101 single-nucleotide polymorphisms covering 3.2 Mb around the lactase gene. In northern European–derived populations, two alleles that are tightly associated with lactase persistence (Enattah et al. ) uniquely mark a common (~77%) haplotype that extends largely undisrupted for >1 Mb. We provide two new lines of genetic evidence that this long, common haplotype arose rapidly due to recent selection: (1) by use of the traditional FST measure and a novel test based on pexcess, we demonstrate large frequency differences among populations for the persistence-associated markers and for flanking markers throughout the haplotype, and (2) we show that the haplotype is unusually long, given its high frequency—a hallmark of recent selection. We estimate that strong selection occurred within the past 5,000–10,000 years, consistent with an advantage to lactase persistence in the setting of dairy farming; the signals of selection we observe are among the strongest yet seen for any gene in the genome.


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