title: 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 1988). It has been suggested (Cavalli-Sforza 1973; Hollox et al. 2001; Enattah et al. 2002; Poulter et al. 2003) that a selective advantage based on additional nutrition from dairy explains these genetically determined population differences (Simoons 1970; Kretchmer 1971; Scrimshaw and Murray 1988; Enattah et al. 2002), 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. 2002) 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 F(ST) measure and a novel test based on p(excess), 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.
authors.affiliation: Divisions of Genetics and Endocrinology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Bersaglieri
authors.forename: Pardis C
authors.initials: PC
authors.lastname: Sabeti
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.forename: Trisha
authors.initials: T
authors.lastname: Vanderploeg
authors.forename: Steve F
authors.initials: SF
authors.lastname: Schaffner
authors.forename: Jared A
authors.initials: JA
authors.lastname: Drake
authors.forename: Matthew
authors.initials: M
authors.lastname: Rhodes
authors.forename: David E
authors.initials: DE
authors.lastname: Reich
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
mesh_terms: D005787:Gene Frequency; D005828:Genetics, Population; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D043322:Lactase / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012641:Selection, Genetic; D044465:White People / Q000235:genetics*
chemical_list: D043322:Lactase