Genetic signatures of strong recent positive selection at the lactase gene.
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.
Bersaglieri
Todd
T
Divisions of Genetics and Endocrinology, Harvard Medical School, Boston, MA 02115, USA.
Sabeti
Pardis C
PC
Patterson
Nick
N
Vanderploeg
Trisha
T
Schaffner
Steve F
SF
Drake
Jared A
JA
Rhodes
Matthew
M
Reich
David E
DE
Hirschhorn
Joel N
JN
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*
D043322:Lactase