For decades, evolutionary biologists have argued that changes in cis-regulatory sequences constitute an important part of the genetic basis for adaptation. Although originally based on first principles, this claim is now empirically well supported: numerous studies have identified cis-regulatory mutations with functionally significant consequences for morphology, physiology and behaviour. The focus has now shifted to considering whether cis-regulatory and coding mutations make qualitatively different contributions to phenotypic evolution. Cases in which parallel mutations have produced parallel trait modifications in particular suggest that some phenotypic changes are more likely to result from cis-regulatory mutations than from coding mutations.

A SNP in the gene encoding lactase (LCT) (C/T-13910) is associated with the ability to digest milk as adults (lactase persistence) in Europeans, but the genetic basis of lactase persistence in Africans was previously unknown. We conducted a genotype-phenotype association study in 470Correspondence should be addressed to S.A.T. (Tishkoff@umd.edu).. 9 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS S.A.T. conceived and supervised the study. S.A.T., K.P., H.M.M., A.R., J.B.H., M.O., M.I., S.A.O., G.L. and T.B.N. were involved in DNA collection and phenotype testing. A.R. performed the resequencing and initial identification of association of candidate SNPs with the phenotype. S.A.T. and F.A.R. selected the SNPs to be genotyped and samples to test for gene expression. P.D., J.G. and S.B. performed the SNP design and genotyping. F.A.R. processed and phased the raw data and performed the genotype-phenotype association analyses, plots of haplotype homozygosity from unphased data, dominance estimates and pairwise plot of LD. B.F.V. performed, and J.K.P. co-supervised, the iHS test to detect positive selection and plots of haplotype homozygosity from phased data as well as rejection-sampling analyses to estimate age of alleles and selection parameters. H.M.M. constructed the haplotype networks. C.C.B., J.S.S. and G.A.W. built the expression constructs, carried out transcription assays and analyzed the results of expression assays. The paper was written primarily by S.A.T., with contributions from F.A.R., B.F.V., J.K.P., C.C.B., G.A.W. and P.D. The supplementary information was written by S.A.T. and F.A.R. with contributions from B.F.V., J.K.P., C.C.B., G.A.W. and P.D. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests.Published online at http://www.nature.com/naturegenetics/ Reprints and permissions information is available online at Published online at http://npg.nature.com/reprintsandpermissions/ Note: Supplementary information is available on the Nature Genetics website. Tanzanians, Kenyans and Sudanese and identified three SNPs (G/C-14010, T/G-13915 and C/ G-13907) that are associated with lactase persistence and that have derived alleles that significantly enhance transcription from the LCT promoter in vitro. These SNPs originated on different haplotype backgrounds from the European C/T-13910 SNP and from each other. Genotyping across a 3-Mb region demonstrated haplotype homozygosity extending >2.0 Mb on chromosomes carrying C-14010, consistent with a selective sweep over the past ~7,000 years. These data provide a marked example of convergent evolution due to strong selective pressure resulting from shared cultural traits-animal domestication and adult milk consumption. Europe PMC Funders GroupIn most humans, the ability to digest lactose, the main carbohydrate present in milk, declines rapidly after weaning because of decreasing levels of the enzyme lactase-phlorizin hydrolase (LPH). LPH is predominantly expressed in the small intestine, wh...

Gene expression is central to the genotype-phenotype relationship in all organisms, and it is an important component of the genetic basis for evolutionary change in diverse aspects of phenotype. However, the evolution of transcriptional regulation remains understudied and poorly understood. Here we review the evolutionary dynamics of promoter, or cis-regulatory, sequences and the evolutionary mechanisms that shape them. Existing evidence indicates that populations harbor extensive genetic variation in promoter sequences, that a substantial fraction of this variation has consequences for both biochemical and organismal phenotype, and that some of this functional variation is sorted by selection. As with protein-coding sequences, rates and patterns of promoter sequence evolution differ considerably among loci and among clades for reasons that are not well understood. Studying the evolution of transcriptional regulation poses empirical and conceptual challenges beyond those typically encountered in analyses of coding sequence evolution: promoter organization is much less regular than that of coding sequences, and sequences required for the transcription of each locus reside at multiple other loci in the genome. Because of the strong context-dependence of transcriptional regulation, sequence inspection alone provides limited information about promoter function. Understanding the functional consequences of sequence differences among promoters generally requires biochemical and in vivo functional assays. Despite these challenges, important insights have already been gained into the evolution of transcriptional regulation, and the pace of discovery is accelerating.

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Wing polyphenism in ants evolved once, 125 million years ago, and has been a key to their amazing evolutionary success. We characterized the expression of several genes within the network underlying the wing primordia of reproductive (winged) and sterile (wingless) ant castes. We show that the expression of several genes within the network is conserved in the winged castes of four ant species, whereas points of interruption within the network in the wingless castes are evolutionarily labile. The simultaneous evolutionary lability and conservation of the network underlying wing development in ants may have played an important role in the morphological diversification of this group and may be a general feature of polyphenic development and evolution in plants and animals.