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.
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.
A literal reading of the fossil record suggests that the animal phyla diverged in an "explosion" near the beginning of the Cambrian period. Calibrated rates of molecular sequence divergence were used to test this hypothesis. Seven independent data sets suggest that invertebrates diverged from chordates about a billion years ago, about twice as long ago as the Cambrian. Protostomes apparently diverged from chordates well before echinoderms, which suggests a prolonged radiation of animal phyla. These conclusions apply specifically to divergence times among phyla; the morphological features that characterize modern animal body plans, such as skeletons and coeloms, may have evolved later.Darwin (1) recognized that the sudden appearance of animal fossils in the Cambrian posed a problem for his theory of natural selection. He suggested that fossils might eventually be found documenting a protracted unfolding of Precambrian metazoan evolution. Many paleontologists today interpret the absence of Precambrian animal fossils that can be assigned to extant clades not as a preservational artifact, but as evidence of a Cambrian or late Vendian origin and divergence of metazoan phyla (2-6). This would make the Cambrian the greatest evolutionary cornucopia in the history of the Earth. Definitive representatives of all readily fossilizable animal phyla (with the exception of bryozoans) have been found in Cambrian rocks, as have representatives of several soft-bodied phyla (6). Recent geochronological studies have reinforced the impression of a "big bang of animal evolution" by narrowing the temporal window of apparent divergences to just a few million years (4).The evidence for a Cambrian explosion of animal phyla is based on the absence of fossils of triploblastic metazoans from rocks predating the Cambrian. This negative evidence is not entirely convincing. Tiny unskeletonized animals with no possibility of preservation in the fossil record may have existed before the Cambrian (7, 8). Even if larger, soft-bodied animals were present, conditions appropriate for their preservation may not have existed for much of the The authors are in the . In particular, the famous Lagerstatten of the Cambrian (8, 10) resulted from taphonomic conditions that are exceptionally rare at other times in the rock record (9). Nevertheless, some Vendian trace fossils and body fossils suggest that animals with coeloms existed before the Cambrian (6, 8, 11, 12). Calibrated rates of gene sequence divergence provide another avenue for dating divergence times between animal phyla (13). An early study by Runnegar, based on hemoglobin, suggested Precambrian divergences (14) but was criticized for not testing assumptions of rate constancy (15). A more recent study based on 18S ribosomal RNA (rRNA) sought evidence of rapid divergences in the inability of sequence data to resolve phylogenetic relationships (16). The burgeoning database of gene sequences provides an opportunity to examine the divergence times of metazoan phyla from large data sets based on severa...
Animals have evolved diverse appendages adapted for locomotion, feeding and other functions. The genetics underlying appendage formation are best understood in insects and vertebrates. The expression of the Distal-less (Dll) homeoprotein during arthropod limb outgrowth and of Dll orthologs (Dlx) in fish fin and tetrapod limb buds led us to examine whether expression of this regulatory gene may be a general feature of appendage formation in protostomes and deuterostomes. We find that Dll is expressed along the proximodistal axis of developing polychaete annelid parapodia, onychophoran lobopodia, ascidian ampullae, and even echinoderm tube feet. Dll͞Dlx expression in such diverse appendages in these six coelomate phyla could be convergent, but this would have required the independent co-option of Dll͞Dlx several times in evolution. It appears more likely that ectodermal Dll͞Dlx expression along proximodistal axes originated once in a common ancestor and has been used subsequently to pattern body wall outgrowths in a variety of organisms. We suggest that this pre-Cambrian ancestor of most protostomes and the deuterostomes possessed elements of the genetic machinery for and may have even borne appendages.
Recent research on disparate psychiatric disorders has implicated rare variants in genes involved in global gene regulation and chromatin modification, as well as many common variants located primarily in regulatory regions of the genome. Understanding precisely how these variants contribute to disease will require a deeper appreciation for the mechanisms of gene regulation in the developing and adult human brain. The PsychENCODE project aims to produce a public resource of multidimensional genomic data using tissue- and cell type–specific samples from approximately 1,000 phenotypically well-characterized, high-quality healthy and disease-affected human post-mortem brains, as well as functionally characterize disease-associated regulatory elements and variants in model systems. We are beginning with a focus on autism spectrum disorder, bipolar disorder and schizophrenia, and expect that this knowledge will apply to a wide variety of psychiatric disorders. This paper outlines the motivation and design of PsychENCODE.
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