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Gregory A Wray

Publications and source records attributed to Gregory A Wray.

At least 19 recordsLinked to original sources
PubMed2006

Convergent adaptation of human lactase persistence in Africa and Europe.

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 470 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 approximately 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.

Adaptation, Biological↗
PubMed2006

Ancient polymorphism and functional variation in the primate MHC-DQA1 5' cis-regulatory region.

Precise regulation of MHC gene expression is critical to vertebrate immune surveillance and response. Polymorphisms in the 5' proximal promoter region of the human class II gene HLA-DQA1 have been shown to influence its transcriptional regulation and may contribute to the pathogenesis of autoimmune diseases. We investigated the evolutionary history of this cis-regulatory region by sequencing the DQA1 5' proximal promoter region in eight nonhuman primate species. We observed unexpectedly high levels of sequence variation and multiple strong signatures of balancing selection in this region. Specifically, the considerable DQA1 promoter region diversity was characterized by abundant shared (or trans-species) polymorphism and a pronounced lack of fixed differences between species. The majority of transcription factor binding sites in the DQA1 promoter region were polymorphic within species, and these binding site polymorphisms were commonly shared among multiple species despite evidence for negative selection eliminating a significant fraction of binding site mutations. We assessed the functional consequences of intraspecific promoter region diversity using a cell line-based reporter assay and detected significant differences among baboon DQA1 promoter haplotypes in their ability to drive transcription in vitro. The functional differentiation of baboon promoter haplotypes, together with the significant deviations from neutral sequence evolution, suggests a role for balancing selection in the evolution of DQA1 transcriptional regulation in primates.

Animals↗
PubMed2006

Endo16 is required for gastrulation in the sea urchin Lytechinus variegatus.

The Endo16 gene encodes a large extracellular protein with several functional domains that provide some insight into the role of this protein during embryonic development. We isolated the full-length cDNA sequence from Lytechinus variegatus and utilized morpholinos to further investigate the role of Endo16 during embryonic development in this species. Endo16-deficient embryos failed to undergo gastrulation and the blastocoele became filled with dissociated cells after 24 h of incubation. Moreover, there was a delay in endoderm differentiation as assayed by staining with an antibody that recognizes Endo1. The differentiation of other cell types including oral ectoderm, primary mesenchymal cells (PMC) and secondary mesenchymal cells (SMC) appeared to be normal, although the patterns of protein expression did not resemble control embryos due to the gross morphological abnormalities elicited by the LvEndo16 morpholino. Microinjection of full-length EGFP mRNA with the LvEndo16 morpholino-targeted sequence confirmed that this phenotype can be attributed specifically to the loss of Endo16 protein. Taken together, our data suggest that Endo16 may be required for the cell-extracellular matrix (ECM) interactions that are required for endoderm differentiation in the sea urchin embryo.

Amino Acid Sequence↗
PubMed2005

The evolutionary dynamics of alpha-satellite.

Alpha-satellite is a family of tandemly repeated sequences found at all normal human centromeres. In addition to its significance for understanding centromere function, alpha-satellite is also a model for concerted evolution, as alpha-satellite repeats are more similar within a species than between species. There are two types of alpha-satellite in the human genome; while both are made up of approximately 171-bp monomers, they can be distinguished by whether monomers are arranged in extremely homogeneous higher-order, multimeric repeat units or exist as more divergent monomeric alpha-satellite that lacks any multimeric periodicity. In this study, as a model to examine the genomic and evolutionary relationships between these two types, we have focused on the chromosome 17 centromeric region that has reached both higher-order and monomeric alpha-satellite in the human genome assembly. Monomeric and higher-order alpha-satellites on chromosome 17 are phylogenetically distinct, consistent with a model in which higher-order evolved independently of monomeric alpha-satellite. Comparative analysis between human chromosome 17 and the orthologous chimpanzee chromosome indicates that monomeric alpha-satellite is evolving at approximately the same rate as the adjacent non-alpha-satellite DNA. However, higher-order alpha-satellite is less conserved, suggesting different evolutionary rates for the two types of alpha-satellite.

Animals↗
PubMed2005

Evolutionary analysis of the well characterized endo16 promoter reveals substantial variation within functional sites.

The evolutionary mechanisms that operate on genetic variation within transcriptional regulatory sequences are not well understood. We present here an evolutionary analysis of an exceptionally well characterized cis-regulatory region, the endo16 promoter of the purple sea urchin. Segregating variation reveals striking differences in the intensity of negative selection among regulatory modules, reflecting their distinct functional roles. Surprisingly, transcription-factor-binding sites are as polymorphic and as likely to contain fixed differences as flanking nucleotides. Whereas nucleotides in protein-binding sites in the most proximal regulatory module exhibit reduced variation, those in other modules tend to be more polymorphic than putatively nonfunctional nucleotides. Two unrelated large insertions at the same position within the promoter are segregating at low frequencies; one is a strong ectodermal repressor that contains 16 verified transcription-factor-binding sites. These results demonstrate that a simple relationship between conservation and function does not exist within this cis-regulatory region and highlight significant population heterogeneity in the fine structure of a well understood promoter.

Animals↗
PubMed2005

Ancient and recent positive selection transformed opioid cis-regulation in humans.

Changes in the cis-regulation of neural genes likely contributed to the evolution of our species' unique attributes, but evidence of a role for natural selection has been lacking. We found that positive natural selection altered the cis-regulation of human prodynorphin, the precursor molecule for a suite of endogenous opioids and neuropeptides with critical roles in regulating perception, behavior, and memory. Independent lines of phylogenetic and population genetic evidence support a history of selective sweeps driving the evolution of the human prodynorphin promoter. In experimental assays of chimpanzee-human hybrid promoters, the selected sequence increases transcriptional inducibility. The evidence for a change in the response of the brain's natural opioids to inductive stimuli points to potential human-specific characteristics favored during evolution. In addition, the pattern of linked nucleotide and microsatellite variation among and within modern human populations suggests that recent selection, subsequent to the fixation of the human-specific mutations and the peopling of the globe, has favored different prodynorphin cis-regulatory alleles in different parts of the world.

Alleles↗
PubMed2004

Positive selection on MMP3 regulation has shaped heart disease risk.

BACKGROUND: The evolutionary forces of mutation, natural selection, and genetic drift shape the pattern of phenotypic variation in nature, but the roles of these forces in defining the distributions of particular traits have been hard to disentangle. To better understand the mechanisms contributing to common variation in humans, we investigated the evolutionary history of a functional polymorphism in the upstream regulatory region of the MMP3 gene. This single base pair insertion/deletion variant, which results in a run of either 5 or 6 thymidines 1608 bp from the transcription start site, alters transcription factor binding and influences levels of MMP3 mRNA and protein. The polymorphism contributes to variation in arterial traits and to the risk of coronary heart disease and its progression. RESULTS: Phylogenetic and population genetic analysis of primate sequences indicate that the binding site region is rapidly evolving and has been a hot spot for mutation for tens of millions of years. We also find evidence for the action of positive selection, beginning approximately 24,000 years ago, increasing the frequency of the high-expression allele in Europe but not elsewhere. Positive selection is evident in statistical tests of differentiation among populations and haplotype diversity within populations. Europeans have greater arterial elasticity and suffer dramatically fewer coronary heart disease events than they would have had this selection not occurred. CONCLUSIONS: Locally elevated mutation rates and strong positive selection on a cis-regulatory variant have shaped contemporary phenotypic variation and public health.

Animals↗
PubMed2004

Molecular phylogeny of naidid worms (Annelida: Clitellata) based on cytochrome oxidase I.

Naidids are tiny, primarily freshwater oligochaete annelids which reproduce asexually by fission. We investigated the phylogenetic relationships within this group by sequencing 1224 bp of the mitochondrial gene cytochrome oxidase I (COI) from 26 species of naidids (representing 13 of the 23 genera currently recognized), as well as from four tubificids, their closest allies. Although not completely concordant, maximum parsimony and Bayesian inference analyses agreed in several important respects, with no well-supported conflicts. Our study, the first detailed molecular investigation of naidid relationships, suggests that naidids fall into two groups, one comprised of the genus Pristina, and another comprised of all other genera sampled. The clear division of naidids into these two groups best matches an early, simple classification of the group by Lastockin (1924); the more recent classifications proposed by Sperber (1948) and Nemec and Brinkhurst (1987) are not as consistent with our results. We note that our study suggests the genus Stylaria is comprised of two distinct species, Stylaria lacustris and Stylaria fossularis, rather than merely two morphotypes of a single species. Based on our phylogenetic results, we suggest that pigmented eyes evolved only once among naidids but must have been lost multiple times, and that the elongation of the prostomium into a proboscis evolved at least twice independently. The simplest form of fission, architomy (fragmentation), occurs in two of the most basally branching naidid genera, and may represent the plesiomorphic condition for naidids.

Amino Acid Sequence↗
PubMed2004

Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the factor VII locus in humans.

The abundance of cis-regulatory polymorphisms in humans suggests that many may have been important in human evolution, but evidence for their role is relatively rare. Four common polymorphisms in the 5' promoter region of factor VII (F7), a coagulation factor, have been shown to affect its transcription and protein abundance both in vitro and in vivo. Three of these polymorphisms have low-frequency alleles that decrease expression of F7 and may provide protection against myocardial infarction (heart attacks). The fourth polymorphism has a minor allele that increases the level of transcription. To look for evidence of natural selection on the cis-regulatory variants flanking F7, we genotyped three of the polymorphisms in six Old World populations for which we also have data from a group of putatively neutral SNPs. Our population genetic analysis shows evidence for selection within humans; surprisingly, the strongest evidence is due to a large increase in frequency of the high-expression variant in Singaporean Chinese. Further characterization of a Japanese population shows that at least part of the increase in frequency of the high-expression allele is found in other East Asian populations. In addition, to examine interspecific patterns of selection we sequenced the homologous 5' noncoding region in chimpanzees, bonobos, a gorilla, an orangutan, and a baboon. Analysis of these data reveals an excess of fixed differences within transcription factor binding sites along the human lineage. Our results thus further support the hypothesis that regulatory mutations have been important in human evolution.

Animals↗
PubMed2003

Positive selection on a human-specific transcription factor binding site regulating IL4 expression.

A single nucleotide polymorphism in the promoter of the multifunctional cytokine Interleukin 4 (IL4) affects the binding of NFAT, a key transcriptional activator of IL4 in T cells. This regulatory polymorphism influences the balance of cytokine signaling in the immune system, with important consequences-positive and negative-for human health. We determined that the NFAT binding site is unique to humans; it arose by point mutation along the lineage separating humans from other great apes. We show that its frequency distribution among human subpopulations has been shaped by the balance of selective forces on IL4's diverse roles. New statistical approaches, based on parametric and nonparametric comparisons to neutral variants typed in the same individuals, indicate that differentiation among subpopulations at the IL4 promoter polymorphism is too great to be attributed to neutral drift. The allele frequencies of this binding site represent local adaptation to diverse pathogenic challenges; disease states associated with the common derived allele are side-effects of positive selection on other IL4 functions.

Animals↗
PubMed2003

The evolution of transcriptional regulation in eukaryotes.

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.

Animals↗
PubMed2003

The effects of selection against spurious transcription factor binding sites.

Most genomes contain nucleotide sequences with no known function; such sequences are assumed to be free of constraints, evolving only according to the vagaries of mutation. Here we show that selection acts to remove spurious transcription factor binding site motifs throughout 52 fully sequenced genomes of Eubacteria and Archaea. Examining the sequences necessary for polymerase binding, we find that spurious binding sites are underrepresented in both coding and noncoding regions. The average proportion of spurious binding sites found relative to the expected is 80% in eubacterial genomes and 89% in archaeal genomes. We also estimate the strength of selection against spurious binding sites in the face of the constant creation of new binding sites via mutation. Under conservative assumptions, we estimate that selection is weak, with the average efficacy of selection against spurious binding sites, Nes, of -0.12 for eubacterial genomes and -0.06 for archaeal genomes, similar to that of codon bias. Our results suggest that both coding and noncoding sequences are constrained by selection to avoid specific regions of sequence space.

Archaea↗
PubMed2003

Conservation of Endo16 expression in sea urchins despite evolutionary divergence in both cis and trans-acting components of transcriptional regulation.

Evolutionary changes in transcriptional regulation undoubtedly play an important role in creating morphological diversity. However, there is little information about the evolutionary dynamics of cis-regulatory sequences. This study examines the functional consequence of evolutionary changes in the Endo16 promoter of sea urchins. The Endo16 gene encodes a large extracellular protein that is expressed in the endoderm and may play a role in cell adhesion. Its promoter has been characterized in exceptional detail in the purple sea urchin, Strongylocentrotus purpuratus. We have characterized the structure and function of the Endo16 promoter from a second sea urchin species, Lytechinus variegatus. The Endo16 promoter sequences have evolved in a strongly mosaic manner since these species diverged approximately 35 million years ago: the most proximal region (module A) is conserved, but the remaining modules (B-G) are unalignable. Despite extensive divergence in promoter sequences, the pattern of Endo16 transcription is largely conserved during embryonic and larval development. Transient expression assays demonstrate that 2.2 kb of upstream sequence in either species is sufficient to drive GFP reporter expression that correctly mimics this pattern of Endo16 transcription. Reciprocal cross-species transient expression assays imply that changes have also evolved in the set of transcription factors that interact with the Endo16 promoter. Taken together, these results suggest that stabilizing selection on the transcriptional output may have operated to maintain a similar pattern of Endo16 expression in S. purpuratus and L. variegatus, despite dramatic divergence in promoter sequence and mechanisms of transcriptional regulation.

Animals↗
PubMed2003

Identification of asteroid genera with species capable of larval cloning.

Asexual reproduction in larvae, larval cloning, is a recently recognized component of the complex life histories of asteroids. We compare DNA sequences of mitochondrial tRNA genes (Ala, Leu, Asn, Pro, and Gln) from larvae in the process of cloning collected in the field with sequences from adults of known species in order to identify asteroid taxa capable of cloning. Neighbor-joining analysis identified four distinct groups of larvae, each having no, or very little, sequence divergence (p distances ranging from 0.00000 to 0.02589); thus, we conclude that each larval group most likely represents a single species. These field-collected larvae cannot be identified to species with certainty, but the close assemblage of known taxa with the four larval groups indicates generic or familial identity. We can assign two of the larval groups discerned here to the genera Luidia and Oreaster and another two to the family Ophidiasteridae. This study is the first to identify field-collected cloning asteroid larvae, and provides evidence that larval cloning is phylogenetically widespread within the Asteroidea. Additionally, we note that cloning occurs regularly and in multiple ways within species that are capable of cloning, emphasizing the need for further investigation of the role of larval cloning in the ecology and evolution of asteroids.

Animals↗
PubMed2003

Transcriptional regulation and the evolution of development.

A growing body of evidence suggests that changes in transcriptional regulation form an important part of the genetic basis for the evolution of development. At a microevolutionary level, all the necessary conditions are present: populations harbor abundant genetic variation for differences in transcription profiles, a substantial fraction of these variants can influence organismal phenotype, and some variants have fitness consequences and are subject to natural selection. At a macroevolutionary level, the evidence is less direct but strongly suggestive: specific differences in anatomy and gene expression are often correlated, while comparisons of transcription profiles among distantly related taxa point to extensive evolutionary changes in regulatory gene networks. Understanding how transcriptional regulatory systems evolve, and what contributions these changes have made to the evolution of phenotype, represents a major challenge for Evo-Devo.

Animals↗