Identifying branch-specific positive selection throughout the regulatory genome using an appropriate proxy neutral.

Background: Adaptive changes in cis-regulatory elements are an essential component of evolution by natural selection. Identifying adaptive and functional noncoding DNA elements throughout the genome is therefore crucial for understanding the relationship between phenotype and genotype.

Results: We used ENCODE annotations to identify appropriate proxy neutral sequences and demonstrate that the conservativeness of the test can be modulated during the filtration of reference alignments.

Gene expression and adaptive noncoding changes during human evolution.

Background: Despite evidence for adaptive changes in both gene expression and non-protein-coding, putatively regulatory regions of the genome during human evolution, the relationship between gene expression and adaptive changes in cis-regulatory regions remains unclear.

Results: Here we present new measurements of gene expression in five tissues of humans and chimpanzees, and use them to assess this relationship. We then compare our results with previous studies of adaptive noncoding changes, analyzing correlations at the level of gene ontology groups, in order to gain statistical power to detect correlations.

Spatio-Temporal Variation in Landscape Composition May Speed Resistance Evolution of Pests to Bt Crops.

Transgenic crops that express insecticide genes from Bacillus thuringiensis (Bt) are used worldwide against moth and beetle pests. Because these engineered plants can kill over 95% of susceptible larvae, they can rapidly select for resistance. Here, we use a model for a pyramid two-toxin Bt crop to explore the consequences of spatio-temporal variation in the area of Bt crop and non-Bt refuge habitat.

The impact of gene expression variation on the robustness and evolvability of a developmental gene regulatory network.

Regulatory interactions buffer development against genetic and environmental perturbations, but adaptation requires phenotypes to change. We investigated the relationship between robustness and evolvability within the gene regulatory network underlying development of the larval skeleton in the sea urchin Strongylocentrotus purpuratus. We find extensive variation in gene expression in this network throughout development in a natural population, some of which has a heritable genetic basis.

Population genetics of cis-regulatory sequences that operate during embryonic development in the sea urchin Strongylocentrotus purpuratus.

Despite the fact that noncoding sequences comprise a substantial fraction of functional sites within all genomes, the evolutionary mechanisms that operate on genetic variation within regulatory elements remain poorly understood. In this study, we examine the population genetics of the core, upstream cis-regulatory regions of eight genes (AN, CyIIa, CyIIIa, Endo16, FoxB, HE, SM30 a, and SM50) that function during the early development of the purple sea urchin, Strongylocentrotus purpuratus. Quantitative and qualitative measures of segregating variation are not conspicuously different between cis-regulatory and closely linked "proxy neutral" noncoding regions containing no known functional sites.

A potential role for glucose transporters in the evolution of human brain size.

Differences in cognitive abilities and the relatively large brain are among the most striking differences between humans and their closest primate relatives. The energy trade-off hypothesis predicts that a major shift in energy allocation among tissues occurred during human origins in order to support the remarkable expansion of a metabolically expensive brain. However, the molecular basis of this adaptive scenario is unknown.

Whole-genome positive selection and habitat-driven evolution in a shallow and a deep-sea urchin.

Comparisons of genomic sequence between divergent species can provide insight into the action of natural selection across many distinct classes of proteins. Here, we examine the extent of positive selection as a function of tissue-specific and stage-specific gene expression in two closely-related sea urchins, the shallow-water Strongylocentrotus purpuratus and the deep-sea Allocentrotus fragilis, which have diverged greatly in their adult but not larval habitats. Genes that are expressed specifically in adult somatic tissue have significantly higher dN/dS ratios than the genome-wide average, whereas those in larvae are indistinguishable from the genome-wide average.

Contrasts between adaptive coding and noncoding changes during human evolution.

Changes in non-protein-coding regulatory DNA sequences have been proposed to play distinctive roles in adaptive evolution. We analyzed correlations between gene functions and evidence for positive selection in a common statistical framework across several large surveys of coding and noncoding sequences throughout the human genome. Strong correlations with both classifications in gene ontologies and measurements of gene expression indicate that neural development and function have adapted mainly through noncoding changes.

Multiple Functional Variants in cis Modulate PDYN Expression.

Understanding genetic variation and its functional consequences within cis-regulatory regions remains an important challenge in human genetics and evolution. Here, we present a fine-scale functional analysis of segregating variation within the cis-regulatory region of prodynorphin, a gene that encodes an endogenous opioid precursor with roles in cognition and disease. In order to characterize the functional consequences of segregating variation in cis in a region under balancing selection in different human populations, we examined associations between specific polymorphisms and gene expression in vivo and in vitro.

Functional consequences of genetic variation in primates on tyrosine hydroxylase (TH) expression in vitro.

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, is known to contain naturally occurring genetic variation in it's promoter region that associates with a number of neuropsychological disorders. As such, examining non-coding regions is important for understanding tyrosine hydroxylase function in human health and disease. We examined approximately 2 kb upstream of the translation start site within humans and non-human primates to obtain a fine resolution map of evolutionarily and functionally relevant cis-regulatory differences.

Genomic features that predict allelic imbalance in humans suggest patterns of constraint on gene expression variation.

Variation in gene expression is an important contributor to phenotypic diversity within and between species. Although this variation often has a genetic component, identification of the genetic variants driving this relationship remains challenging. In particular, measurements of gene expression usually do not reveal whether the genetic basis for any observed variation lies in cis or in trans to the gene, a distinction that has direct relevance to the physical location of the underlying genetic variant, and which may also impact its evolutionary trajectory.

Evolution of incompatibility-inducing microbes in subdivided host populations.

Many insects, other arthropods, and nematodes harbor maternally inherited bacteria inducing "cytoplasmic incompatibility" (CI), reduced egg hatch when infected males mate with uninfected females. Although CI drives the spread of these microbes, selection on alternative, mutually compatible strains in panmictic host populations does not act directly on CI intensity but favors higher "effective fecundity," the number of infected progeny an infected female produces. We analyze the consequences of host population subdivision using deterministic and stochastic models.

Evolutionary analysis of the cis-regulatory region of the spicule matrix gene SM50 in strongylocentrotid sea urchins.

An evolutionary analysis of transcriptional regulation is essential to understanding the molecular basis of phenotypic diversity. The sea urchin is an ideal system in which to explore the functional consequence of variation in cis-regulatory sequences. We are particularly interested in the evolution of genes involved in the patterning and synthesis of its larval skeleton.

When two is better than one.

Gene duplication and divergence has long been considered an important route to adaptation and phenotypic evolution. Reporting in Nature, Hittinger and Carroll (2007) provide the first clear example of adaptations in both regulatory regions and protein-coding regions after gene duplication. This combination of evolutionary changes appears to have resolved an adaptive conflict, leading to increased organismal fitness.

Migration load and the coexistence of ecologically similar sexuals and asexuals.

The frozen niche variation hypothesis suggests that sexuals can coexist with closely related, ecologically similar asexuals because sexuals and narrowly adapted asexual clones use different resources. However, because a collection of clones can potentially dominate the entire resource axis, such coexistence is not stable. We show that if the sexual population inhabits multiple selection regimes and asexuals are intrinsically slightly less fit than sexuals, migration load in the sexual population allows sexuals and asexuals to coexist stably at the regional level.

Promoter regions of many neural- and nutrition-related genes have experienced positive selection during human evolution.

Surveys of protein-coding sequences for evidence of positive selection in humans or chimpanzees have flagged only a few genes known to function in neural or nutritional processes, despite pronounced differences between humans and chimpanzees in behavior, cognition and diet. It may be that most such differences are due to changes in gene regulation rather than protein structure. Here, we present the first survey of promoter (5'-flanking) regions, which are rich in cis-regulatory sequences, for evidence of positive selection in humans.

The genome of the sea urchin Strongylocentrotus purpuratus.

We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus, a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome.

Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. Mutation rate and the cost of complexity.

Two recent theoretical studies of adaptation suggest that more complex organisms tend to adapt more slowly. Specifically, in Fisher's "geometric" model of a finite population where multiple traits are under optimizing selection, the average progress ensuing from a single mutation decreases as the number of traits increases--the "cost of complexity." Here, I draw on molecular and histological data to assess the extent to which on a large phylogenetic scale, this predicted decrease in the rate of adaptation per mutation is mitigated by an increase in the number of mutations per generation as complexity increases.

Sexual conflict and protein polymorphism.

Sexual conflict, where male and female reproductive interests differ, is probably widespread and often mediated by male or sperm proteins and female or egg proteins that bind to each other during mating or fertilization. One potential consequence is maintenance of polymorphism in these proteins, which might result in reproductive isolation between sympatric subpopulations. I investigate the conditions for polymorphism maintenance in a series of mathematical models of sexual conflict over mating or fertilization frequency.

Consequences of recurrent gene flow from crops to wild relatives.

Concern about gene flow from crops to wild relatives has become widespread with the increasing cultivation of transgenic crops. Possible consequences of such gene flow include genetic assimilation, wherein crop genes replace wild ones, and demographic swamping, wherein hybrids are less fertile than their wild parents, and wild populations shrink. Using mathematical models of a wild population recurrently receiving pollen from a genetically fixed crop, we find that the conditions for genetic assimilation are not stringent, and progress towards replacement can be fast, even for disfavoured crop genes.

Coexistence in MacArthur-style consumer-resource models.

The nature of and conditions for permanent coexistence of consumers and resources are characterized in a family of models that generalize MacArthur's consumer-resource model. The generalization is of the resource dynamics, which need not be of Lotka-Volterra form but are subject only to certain restrictions loose enough to admit many resource dynamics of biological interest. For any such model, (1) if there is an interior equilibrium, then it is globally attracting, else some boundary equilibrium is globally attracting-thus permanent coexistence is coexistence at a globally attracting equilibrium; (2) there is an interior equilibrium if and only if for any species, the equilibrium approached in the absence of that species and the presence of the others is invasible by that species--thus permanent coexistence is equivalent to mutual invasibility; (3) for resources without direct interactions, the conditions for permanent coexistence of the consumers admit an instructive formulation in terms of regression statistics.

alpha-1 and alpha-2 Adrenergic antagonists relieve thermal hyperalgesia in experimental mononeuropathy from chronic constriction injury.

Phentolamine, a nonspecific alpha 1- and alpha 2-adrenergic antagonist, relieves pain in patients with reflex sympathetic dystrophy. We sought to determine whether phentolamine, prazosin (alpha 1 antagonist), or SKF86466 (alpha 2 antagonist) relieve thermal hyperalgesia in rats with neuropathic pain. Four days after producing a chronic constriction injury (CCI), thermal hyperalgesia was tested by measuring paw withdrawal latency (PWL).