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1.
Mol Ecol ; 25(16): 3901-11, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27297514

ABSTRACT

Isolated populations with novel phenotypes present an exciting opportunity to uncover the genetic basis of ecologically significant adaptation, and genomic scans have often, but not always, led to candidate genes directly related to an adaptive phenotype. However, in many cases these populations were established by a severe bottleneck, which can make identifying targets of selection problematic. Here, we simulate severe bottlenecks and subsequent selection on standing variation, mimicking adaptation after establishment of a new small population, such as an island or an artificial selection experiment. Using simulations of single loci under positive selection and population genetics theory, we examine how population size and age of the population isolate affect the ability of outlier scans for selection to identify adaptive alleles using both single-site measures and haplotype structure. We find and explain an optimal combination of selection strength, starting frequency, and age of the adaptive allele, which we refer to as a Goldilocks zone, where adaptation is likely to occur and yet the adaptive variants are most likely to derive from a single ancestor (a 'hard' selective sweep); in this zone, four commonly used statistics detect selection with high power. Real-world examples of both island colonization and experimental evolution studies are discussed. Our study provides concrete considerations to be made before embarking on whole-genome sequencing of differentiated populations.


Subject(s)
Adaptation, Physiological/genetics , Genetics, Population , Models, Genetic , Selection, Genetic , Alleles , Haplotypes , Phenotype
2.
Front Genet ; 4: 235, 2013.
Article in English | MEDLINE | ID: mdl-24273554

ABSTRACT

With the increasing availability and quality of whole genome population data, various methodologies of population genetic inference are being utilized in order to identify and quantify recent population-level selective events. Though there has been a great proliferation of such methodology, the type-I and type-II error rates of many proposed statistics have not been well-described. Moreover, the performance of these statistics is often not evaluated for different biologically relevant scenarios (e.g., population size change, population structure), nor for the effect of differing data sizes (i.e., genomic vs. sub-genomic). The absence of the above information makes it difficult to evaluate newly available statistics relative to one another, and thus, difficult to choose the proper toolset for a given empirical analysis. Thus, we here describe and compare the performance of four widely used tests of selection: SweepFinder, SweeD, OmegaPlus, and iHS. In order to consider the above questions, we utilize simulated data spanning a variety of selection coefficients and beneficial mutation rates. We demonstrate that the LD-based OmegaPlus performs best in terms of power to reject the neutral model under both equilibrium and non-equilibrium conditions-an important result regarding the relative effectiveness of linkage disequilibrium relative to site frequency spectrum based statics. The results presented here ought to serve as a useful guide for future empirical studies, and provides a guide for statistical choice depending on the history of the population under consideration. Moreover, the parameter space investigated and the Type-I and Type-II error rates calculated, represent a natural benchmark by which future statistics may be assessed.

3.
PLoS Biol ; 10(11): e1001427, 2012.
Article in English | MEDLINE | ID: mdl-23185133

ABSTRACT

Cognitive abilities and disorders unique to humans are thought to result from adaptively driven changes in brain transcriptomes, but little is known about the role of cis-regulatory changes affecting transcription start sites (TSS). Here, we mapped in human, chimpanzee, and macaque prefrontal cortex the genome-wide distribution of histone H3 trimethylated at lysine 4 (H3K4me3), an epigenetic mark sharply regulated at TSS, and identified 471 sequences with human-specific enrichment or depletion. Among these were 33 loci selectively methylated in neuronal but not non-neuronal chromatin from children and adults, including TSS at DPP10 (2q14.1), CNTN4 and CHL1 (3p26.3), and other neuropsychiatric susceptibility genes. Regulatory sequences at DPP10 and additional loci carried a strong footprint of hominid adaptation, including elevated nucleotide substitution rates and regulatory motifs absent in other primates (including archaic hominins), with evidence for selective pressures during more recent evolution and adaptive fixations in modern populations. Chromosome conformation capture at two neurodevelopmental disease loci, 2q14.1 and 16p11.2, revealed higher order chromatin structures resulting in physical contact of multiple human-specific H3K4me3 peaks spaced 0.5-1 Mb apart, in conjunction with a novel cis-bound antisense RNA linked to Polycomb repressor proteins and downregulated DPP10 expression. Therefore, coordinated epigenetic regulation via newly derived TSS chromatin could play an important role in the emergence of human-specific gene expression networks in brain that contribute to cognitive functions and neurological disease susceptibility in modern day humans.


Subject(s)
DNA Methylation , Histones/metabolism , Neurons/metabolism , Prefrontal Cortex/cytology , Transcription Initiation Site , Adult , Animals , Base Sequence , Child , Chromatin/metabolism , Chromatin Assembly and Disassembly , Chromosome Mapping , Cognition , Contactins/genetics , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Epigenesis, Genetic , Evolution, Molecular , Gene Regulatory Networks , Genetic Loci , Histones/genetics , Humans , Lysine/metabolism , Macaca/genetics , Mental Disorders/genetics , Neurons/cytology , Pan troglodytes/genetics , Phylogeny , Polycomb-Group Proteins/metabolism , Prefrontal Cortex/metabolism , Regulatory Sequences, Nucleic Acid , Species Specificity , Transcription, Genetic
4.
J Hered ; 103(2): 287-96, 2012.
Article in English | MEDLINE | ID: mdl-22246406

ABSTRACT

The recent availability of whole-genome sequencing data affords tremendous power for statistical inference. With this, there has been great interest in the development of polymorphism-based approaches for the estimation of population genetic parameters. These approaches seek to estimate, for example, recently fixed or sweeping beneficial mutations, the rate of recurrent positive selection, the distribution of selection coefficients, and the demographic history of the population. Yet despite estimating similar parameters using similar data sets, results between methodologies are far from consistent. We here summarize the current state of the field, compare existing approaches, and attempt to reconcile emerging discrepancies. We also discuss the biases in selection estimators introduced by ignoring the demographic history of the population, discuss the biases in demographic estimators introduced by assuming neutrality, and highlight the important challenge to the field of achieving a true joint estimation procedure to circumvent these confounding effects.


Subject(s)
Genetics, Population/methods , Genome/genetics , Models, Genetic , Polymorphism, Genetic/genetics , Selection, Genetic , Animals , Demography , Drosophila , Genetics, Population/trends , Haplotypes/genetics , Species Specificity
5.
Genome Biol Evol ; 3: 791-8, 2011.
Article in English | MEDLINE | ID: mdl-21803765

ABSTRACT

Ever since the first draft of the human genome was completed in 2001, there has been increased interest in identifying genetic changes that are uniquely human, which could account for our distinct morphological and cognitive capabilities with respect to other apes. Recently, draft sequences of two extinct hominin genomes, a Neanderthal and Denisovan, have been released. These two genomes provide a much greater resolution to identify human-specific genetic differences than the chimpanzee, our closest extant relative. The Neanderthal genome paper presented a list of regions putatively targeted by positive selection around the time of the human-Neanderthal split. We here seek to characterize the evolutionary history of these candidate regions-examining evidence for selective sweeps in modern human populations as well as for accelerated adaptive evolution across apes. Results indicate that 3 of the top 20 candidate regions show evidence of selection in at least one modern human population (P < 5 × 10(5)). Additionally, four genes within the top 20 regions show accelerated amino acid substitutions across multiple apes (P < 0.01), suggesting importance across deeper evolutionary time. These results highlight the importance of evaluating evolutionary processes across both recent and ancient evolutionary timescales and intriguingly suggest a list of candidate genes that may have been uniquely important around the time of the human-Neanderthal split.


Subject(s)
Amino Acid Substitution/genetics , Genome, Human/genetics , Hominidae/genetics , Neanderthals/genetics , Adaptation, Biological/genetics , Animals , Biological Evolution , Humans , Pan troglodytes/genetics , Selection, Genetic
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