An investigation of the statistical power of neutrality tests based on comparative and population genetic data

In this report, we investigate the statistical power of several tests of selective neutrality based on patterns of genetic diversity within and between species. The goal is to compare tests based solely on population genetic data with tests using comparative data or a combination of comparative and population genetic data. We show that in the presence of repeated selective sweeps on relatively neutral background, tests based on the d(N)/d(S) ratios in comparative data almost always have more power to detect selection than tests based on population genetic data, even if the overall level of divergence is low. Tests based solely on the distribution of allele frequencies or the site frequency spectrum, such as the Ewens-Watterson test or Tajima's D, have less power in detecting both positive and negative selection because of the transient nature of positive selection and the weak signal left by negative selection. The Hudson-Kreitman-Aguadé test is the most powerful test for detecting positive selection among the population genetic tests investigated, whereas McDonald-Kreitman test typically has more power to detect negative selection. We discuss our findings in the light of the discordant results obtained in several recently published genomic scans.     

Correcting Estimators of θ and Tajima's D for Ascertainment Biases Caused by the Single-Nucleotide Polymorphism Discovery Process

Most single-nucleotide polymorphism (SNP) data suffer from an ascertainment bias caused by the process of SNP discovery followed by SNP genotyping. The final genotyped data are biased toward an excess of common alleles compared to directly sequenced data, making standard genetic methods of analysis inapplicable to this type of data. We here derive corrected estimators of the fundamental population genetic parameter θ = 4N_eμ (N_e, effective population size; μ, mutation rate) on the basis of the average number of pairwise differences and on the basis of the number of segregating sites. We also derive the variances and covariances of these estimators and provide a corrected version of Tajima's D statistic. We reanalyze a human genomewide SNP data set and find substantial differences in the results with or without ascertainment bias correction.     

Straightforward and complete deposition of NMR data to the PDBe

We present a suite of software for the complete and easy deposition of NMR data to the PDB and BMRB. This suite uses the CCPN framework and introduces a freely downloadable, graphical desktop application called CcpNmr Entry Completion Interface (ECI) for the secure editing of experimental information and associated datasets through the lifetime of an NMR project. CCPN projects can be created within the CcpNmr Analysis software or by importing existing NMR data files using the CcpNmr FormatConverter. After further data entry and checking with the ECI, the project can then be rapidly deposited to the PDBe using AutoDep, or exported as a complete deposition NMR-STAR file. In full CCPN projects created with ECI, it is straightforward to select chemical shift lists, restraint data sets, structural ensembles and all relevant associated experimental collection details, which all are or will become mandatory when depositing to the PDB. Instructions and download information for the ECI are available from the PDBe web site at http://www.ebi.ac.uk/pdbe/nmr/deposition/eci.html.     

Intercolony transplantation of Oecophylla smaragdina (Hymenoptera: Formicidae) larvae

Oecophylla ants are utilized for biological control in fruit plantations in Australia and Asia. In Asia, queen larvae and alates are sold on commercial markets for human and animal consumption. This double utilization has induced an increasing interest in the domestication of these ants, but attempts to rear live colonies have been hindered partly by the length of time it takes from the founding of a colony until it can be utilized commercially. Early growth of a colony may be increased if ants from other colonies are adopted. The present experiments show that Oecophylla smaragdina larvae transplanted from other colonies are readily tolerated by non-nestmate workers and are reared to imagos. These results are fundamental for the future domestication of Oecophylla and elucidate the need for further studies of chemical nestmate recognition.     

Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation

A remarkable characteristic of the human major histocompatibility complex (MHC) is its extreme genetic diversity, which is maintained by balancing selection. In fact, the MHC complex remains one of the best-known examples of natural selection in humans, with well-established genetic signatures and biological mechanisms for the action of selection. Here, we present genetic and functional evidence that another gene with a fundamental role in MHC class I presentation, endoplasmic reticulum aminopeptidase 2 (ERAP2), has also evolved under balancing selection and contains a variant that affects antigen presentation. Specifically, genetic analyses of six human populations revealed strong and consistent signatures of balancing selection affecting ERAP2. This selection maintains two highly differentiated haplotypes (Haplotype A and Haplotype B), with frequencies 0.44 and 0.56, respectively. We found that ERAP2 expressed from Haplotype B undergoes differential splicing and encodes a truncated protein, leading to nonsense-mediated decay of the mRNA. To investigate the consequences of ERAP2 deficiency on MHC presentation, we correlated surface MHC class I expression with ERAP2 genotypes in primary lymphocytes. Haplotype B homozygotes had lower levels of MHC class I expressed on the surface of B cells, suggesting that naturally occurring ERAP2 deficiency affects MHC presentation and immune response. Interestingly, an ERAP2 paralog, endoplasmic reticulum aminopeptidase 1 (ERAP1), also shows genetic signatures of balancing selection. Together, our findings link the genetic signatures of selection with an effect on splicing and a cellular phenotype. Although the precise selective pressure that maintains polymorphism is unknown, the demonstrated differences between the ERAP2 splice forms provide important insights into the potential mechanism for the action of selection.     

A group of alpha-1,4-glucan lyases and their genes from the red alga Gracilariopsis lemaneiformis: purification, cloning, and heterologous expression

We present here the first report of a group of alpha-1,4-glucan lyases (EC 4.2.2.13) and their genes. The lyases produce 1, 5-anhydro-D-fructose from starch and related oligomers and polymers. The enzymes were isolated from the red alga Gracilariopsis lemaneiformis from the Pacific coasts of China and USA, and the Atlantic Coast of Venezuela. Three lyase isozymes (GLq1, GLq2 and GLq3) from the Chinese subspecies, two lyase isozymes (GLs1 and GLs2) from the USA subspecies and one lyase (GLa1) from the Venezuelan subspecies were identified and investigated. GLq1, GLq3, GLs1 and GLa1 were purified and partially sequenced. Based on the amino acid sequences obtained, three lyase genes or their cDNAs (GLq1, GLq2 and GLs1) were cloned and completely sequenced and two other genes (GLq3 and GLs2) were partially sequenced. The coding sequences of the lyase genes GLq1, GLq2 and GLs1 are 3267, 3276 and 3279 bp, encoding lyases of 1088, 1091 and 1092 amino acids, respectively. The deduced molecular masses of the mature lyases from the coding sequences are 117030, 117667 and 117790 Da, respectively, close to those determined by mass spectrometry using purified lyases. The amino acid sequence identity is more than 70% among the six algal lyase isozymes. The algal GLq1 gene was expressed in Pichia pastoris and Aspergillus niger, and the expression product was identical to the wild-type enzyme.     

Linkage disequilibrium as a signature of selective sweeps

The hitchhiking effect of a beneficial mutation, or a selective sweep, generates a unique distribution of allele frequencies and spatial distribution of polymorphic sites. A composite-likelihood test was previously designed to detect these signatures of a selective sweep, solely on the basis of the spatial distribution and marginal allele frequencies of polymorphisms. As an excess of linkage disequilibrium (LD) is also known to be a strong signature of a selective sweep, we investigate how much statistical power is increased by the inclusion of information regarding LD. The expected pattern of LD is predicted by a genealogical approach. Both theory and simulation suggest that strong LD is generated in narrow regions at both sides of the location of beneficial mutation. However, a lack of LD is expected across the two sides. We explore various ways to detect this signature of selective sweeps by statistical tests. A new composite-likelihood method is proposed to incorporate information regarding LD. This method enables us to detect selective sweeps and estimate the parameters of the selection model better than the previous composite-likelihood method that does not take LD into account. However, the improvement made by including LD is rather small, suggesting that most of the relevant information regarding selective sweeps is captured by the spatial distribution and marginal allele frequencies of polymorphisms.     

Multilocus methods for estimating population sizes, migration rates and divergence time, with applications to the divergence of Drosophila pseudoobscura and D. persimilis

The genetic study of diverging, closely related populations is required for basic questions on demography and speciation, as well as for biodiversity and conservation research. However, it is often unclear whether divergence is due simply to separation or whether populations have also experienced gene flow. These questions can be addressed with a full model of population separation with gene flow, by applying a Markov chain Monte Carlo method for estimating the posterior probability distribution of model parameters. We have generalized this method and made it applicable to data from multiple unlinked loci. These loci can vary in their modes of inheritance, and inheritance scalars can be implemented either as constants or as parameters to be estimated. By treating inheritance scalars as parameters it is also possible to address variation among loci in the impact via linkage of recurrent selective sweeps or background selection. These methods are applied to a large multilocus data set from Drosophila pseudoobscura and D. persimilis. The species are estimated to have diverged approximately 500,000 years ago. Several loci have nonzero estimates of gene flow since the initial separation of the species, with considerable variation in gene flow estimates among loci, in both directions between the species.     

Microsatellite mutation models: insights from a comparison of humans and chimpanzees

Using genomic data from homologous microsatellite loci of pure AC repeats in humans and chimpanzees, several models of microsatellite evolution are tested and compared using likelihood-ratio tests and the Akaike information criterion. A proportional-rate, linear-biased, one-phase model emerges as the best model. A focal length toward which the mutational and/or substitutional process is linearly biased is a crucial feature of microsatellite evolution. We find that two-phase models do not lead to a significantly better fit than their one-phase counterparts. The performance of models based on the fit of their stationary distributions to the empirical distribution of microsatellite lengths in the human genome is consistent with that based on the human-chimp comparison. Microsatellites interrupted by even a single point mutation exhibit a twofold decrease in their mutation rate when compared to pure AC repeats. In general, models that allow chimps to have a larger per-repeat unit slippage rate and/or a shorter focal length compared to humans give a better fit to the human-chimp data as well as the human genomic data.     

Interaction of the anaphase-promoting complex/cyclosome and proteasome protein complexes with multiubiquitin chain-binding proteins

Fission yeast Rhp23 and Pus1 represent two families of multiubiquitin chain-binding proteins that associate with the proteasome. We show that both proteins bind to different regions of the proteasome subunit Mts4. The binding site for Pus1 was mapped to a cluster of repetitive sequences also found in the proteasome subunit SpRpn2 and the anaphase-promoting complex/cyclosome (APC/C) subunit Cut4. The putative role of Pus1 as a factor involved in allocation of ubiquitinylated substrates for the proteasome is discussed.