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Wed, 13 Jan 2010 11:39:48 PST

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Wed, 13 Jan 2010 11:39:48 PST

Hypervariability of Ascidian Mitochondrial Gene Order: Exposing the Myth of Deuterostome Organelle Genome Stability

Gissi, C., Pesole, G., Mastrototaro, F., Iannelli, F., Guida, V., Griggio, F. — Wed, 13 Jan 2010 11:39:49 PST

The few sequenced mitochondrial (mt) genomes of the class Ascidiacea (Chordata, Tunicata), mostly belonging to congeneric species of the Phlebobranchia order, show extraordinary gene order rearrangements. In order to assess if this hypervariability in gene order is a general feature of Ascidiacea, we report here the gene arrangement of five ascidians belonging to the Aplousobranchia and Stolidobranchia orders. Our data show that Ascidiacea are characterized by: 1) extensive gene order rearrangements both within and between the three major lineages; 2) lack of significant similarities to the gene order of other deuterostomes; and 3) an extent of rearrangements comparable with that of Mollusca (especially the Gastropoda, Bivalvia, and Scaphopoda classes), a phylum with highly rearranged mtDNAs. The only conserved feature is the location of all genes on the same strand, which suggests that selective constraints are related to the mt transcription. Finally, a higher mobility of the tRNA genes is undetectable because of saturation effect, and only the partially conserved cox2–cob gene block seems to retain some phylogenetic signals.

Chordate Hox and ParaHox Gene Clusters Differ Dramatically in Their Repetitive Element Content

Osborne, P. W., Ferrier, D. E.K. — Wed, 13 Jan 2010 11:39:49 PST

The ParaHox and Hox gene clusters control aspects of animal anterior–posterior development and are related as paralogous evolutionary sisters. Despite this relationship, it is not clear if the clusters operate in similar ways, with similar constraints. To compare clusters, we examined the transposable-element (TE) content of amphioxus and mammalian ParaHox and Hox clusters. Chordate Hox clusters are known to be largely devoid of TEs, possibly due to gene regulation and constraints on clustering in these animals. Here, we describe several novel amphioxus TEs and show that the amphioxus ParaHox cluster is a hotspot for TE insertion. TE contents of mammalian ParaHox loci are at background levels, in stark contrast to chordate Hox clusters. This marks a significant difference between Hox and ParaHox clusters. The presence of so many potentially disruptive elements implies selection constrains these ParaHox clusters as they have not dispersed despite 500 My of evolution for each lineage.

SeaView Version 4: A Multiplatform Graphical User Interface for Sequence Alignment and Phylogenetic Tree Building

Gouy, M., Guindon, S., Gascuel, O. — Wed, 13 Jan 2010 11:39:49 PST

We present SeaView version 4, a multiplatform program designed to facilitate multiple alignment and phylogenetic tree building from molecular sequence data through the use of a graphical user interface. SeaView version 4 combines all the functions of the widely used programs SeaView (in its previous versions) and Phylo_win, and expands them by adding network access to sequence databases, alignment with arbitrary algorithm, maximum-likelihood tree building with PhyML, and display, printing, and copy-to-clipboard of rooted or unrooted, binary or multifurcating phylogenetic trees. In relation to the wide present offer of tools and algorithms for phylogenetic analyses, SeaView is especially useful for teaching and for occasional users of such software. SeaView is freely available at http://pbil.univ-lyon1.fr/software/seaview.

Retracing Evolution of Red Fluorescence in GFP-Like Proteins from Faviina Corals

Field, S. F., Matz, M. V. — Wed, 13 Jan 2010 11:39:49 PST

Proteins of the green fluorescent protein family represent a convenient experimental model to study evolution of novelty at the molecular level. Here, we focus on the origin of Kaede-like red fluorescent proteins characteristic of the corals of the Faviina suborder. We demonstrate, using an original approach involving resurrection and analysis of the library of possible evolutionary intermediates, that it takes on the order of 12 mutations, some of which strongly interact epistatically, to fully recapitulate the evolution of a red fluorescent phenotype from the ancestral green. Five of the identified mutations would not have been found without the help of ancestral reconstruction, because the corresponding site states are shared between extant red and green proteins due to their recent descent from a dual-function common ancestor. Seven of the 12 mutations affect residues that are not in close contact with the chromophore and thus must exert their effect indirectly through adjustments of the overall protein fold; the relevance of these mutations could not have been anticipated from the purely theoretical analysis of the protein's structure. Our results introduce a powerful experimental approach for comparative analysis of functional specificity in protein families even in the cases of pronounced epistasis, provide foundation for the detailed studies of evolutionary trajectories leading to novelty and complexity, and will help rational modification of existing fluorescent labels.

A Genome-Sequence Survey for Ascogregarina taiwanensis Supports Evolutionary Affiliation but Metabolic Diversity between a Gregarine and Cryptosporidium

Wed, 13 Jan 2010 11:39:49 PST

We have performed a whole-genome-sequence survey for the gregarine, Ascogregarina taiwanensis and herein describe both features unique to this early diverging apicomplexan and properties that unite it with Cryptosporidium, the Coccidia, and the Apicomplexa. Phylogenetic trees inferred from a concatenated protein sequence comprised of 10,750 amino acid positions, as well as the large subunit rRNA genes, robustly support phylogenetic affinity of Ascogregarina with Cryptosporidium at the base of the apicomplexan clade. Unlike Cryptosporidium, Ascogregarina possesses numerous mitochondrion-associated pathways and proteins, including enzymes within the Krebs cycle and a cytochrome-based respiratory chain. Ascogregarina further differs in the capacity for de novo synthesis of pyrimidines and amino acids. Ascogregarina shares with Cryptosporidium a Type I fatty acid synthase and likely a polyketide synthase. Cryptosporidium and Ascogregarina possess a large repertoire of multidomain surface proteins that align it with Toxoplasma and are proposed to be involved in coccidian-like functions. Four families of retrotransposable elements were identified, and thus, retroelements are present in Ascogregarina and Eimeria but not in other apicomplexans that have been analyzed. The sum observations suggest that Ascogregarina and Cryptosporidium share numerous molecular similarities, not only including coccidian-like features to the exclusion of Haemosporidia and Piroplasmida but also differ from each other significantly in their metabolic capacity.

Rapid Likelihood Analysis on Large Phylogenies Using Partial Sampling of Substitution Histories

de Koning, A. P. J., Gu, W., Pollock, D. D. — Wed, 13 Jan 2010 11:39:49 PST

Likelihood-based approaches can reconstruct evolutionary processes in greater detail and with better precision from larger data sets. The extremely large comparative genomic data sets that are now being generated thus create new opportunities for understanding molecular evolution, but analysis of such large quantities of data poses escalating computational challenges. Recently developed Markov chain Monte Carlo methods that augment substitution histories are a promising approach to alleviate these computational costs. We analyzed the computational costs of several such approaches, considering how they scale with model and data set complexity. This provided a theoretical framework to understand the most important computational bottlenecks, leading us to combine novel variations of our conditional pathway integration approach with recent advances made by others. The resulting technique ("partial sampling" of substitution histories) is considerably faster than all other approaches we considered. It is accurate, simple to implement, and scales exceptionally well with dimensions of model complexity and data set size. In particular, the time complexity of sampling unobserved substitution histories using the new method is much faster than previously existing methods, and model parameter and branch length updates are independent of data set size. We compared the performance of methods on a 224-taxon set of mammalian cytochrome-b sequences. For a simple nucleotide substitution model, partial sampling was at least 10 times faster than the PhyloBayes program, which samples substitutions in continuous time, and about 100 times faster than when using fully integrated substitution histories. Under a general reversible model of amino acid substitution, the partial sampling method was 1,600 times faster than when using fully integrated substitution histories, confirming significantly improved scaling with model state-space complexity. Partial sampling of substitutions thus dramatically improves the utility of likelihood approaches for analyzing complex evolutionary processes on large data sets.

Nucleotide Polymorphism at a Gene (Pgi) under Balancing Selection in a Butterfly Metapopulation

Wheat, C. W., Haag, C. R., Marden, J. H., Hanski, I., Frilander, M. J. — Wed, 13 Jan 2010 11:39:49 PST

The Glanville fritillary butterfly (Melitaea cinxia, Nymphalidae) has a large, well-studied metapopulation in the Åland Islands in Finland. Previous studies have found that the common allozyme genotypes at the phosphoglucose isomerase (PGI) locus are associated with individual variation in performance and fitness, with phenotypic data suggesting ongoing balancing selection via heterozygote advantage. Here, we analyze nucleotide polymorphism in the coding region of the Pgi gene. Pgi is exceptionally polymorphic, in contrast to three other metabolic genes (Mdh, Idh, and Gapdh) with low levels of polymorphism. Most of the variation is due to two common haplotype clades, which are highly divergent and exhibit extensive linkage disequilibrium. These two clades correspond to the two most common allozyme alleles previously studied. Molecular tests of selection and coalescence simulations indicate that patterns of nucleotide polymorphism depart from neutrality and are consistent with long-term balancing selection. The split between the two main haplotype clades is estimated to predate the last common ancestor of a clade of five extant Melitaea species. Comparative structural analysis of Pgi polymorphism in M. cinxia and the unrelated Colias eurytheme butterfly suggests a similar but not identical target of balancing selection. Our results indicate convergent evolution between these two species at both the phenotypic and molecular levels.

Isoform Divergence of the Filamin Family of Proteins

Kesner, B. A., Milgram, S. L., Temple, B. R.S., Dokholyan, N. V. — Wed, 13 Jan 2010 11:39:49 PST

The vertebrate filamin family (A, B, and C) is part of the spectrin family of actin cross-linking proteins. Family members share high sequence similarity (>64%) and have both common and isoform-distinct functionalities. To identify the basis for isoform-specific functionality, we perform an evolutionary trace of chordate filamin at the granularity of single residues. Our trace methodology is constrained to focus on neofunctionality by requiring that one isoform remain the ancestral type, whereas at least one isoform has an accepted mutation. We call divergence meeting these characteristics "class-distinctive." To obtain a temporal and spatial context for class-distinctive residues, we derive an all-atom model of full-length filamin A by homology modeling and joining individual domains. We map onto our model both conserved and class-distinctive residues along with the period (Teleostei, Amphibian, and Mammalian) in which they diverged. Our phylogenetic analysis suggests that filamins diverged from a common ancestral gene between urochordate and vertebrate lineages. Filamins also diverged the most just after gene duplication, in the Teleostei period, with filamin C remaining closest to ancestral filamin. At the residue level, domains with well-characterized interfaces, IgFLN 17 and IgFLN 21 (immunoglobulin, Ig), have diverged in potentially critical residues in their adhesion protein–binding interfaces, signifying that isoforms may bind or regulate ligand binding differentially. Similarly, isoform divergence in a region associated with F actin–binding regulation suggests that isoforms differentially regulate F-actin binding. In addition, we observe some class-distinctive residues in the vicinity of missense mutations that cause filamin A and B–associated skeletal disorders. Our analysis, utilizing both spatial and temporal granularity, has identified potentially important residues responsible for vertebrate filamin isoform–specific divergence—significantly in regions where few binding partners have been discovered to date— and suggests yet to be discovered filamin-binding partners and isoform-specific differential regulation with these binding partners.

How Robust Are "Isolation with Migration" Analyses to Violations of the IM Model? A Simulation Study

Strasburg, J. L., Rieseberg, L. H. — Wed, 13 Jan 2010 11:39:49 PST

Methods developed over the past decade have made it possible to estimate molecular demographic parameters such as effective population size, divergence time, and gene flow with unprecedented accuracy and precision. However, they make simplifying assumptions about certain aspects of the species’ histories and the nature of the genetic data, and it is not clear how robust they are to violations of these assumptions. Here, we use simulated data sets to examine the effects of a number of violations of the "Isolation with Migration" (IM) model, including intralocus recombination, population structure, gene flow from an unsampled species, linkage among loci, and divergent selection, on demographic parameter estimates made using the program IMA. We also examine the effect of having data that fit a nucleotide substitution model other than the two relatively simple models available in IMA. We find that IMA estimates are generally quite robust to small to moderate violations of the IM model assumptions, comparable with what is often encountered in real-world scenarios. In particular, population structure within species, a condition encountered to some degree in virtually all species, has little effect on parameter estimates even for fairly high levels of structure. Likewise, most parameter estimates are robust to significant levels of recombination when data sets are pared down to apparently nonrecombining blocks, although substantial bias is introduced to several estimates when the entire data set with recombination is included. In contrast, a poor fit to the nucleotide substitution model can result in an increased error rate, in some cases due to a predictable bias and in other cases due to an increase in variance in parameter estimates among data sets simulated under the same conditions.

Phylogenetic Distributions and Histories of Proteins Involved in Anaerobic Pyruvate Metabolism in Eukaryotes

Hug, L. A., Stechmann, A., Roger, A. J. — Wed, 13 Jan 2010 11:39:49 PST

Protists that live in low oxygen conditions often oxidize pyruvate to acetate via anaerobic ATP-generating pathways. Key enzymes that commonly occur in these pathways are pyruvate:ferredoxin oxidoreductase (PFO) and [FeFe]-hydrogenase (H₂ase) as well as the associated [FeFe]-H₂ase maturase proteins HydE, HydF, and HydG. Determining the origins of these proteins in eukaryotes is of key importance to understanding the origins of anaerobic energy metabolism in microbial eukaryotes. We conducted a comprehensive search for genes encoding these proteins in available whole genomes and expressed sequence tag data from diverse eukaryotes. Our analyses of the presence/absence of eukaryotic PFO, [FeFe]-H₂ase, and H₂ase maturase sequences across eukaryotic diversity reveal orthologs of these proteins encoded in the genomes of a variety of protists previously not known to contain them. Our phylogenetic analyses revealed: 1) extensive lateral gene transfers of both PFO and [FeFe]-H₂ase in eubacteria, 2) decreased support for the monophyly of eukaryote PFO domains, and 3) that eukaryotic [FeFe]-H₂ases are not monophyletic. Although there are few eukaryote [FeFe]-H₂ase maturase orthologs characterized, phylogenies of these proteins do recover eukaryote monophyly, although a consistent eubacterial sister group for eukaryotic homologs could not be determined. An exhaustive search for these five genes in diverse genomes from two representative eubacterial groups, the Clostridiales and the -proteobacteria, shows that although these enzymes are nearly universally present within the former group, they are very rare in the latter. No -proteobacterial genome sequenced to date encodes all five proteins. Molecular phylogenies and the extremely restricted distribution of PFO, [FeFe]-H₂ases, and their associated maturases within the -proteobacteria do not support a mitochondrial origin for these enzymes in eukaryotes. However, the unexpected prevalence of PFO, pyruvate:NADP oxidoreductase, [FeFe]-H₂ase, and the maturase proteins encoded in genomes of diverse eukaryotes indicates that these enzymes have an important role in the evolution of microbial eukaryote energy metabolism.

Heterogeneous Patterns of Gene-Expression Diversification in Mammalian Gene Duplicates

Farre, D., Alba, M. M. — Wed, 13 Jan 2010 11:39:49 PST

Gene duplication is a major mechanism for molecular evolutionary innovation. Young gene duplicates typically exhibit elevated rates of protein evolution and, according to a number of recent studies, increased expression divergence. However, the nature of these changes is still poorly understood. To gain novel insights into the functional consequences of gene duplication, we have undertaken an in-depth analysis of a large data set of gene families containing primate- and/or rodent-specific gene duplicates. We have found a clear tendency toward an increase in protein, promoter, and expression divergence with increasing number of duplication events undergone by each gene since the human–mouse split. In addition, gene duplication is significantly associated with a reduction in expression breadth and intensity. Interestingly, it is possible to identify three main groups regarding the evolution of gene expression following gene duplication. The first group, which comprises around 25% of the families, shows patterns compatible with tissue-expression partitioning. The second and largest group, comprising 33–53% of the families, shows broad expression of one of the gene copies and reduced, overlapping, expression of the other copy or copies. This can be attributed, in most cases, to loss of expression in several tissues of one or more gene copies. Finally, a substantial number of families, 19–35%, maintain a very high level of tissue-expression overlap (>0.8) after tens of millions of years of evolution. These families may have been subject to selection for increased gene dosage.

A Statistical Evaluation of Models for the Initial Settlement of the American Continent Emphasizes the Importance of Gene Flow with Asia

Wed, 13 Jan 2010 11:39:49 PST

Although there is agreement in that the Bering Strait was the entry point for the initial colonization of the American continent, there is considerable uncertainty regarding the timing and pattern of human migration from Asia to America. In order to perform a statistical assessment of the relative probability of alternative migration scenarios and to estimate key demographic parameters associated with them, we used an approximate Bayesian computation framework to analyze a data set of 401 autosomal microsatellite loci typed in 29 native American populations. A major finding is that a single, discrete, wave of colonization is highly inconsistent with observed levels of genetic diversity. A scenario with two discrete migration waves is also not supported by the data. The current genetic diversity of Amerindian populations is best explained by a third model involving recurrent gene flow between Asia and America, after initial colonization. We estimate that this colonization involved about 100 individuals and occurred some 13,000 years ago, in agreement with well-established archeological data.

Infrequent Transitions between Saline and Fresh Waters in One of the Most Abundant Microbial Lineages (SAR11)

Logares, R., Brate, J., Heinrich, F., Shalchian-Tabrizi, K., Bertilsson, S. — Wed, 13 Jan 2010 11:39:49 PST

The aquatic bacterial group SAR11 is one of the most abundant organisms on Earth, with an estimated global population size of 2.4 x 10²⁸ cells in the oceans. Members of SAR11 have also been detected in brackish and fresh waters, but the evolutionary relationships between the species present in the different environments have been ambiguous. In particular, it was not clear how frequently this lineage has crossed the saline–freshwater boundary during its evolutionary diversification. Due to the huge population size of SAR11 and the potential of microbes for long-distance dispersal, we hypothesized that environmental transitions could have occurred repeatedly during the evolutionary diversification of this group. Here, we have constructed extensive 16S rDNA–based molecular phylogenies and undertaken metagenomic data analyses to assess the frequency of saline–freshwater transitions in SAR11 and to investigate the evolutionary implications of this process. Our analyses indicated that very few saline–freshwater transitions occurred during the evolutionary diversification of SAR11, generating genetically distinct saline and freshwater lineages that do not appear to exchange genes extensively via horizontal gene transfer. In contrast to lineages from saline environments, extant freshwater taxa from diverse, and sometimes distant, geographic locations were very closely related. This points to a rapid diversification and dispersal in fresh waters or to slower evolutionary rates in fresh water SAR11 when compared with marine counterparts. In addition, the colonization of both saline and fresh waters appears to have occurred early in the evolution of SAR11. We conclude that the different biogeochemical conditions that prevail in saline and fresh waters have likely prevented the environmental transitions in SAR11, promoting the evolution of clearly distinct lineages in each environment.

The Cytophaga hutchinsonii ChTPSP: First Characterized Bifunctional TPS-TPP Protein as Putative Ancestor of All Eukaryotic Trehalose Biosynthesis Proteins

Avonce, N., Wuyts, J., Verschooten, K., Vandesteene, L., Van Dijck, P. — Wed, 13 Jan 2010 11:39:49 PST

The most widely distributed pathway to synthesize trehalose in nature consists of two consecutive enzymatic reactions with a trehalose-6-P (T6P)-synthase (TPS) enzyme, producing the intermediate T6P, and a T6P-phosphatase (TPP) enzyme, which dephosphorylates T6P to produce trehalose and inorganic phosphate. In plants, these enzymes are called Class I and Class II proteins, respectively, with some Class I proteins being active enzymes. The Class II proteins possess both TPS and TPP consensus regions but appear to have lost enzymatic activity during evolution. Plants also contain an extra group of enzymes of small protein size, of which some members have been characterized as functional TPPs. These Class III proteins have less sequence similarity with the Class I and Class II proteins. Here, we characterize for the first time, by using biochemical analysis and yeast growth complementation assays, the existence of a natural TPS–TPP bifunctional enzyme found in the bacterial species Cytophaga hutchinsonii. Through phylogenetic analysis, we show that prokaryotic genes such as ChTPSP might be the ancestor of the eukaryotic trehalose biosynthesis genes. Second, we show that plants have recruited during evolution, possibly by horizontal transfer from bacteria such as Rhodoferax ferrireducens, a new type of small protein, encoding TPP activity, which have been named Class III proteins. RfTPP has very high TPP activity upon expression in yeast. Finally, we demonstrate that TPS gene duplication, the recruitment of the Class III enzymes, and recruitment of an N-terminal regulatory element, which regulates the Class I enzyme activity in higher plants, were initiated very early in eukaryan evolution as the three classes of trehalose biosynthesis genes are already present in the alga Ostreococcus tauri.

A Dirichlet Process Covarion Mixture Model and Its Assessments Using Posterior Predictive Discrepancy Tests

Zhou, Y., Brinkmann, H., Rodrigue, N., Lartillot, N., Philippe, H. — Wed, 13 Jan 2010 11:39:49 PST

Heterotachy, the variation of substitution rate at a site across time, is a prevalent phenomenon in nucleotide and amino acid alignments, which may mislead probabilistic-based phylogenetic inferences. The covarion model is a special case of heterotachy, in which sites change between the "ON" state (allowing substitutions according to any particular model of sequence evolution) and the "OFF" state (prohibiting substitutions). In current implementations, the switch rates between ON and OFF states are homogeneous across sites, a hypothesis that has never been tested. In this study, we developed an infinite mixture model, called the covarion mixture (CM) model, which allows the covarion parameters to vary across sites, controlled by a Dirichlet process prior. Moreover, we combine the CM model with other approaches. We use a second independent Dirichlet process that models the heterogeneities of amino acid equilibrium frequencies across sites, known as the CAT model, and general rate-across-site heterogeneity is modeled by a gamma distribution. The application of the CM model to several large alignments demonstrates that the covarion parameters are significantly heterogeneous across sites. We describe posterior predictive discrepancy tests and use these to demonstrate the importance of these different elements of the models.

A Worldwide Survey of Human Male Demographic History Based on Y-SNP and Y-STR Data from the HGDP-CEPH Populations

Wed, 13 Jan 2010 11:39:49 PST

We have investigated human male demographic history using 590 males from 51 populations in the Human Genome Diversity Project - Centre d’Étude du Polymorphisme Humain worldwide panel, typed with 37 Y-chromosomal Single Nucleotide Polymorphisms and 65 Y-chromosomal Short Tandem Repeats and analyzed with the program Bayesian Analysis of Trees With Internal Node Generation. The general patterns we observe show a gradient from the oldest population time to the most recent common ancestors (TMRCAs) and expansion times together with the largest effective population sizes in Africa, to the youngest times and smallest effective population sizes in the Americas. These parameters are significantly negatively correlated with distance from East Africa, and the patterns are consistent with most other studies of human variation and history. In contrast, growth rate showed a weaker correlation in the opposite direction. Y-lineage diversity and TMRCA also decrease with distance from East Africa, supporting a model of expansion with serial founder events starting from this source. A number of individual populations diverge from these general patterns, including previously documented examples such as recent expansions of the Yoruba in Africa, Basques in Europe, and Yakut in Northern Asia. However, some unexpected demographic histories were also found, including low growth rates in the Hazara and Kalash from Pakistan and recent expansion of the Mozabites in North Africa.

Novel Venom Proteins Produced by Differential Domain-Expression Strategies in Beaded Lizards and Gila Monsters (genus Heloderma)

Wed, 13 Jan 2010 11:39:49 PST

The origin and evolution of venom proteins in helodermatid lizards were investigated by multidisciplinary techniques. Our analyses elucidated novel toxin types resultant from three unique domain-expression processes: 1) The first full-length sequences of lethal toxin isoforms (helofensins) revealed this toxin type to be constructed by an ancestral monodomain, monoproduct gene (beta-defensin) that underwent three tandem domain duplications to encode a tetradomain, monoproduct with a possible novel protein fold; 2) an ancestral monodomain gene (encoding a natriuretic peptide) was medially extended to become a pentadomain, pentaproduct through the additional encoding of four tandemly repeated proline-rich peptides (helokinestatins), with the five discrete peptides liberated from each other by posttranslational proteolysis; and 3) an ancestral multidomain, multiproduct gene belonging to the vasoactive intestinal peptide (VIP)/glucagon family being mutated to encode for a monodomain, monoproduct (exendins) followed by duplication and diversification into two variant classes (exendins 1 and 2 and exendins 3 and 4). Bioactivity characterization of exendin and helokinestatin elucidated variable cardioactivity between isoforms within each class. These results highlight the importance of utilizing evolutionary-based search strategies for biodiscovery and the virtually unexplored potential of lizard venoms in drug design and discovery.

Indel-Associated Mutation Rate Varies with Mating System in Flowering Plants

Hollister, J. D., Ross-Ibarra, J., Gaut, B. S. — Wed, 13 Jan 2010 11:39:49 PST

A recently proposed mutational mechanism, indel-associated mutation (IDAM), posits that heterozygous insertions/deletions (indels) increase the point mutation rate at nearby nucleotides due to errors during meiosis. This mechanism could have especially dynamic consequences for the evolution of plant genomes, because the high degree of variation in the rate of self-fertilization among plant species causes differences in the heterozygosity of alleles, including indel alleles, segregating in plant species. In this study, we investigated the consequences of IDAM for species differing in mating system using both forward population genetic simulations and genomewide DNA resequencing data from Arabidopsis thaliana, Oryza sativa, and Oryza rufipogon. Simulations of different levels of selfing suggest that the effect of IDAM on surrounding nucleotide diversity should decrease with increasing selfing rate. Further simulations incorporating selfing rates and the time of onset of selfing suggest that the time since the switch to selfing also affects patterns of nucleotide diversity due to IDAM. Population genetic analyses of A. thaliana and Oryza DNA sequence data sets empirically confirmed our simulation results, revealing the strongest effect of IDAM in the outcrossing O. rufipogon, a weaker effect in the recently evolved selfer O. sativa, and the weakest effect in the relatively ancient selfer A. thaliana. These results support the novel idea that differences in life history, such as the level of selfing, can affect the per-individual mutation rate among species.

Phylodynamics of HIV-1 from a Phase-III AIDS Vaccine Trial in North America

Wed, 13 Jan 2010 11:39:49 PST

In 2003, a phase III placebo-controlled trial (VAX004) of a candidate HIV-1 vaccine (AIDSVAX B/B) was completed in 5,403 volunteers at high risk for HIV-1 infection from North America and the Netherlands. A total of 368 individuals became infected with HIV-1 during the trial. The envelope glycoprotein gene (gp120) from the HIV-1 subtype B viruses infecting 349 patients was sequenced from clinical samples taken as close as possible to the time of diagnosis, rendering a final data set of 1,047 sequences (1,032 from North America and 15 from the Netherlands). Here, we used these data in combination with other sequences available in public databases to assess HIV-1 variation as a function of vaccination treatment, geographic region, race, risk behavior, and viral load. Viral samples did not show any phylogenetic structure for any of these factors, but individuals with different viral loads showed significant differences (P = 0.009) in genetic diversity. The estimated time of emergence of HIV-1 subtype B was 1966–1970. Despite the fact that the number of AIDS cases has decreased in North America since the early 90s, HIV-1 genetic diversity seems to have remained almost constant over time. This study represents one of the largest molecular epidemiologic surveys of viruses responsible for new HIV-1 infections in North America and could help the selection of epidemiologically representative vaccine antigens to include in the next generation of candidate HIV-1 vaccines.

Bacterial Genetic Signatures of Human Social Phenomena among M. tuberculosis from an Aboriginal Canadian Population

Wed, 13 Jan 2010 11:39:49 PST

Despite a widespread global distribution and highly variable disease phenotype, there is little DNA sequence diversity among isolates of Mycobacterium tuberculosis. In addition, many regional population genetic surveys have revealed a stereotypical structure in which a single clone, lineage, or clade makes up the majority of the population. It is often assumed that dominant clones are highly adapted, that is, the overall structure of M. tuberculosis populations is the result of positive selection. In order to test this assumption, we analyzed genetic data from extant populations of bacteria circulating in Aboriginal communities in Saskatchewan, Canada. Demographic parameters of the bacterial population were estimated from archival epidemiological data collected over ~130 years since the onset of epidemic tuberculosis in the host communities. Bacterial genetic data were tested against neutral theory expectations and the local evolutionary history of M. tuberculosis investigated by phylogenetic analysis. Our findings are not consistent with positive selection on the bacterial population. Instead, we uncovered founder effects persisting over decades and barriers to gene flow within the bacterial population. Simulation experiments suggested that a combination of these neutral influences could result in the stereotypical structure of M. tuberculosis populations. Some aspects of population structure were suggestive of background selection, and data were on the whole consistent with combined effects of population bottlenecks, subdivision, and background selection. Neutral phenomena, namely, bottlenecks and partitions within populations, are prominent influences on the evolution of M. tuberculosis and likely contribute to restricted genetic diversity observed within this species. Given these influences, a complex evolutionary model will be required to define the relative fitness of different M. tuberculosis lineages and, ultimately, to uncover the genetic basis for its success as a pathogen.

Large-Scale Parsimony Analysis of Metazoan Indels in Protein-Coding Genes

Belinky, F., Cohen, O., Huchon, D. — Wed, 13 Jan 2010 11:39:49 PST

Insertions and deletions (indels) are considered to be rare evolutionary events, the analysis of which may resolve controversial phylogenetic relationships. Indeed, indel characters are often assumed to be less homoplastic than amino acid and nucleotide substitutions and, consequently, more reliable markers for phylogenetic reconstruction. In this study, we analyzed indels from over 1,000 metazoan orthologous genes. We studied the impact of different species sampling, ortholog data sets, lengths of included indels, and indel-coding methods on the resulting metazoan tree. Our results show that, similar to sequence substitutions, indels are homoplastic characters, and their analysis is sensitive to the long-branch attraction artifact. Furthermore, improving the taxon sampling and choosing a closely related outgroup greatly impact the phylogenetic inference. Our indel-based inferences support the Ecdysozoa hypothesis over the Coelomata hypothesis and suggest that sponges are a sister clade to other animals.

An Explicit Signature of Balancing Selection for Color-Vision Variation in New World Monkeys

Wed, 13 Jan 2010 11:39:49 PST

Color vision is an important characteristic of primates and, intriguingly, Neotropical monkeys are highly polymorphic for this trait. Recent field studies have challenged the conventional view that trichromatic color vision is more adaptive than dichromatic color vision. No study has investigated the pattern of genetic variation in the long to middle wavelength–sensitive (L-M or red–green) opsin gene as compared with that of other genomic regions (neutral references) in wild populations of New World monkeys to look for the signature of natural selection. Here, we report such a study conducted on spider monkeys and capuchin monkeys inhabiting Santa Rosa National Park, Costa Rica. The nucleotide sequence of the L-M opsin gene was more polymorphic than the sequences of the neutral references, although the opsin-gene sequences were not more divergent between the two species than were the sequences of the neutral references. In a coalescence simulation that took into account the observed nucleotide diversity of the neutral references, the Tajima's D value of the L-M opsin gene deviated significantly in a positive direction from the expected range. These results are the first to statistically demonstrate balancing selection acting on the polymorphic L-M opsin gene of New World monkeys. Taking the results of behavioral and genetic studies together, the balancing selection we detected may indicate that coexistence of different color-vision types in the same population, also characteristic of humans, is adaptive.

Multiple Functional Variants in cis Modulate PDYN Expression

Wed, 13 Jan 2010 11:39:49 PST

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. We identified five polymorphisms within the 5' flanking region that affect transcript abundance: a 68-bp repeat recognized in prior studies, as well as two microsatellites and two single nucleotide polymorphisms not previously implicated as functional variants. The impact of these variants on transcription differs by brain region, sex, and cell type, implying interactions between cis genotype and the differentiated state of cells. The effects of individual variants on expression level are not additive in some combinations, implying epistatic interactions between nearby variants. These data reveal an unexpectedly complex relationship between segregating genetic variation and its expression-trait consequences and highlights the importance of close functional scrutiny of natural genetic variation within even relatively well-studied cis-regulatory regions.

Divergence of Recently Duplicated M{gamma}-Type MADS-Box Genes in Petunia

Bemer, M., Gordon, J., Weterings, K., Angenent, G. C. — Wed, 13 Jan 2010 11:39:49 PST

The MADS-box transcription factor family has expanded considerably in plants via gene and genome duplications and can be subdivided into type I and MIKC-type genes. The two gene classes show a different evolutionary history. Whereas the MIKC-type genes originated during ancient genome duplications, as well as during more recent events, the type I loci appear to experience high turnover with many recent duplications. This different mode of origin also suggests a different fate for the type I duplicates, which are thought to have a higher chance to become silenced or lost from the genome. To get more insight into the evolution of the type I MADS-box genes, we isolated nine type I genes from Petunia, which belong to the M subclass, and investigated the divergence of their coding and regulatory regions. The isolated genes could be subdivided into two categories: two genes were highly similar to Arabidopsis M-type genes, whereas the other seven genes showed less similarity to Arabidopsis genes and originated more recently. Two of the recently duplicated genes were found to contain deleterious mutations in their coding regions, and expression analysis revealed that a third paralog was silenced by mutations in its regulatory region. However, in addition to the three genes that were subjected to nonfunctionalization, we also found evidence for neofunctionalization of one of the Petunia M-type genes. Our study shows a rapid divergence of recently duplicated M-type MADS-box genes and suggests that redundancy among type I paralogs may be less common than expected.