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Evolutionary dynamics of human retroviruses investigated through full-genome scanning.

To test hypotheses on the differences in retroviral genetic diversity, we compared the evolutionary dynamics of the human immunodeficiency virus type 1 (HIV-1) group M and the primate T-cell lymphotropic virus (PTLV) using a full-genome analysis. Evolutionary rates and nonsynonymous/synonymous substitution rate ratios were estimated across the genome using a maximum likelihood sliding window approach, and molecular clock properties were investigated. We confirm a remarkable difference in genetic stability and selective pressure at the interhost level. While there is evidence for adaptive evolution in HIV-1, the evolution of PTLV is almost exclusively characterized by negative selection or nearly neutral processes. For both retroviruses, evolutionary rate estimates across the genome reflect the differential selective constraints. However, based on the relationship between evolutionary rate and selective pressure and based on the comparison of synonymous substitution rates, the differences in rate between HIV-1 and PTLV cannot be explained by selective forces only. Several evolutionary and statistical assumptions, examined using a Bayesian coalescent method, were shown to have little influence on our inference.

Bayes Theorem↗

The "fish-specific" Hox cluster duplication is coincident with the origin of teleosts.

The Hox gene complement of zebrafish, medaka, and fugu differs from that of other gnathostome vertebrates. These fishes have seven to eight Hox clusters compared to the four Hox clusters described in sarcopterygians and shark. The clusters in different teleost lineages are orthologous, implying that a "fish-specific" Hox cluster duplication has occurred in the stem lineage leading to the most recent common ancestor of zebrafish and fugu. The timing of this event, however, is unknown. To address this question, we sequenced four Hox genes from taxa representing basal actinopterygian and teleost lineages and compared them to known sequences from shark, coelacanth, zebrafish, and other teleosts. The resulting gene genealogies suggest that the fish-specific Hox cluster duplication occurred coincident with the origin of crown group teleosts. In addition, we obtained evidence for an independent Hox cluster duplication in the sturgeon lineage (Acipenseriformes). Finally, results from HoxA11 suggest that duplicated Hox genes have experienced diversifying selection immediately after the duplication event. Taken together, these results support the notion that the duplicated Hox genes of teleosts were causally relevant to adaptive evolution during the initial teleost radiation.

Animals↗

Prediction of function divergence in protein families using the substitution rate variation parameter alpha.

Protein families typically embody a range of related functions and may thus be decomposed into subfamilies with, for example, distinct substrate specificities. Detection of functionally divergent subfamilies is possible by methods for recognizing branches of adaptive evolution in a gene tree. As the number of genome sequences is growing rapidly, it is highly desirable to automatically detect subfamily function divergence. To this end, we here introduce a method for large-scale prediction of function divergence within protein families. It is called the alpha shift measure (ASM) as it is based on detecting a shift in the shape parameter (alpha [alpha]) of the substitution rate gamma distribution. Four different methods for estimating alpha were investigated. We benchmarked the accuracy of ASM using function annotation from Enzyme Commission numbers within Pfam protein families divided into subfamilies by the automatic tree-based method BETE. In a test using 563 subfamily pairs in 162 families, ASM outperformed functional site-based methods using rate or conservation shifting (rate shift measure [RSM] and conservation shift measure [CSM]). The best results were obtained using the "GZ-Gamma" method for estimating alpha. By combining ASM with RSM and CSM using linear discriminant analysis, the prediction accuracy was further improved.

Algorithms↗

Higher intensity of purifying selection on >90% of the human genes revealed by the intrinsic replacement mutation rates.

For over 3 decades, the rate of replacement mutations has been assumed to be equal to, and estimated from, the rate of "strictly" neutral sequence divergence in noncoding regions and in silent-codon positions where mutations do not alter the amino acid encoded. This assumption is fundamental to estimating the fraction of harmful protein mutations and to identifying adaptive evolution at individual codons and proteins. We show that the assumption is not justifiable because a much larger fraction of codon positions is involved in hypermutable CpG dinucleotides as compared with the introns, leading to a higher expected replacement mutation rate per site in a vast majority of the genes. Consideration of this difference reveals a higher intensity of purifying natural selection than previously inferred in human genes. We also show that a much smaller number of genes are expected to be evolving with positive selection than that predicted using sequence divergence at intron and silent positions in the human genome. These patterns indicate the need for using new approaches for estimating rates of amino acid-altering mutations in order to find positively selected genes and codons in genomes that contain hypermutable CpG's.

Animals↗

Not born equal: increased rate asymmetry in relocated and retrotransposed rodent gene duplicates.

Duplicated genes frequently evolve at different rates. This asymmetry is evidence of natural selection's ability to discriminate between the 2 copies, subjecting them to different levels of purifying selection or even permitting adaptive evolution of one or both copies. However, if gene duplication creates pairs of protein-coding sequences that are initially identical, this raises the question of how selection tells the 2 copies apart. Here, we investigated asymmetric sequence divergence of recently duplicated genes in rodents and related this to 2 possible sources of such asymmetry: gene relocation as a consequence of duplication and retrotransposition as a mechanism of gene duplication. We found that most young rodent duplicates that have been relocated were created by retrotransposition. The degree of rate asymmetry in gene pairs where one copy has been relocated (either by retrotransposition or DNA-based duplication) is greater than in pairs formed by local DNA-based duplication events. Furthermore, by considering the direction of transposition for distant duplicates, we found a consistent tendency for retrogenes to undergo accelerated protein evolution relative to their static paralogs, whereas DNA-based transpositions showed no such tendency. Finally, we demonstrate that the faster sequence evolution of retrogenes correlates with the profound alteration of their expression pattern that is precipitated by retrotransposition.

Animals↗

The evolutionary history of human and chimpanzee Y-chromosome gene loss.

Recent studies have suggested that gene gain and loss may contribute significantly to the divergence between humans and chimpanzees. Initial comparisons of the human and chimpanzee Y-chromosomes indicate that chimpanzees have a disproportionate loss of Y-chromosome genes, which may have implications for the adaptive evolution of sex-specific as well as reproductive traits, especially because one of the genes lost in chimpanzees is critically involved in spermatogenesis in humans. Here we have characterized Y-chromosome sequences in gorilla, bonobo, and several chimpanzee subspecies for 7 chimpanzee gene-disruptive mutations. Our analyses show that 6 of these gene-disruptive mutations predate chimpanzee-bonobo divergence at approximately 1.8 MYA, which indicates significant Y-chromosome change in the chimpanzee lineage relatively early in the evolutionary divergence of humans and chimpanzees.

Amino Acid Sequence↗

Mating propensities and variations in enzyme activities in long-term cage populations of Drosophila melanogaster.

Environment-dependent reproductive isolation was established between cage populations (Bs) of Drosophila melanogaster originated from a Greek natural population (summer 1973) and maintained for about five years under different diets (poor-rich). The detected deviation from random mating involved no homogametic or heterogametic preference but rather, a significantly increased activity of males from populations maintained on the rich food medium. This observation indicates that the male parental investment is not negligible and under certain conditions sexual isolation can be a function not only of female behavior but also of male behavior. Differences also were found in various enzyme activities on the inter- and intra-population levels. Given those observations as well as the observed different behavioral patterns of Bs and Cs-Ds populations 19, a preliminary attempt was made to associate adaptive evolution with differences in enzyme activities. The differences in enzyme activities between populations reared on different media are not due to allozymic differences. It also was shown that in some populations environmental effects do not always elicit differences in enzyme activity. It was concluded, therefore, that the observed variations were the result of environmental effects interacting with modifier genes.

Animals↗

Amino acid replacements and wavelength absorption of visual pigments in vertebrates.

An important unanswered question in phototransduction is how visual pigments (VPs) regulate their wavelength of maximal absorption (lambda max). By constructing the evolutionary tree for 28 opsins with known lambda max values, we can identify the times and directions of lambda max shift of different VPs. A total of 55 amino acid changes are shown to correlate with the directions of lambda max shift and might have been important in determining lambda max of a VP. Among these, three amino acid changes are already proven to be responsible in modifying the green-sensitive VP to the red-sensitive VP. The present evolutionary analysis opens a new direction in understanding the mechanism for the regulation of wavelength absorption by a VP and, more generally, in studying molecular mechanism involved in adaptive evolution.

Amino Acid Sequence↗

Large-scale modelling as a route to multiple surface comparisons of the CCP module family.

Numerous mammalian proteins are constructed from a limited repertoire of module-types. Proteins belonging to the regulators of complement activation family--crucial for ensuring a complement-mediated immune response is targeted against infectious agents--are composed solely of complement control protein (CCP) modules. In the current study, CCP module sequences were grouped to allow selection of the most appropriate experimentally determined structures to serve as templates in an automated large-scale structure modelling procedure. The resulting 135 individual CCP module models, valuable in their own right, are available at the online database http://www.bru.ed.ac.uk/~dinesh/ccp-db.html. Comparisons of surface properties within a particular family of modules should be more informative than sequence alignments alone. A comparison of surface electrostatic features was undertaken for the first 28 CCP modules of complement receptor type 1 (CR1). Assignments to clusters based on surface properties differ from assignments to clusters based on sequences. This observation might reflect adaptive evolution of surface-exposed residues involved in protein-protein interactions. This illustrative example of a multiple surface-comparison was indeed able to pinpoint functional sites in CR1.

Amino Acid Sequence↗

Heritability of the timing of autumn migration in a natural bird population.

In recent decades, global temperature has increased at an unprecedented rate. This has been causing rapid environmental shifts that have altered the selective regimes determining the annual organization of birds. In order to assess the potential for adaptive evolution in the timing of autumn migration, we estimated heritabilities of the onset of migratory activity in a southern German blackcap (Sylvia atricapilla) population. Heritabilities (h2=0.34-0.45) and coefficients of additive genetic variation (CV(A)=4.7-5.7) were significant and consistent when estimated by different methods, irrespective of whether they were derived from birds hatched in the wild or bred in captivity. In an artificial selection experiment, we selected for later onset of migratory activity, simulating expected natural selection on this trait. We obtained a significant delay in the mean onset of migratory activity by more than one week after two generations of selection. Realized heritability (h2=0.55) was in agreement with expected heritability in the cohort that the selection line was derived from. Our results suggest that evolutionary changes in the timing of autumn migration may take place over a very short time period and will most probably be unconstrained by the lack of additive genetic variation.

Acclimatization↗

Cryptic diversity in European bats.

Different species of bat can be morphologically very similar. In order to estimate the amount of cryptic diversity among European bats we screened the intra- and interspecific genetic variation in 26 European vespertilionid bat species. We sequenced the DNA of subunit 1 of the mitochondrial protein NADH dehydrogenase (ND1) from several individuals of a species, which were sampled in a variety of geographical regions. A phylogeny based on the mitochondrial (mt) DNA data is in good agreement with the current classification in the family. Highly divergent mitochondrial lineages were found in two taxa, which differed in at least 11% of their ND1 sequence. The two mtDNA lineages in Plecotus austriacus correlated with the two subspecies Plecotus austriacus austriacus and Plecotus austriacus kolombatovici. The two mtDNA lineages in Myotis mystacinus were partitioned among two morphotypes. The evidence for two new bat species within Europe is discussed. Convergent adaptive evolution might have contributed to the morphological similarity among distantly related species if they occupy similar ecological niches. Closely related species may differ in their ecology but not necessarily in their morphology. On the other hand, two morphologically clearly different species (Eptesicus serotinus and Eptesicus nilssonii) were found to be genetically very similar. Neither morphological nor mitochondrial DNA sequence analysis alone can be guaranteed to identify species.

Animals↗

Protein structure and function at low temperatures.

Proteins represent the major components in the living cell that provide the whole repertoire of constituents of cellular organization and metabolism. In the process of evolution, adaptation to extreme conditions mainly referred to temperature, pH and low water activity. With respect to life at low temperatures, effects on protein structure, protein stability and protein folding need consideration. The sequences and topologies of proteins from psychrophilic, mesophilic and thermophilic organisms are found to be highly homologous. Commonly, adaptive changes refer to multiple alterations of the amino acid sequence, which presently cannot be correlated with specific changes of structure and stability; so far it has not been possible to attribute specific increments in the free energy of stabilization to well-defined amino-acid exchanges in an unambiguous way. The stability of proteins is limited at high and low temperatures. Their expression and self-organization may be accomplished under conditions strongly deviating from optimum growth conditions. Molecular adaptation to extremes of temperature seems to be accompanied by a flattening of the temperature profile of the free energy of stabilization. In principle, the free energy of stabilization of proteins is small compared to the total molecular energy. As a consequence, molecular adaptation to extremes of physical conditions only requires marginal alterations of the intermolecular interactions and packing density. Careful statistical and structural analyses indicate that altering the number of ion pairs and hydrophobic interactions allows the flexibility of proteins to be adjusted so that full catalytic function is maintained at varying temperatures.

Drug Stability↗

Phylogeny of North American Powassan virus.

To determine whether Powassan virus (POW) and deer tick virus (DTV) constitute distinct flaviviral populations transmitted by ixodid ticks in North America, we analysed diverse nucleotide sequences from 16 strains of these viruses. Two distinct genetic lineages are evident, which may be defined by geographical and host associations. The nucleotide and amino acid sequences of lineage one (comprising New York and Canadian POW isolates) are highly conserved across time and space, but those of lineage two (comprising isolates from deer ticks and a fox) are more variable. The divergence between lineages is much greater than the variation within either lineage, and lineage two appears to be more diverse genetically than is lineage one. Application of McDonald-Kreitman tests to the sequences of these strains indicates that adaptive evolution of the envelope protein separates lineage one from lineage two. The two POW lineages circulating in North America possess a pattern of genetic diversity suggesting that they comprise distinct subtypes that may perpetuate in separate enzootic cycles.

3' Untranslated Regions↗

Evolutionary dynamics of hepatitis C virus envelope genes during chronic infection.

Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are important targets for the host immune response. The genes encoding these proteins exhibit a high degree of variability that gives rise to differing phenotypic traits, including alterations in receptor-binding affinity and immune recognition and escape. In order to elucidate patterns of adaptive evolution during chronic infection, a panel of full-length E1E2 clones was generated from sequential serum samples obtained from four chronically infected individuals. By using likelihood-based methods for phylogenetic inference, the evolutionary dynamics of circulating HCV quasispecies populations were assessed and a site-by-site analysis of the d(N)/d(S) ratio was performed, to identify specific codons undergoing diversifying positive selection. HCV phylogenies, coupled with the number and distribution of selected sites, differed markedly between patients, highlighting that HCV evolution during chronic infection is a patient-specific phenomenon. This analysis shows that purifying selection is the major force acting on HCV populations in chronic infection. Whilst no significant evidence for positive selection was observed in E1, a number of sites under positive selection were identified within the ectodomain of the E2 protein. All of these sites were located in regions hypothesized to be exposed to the selective environment of the host, including a number of functionally defined domains that have been reported to be involved in immune evasion and receptor binding. Dated-tip methods for estimation of underlying HCV mutation rates were also applied to the data, enabling prediction of the most recent common ancestor for each patient's quasispecies.

Amino Acid Sequence↗

Comparative evolutionary genomics of androgen-binding protein genes.

Allelic variation within the mouse androgen-binding protein (ABP) alpha subunit gene (Abpa) has been suggested to promote assortative mating and thus prezygotic isolation. This is consistent with the elevated evolutionary rates observed for the Abpa gene, and the Abpb and Abpg genes whose products (ABPbeta and ABPgamma) form heterodimers with ABPalpha. We have investigated the mouse sequence that contains the three Abpa/b/g genes, and orthologous regions in rat, human, and chimpanzee genomes. Our studies reveal extensive "remodeling" of this region: Duplication rates of Abpa-like and Abpbg-like genes in mouse are >2 orders of magnitude higher than the average rate for all mouse genes; synonymous nucleotide substitution rates are twofold higher; and the Abpabg genomic region has expanded nearly threefold since divergence of the rodents. During this time, one in six amino acid sites in ABPbetagamma-like proteins appear to have been subject to positive selection; these may constitute a site of interaction with receptors or ligands. Greater adaptive variation among Abpbg-like sequences than among Abpa-like sequences suggests that assortative mating preferences are more influenced by variation in Abpbg-like genes. We propose a role for ABPalpha/beta/gamma proteins as pheromones, or in modulating odorant detection. This would account for the extraordinary adaptive evolution of these genes, and surrounding genomic regions, in murid rodents.

Amino Acid Sequence↗

Sequence-related human proteins cluster by degree of evolutionary conservation.

Gene duplication followed by adaptive evolution is thought to be a central mechanism for the emergence of novel genes. To illuminate the contribution of duplicated protein-coding sequences to the complexity of the human genome, we study the connectivity of pairwise sequence-related human proteins and construct a network (N) of linked protein sequences with shared similarities. We find that (i) the connectivity distribution P (k) for k sequence-related proteins decays as a power law P (k) approximately k(-gamma) with gamma approximately 1.2 , (ii) the top rank of N consists of a single large cluster of proteins ( approximately 70%) , while bottom ranks consist of multiple isolated clusters, and (iii) structural characteristics of N show both a high degree of clustering and an intermediate connectivity ("small-world" features). We gain further insight into structural properties of N by studying the relationship between the connectivity distribution and the phylogenetic conservation of proteins in bacteria, plants, invertebrates, and vertebrates. We find that (iv) the proportion of sequence-related proteins increases with increasing extent of evolutionary conservation. Our results support that small-world network properties constitute a footprint of an evolutionary mechanism and extend the traditional interpretation of protein families.

Chromosome Mapping↗

Self-organizing nets for optimization.

Given some optimization problem and a series of typically expensive trials of solution candidates sampled from a search space, how can we efficiently select the next candidate? We address this fundamental problem by embedding simple optimization strategies in learning algorithms inspired by Kohonen's self-organizing maps and neural gas networks. Our adaptive nets or grids are used to identify and exploit search space regions that maximize the probability of generating points closer to the optima. Net nodes are attracted by candidates that lead to improved evaluations, thus, quickly biasing the active data selection process toward promising regions, without loss of ability to escape from local optima. On standard benchmark functions, our techniques perform more reliably than the widely used covariance matrix adaptation evolution strategy. The proposed algorithm is also applied to the problem of drag reduction in a flow past an actively controlled circular cylinder, leading to unprecedented drag reduction.

Neural Networks, Computer↗

Quantitative genetics of geometric shape in the mouse mandible.

We combine the methods of geometric morphometrics and multivariate quantitative genetics to study the patterns of phenotypic and genetic variation of mandible shape in random-bred mice. The data are the positions of 11 landmarks on the mandibles of 1,241 mice from a parent-offspring breeding design. We use Procrustes superimposition to extract shape variation and restricted maximum likelihood to estimate the additive genetic and environmental components of variance and covariance. Matrix permutation tests showed that the genetic and phenotypic as well as the genetic and environmental covariance matrices were similar, but not identical. Likewise, principal component analyses revealed correspondence in the patterns of phenotypic and genetic variation. Patterns revealed in these analyses also showed similarities to features previously found in the effects of quantitative trait loci and in the phenotypes generated in gene knockout experiments. We used the multivariate version of the breeders' equation to explore the potential for short-term response to selection on shape. In general, the correlated response is substantial and regularly exceeds the direct response: Selection applied locally to one landmark usually produces a response in other parts of the mandible as well. Moreover, even selection for shifts of the same landmark in different directions can yield dramatically different responses. These results demonstrate the role of the geometry and anatomical structure of the mandible, which are key determinants of the patterns of the genetic and phenotypic covariance matrices, in molding the potential for adaptive evolution.

Animals↗