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Skin Game: Study Peels Back Details on Mammalian Keratin Genes and Adaptation to Living on Land or in Water

Thu, 31 Jan 2019 00:00:00 GMT

Whether by land or by sea, mammals live in a diverse variety of protective skins adapted against the elements, from swimming in the deepest azure oceans to climbing precipitous mountain peaks.

Scorpion Toxins: Positive Selection at a Distal Site Modulates Functional Evolution at a Bioactive Site

Tue, 18 Dec 2018 00:00:00 GMT

The bioactive sites of proteins are those that directly interact with their targets. In many immunity- and predation-related proteins, they frequently experience positive selection for dealing with the changes of their targets from competitors. However, some sites that are far away from the interface between proteins and their targets are also identified to evolve under positive selection. Here, we explore the evolutionary implication of such a site in scorpion α-type toxins affecting sodium (Na⁺) channels (abbreviated as α-ScNaTxs) using a combination of experimental and computational approaches. We found that despite no direct involvement in interaction with Na⁺ channels, mutations at this site by different types of amino acids led to toxicity change on both rats and insects in three α-ScNaTxs, accompanying differential effects on their structures. Molecular dynamics simulations indicated that the mutations changed the conformational dynamics of the positively selected bioactive site-containing functional regions by allosteric communication, suggesting a potential evolutionary correlation between these bioactive sites and the distant nonbioactive site. Our results reveal for the first time the cause of fast evolution at nonbioactive sites of scorpion neurotoxins, which is presumably to adapt to the change of their bioactive sites through coevolution to maintain an active conformation for channel binding. This might aid rational design of scorpion Na⁺ channel toxins with improved phyletic selectivity via modification of a distant nonbioactive site.

Evolution of the Yeast Recombination Landscape

Fri, 07 Dec 2018 00:00:00 GMT

Meiotic recombination comprises crossovers and noncrossovers. Recombination, crossover in particular, shuffles mutations and impacts both the level of genetic polymorphism and the speed of adaptation. In many species, the recombination rate varies across the genome with hot and cold spots. The hotspot paradox hypothesis asserts that recombination hotspots are evolutionarily unstable due to self-destruction. However, the genomic landscape of double-strand breaks (DSBs), which initiate recombination, is evolutionarily conserved among divergent yeast species, casting doubt on the hotspot paradox hypothesis. Nonetheless, because only a subset of DSBs are associated with crossovers, the evolutionary conservation of the crossover landscape could differ from that of DSBs. Here, we investigate this possibility by generating a high-resolution recombination map of the budding yeast Saccharomyces paradoxus through whole-genome sequencing of 50 meiotic tetrads and by comparing this recombination map with that of S. cerevisiae. We observe a 40% lower recombination rate in S. paradoxus than in S. cerevisiae. Compared with the DSB landscape, the crossover landscape is even more conserved. Further analyses indicate that the elevated conservation of the crossover landscape is explained by a near-subtelomeric crossover preference in both yeasts, which we find to be attributable at least in part to crossover interference. We conclude that the yeast crossover landscape is highly conserved and that the evolutionary conservation of this landscape can differ from that of the DSB landscape.

Insights into the Evolution of the Suppressors of Cytokine Signaling (SOCS) Gene Family in Vertebrates

Wed, 05 Dec 2018 00:00:00 GMT

The SOCS family are key negative regulators of cytokine and growth factor signaling. Typically, 8–17 SOCS genes are present in vertebrate species with eight known in mammals, classified as type I (SOCS4–7) and type II (CISH and SOCS1–3) SOCS. It was believed that the type II SOCS were expanded through the two rounds of whole genome duplication (1R and 2R WGDs) from a single CISH/SOCS1–3 precursor. Previously, 12 genes were identified in rainbow trout but here we report 15 additional loci are present, and confirm 26 of the genes are expressed, giving rainbow trout the largest SOCS gene repertoire identified to date. The discovery of the additional SOCS genes in trout has led to a novel model of SOCS family evolution, whereby the vertebrate SOCS gene family was derived from CISH/SOCS2, SOCS1/SOCS3, SOCS4/5, SOCS6, and SOCS7 ancestors likely present before the two WGD events. It is also apparent that teleost SOCS2b, SOCS4, and SOCS5b molecules are not true orthologues of mammalian SOCS2, SOCS4, and SOCS5, respectively. The rate of SOCS gene structural changes increased from 2R vertebrates, to 4R rainbow trout, and the genes with structural changes show large differences and low correlation coefficient of expression levels relative to their paralogues, suggesting a role of structural changes in expression and functional diversification. This study has important impacts in the functional prediction and understanding of the SOCS gene family in different vertebrates, and provides a framework for determining how many SOCS genes could be expected in a particular vertebrate species/lineage.

Structural Patching Fosters Divergence of Mitochondrial Ribosomes

Tue, 04 Dec 2018 00:00:00 GMT

Mitochondrial ribosomes (mitoribosomes) are essential components of all mitochondria that synthesize proteins encoded by the mitochondrial genome. Unlike other ribosomes, mitoribosomes are highly variable across species. The basis for this diversity is not known. Here, we examine the composition and evolutionary history of mitoribosomes across the phylogenetic tree by combining three-dimensional structural information with a comparative analysis of the secondary structures of mitochondrial rRNAs (mt-rRNAs) and available proteomic data. We generate a map of the acquisition of structural variation and reconstruct the fundamental stages that shaped the evolution of the mitoribosomal large subunit and led to this diversity. Our analysis suggests a critical role for ablation and expansion of rapidly evolving mt-rRNA. These changes cause structural instabilities that are “patched” by the acquisition of pre-existing compensatory elements, thus providing opportunities for rapid evolution. This mechanism underlies the incorporation of mt-tRNA into the central protuberance of the mammalian mitoribosome, and the altered path of the polypeptide exit tunnel of the yeast mitoribosome. We propose that since the toolkits of elements utilized for structural patching differ between mitochondria of different species, it fosters the growing divergence of mitoribosomes.

Irreversible Activation of Rho-activated Kinases Resulted from Evolution of Proteolytic Sites within Disordered Regions in Coiled-coil Domain

Tue, 04 Dec 2018 00:00:00 GMT

Activation of Rho-associated protein kinase 1 (ROCK1) and myotonic dystrophy kinase-related CDC42-binding kinase alpha (MRCKα) by caspases during apoptosis in vertebrates represents a prototypical example of co-option of kinases by proteases. How caspases acquired the ability to control these proteins during evolution of vertebrates is still unknown. Here, we report a phylogenetic and molecular study on the acquisition of caspase-cleavage sites in the family of Rho-activated kinases (RaKs). We demonstrate that the acquisition of such sites has more frequently occurred in identifiable intrinsically disordered regions (IDRs) within or flanking the coiled-coil domain. Thanks to computational identification of IDRs in protein sequences of different organisms, we predicted and validated the independent evolution of two caspase-cleavage sites in ROCK of arthropods and the loss of one of the MRCKα caspase-cleavage sites in ray-finned fishes. In conclusion, we shed light on the propensity of RaKs to evolve novel proteolytic sites, causing kinase activation and uniform subcellular distribution.

The Unreasonable Effectiveness of Convolutional Neural Networks in Population Genetic Inference

Tue, 04 Dec 2018 00:00:00 GMT

Population-scale genomic data sets have given researchers incredible amounts of information from which to infer evolutionary histories. Concomitant with this flood of data, theoretical and methodological advances have sought to extract information from genomic sequences to infer demographic events such as population size changes and gene flow among closely related populations/species, construct recombination maps, and uncover loci underlying recent adaptation. To date, most methods make use of only one or a few summaries of the input sequences and therefore ignore potentially useful information encoded in the data. The most sophisticated of these approaches involve likelihood calculations, which require theoretical advances for each new problem, and often focus on a single aspect of the data (e.g., only allele frequency information) in the interest of mathematical and computational tractability. Directly interrogating the entirety of the input sequence data in a likelihood-free manner would thus offer a fruitful alternative. Here, we accomplish this by representing DNA sequence alignments as images and using a class of deep learning methods called convolutional neural networks (CNNs) to make population genetic inferences from these images. We apply CNNs to a number of evolutionary questions and find that they frequently match or exceed the accuracy of current methods. Importantly, we show that CNNs perform accurate evolutionary model selection and parameter estimation, even on problems that have not received detailed theoretical treatments. Thus, when applied to population genetic alignments, CNNs are capable of outperforming expert-derived statistical methods and offer a new path forward in cases where no likelihood approach exists.

Differential Evolution of the Epidermal Keratin Cytoskeleton in Terrestrial and Aquatic Mammals

Tue, 04 Dec 2018 00:00:00 GMT

Keratins are the main intermediate filament proteins of epithelial cells. In keratinocytes of the mammalian epidermis they form a cytoskeleton that resists mechanical stress and thereby are essential for the function of the skin as a barrier against the environment. Here, we performed a comparative genomics study of epidermal keratin genes in terrestrial and fully aquatic mammals to determine adaptations of the epidermal keratin cytoskeleton to different environments. We show that keratins K5 and K14 of the innermost (basal), proliferation-competent layer of the epidermis are conserved in all mammals investigated. In contrast, K1 and K10, which form the main part of the cytoskeleton in the outer (suprabasal) layers of the epidermis of terrestrial mammals, have been lost in whales and dolphins (cetaceans) and in the manatee. Whereas in terrestrial mammalian epidermis K6 and K17 are expressed only upon stress-induced epidermal thickening, high levels of K6 and K17 are consistently present in dolphin skin, indicating constitutive expression and substitution of K1 and K10. K2 and K9, which are expressed in a body site-restricted manner in human and mouse suprabasal epidermis, have been lost not only in cetaceans and manatee but also in some terrestrial mammals. The evolution of alternative splicing of K10 and differentiation-dependent upregulation of K23 have increased the complexity of keratin expression in the epidermis of terrestrial mammals. Taken together, these results reveal evolutionary diversification of the epidermal cytoskeleton in mammals and suggest a complete replacement of the quantitatively predominant epidermal proteins of terrestrial mammals by originally stress-inducible keratins in cetaceans.

Repeated Evolution of Asexuality Involves Convergent Gene Expression Changes

Fri, 16 Nov 2018 00:00:00 GMT

Asexual reproduction has evolved repeatedly from sexual ancestors across a wide range of taxa. Whereas the costs and benefits associated with asexuality have received considerable attention, the molecular changes underpinning the evolution of asexual reproduction remain relatively unexplored. In particular, it is completely unknown whether the repeated evolution of asexual phenotypes involves similar molecular changes, as previous studies have focused on changes occurring in single lineages. Here, we investigate the extent of convergent gene expression changes across five independent transitions to asexuality in stick insects. We compared gene expression of asexual females to females of close sexual relatives in whole-bodies, reproductive tracts, and legs. We identified a striking amount of convergent gene expression change (up to 8% of genes), greatly exceeding that expected by chance. Convergent changes were also tissue-specific, and most likely driven by selection for functional changes. Genes showing convergent changes in the reproductive tract were associated with meiotic spindle formation and centrosome organization. These genes are particularly interesting as they can influence the production of unreduced eggs, a key barrier to asexual reproduction. Changes in legs and whole-bodies were likely involved in female sexual trait decay, with enrichment in terms such as sperm-storage and pigmentation. By identifying changes occurring across multiple independent transitions to asexuality, our results provide a rare insight into the molecular basis of asexual phenotypes and suggest that the evolutionary path to asexuality is highly constrained, requiring repeated changes to the same key genes.

Cytonuclear Coevolution following Homoploid Hybrid Speciation in Aegilops tauschii

Fri, 16 Nov 2018 00:00:00 GMT

The diploid D-genome lineage of the Triticum/Aegilops complex has an evolutionary history involving genomic contributions from ancient A- and B/S-genome species. We explored here the possible cytonuclear evolutionary responses to this history of hybridization. Phylogenetic analysis of chloroplast DNAs indicates that the D-genome lineage has a maternal origin of the A-genome or some other closely allied lineage. Analyses of the nuclear genome in the D-genome species Aegilops tauschii indicate that accompanying and/or following this ancient hybridization, there has been biased maintenance of maternal A-genome ancestry in nuclear genes encoding cytonuclear enzyme complexes (CECs). Our study provides insights into mechanisms of cytonuclear coevolution accompanying the evolution and eventual stabilization of homoploid hybrid species. We suggest that this coevolutionary process includes likely rapid fixation of A-genome CEC orthologs as well as biased retention of A-genome nucleotides in CEC homologs following population level recombination during the initial generations.

The Genome Landscape of Tibetan Sheep Reveals Adaptive Introgression from Argali and the History of Early Human Settlements on the Qinghai–Tibetan Plateau

Fri, 16 Nov 2018 00:00:00 GMT

Tibetan sheep are the most common and widespread domesticated animals on the Qinghai–Tibetan Plateau (QTP) and have played an essential role in the permanent human occupation of this high-altitude region. However, the precise timing, route, and process of sheep pastoralism in the QTP region remain poorly established, and little is known about the underlying genomic changes that occurred during the process. Here, we investigate the genomic variation in Tibetan sheep using whole-genome sequences, single nucleotide polymorphism arrays, mitochondrial DNA, and Y-chromosomal variants in 986 samples throughout their distribution range. We detect strong signatures of selection in genes involved in the hypoxia and ultraviolet signaling pathways (e.g., HIF-1 pathway and HBB and MITF genes) and in genes associated with morphological traits such as horn size and shape (e.g., RXFP2). We identify clear signals of argali (Ovis ammon) introgression into sympatric Tibetan sheep, covering 5.23–5.79% of their genomes. The introgressed genomic regions are enriched in genes related to oxygen transportation system, sensory perception, and morphological phenotypes, in particular the genes HBB and RXFP2 with strong signs of adaptive introgression. The spatial distribution of genomic diversity and demographic reconstruction of the history of Tibetan sheep show a stepwise pattern of colonization with their initial spread onto the QTP from its northeastern part ∼3,100 years ago, followed by further southwest expansion to the central QTP ∼1,300 years ago. Together with archeological evidence, the date and route reveal the history of human expansions on the QTP by the Tang–Bo Ancient Road during the late Holocene. Our findings contribute to a depth understanding of early pastoralism and the local adaptation of Tibetan sheep as well as the late-Holocene human occupation of the QTP.

Evolution of the Mutational Process under Relaxed Selection in Caenorhabditis elegans

Thu, 15 Nov 2018 00:00:00 GMT

The mutational process varies at many levels, from within genomes to among taxa. Many mechanisms have been linked to variation in mutation, but understanding of the evolution of the mutational process is rudimentary. Physiological condition is often implicated as a source of variation in microbial mutation rate and may contribute to mutation rate variation in multicellular organisms.Deleterious mutations are an ubiquitous source of variation in condition. We test the hypothesis that the mutational process depends on the underlying mutation load in two groups of Caenorhabditis elegans mutation accumulation (MA) lines that differ in their starting mutation loads. “First-order MA” (O1MA) lines maintained under minimal selection for ∼250 generations were divided into high-fitness and low-fitness groups and sets of “second-order MA” (O2MA) lines derived from each O1MA line were maintained for ∼150 additional generations. Genomes of 48 O2MA lines and their progenitors were sequenced. There is significant variation among O2MA lines in base-substitution rate (µbs), but no effect of initial fitness; the indel rate is greater in high-fitness O2MA lines. Overall, µbs is positively correlated with recombination and proximity to short tandem repeats and negatively correlated with 10 bp and 1 kb GC content. However, probability of mutation is sufficiently predicted by the three-nucleotide motif alone. Approximately 90% of the variance in standing nucleotide variation is explained by mutability. Total mutation rate increased in the O2MA lines, as predicted by the “drift barrier” model of mutation rate evolution. These data, combined with experimental estimates of fitness, suggest that epistasis is synergistic.

Methods for Estimating Demography and Detecting Between-Locus Differences in the Effective Population Size and Mutation Rate

Wed, 14 Nov 2018 00:00:00 GMT

It is known that the effective population size (N_e) and the mutation rate (u) vary across the genome. Here, we show that ignoring this heterogeneity may lead to biased estimates of past demography. To solve the problem, we develop new methods for jointly inferring past changes in population size and detecting variation in N_e and u between loci. These methods rely on either polymorphism data alone or both polymorphism and divergence data. In addition to inferring demography, we can use the methods to study a variety of questions: 1) comparing sex chromosomes with autosomes (for finding evidence for male-driven evolution, an unequal sex ratio, or sex-biased demographic changes) and 2) analyzing multilocus data from within autosomes or sex chromosomes (for studying determinants of variability in N_e and u). Simulations suggest that the methods can provide accurate parameter estimates and have substantial statistical power for detecting difference in N_e and u. As an example, we use the methods to analyze a polymorphism data set from Drosophila simulans. We find clear evidence for rapid population expansion. The results also indicate that the autosomes have a higher mutation rate than the X chromosome and that the sex ratio is probably female-biased. The new methods have been implemented in a user-friendly package.

The Many Nuanced Evolutionary Consequences of Duplicated Genes

Wed, 14 Nov 2018 00:00:00 GMT

Gene duplication is seen as a major source of structural and functional divergence in genome evolution. Under the conventional models of sub or neofunctionalization, functional changes arise in one of the duplicates after duplication. However, we suggest here that the presence of a duplicated gene can result in functional changes to its interacting partners. We explore this hypothesis by in silico evolution of a heterodimer when one member of the interacting pair is duplicated. We examine how a range of selection pressures and protein structures leads to differential patterns of evolutionary divergence. We find that a surprising number of distinct evolutionary trajectories can be observed even in a simple three member system. Further, we observe that selection to correct dosage imbalance can affect the evolution of the initial function in several unexpected ways. For example, if a duplicate is under selective pressure to avoid binding its original binding partner, this can lead to changes in the binding interface of a nonduplicated interacting partner to exclude the duplicate. Hence, independent of the fate of the duplicate, its presence can impact how the original function operates. Additionally, we introduce a conceptual framework to describe how interacting partners cope with dosage imbalance after duplication. Contextualizing our results within this framework reveals that the evolutionary path taken by a duplicate’s interacting partners is highly stochastic in nature. Consequently, the fate of duplicate genes may not only be controlled by their own ability to accumulate mutations but also by how interacting partners cope with them.

Genomic Evidence of Local Adaptation to Climate and Diet in Indigenous Siberians

Wed, 14 Nov 2018 00:00:00 GMT

The indigenous inhabitants of Siberia live in some of the harshest environments on earth, experiencing extended periods of severe cold temperatures, dramatic variation in photoperiod, and limited and highly variable food resources. While the successful long-term settlement of this area by humans required multiple behavioral and cultural innovations, the nature of the underlying genetic changes has generally remained elusive. In this study, we used a three-part approach to identify putative targets of positive natural selection in Siberians. We first performed selection scans on whole exome and genome-wide single nucleotide polymorphism array data from multiple Siberian populations. We then annotated candidates in the tails of the empirical distributions, focusing on candidates with evidence linking them to biological processes and phenotypes previously identified as relevant to adaptation in circumpolar groups. The top candidates were then genotyped in additional populations to determine their spatial allele frequency distributions and associations with climate variables. Our analysis reveals missense mutations in three genes involved in lipid metabolism (PLA2G2A, PLIN1, and ANGPTL8) that exhibit genomic and spatial patterns consistent with selection for cold climate and/or diet. These variants are unified by their connection to brown adipose tissue and may help to explain previously observed physiological differences in Siberians such as low serum lipid levels and increased basal metabolic rate. These results support the hypothesis that indigenous Siberians have genetically adapted to their local environment by selection on multiple genes.

Localizing and Classifying Adaptive Targets with Trend Filtered Regression

Tue, 06 Nov 2018 00:00:00 GMT

Identifying genomic locations of natural selection from sequence data is an ongoing challenge in population genetics. Current methods utilizing information combined from several summary statistics typically assume no correlation of summary statistics regardless of the genomic location from which they are calculated. However, due to linkage disequilibrium, summary statistics calculated at nearby genomic positions are highly correlated. We introduce an approach termed Trendsetter that accounts for the similarity of statistics calculated from adjacent genomic regions through trend filtering, while reducing the effects of multicollinearity through regularization. Our penalized regression framework has high power to detect sweeps, is capable of classifying sweep regions as either hard or soft, and can be applied to other selection scenarios as well. We find that Trendsetter is robust to both extensive missing data and strong background selection, and has comparable power to similar current approaches. Moreover, the model learned by Trendsetter can be viewed as a set of curves modeling the spatial distribution of summary statistics in the genome. Application to human genomic data revealed positively selected regions previously discovered such as LCT in Europeans and EDAR in East Asians. We also identified a number of novel candidates and show that populations with greater relatedness share more sweep signals.

Tipping the Scales: The Migration–Selection Balance Leans toward Selection in Snake Venoms

Sat, 03 Nov 2018 00:00:00 GMT

The migration–selection interaction is the strongest determinant of whether a beneficial allele increases in frequency within a population. Results of empirical studies examining the role of gene flow in an adaptive context, however, have largely been equivocal, with examples of opposing outcomes being repeatedly documented (e.g., local adaptation with high levels of gene flow vs. gene swamping). We compared neutral genomic and venom expression divergence for three sympatric pit vipers with differing ecologies to determine if and how migration–selection disequilibria result in local adaptation. We specifically tested whether neutral differentiation predicted phenotypic differentiation within an isolation-by-distance framework. The decoupling of neutral and phenotypic differentiation would indicate selection led to adaptive divergence irrespective of migration, whereas a significant relationship between neutral and venom expression differentiation would provide evidence in favor of the constraining force of gene flow. Neutral differentiation and geographic distance predicted phenotypic differentiation only in the generalist species, indicating that selection was the predominant mechanism in the migration–selection balance underlying adaptive venom evolution in both specialists. Dispersal is thought to be a stronger influence on genetic differentiation than specialization, but our results suggest the opposite. Greater specialization may lead to greater diversification rates, and extreme spatial and temporal variation in selective pressures can favor generalist phenotypes evolving under strong stabilizing selection. Our results are consistent with these expectations, suggesting that the equivocal findings of studies examining the role of gene flow in an adaptive context may be explained by ecological specialization theory.