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Abstract Background Genome sequences vary strongly in their repetitiveness and the causes for this are still debated. Here we propose a novel measure of genome repetitiveness, the index of repetitiveness, Ir, which can be computed in time proportional to the length of the sequences analyzed. We apply it to 336 genomes from all three domains of life. Results The expected value of Ir is zero for random sequences of any G/C content and greater than zero for sequences with excess repeats. We find that the Ir of archaea is significantly smaller than that of eubacteria, which in turn is smaller than that of eukaryotes. Mouse chromosomes have a significantly higher Ir than human chromosomes and within each genome the Y chromosome is most repetitive. A sliding window analysis reveals that the human HOXA cluster and two surrounding genes are characterized by local minima in Ir. A program for calculating the Ir is freely available at http://adenine.biz.fh-weihenstephan.de/ir/. Conclusion The general measure of DNA repetitiveness proposed in this paper can be efficiently computed on a genomic scale. This reveals a broad spectrum of repetitiveness among diverse genomes which agrees qualitatively with previous studies of repeat content. A sliding window analysis helps to analyze the intragenomic distribution of repeats.

Abstract Background Sequence comparison by alignment is a fundamental tool of molecular biology. In this paper we show how a number of sequence comparison tasks, including the detection of unique genomic regions, can be accomplished efficiently without an alignment step. Our procedure for nucleotide sequence comparison is based on shortest unique substrings. These are substrings which occur only once within the sequence or set of sequences analysed and which cannot be further reduced in length without losing the property of uniqueness. Such substrings can be detected using generalized suffix trees. Results We find that the shortest unique substrings in Caenorhabditis elegans, human and mouse are no longer than 11 bp in the autosomes of these organisms. In mouse and human these unique substrings are significantly clustered in upstream regions of known genes. Moreover, the probability of finding such short unique substrings in the genomes of human or mouse by chance is extremely small. We derive an analytical expression for the null distribution of shortest unique substrings, given the GC-content of the query sequences. Furthermore, we apply our method to rapidly detect unique genomic regions in the genome of Staphylococcus aureus strain MSSA476 compared to four other staphylococcal genomes. Conclusion We combine a method to rapidly search for shortest unique substrings in DNA sequences and a derivation of their null distribution. We show that unique regions in an arbitrary sample of genomes can be efficiently detected with this method. The corresponding programs shustring (SHortest Unique subSTRING) and shulen are written in C and available at http://adenine.biz.fh-weihenstephan.de/shustring/.

Genes with multiple copies are likely to be maintained by stabilizing selection, which puts a bound to unlimited expansion of copy number. We designed a model in which copy number variation is generated by unequal recombination, which fits well with several genes surveyed in three human populations. Based on this theoretical model and computer simulations, we were interested in determining whether the gene copy number distribution in the derived European and Asian populations can be explained by a purely demographic scenario or whether shifts in the distribution are signatures of adaptation. Although the copy number distribution in most of the analyzed gene clusters can be explained by a bottleneck, such as in the out-of-Africa expansion of Homo sapiens 60-10 kyrs ago, we identified several candidate genes, such as AMY1A and PGA3, whose copy numbers are likely to differ among African, Asian, and European populations., (© 2024. The Author(s).)

Copy number variation in large gene families is well characterized for plant resistance genes, but similar studies are rare in animals. The zebrafish ( Danio rerio ) has hundreds of NLR immune genes, making this species ideal for studying this phenomenon. By sequencing 93 zebrafish from multiple wild and laboratory populations, we identified a total of 1513 NLRs, many more than the previously known 400. Approximately half of those are present in all wild populations, but only 4% were found in 80% or more of the individual fish. Wild fish have up to two times as many NLRs per individual and up to four times as many NLRs per population than laboratory strains. In contrast to the massive variability of gene copies, nucleotide diversity in zebrafish NLR genes is very low: around half of the copies are monomorphic and the remaining ones have very few polymorphisms, likely a signature of purifying selection., Competing Interests: YS, KP, ML, AW, TW, JS No competing interests declared, (© 2024, Schäfer et al.)

Asexual reproduction is assumed to lead to the accumulation of deleterious mutations, and reduced heterozygosity due to the absence of recombination. Panagrolaimid nematode species display different modes of reproduction. Sexual reproduction with distinct males and females, asexual reproduction through parthenogenesis in the genus Panagrolaimus , and hermaphroditism in Propanagrolaimus . Here, we compared genomic features of free-living nematodes in populations and species isolated from geographically distant regions to study diversity, and genome-wide differentiation under different modes of reproduction. We firstly estimated genome-wide spontaneous mutation rates in a triploid parthenogenetic Panagrolaimus , and a diploid hermaphroditic Propanagrolaimus via long-term mutation accumulation lines. Secondly, we calculated population genetic parameters including nucleotide diversity, and fixation index ( F ST ) between populations of asexually and sexually reproducing nematodes. Thirdly, we used phylogenetic network methods on sexually and asexually reproducing Panagrolaimus populations to understand evolutionary relationships between them. The estimated mutation rate was slightly lower for the asexual population, as expected for taxa with this reproductive mode. Natural polyploid asexual populations revealed higher nucleotide diversity. Despite their common ancestor, a gene network revealed a high level of genetic differentiation among asexual populations. The elevated heterozygosity found in the triploid parthenogens could be explained by the third genome copy. Given their tendentially lower mutation rates it can be hypothesized that this is part of the mechanism to evade Muller's ratchet. Our findings in parthenogenetic triploid nematode populations seem to challenge common expectations of evolution under asexuality., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

The Structured Coalescent was introduced to describe the coalescent process in spatially subdivided populations with migration. Here, we re-interpret migration routes of individuals in the original model as "migration routes" of single genes in tandemly arranged gene arrays. A gene copy may change its position within the array via unequal recombination. Hence, in a coalescent framework, two copies sampled from two chromosomes may coalesce only if they are at exactly homologous positions. Otherwise, one or multiple recombination events have to occur before they can coalesce, thereby increasing mean coalescence time and expected genetic diversity among the copies in a gene array. We explicitly calculate the transition probabilities on these routes backward in time. We simulate the structured coalescent with migration and coalescence rates informed by the unequal recombination process of gene copies. With this novel interpretation of population structure models we determine coalescence times and expected genetic diversity in samples of orthologous and paralogous copies from a gene family. As a case study, we discuss the site frequency spectrum of a small gene family in the two scenarios of high and of no gene copy number variation among individuals. These examples underline the significance of our model, since standard test-statistics may lead to misinterpretations when analyzing sequence data of multi-copy genes due to their different expected genetic diversity., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multigene families-immunity genes or sensory receptors, for instance-are often subject to diversifying selection. Allelic diversity may be favored not only through balancing or frequency-dependent selection at individual loci but also by associating different alleles in multicopy gene families. Using a combination of analytical calculations and simulations, we explored a population genetic model of epistatic selection and unequal recombination, where a trade-off exists between the benefit of allelic diversity and the cost of copy abundance. Starting from the neutral case, where we showed that gene copy number is Gamma distributed at equilibrium, we derived also the mean and shape of the limiting distribution under selection. Considering a more general model, which includes variable population size and population substructure, we explored by simulations mean fitness and some summary statistics of the copy number distribution. We determined the relative effects of selection, recombination, and demographic parameters in maintaining allelic diversity and shaping the mean fitness of a population. One way to control the variance of copy number is by lowering the rate of unequal recombination. Indeed, when encoding recombination by a rate modifier locus, we observe exactly this prediction. Finally, we analyzed the empirical copy number distribution of 3 genes in human and estimated recombination and selection parameters of our model., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America.)

The Kingman coalescent process is a classical model of gene genealogies in population genetics. It generates Yule-distributed, binary ranked tree topologies - also called histories - with a finite number of n leaves, together with n-1 exponentially distributed time lengths: one for each layer of the history. Using a discrete approach, we study the lengths of the external branches of Yule distributed histories, where the length of an external branch is defined as the rank of its parent node. We study the multiplicity of external branches of given length in a random history of n leaves. A correspondence between the external branches of the ordered histories of size n and the non-peak entries of the permutations of size n-1 provides easy access to the length distributions of the first and second longest external branches in a random Yule history and coalescent tree of size n. The length of the longest external branch is also studied in dependence of root balance of a random tree. As a practical application, we compare the observed and expected number of mutations on the longest external branches in samples from natural populations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The Cambrian explosion was a unique animal radiation ~540 million years ago that produced the full range of body plans across bilaterians. The genetic mechanisms underlying these events are unknown, leaving a fundamental question in evolutionary biology unanswered. Using large-scale comparative genomics and advanced orthology evaluation techniques, we identified 157 bilaterian-specific genes. They include the entire Nodal pathway, a key regulator of mesoderm development and left-right axis specification; components for nervous system development, including a suite of G-protein-coupled receptors that control physiology and behaviour, the Robo-Slit midline repulsion system, and the neurotrophin signalling system; a high number of zinc finger transcription factors; and novel factors that previously escaped attention. Contradicting the current view, our study reveals that genes with bilaterian origin are robustly associated with key features in extant bilaterians, suggesting a causal relationship., Competing Interests: PH, WZ, AR, KP, TW No competing interests declared, (© 2020, Heger et al.)

We know from human genetic studies that practically all aspects of biology are strongly influenced by the genetic background, as reflected in the advent of "personalized medicine." Yet, with few exceptions, this is not taken into account when using laboratory populations as animal model systems for research in these fields. Laboratory strains of zebrafish (Danio rerio) are widely used for research in vertebrate developmental biology, behavior, and physiology, for modeling diseases, and for testing pharmaceutic compounds in vivo. However, all of these strains are derived from artificial bottleneck events and therefore are likely to represent only a fraction of the genetic diversity present within the species. Here, we use restriction site-associated DNA sequencing to genetically characterize wild populations of zebrafish from India, Nepal, and Bangladesh, and to compare them to previously published data on four common laboratory strains. We measured nucleotide diversity, heterozygosity, and allele frequency spectra, and find that wild zebrafish are much more diverse than laboratory strains. Further, in wild zebrafish, there is a clear signal of GC-biased gene conversion that is missing in laboratory strains. We also find that zebrafish populations in Nepal and Bangladesh are most distinct from all other strains studied, making them an attractive subject for future studies of zebrafish population genetics and molecular ecology. Finally, isolates of the same strains kept in different laboratories show a pattern of ongoing differentiation into genetically distinct substrains. Together, our findings broaden the basis for future genetic, physiological, pharmaceutic, and evolutionary studies in Danio rerio., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

We study the evolution of the population genealogy in the classic neutral Moran Model of finite size n∈N and in discrete time. The stochastic transformations that shape a Moran population can be realized directly on its genealogy and give rise to a process on a state space consisting of n-sized binary increasing trees. We derive a number of properties of this process, and show that they are in agreement with existing results on the infinite-population limit of the Moran Model. Most importantly, this process admits time reversal, which makes it possible to simplify the mechanisms determining state changes, and allows for a thorough investigation of the Most Recent Common Ancestorprocess., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Most animal species reproduce sexually and fully parthenogenetic lineages are usually short lived in evolution. Still, parthenogenesis may be advantageous as it avoids the cost of sex and permits colonization by single individuals. Panagrolaimid nematodes have colonized environments ranging from arid deserts to Arctic and Antarctic biomes. Many are obligatory meiotic parthenogens, and most have cryptobiotic abilities, being able to survive repeated cycles of complete desiccation and freezing. To identify systems that may contribute to these striking abilities, we sequenced and compared the genomes and transcriptomes of parthenogenetic and outcrossing panagrolaimid species, including cryptobionts and non-cryptobionts. The parthenogens are triploids, most likely originating through hybridization. Adaptation to cryptobiosis shaped the genomes of panagrolaimid nematodes and is associated with the expansion of gene families and signatures of selection on genes involved in cryptobiosis. All panagrolaimids have acquired genes through horizontal gene transfer, some of which are likely to contribute to cryptobiosis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Selective sweeps, the genetic footprint of positive selection, have been extensively studied in the past decades, with dozens of methods developed to identify swept regions. However, these methods suffer from both false positive and false negative reports, and the candidates identified with different methods are often inconsistent with each other. We propose that a biological cause of this problem can be population subdivision, and a technical cause can be incomplete, or inaccurate, modeling of the dynamic process associated with sweeps. Here we used simulations to show how these effects interact and potentially cause bias. In particular, we show that sweeps maybe misclassified as either hard or soft, when the true time stage of a sweep and that implied, or pre-supposed, by the model do not match. We call this "temporal misclassification". Similarly, "spatial misclassification (softening)" can occur when hard sweeps, which are imported by migration into a new subpopulation, are falsely identified as soft. This can easily happen in case of local adaptation, i.e. when the sweeping allele is not under positive selection in the new subpopulation, and the underlying model assumes panmixis instead of substructure. The claim that most sweeps in the evolutionary history of humans were soft, may have to be reconsidered in the light of these findings., Competing Interests: The authors have declared that no competing interests exist.

In this study, by exploring chromatin conformation capture data, we show that the nuclear segregation of Topologically Associated Domains (TADs) is contributed by DNA sequence composition. GC-peaks and valleys of TADs strongly influence interchromosomal interactions and chromatin 3D structure. To gain insight on the compositional and functional constraints associated with chromatin interactions and TADs formation, we analysed intra-TAD and intra-loop GC variations. This led to the identification of clear GC-gradients, along which, the density of genes, super-enhancers, transcriptional activity, and CTCF binding sites occupancy co-vary non-randomly. Further, the analysis of DNA base composition of nucleolar aggregates and nuclear speckles showed strong sequence-dependant effects. We conjecture that dynamic DNA binding affinity and flexibility underlay the emergence of chromatin condensates, their growth is likely promoted in mechanically soft regions (GC-rich) of the lowest chromatin and nucleosome densities. As a practical perspective, the strong linear association between sequence composition and interchromosomal contacts can help define consensus chromatin interactions, which in turn may be used to study alternative states of chromatin architecture.

Recent findings established a link between DNA sequence composition and interphase chromatin architecture and explained the evolutionary conservation of TADs (Topologically Associated Domains) and LADs (Lamina Associated Domains) in mammals. This prompted us to analyse conformation capture and recombination rate data to study the relationship between chromatin architecture and recombination landscape of human and mouse genomes. The results reveal that: (1) low recombination domains and blocks of elevated linkage disequilibrium tend to coincide with TADs and isochores, indicating co-evolving regulatory elements and genes in insulated neighbourhoods; (2) double strand break (DSB) and recombination frequencies increase in the short loops of GC-rich TADs, whereas recombination cold spots are typical of LADs and (3) the binding and loading of proteins, which are critical for DSB and meiotic recombination (SPO11, DMC1, H3K4me3 and PRMD9) are higher in GC-rich TADs. One explanation for these observations is that the occurrence of DSB and recombination in meiotic cells are associated with compositional and epigenetic features (genomic code) that influence DNA stiffness/flexibility and appear to be similar to those guiding the chromatin architecture in the interphase nucleus of pre-leptotene cells., Competing Interests: The authors have declared that no competing interests exist.

We revisit the classical, and introduce a novel, concept of two-locus linkage disequilibrium (LD). In contrast to defining haplotypes as allele combinations at two marker loci, we concentrate on the clustering of a sample of chromosomes induced by their coalescent genealogy. The root of a binary coalescent tree defines two clusters of chromosomes, each one of them containing the left and right descendants of the root. At two different loci this assignment may be different as a result of recombination. We show that the proportion of shared chromosomes among clusters at two different loci, measured by the squared correlation, constitutes a natural measure of LD. We call this topological LD (tLD) since it is induced by the topology of the coalescent tree. We find that it is, on average, larger than classical LD for any given distance between loci. Furthermore, tLD has a smaller coefficient of variation, which should provide an advantage, compared to the use of classical LD, for any kind of mapping purposes. We conclude with a practical application to the LCT region in human populations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We introduce the conditional Site Frequency Spectrum (SFS) for a genomic region linked to a focal mutation of known frequency. An exact expression for its expected value is provided for the neutral model without recombination. Its relation with the expected SFS for two sites, 2-SFS, is discussed. These spectra derive from the coalescent approach of Fu (1995) for finite samples, which is reviewed. Remarkably simple expressions are obtained for the linked SFS of a large population, which are also solutions of the multi-allelic Kolmogorov equations. These formulae are the immediate extensions of the well known single site θ∕f neutral SFS. Besides the general interest in these spectra, they relate to relevant biological cases, such as structural variants and introgressions. As an application, a recipe to adapt Tajima's D and other SFS-based neutrality tests to a non-recombining region containing a neutral marker is presented., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Many population genomic studies have been conducted in the past to search for traces of recent events of positive selection. These traces, however, can be obscured by temporal variation of population size or other demographic factors. To reduce the confounding impact of demography, the coalescent tree topology has been used as an additional source of information for detecting recent positive selection in a population or a species. Based on the branching pattern at the root, we partition the hypothetical coalescent tree, inferred from a sequence sample, into two subtrees. The reasoning is that positive selection could impose a strong impact on branch length in one of the two subtrees while demography has the same effect on average on both subtrees. Thus, positive selection should be detectable by comparing statistics calculated for the two subtrees. Simulations demonstrate that the proposed test based on these principles has high power to detect recent positive selection even when DNA polymorphism data from only one locus is available, and that it is robust to the confounding effect of demography. One feature is that all components in the summary statistics ([Formula: see text]) can be computed analytically. Moreover, misinference of derived and ancestral alleles is seen to have only a limited effect on the test, and it therefore avoids a notorious problem when searching for traces of recent positive selection., (Copyright © 2018 by the Genetics Society of America.)

The CCCTC-binding factor (CTCF) is multi-functional, ubiquitously expressed, and highly conserved from Drosophila to human. It has important roles in transcriptional insulation and the formation of a high-dimensional chromatin structure. CTCF has a paralog called "Brother of Regulator of Imprinted Sites" (BORIS) or "CTCF-like" (CTCFL). It binds DNA at sites similar to those of CTCF. However, the expression profiles of the two proteins are quite different. We investigated the evolutionary trajectories of the two proteins after the duplication event using a phylogenomic and interactomic approach. We find that CTCF has 52 direct interaction partners while CTCFL only has 19. Almost all interactors already existed before the emergence of CTCF and CTCFL. The unique secondary loss of CTCF from several nematodes is paralleled by a loss of two of its interactors, the polycomb repressive complex subunit SuZ12 and the multifunctional transcription factor TYY1. In contrast to earlier studies reporting the absence of BORIS from birds, we present evidence for a multigene synteny block containing CTCFL that is conserved in mammals, reptiles, and several species of birds, indicating that not the entire lineage of birds experienced a loss of CTCFL. Within this synteny block, BORIS and its genomic neighbors seem to be partitioned into two nested chromatin loops. The high expression of SPO11, RAE1, RBM38, and PMEPA1 in male tissues suggests a possible link between CTCFL, meiotic recombination, and fertility-associated phenotypes. Using the 65,700 exomes and the 1000 genomes data, we observed a higher number of intergenic, non-synonymous, and loss-of-function mutations in CTCFL than in CTCF, suggesting a reduced strength of purifying selection, perhaps due to less functional constraint., Competing Interests: The authors declare no conflict of interest.

We investigate the dependence of the site frequency spectrum on the topological structure of genealogical trees. We show that basic population genetic statistics, for instance, estimators of θ or neutrality tests such as Tajima's D , can be decomposed into components of waiting times between coalescent events and of tree topology. Our results clarify the relative impact of the two components on these statistics. We provide a rigorous interpretation of positive or negative values of an important class of neutrality tests in terms of the underlying tree shape. In particular, we show that values of Tajima's D and Fay and Wu's H depend in a direct way on a peculiar measure of tree balance, which is mostly determined by the root balance of the tree. We present a new test for selection in the same class as Fay and Wu's H and discuss its interpretation and power. Finally, we determine the trees corresponding to extreme expected values of these neutrality tests and present formulas for these extreme values as a function of sample size and number of segregating sites., (Copyright © 2017 by the Genetics Society of America.)

Background: Body plan development in multi-cellular organisms is largely determined by homeotic genes. Expression of homeotic genes, in turn, is partially regulated by insulator binding proteins (IBPs). While only a few enhancer blocking IBPs have been identified in vertebrates, the common fruit fly Drosophila melanogaster harbors at least twelve different enhancer blocking IBPs. We screened recently compiled insect transcriptomes from the 1KITE project and genomic and transcriptomic data from public databases, aiming to trace the origin of IBPs in insects and other arthropods., Results: Our study shows that the last common ancestor of insects (Hexapoda) already possessed a substantial number of IBPs. Specifically, of the known twelve insect IBPs, at least three (i.e., CP190, Su(Hw), and CTCF) already existed prior to the evolution of insects. Furthermore we found GAF orthologs in early branching insect orders, including Zygentoma (silverfish and firebrats) and Diplura (two-pronged bristletails). Mod(mdg4) is most likely a derived feature of Neoptera, while Pita is likely an evolutionary novelty of holometabolous insects. Zw5 appears to be restricted to schizophoran flies, whereas BEAF-32, ZIPIC and the Elba complex, are probably unique to the genus Drosophila. Selection models indicate that insect IBPs evolved under neutral or purifying selection., Conclusions: Our results suggest that a substantial number of IBPs either pre-date the evolution of insects or evolved early during insect evolution. This suggests an evolutionary history of insulator binding proteins in insects different to that previously thought. Moreover, our study demonstrates the versatility of the 1KITE transcriptomic data for comparative analyses in insects and other arthropods.

Gene duplication is an important mechanism of molecular evolution. It offers a fast track to modification, diversification, redundancy or rescue of gene function. However, duplication may also be neutral or (slightly) deleterious, and often ends in pseudo-geneisation. Here, we investigate the phylogenetic distribution of ultra large gene families on long and short evolutionary time scales. In particular, we focus on a family of NACHT-domain and leucine-rich-repeat-containing (NLR)-genes, which we previously found in large numbers to occupy one chromosome arm of the zebrafish genome. We were interested to see whether such a tight clustering is characteristic for ultra large gene families. Our data reconfirm that most gene family inflations are lineage-specific, but we can only identify very few gene clusters. Based on our observations we hypothesise that, beyond a certain size threshold, ultra large gene families continue to proliferate in a mechanism we term "run-away evolution". This process might ultimately lead to the failure of genomic integrity and drive species to extinction., Competing Interests: The authors declare no conflict of interest.

Multicellular eukaryotes have evolved a range of mechanisms for immune recognition. A widespread family involved in innate immunity are the NACHT-domain and leucine-rich-repeat-containing (NLR) proteins. Mammals have small numbers of NLR proteins, whereas in some species, mostly those without adaptive immune systems, NLRs have expanded into very large families. We describe a family of nearly 400 NLR proteins encoded in the zebrafish genome. The proteins share a defining overall structure, which arose in fishes after a fusion of the core NLR domains with a B30.2 domain, but can be subdivided into four groups based on their NACHT domains. Gene conversion acting differentially on the NACHT and B30.2 domains has shaped the family and created the groups. Evidence of positive selection in the B30.2 domain indicates that this domain rather than the leucine-rich repeats acts as the pathogen recognition module. In an unusual chromosomal organization, the majority of the genes are located on one chromosome arm, interspersed with other large multigene families, including a new family encoding zinc-finger proteins. The NLR-B30.2 proteins represent a new family with diversity in the specific recognition module that is present in fishes in spite of the parallel existence of an adaptive immune system., (© 2016 The Authors.)

Despite progress in understanding genome organization and gene expression during the last decade, the evolutionary pathways that led to the intricate patterns of gene expression in different cells of an organism are still poorly understood. Important steps in this regulation take place at the level of chromatin, where the (epi)genomic environment of a gene determines its expression in time and space. Although the basic mechanisms of gene expression apply to all eukaryotes, multicellular organisms face the additional challenge of coordinating gene expression during development. In this review we summarize and put into evolutionary context current knowledge about chromatin insulators, an important class of regulatory factors mediating these tasks. Our interpretation of historical and recent findings points to a dynamic and ongoing evolution of insulator proteins characterized by multiple instances of convergent evolution, gene loss, and binding site changes in different organisms. The idea of two autonomously evolving insulator functions (as a barrier element and an enhancer blocker) further suggests that the evolution of metazoans and their enhancer-rich gene regulatory repertoire might be connected to the radiation of enhancer blocking insulators. Although speculative at the moment, such coevolution might create tools for complex gene regulation and therefore influence the evolutionary roadmaps of metazoans., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The Yule process generates a class of binary trees which is fundamental to population genetic models and other applications in evolutionary biology. In this paper, we introduce a family of sub-classes of ranked trees, called Ω-trees, which are characterized by imbalance of internal nodes. The degree of imbalance is defined by an integer 0 ≤ ω. For caterpillars, the extreme case of unbalanced trees, ω = 0. Under models of neutral evolution, for instance the Yule model, trees with small ω are unlikely to occur by chance. Indeed, imbalance can be a signature of permanent selection pressure, such as observable in the genealogies of certain pathogens. From a mathematical point of view it is interesting to observe that the space of Ω-trees maintains several statistical invariants although it is drastically reduced in size compared to the space of unconstrained Yule trees. Using generating functions, we study here some basic combinatorial properties of Ω-trees. We focus on the distribution of the number of subtrees with two leaves. We show that expectation and variance of this distribution match those for unconstrained trees already for very small values of ω., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Alteration of regulatory DNA elements or their binding proteins may have drastic consequences for morphological evolution. Chromatin insulators are one example of such proteins and play a fundamental role in organizing gene expression. While a single insulator protein, CTCF (CCCTC-binding factor), is known in vertebrates, Drosophila melanogaster utilizes six additional factors. We studied the evolution of these proteins and show here that-in contrast to the bilaterian-wide distribution of CTCF-all other D. melanogaster insulators are restricted to arthropods. The full set is present exclusively in the genus Drosophila whereas only two insulators, Su(Hw) and CTCF, existed at the base of the arthropod clade and all additional factors have been acquired successively at later stages. Secondary loss of factors in some lineages further led to the presence of different insulator subsets in arthropods. Thus, the evolution of insulator proteins within arthropods is an ongoing and dynamic process that reshapes and supplements the ancient CTCF-based system common to bilaterians. Expansion of insulator systems may therefore be a general strategy to increase an organism's gene regulatory repertoire and its potential for morphological plasticity., (© 2013 The Authors. Evolution published by Wiley Periodicals, Inc. on behalf of The Society for the Study of Evolution.)

The coalescent with recombination is a fundamental model to describe the genealogical history of DNA sequence samples from recombining organisms. Considering recombination as a process which acts along genomes and which creates sequence segments with shared ancestry, we study the influence of single recombination events upon tree characteristics of the coalescent. We focus on properties such as tree height and tree balance and quantify analytically the changes in these quantities incurred by recombination in terms of probability distributions. We find that changes in tree topology are often relatively mild under conditions of neutral evolution, while changes in tree height are on average quite large. Our results add to a quantitative understanding of the spatial coalescent and provide the neutral reference to which the impact by other evolutionary scenarios, for instance tree distortion by selective sweeps, can be compared.

We consider exact enumerations and probabilistic properties of ranked trees when generated under the random coalescent process. Using a new approach, based on generating functions, we derive several statistics such as the exact probability of finding k cherries in a ranked tree of fixed size n. We then extend our method to consider also the number of pitchforks. We find a recursive formula to calculate the joint and conditional probabilities of cherries and pitchforks when the size of the tree is fixed. These results provide insights into structural properties of coalescent trees under the model of neutral evolution., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Selective sweeps are at the core of adaptive evolution. We study how the shape of coalescent trees is affected by recent selective sweeps. To do so we define a coarse-grained measure of tree topology. This measure has appealing analytical properties, its distribution is derived from a uniform, and it is easy to estimate from experimental data. We show how it can be cast into a test for recent selective sweeps using microsatellite markers and present an application to an experimental data set from Plasmodium falciparum.

The great majority of metazoans belong to bilaterian phyla. They diversified during a short interval in Earth's history known as the Cambrian explosion, ~540 million years ago. However, the genetic basis of these events is poorly understood. Here we argue that the vertebrate genome organizer CTCF (CCCTC-binding factor) played an important role for the evolution of bilaterian animals. We provide evidence that the CTCF protein and a genome-wide abundance of CTCF-specific binding motifs are unique to bilaterian phyla, but absent in other eukaryotes. We demonstrate that CTCF-binding sites within vertebrate and Drosophila Hox gene clusters have been maintained for several hundred million years, suggesting an ancient origin of the previously known interaction between Hox gene regulation and CTCF. In addition, a close correlation between the presence of CTCF and Hox gene clusters throughout the animal kingdom suggests conservation of the Hox-CTCF link across the Bilateria. On the basis of these findings, we propose the existence of a Hox-CTCF kernel as principal organizer of bilaterian body plans. Such a kernel could explain (i) the formation of Hox clusters in Bilateria, (ii) the diversity of bilaterian body plans, and (iii) the uniqueness and time of onset of the Cambrian explosion.

Abstract Alignment-free distance measures are generally less accurate but more efficient than traditional alignment-based metrics. In the context of genome sequence analysis, the efficiency gain is often so substantial that it outweights the loss in accuracy. However, a further disadvantage of alignment-free distances is that their relationship to evolutionary events such as substitutions is generally unknown. We have therefore derived an estimator of the number of substitutions per site between two unaligned DNA sequences, K(r). Simulations show that this estimator works well with "ideal" data. We compare K(r) to two alternative alignment-free distances: a k-tuple distance and a measure of relative entropy based on average common substring length. All three measures are applied to 27 primate mitochondrial genomes, eight whole genomes of Streptococcus agalactiae strains, and 12 whole genomes of Drosophila species. In each case, the cluster diagrams based on K(r) are equivalent to or significantly better than those based on the two alternative measures. This is due to the fact that in contrast to the alternative measures K(r) is derived from an explicit model of evolution. The computation of K(r) is efficiently implemented in the program kr, which can be downloaded freely from the internet.

Computer simulation is an essential tool in the analysis of DNA sequence variation for mapping events of recent adaptive evolution in the genome. Various simulation methods are employed to predict the signature of selection in sequence variation. The most informative and efficient method currently in use is coalescent simulation. However, this method is limited to simple models of directional selection. Whole-population forward-in-time simulations are the alternative to coalescent simulations for more complex models. The notorious problem of excessive computational cost in forward-in-time simulations can be overcome by various simplifying amendments. Overall, the success of simulations depends on the creative application of some population genetic theory to the simulation algorithm.

Genome scans of polymorphisms promise to provide insights into the patterns and frequencies of positive selection under natural conditions. The use of microsatellites as markers has the potential to focus on very recent events, since in contrast to SNPs, their high mutation rates should remove signatures of older events. We assess this concept here in a large-scale study. We have analyzed two population pairs of the house mouse, one pair of the subspecies Mus musculus domesticus and the other of M. m. musculus. A total of 915 microsatellite loci chosen to cover the whole genome were assessed in a prescreening procedure, followed by individual typing of candidate loci. Schlötterer's ratio statistics (lnRH) were applied to detect loci with significant deviations from patterns of neutral expectation. For eight loci from each population pair we have determined the size of the potential sweep window and applied a second statistical procedure (linked locus statistics). For the two population pairs, we find five and four significant sweep loci, respectively, with an average estimated window size of 120 kb. On the basis of the analysis of individual allele frequencies, it is possible to identify the most recent sweep, for which we estimate an onset of 400-600 years ago. Given the known population history for the French-German population pair, we infer that the average frequency of selective sweeps in these populations is higher than 1 in 100 generations across the whole genome. We discuss the implications for adaptation processes in natural populations.

The identification of genomic regions that have been exposed to positive selection is a major challenge in population genetics. Since selective sweeps are expected to occur during environmental changes or when populations are colonizing a new habitat, statistical tests constructed on the assumption of constant population size are biased by the co-occurrence of population size changes and selection. To delimit this problem and gain better insights into demographic factors, theoretical results regarding the second-order moments of segregating sites, such as the variance of segregating sites, have been derived. Driven by emerging genomewide surveys, which allow the estimation of demographic parameters, a generalized version of Tajima's D has been derived that takes into account a previously estimated demographic scenario to test single loci for traces of selection against the null hypothesis of neutral evolution under variable population size.