In 2007, David S. Wilson and Edward O. Wilson (27) pointed out that, Richard Dawkins had admitted that, contrary to what he had claimed in his book The Selfish Gene (1976) (7), the idea that only the gene is a fundamental unit of selection cannot be used as an argument against the notion of group selection. This elicited a sharp denial from Dawkins (30), which was followed by an explanatory reply by Wilson and Wilson (33) and another vehement denial by Dawkins (34). I analyse the prehistory of this surprisingly complex and convoluted dispute and subsequently disentangle it. My conclusion is that much of it is based on a series of misunderstandings. First, Wilson's and Wilson's (27) original interpretation of Dawkins' selfish gene argument was incorrect. Second, in their explanatory reply (33), they distinguished between two kinds of group selection: the idea that groups can be units of selection (theoretical group selection) and the idea that group selection plays a functional role in evolution (functional group selection). They clarified that their claim concerned theoretical group selection, not functional group selection. Third, that clarified claim was correct and not correct. It was incorrect because Dawkins has never explicitly acknowledged that he had erred by developing his selfish gene theory as an implicit argument against this kind of group selection. However, the distinction that he made, by 1978, between two kinds of unit of selection, replicators (genes) and vehicles (somas), does imply such an acknowledgment since it holds that groups can be units of selection (vehicles). In this important sense, Wilson's and Wilson's clarified claim (33) was correct. Fourth, Dawkins' second denial (34) concerned functional group selection, not theoretical group selection.

Based on the Recognition Concept of species, the specific-mate contact model posits that mating systems develop as combinations of two fundamental courtship strategies that we interpret here in terms of behavioural heterochrony: territorial mate-attraction evolved as an effect of peramorphosis whereas group-living mate-seeking evolved as an effect of paedomorphosis. We tested this hypothesis on primates in a phylogenetic and paleo-climatic context. Our results suggest that primate promiscuity (both males and females are mate-seekers) evolved with group-living from ancestral pair-living monogamy (both males and females are mate-attractors) in the Palaeogene, as the result of a slowdown in growth (neoteny) caused by increased environmental predictability. A secondary return to territorial monogamy probably evolved as the result of accelerated growth driven by seasonality (acceleration). Polygamy evolved in the Neogene during periods of forest fragmentation and environmental unpredictability. Small monogamous ancestors evolved seasonal polyandry (female attraction) as an effect of truncated development (progenesis). Large promiscuous, neotenic ancestors evolved non-seasonal polygyny (male attraction) as an effect of prolonged development (hypermorphosis) in males. We conclude that social heterochrony offers alternative explanations for the coevolution of life history and mating be-haviour; and we discuss the implications of our model for human social evolution.

Since the ENCODE project published its final results in a series of articles in 2012, there is no consensus on what its implications are. ENCODE's central and most controversial claim was that there is essentially no junk DNA: most sections of the human genome believed to be «junk» are functional. This claim was met with many reservations. If researchers disagree about whether there is junk DNA, they have first to agree on a concept of function and how function, given a particular definition, can be discovered. The ENCODE debate centered on a notion of function that assumes a strong dichotomy between evolutionary and non-evolutionary function and causes, prevalent in the Modern Evolutionary Synthesis. In contrast to how the debate is typically portrayed, both sides share a commitment to this distinction. This distinction is, however, much debated in alternative approaches to evolutionary theory, such as the EES. We show that because the ENCODE debate is grounded in a particular notion of function, it is unclear how it connects to broader debates about what is the correct evolutionary framework. Furthermore, we show how arguments brought forward in the controversy, particularly arguments from mathematical population genetics, are deeply embedded in their particular disciplinary contexts, and reflect substantive assumptions about the evolution of genomes. With this article, we aim to provide an anatomy of the ENCODE debate that offers a new perspective on the notions of function both sides employed, as well as to situate the ENCODE debate within wider debates regarding the forces operating in evolution.

Although most discussions on the origin and evolution of insect wings and metamorphosis have assumed that the ancestors of winged insects were terrestrial, it now seems possible that they were actually aquatic. Changing the basic assumptions affects our interpretations of the origin of metamorphosis and our understanding of insect diversity. It is argued that the ancestors of winged insects were similar to primitive mayflies, developing from aquatic larvae into terrestrial adults, and that metamorphosis originated as an inevitable consequence of an amphibiotic life cycle. It is suggested that the first pupae resembled those of Megaloptera.

We may induce from a longue durée examination of Anglo-American History of Biology that the impulse to reject reduc - tionism persists and will continue to percolate cyclically. This impulse I deem "bioexceptionalism": an intuition, stance, attitude, or activating metaphor that the study of living beings requires explanations in addition to exclusively bottom-up causal explanations and the research programs constructed upon that bottom-up philosophical foundation by non-organismal biologists, biochemists, and biophysicists - the explanations, in other words, that Wadding - ton (1977) humorously termed the "Conventional Wisdom of the Dominant Group, or cowdung." Bioexceptionalism might indicate an ontological assertion, like vitalism. Yet most often in the last century, it has been defined by a variety of methodological or even sociological positions. On three occasions in the interval from the late nineteenth century to the present, a small but significant group of practicing biologists and allies in other research disciplines in the UK and US adopted a species of bioexceptionalism, rejecting the dominant explanatory philosophy of reductionistic mechanism. Yet they also rejected the vitalist alternative. We can refer to their subset of bioexceptionalism as a "Third-Way" approach, though participants at the time called it by a variety of names, including "organicism." Today's appeals to a Third-Way are but the latest eruption of this older dissensus and retain at least heuristic value apart from any explanatory success.

The idea of The Selfish Gene, first published in 1976, grew out of the Modern Synthesis of evolutionary biology formulated by Julian Huxley in 1942, and more specifically from George Williams' Adaptation and Natu - ral Selection in 1966. It presents a severely narrowed down version of Huxley's synthesis, which developed in the 1960s following the formulation of the Cen tral Dogma of molecular biology by Francis Crick. The idea rests on three assumptions: the isolation of the genome from any influences by the soma and its development in interaction with the environment (the Weis - mann Barrier), one-way causation from DNA to proteins (The Central Dogma), and the autoreplication of DNA (Schrödinger's aperiodic crystal). All three of these assumptions have now been shown to be incorrect. The 'replicator' (DNA) is not independent of the 'vehicle', the organism itself, so that The Selfish Gene can no longer be regarded as a valid scientific hypothesis.

The case has been made that the-gene-centric approach to biology, which has prevailed over the past ~100 years, should be replaced by a fundamental framework based on the cell being a far from equilibrium complex dissipative system, regulated and governed by its phenotype (1, 2), the metaphor for which is a brain. This independent attractor (IA) model is a radical departure from the conventional view based on Wilhelm Johannsen's genotype-conception which has prevailed since 1910. In this prevailing paradigm the gene and the genotype are fundamental in accounting for inheritance, evolution, development, and morphogenesis: the phenotype, upon which natural selection is deemed to act, plays little or no role in these crucial aspects of biology. Here I discuss how the process of evolution might be viewed under the IA model. Based on empirical evidence, evolution can be seen as a two-part process, one part based on thermodynamics and resulting in increased resilience to perturbation of the cellular phenotype (conditioning), and the other part, based on agency exhibited by the evolving organisms. A crucial open question is: should we view the realisation of the phenotype as a matter for biochemistry, or physics.

A major theoretical issue in evolutionary biology over the past two decades has concerned the rise of complexity over time in the natural world, and a search has been underway for "a Grand Unified Theory" - as biologist Daniel McShea characterized it - that is consistent with Darwin's great vision. As it happens, such a theory already exists. It was first proposed many years ago in The Synergism Hypothesis: A Theory of Progressive Evolution, and it involves an economic (or perhaps bioeconomic) theory of complexity. Simply stated, cooperative interactions of various kinds, however they may occur, can produce novel combined effects - synergies - with functional advantages that may, in turn, become direct causes of natural selection. In other words, the Synergism Hypothesis is a theory about the unique combined effects produced by the relationships between things. I refer to it as Holistic Darwinism; it is entirely con - sistent with natural selection theory, properly understood. Because the Synergism Hypothesis was first proposed during a time when the genecentric, neo-Darwinist paradigm was domi nant in evolutionary biology, it was largely overlooked. But times have changed. Biologist Richard Michod has concluded that "cooperation is now seen as the primary creative force behind ever greater levels of complexity and organization in all of biology." And Martin Nowak has called cooperation "the master architect of evolution." Here I will revisit this theory in the light of the many theoretical developments and research findings in recent years that are supportive of it, including the role of symbiogenesis in evolution, the phenomenon of hybridization, lateral gene transfer in prokaryotes, "developmental plasticity" (evo-devo), epigenetic inheritance, the role of behaviour (and teleonomy) in evolution, and gene-culture coevolution. The Synergism Hypothesis is especially relevant to the evolution of humankind.

It is logical to define "Life" prior to uncovering the mechanisms that allow changes, e.g. short (development) and long (evolution). In retrospect, however, the opposite happened. Darwin, Wallace, Lamarck, and other pioneers who lived when modern science was in its infancy, formulated their ideas on evolution asking "how new species come into existence", and not "How does 'Life' evolve?". It led to revolutionary concepts of Common Descent and Natural Selection. It took until the advent of communication sciences in the 20th century that the computer/ digital vocabulary was gradually embraced by many disciplines, as well as in daily language. Concurrently, substantial progress was also realized in the majority of the exact sciences and in the humanities. Therefore the question - asked in 2014 - whether the classical neo-Darwinism-based evolutionary theory needs a rethink was then justified and appropriate (too early for some, too late for others). This paper, summarizes the gradual development of my ideas why a switch in paradigm, from "The cell is the basic building block structure and function of all living compartments" to "a sender-receiver alternative" offers a novel and better perspective. Indeed, it introduces a new communicationbased potent concept and approach for analyzing various as yet undervalued aspects in the evolution of "Life". Of particular importance is the view that any act of communication is a problem-solving act because all messages are coded and need to be decoded before they can yield a response.

The theory of organic evolution is incomplete until it can explain life's meaningmaking capacity and its role in the evolutionary processes, i.e. until semiosis is included. The extended synthesis theory of evolution has made a decisive step towards such an integrative theory, yet the explicit inclusion of semiotics of life is still to come. Here, we describe the steps made towards the semiotics-based theory of evolution, as the next stage after evo-devo and eco-evo-devo approaches. This includes demonstration of independent roles that natural selection, plastic adjustment, and interpretative choice have in adaptive evolution, and the distinction between adaptive and neutral modifications in genetic, plastic and interpretative mechanisms. Real meaning-making takes place only due to organism's interpretative processes. It should be complemented with a description of the ways by which knowledge (defined as products of semiotic learning), or rather the constraints of semiosis, can be inherited. This will complete the inclusion of semiosis into the extended mechanism of evolution.

An enduring problem concerning the evolution of RNA viruses stems from the fact that their long-term rates of evolution (substitutions/ site/year) are lower than those calculated by comparing sequences of isolates collected over short time periods or within a single host (shortterm or intra-host evolution). This inconsistency has been attributed to several reasons, including deviations from the assumption of a molecularclock (constancy of mutational inputs as a function of time) and variations in viral multiplication rates, among others. We previously proposed a non-phylogenetic method for extracting information contained in mRNAs, that cannot be identified from examination of primary sequences alone, and that we called «archaeological» information. In this new approach, mRNAs are of interest as molecules, not for their primary sequence or encoded proteins but for encrypted information established in a remote past. In the present article, we propose that an archaeological approach may also contribute to explain higher short-term than long-term evolution rates in RNA viruses, in this case, by using the archaeological concept of palimpsest. The palimpsest is a record of historical changes, but it is not a successively ordered or a complete record, rather it is the product of two opposing activities, one of writing and rewriting and the other of erasing. In RNA virus quasispecies, the gain or loss of mutations is reflected in changes in the submolar frequency of myriads of variants in the population. The fact that mutation elimination is not always complete, turns viral quasispecies into complex palimpsests of viral variants or sub-populations thereof. Here we relate two main different temporalities of the quasispecies palimpsest (short- and long-term) to the stability of mutations in response to changes related to three components of the virus: the virions, the infected cell and the host cell lineage. Host cell lineage-related viral memory would be mostly irre versible as they are adaptive products to host cell changes. In contrast, memories related to the environment of the virion or responsive to the environment of the infected cell, which is shortterm mutational input, is less constrained provided the alteration in the ancestral information carried by the RNA is only transient. The two intermixed memory components result in two differently contributing mutation rates whose influence in the final result depends on whether the timescales used to take the sequences for comparison are short or long term.

Multilevel interpretations of development and evolution take to heart the contextual nature of both those processes, and so necessarily assume top-down causation occurs, right down to the physics level. In this article we revisit the Principle of Biological Relativity proposed by Noble in 2012, where all emergent levels of organisation are equally causally valid. While this is true in general for physical interactions between levels, we argue that in the case of conscious organisms making rational choices, there is indeed a preferred causal origin - namely the overall embracing influence of meaning and values. This is the opposite of what is suggested by a reductionist viewpoint, where it is the bottom-most physical level that is stated to be causally preferred (by some physicists), or the genetic level (by some evolutionary theorists). Charles Darwin was therefore correct to distinguish between Artificial (conscious) Selection, where values enter, and Natural Selection. The Modern Synthesis was wrong to exclude Darwin's distinction.

The Third Way of Evolution was founded in 2014 to make the public aware that contemporary evolution science is not limited to the neo-Darwinian Modern Synthesis of the past century. This was important to do because evolution was challenged as incapable of explaining biological complexity by the Intelligent Design movement. Expounding biological theories like the Modern Synthesis is always subject to limited empirical evidence, fundamental concepts that inevitably change over time, and conceptual preferences that often prove to be misleading. The Modern Synthesis was based on Darwin's preference for the phyletic gradualism necessary to elevate Natural Selection as the sole force determining the direction of evolutionary change. In contradiction to this principle, agricultural crop breeding, direct observation in nature, and genomics have shown that genome change following symbiogenetic cell fusions or interspecific hybridization, not selection, are empirically the most effective methods for originating novel life forms and new species. By asserting that the accumulation of random "slight" variations was the basic mode of both short-term and long-term evolutionary change, the Modern Synthesis also ignored the distinction between (1) microevolutionary change within species by localized mutations and (2) macroevolutionary origination of new species and taxa by genome restructuring. In so doing, the Modern Synthesis failed to recognize the evolutionary importance of cellular capacities to generate large-scale genome changes. By focusing on individual protein-coding genes as the fundamental units of genetic information, the Modern Synthesis did not successfully incorporate either the full non-coding informa tion content in genomes or the major evolutionary potential of mobile DNA elements to generate multisite intragenomic networks necessary for the development of complex organisms. When all of the phenomena overlooked by the Modern Synthesis are taken into consideration, it is not difficult to answer Intelligent Design arguments and show that science is making real progress in understanding the evolution of biological complexity.

While the modern synthesis has at its core the claim that evolution can be entirely explained by the natural selection of random variations, neither "random" nor "variation" is adequately defined. Neo-Darwinists explicitly deny that they use random with the meaning of haphazard, but it is what they assume in their work; if they did not, they could not justify their total concentration on selection and neglect of variations. They conflate variations in the genotype with those in the phenotype. This might be justifiable if the connection between the two were simple and straightforward, but it is not. Like Darwin, neo-Darwinists are committed to the belief that evolution is always gradual. Also like Darwin, they justify this on theoretical rather than empirical grounds and despite acknowledging that the evidence does not support them. The paradox could be resolved by relaxing the commitment to gradualism, but only at the cost of significant consequences for the paradigm.

For nearly a century the main focus in biological disciplines such as molecular biology, biochemistry, genetics and evolutionary theory was cellular life as a machine like process in which mechanistic pathways regulate metabolism, genetic reading and translation into proteins and evolution by variations (random error replications) and selection. Modern biochemistry started with the cellular theory of life. Also the modern synthesis focused on cells at the starting event of life. The dominance of this paradigm lasted until ten years ago. Then the comeback of virology offered new empirical data and explanatory models of how viruses determine cellular life through an abundance of parasite host interactions that overrule cellular processes. The RNA world hypothesis demonstrated that prior to cellular life RNA group interactions were at the beginning of biological selection before cellular life emerged. Last but not least the central dogma of molecular biology collapsed when epigenetics demonstrated that history and developmental experiences of the past can be epigenetically imprinted and serve as identity markings that in every replication process of any cell in any organism on this planet the timely and locally coordinated replication is regulated and orchestrated by these programmings. In the light of this knowledge a better explanatory model than an extension of the modern synthesis will be more successful in the 21st century.

Multiple technologies which measure the same omics data set but are based on different aspects of the molecules exist. In practice, studies use different technologies and have therefore different biomarkers. An example is the glycan age index, which is constructed by three different ultra-performance liquid chromatography (UPLC) IgG glycans, and is a biomarker for biological age. A second technology is liquid chromatography- mass spectrometry (LCMS). To estimate the effect of a biomarker on an outcome variable, two issues need to be addressed. Firstly, a measurement error is needed to map one technology to the other one using a calibration study. Here, we consider two approaches, namely one based on the chemical properties of the two technologies and one based on the estimation of this relationship using O2PLS. Secondly, the use of an approximation of the biomarker in the main study needs to be taken into account by use of a regression calibration method. The performance of the two approaches is studied via simulations. The methods are used to estimate the relationship between glycan age and menopause. We have data from two cohorts, namely Korcula and Vis. In conclusion, (1) both measurement error models give similar results and suggest that there is an association between the glycan age index and the menopause status, (2) the chemical mapping approach outperforms O2PLS in the low measurement error variance, while on the larger measurement error variance, O2PLS works better, (3) statistical efficiency is lost due to increased noise level by adding irrelevant information.

The use of statistical methods to predict outcomes using high dimensional datasets in medicine is becoming increasingly popular for forecasting and monitoring patient health. Our work is motivated by a longitudinal dataset containing 1H NMR spectra of metabolites of 18 patients undergoing a kidney transplant alongside their graft outcomes that fall into one of three categories: acute rejection, delayed graft function and primary function. We proposed a functional partial least squares (FPLS) model that extends existing PLS methods for the analysis of longitudinally measured scalar omics datasets to the case of longitudinally measured functional datasets. We designed an iterative algorithm to link multiple time points, and then applied our proposed method to analyse the data from kidney transplant patients. Finally, we compared the AUC of our method to the AUC of the univariate methods which only use the information of one time-point information. It appeared that our method outperforms the existing methods. A simulation study was performed to mimic the kidney transplant dataset but with a larger sample size and different scenarios performed to evaluate the performance of the new method in larger datasets. We consider scenarios which vary in the difficulty to distinguish the two groups. It appeared that the three time-points model performs better than any of the individual models with average AUCs of 0.909 and 0.811 respectively.

DNA methylation studies usually focus on the groups of CpG sites. Neighbouring CpG sites are analyzed together due to their group behaviour. However, this approach ignores the possible interaction between more distant CpG sites. In this work, we investigate the complete methylation correlation structure of chromosome 21. Two data sets were used for the correlation analysis, smaller data set with methylation measurements from Down syndrome patients and their family members and larger data set with healthy subjects. This allowed us to examine the general properties of the methylation correlation structure as well as its modifications in presence of an extra copy of the chromosome. We observed that the CpG sites work in small highly correlated groups. While some groups coincided with CpG islands, other groups contained CpG sites scattered across the whole chromosome. Groups of highly correlated CpG sites remained preserved in the case of Down syndrome. Moreover, the methylome of a Down syndrome patient had newly formed correlations between CpG sites suggesting that the methylation correlation structure in Down syndrome is stronger than in case of an unaffected individual.