The process of antigenic variation in parasitic African trypanosomes is a remarkable mechanism for outwitting the immune system of the mammalian host, but it requires a delicate balancing act for the monoallelic expression, folding and transport of a single variant surface glycoprotein (VSG). Only one of hundreds of VSG genes is expressed at time, and this from just one of ≈15 dedicated expression sites. By switching expression of VSGs the parasite presents a continuously shifting antigenic facade leading (...) to prolonged chronic infections lasting months to years. The basics of VSG structure and switching have been known for several decades, but recent studies have brought higher resolution to many aspects this process. New VSG structures, in silico modeling of infections, studies of VSG codon usage, and experimental ablation of VSG expression provide insights that inform how this remarkable system may have evolved. (shrink)

Among pathogenic micro‐organisms that evade the mammalian immune responses, Trypanosoma brucei has developed the most elaborate capacity for antigenic variation. Trypanosomes branched early during eukaryotic evolution. They are characterized by many aberrations, ranging from the unusual compartmentation of metabolic pathways to the heresy of RNA editing. The ubiquitous phenomenon of glycosylphosphatidylinositol‐anchoring of eukaryotic plasma membrane proteins and RNA trans‐splicing (trypanosome genes contain no introns), which adds an identical leader sequence to all trypanosome mRNAs, were first defined during studies (...) of antigenic variation. Genetic transformation of trypanosomes and the high efficiency of gene targeting provide new opportunities to investigate the regulation of antigenic variation. There is every reason to expect trypanosomes to provide further surprises and insights into the evolution of genetic regulatory mechanisms. (shrink)

African trypanosomes, which cause sleeping sickness in man and other mammals, are able to evade immune destruction in their hosts by altering the expression of a major cell surface molecule, the variant surface glycoprotein (VSG). The VSGs are encoded by a multigene family, and antigenic variation occurs when the trypanosome switches from expression of one VSG gene to another. This switching process involves changes in the arrangement of the trypanosome genomic DNA.

Neisseria gonorrhoeae, the bacterium that causes the sexually transmitted disease gonorrhea, demonstrates extensive antigenic heterogeneity in its surface components. The organism has the capacity to switch on and off the synthesis of different versions of components such as pili, outer membrane proteins, and lipopolysaccharide. Recent studies have shown that the gonococcus uses novel and complex mechanisms, of types not described previously, to store different versions of genetic information for surface proteins, and to regulate expression of those genes.

The ABO histo‐blood group, first discovered over a century ago, is found not only in humans but also in many other primate species, with the same genetic variants maintained for at least 20 million years. Polymorphisms in ABO have been associated with susceptibility to a large number of human diseases, from gastric cancers to immune or artery diseases, but the adaptive phenotypes to which the polymorphism contributes remain unclear. We suggest that variation in ABO has been maintained by frequency‐dependent (...) or fluctuating selection pressures, potentially arising from co‐evolution with gut pathogens. We further hypothesize that the histo‐blood group labels A, B, AB, and O do not offer a full description of variants maintained by natural selection, implying that there are unrecognized, functionally important, antigens beyond the ABO group in humans and other primates. (shrink)

Hemagglutinin is a major virulence factor of influenza viruses and plays an important role in viral pathogenesis. Analysis of amino acid changes, epitopes’ regions, glycosylation and phosphorylation sites have greatly contributed to the development of new generations of vaccine. The hemagglutinins of 10 selected isolates, 8 of 2010 and 2 of 2013 samples were sequenced and analyzed by several bioinformatic softwares and the results were compared with those of 3 vaccine isolates. The study detected several amino acid changes related to (...) altered epitopes’ sites, modification sites and physico-chemical properties. The results showed some conserved modification sites in HA structure. This study is the first analytical research on isolates obtained from Shiraz, Iran, and our results can be used to better understand the genetic diversity and antigenic variations in Iranian and Asian H1N1 pathogenic strains. (shrink)

Trypanosoma brucei is the causal agent of African Trypanosomiasis in humans and other animals. It maintains a long‐term infection through an antigenic variation based population survival strategy. To proliferate in a mammal, T. brucei acquires iron and haem through the receptor mediated uptake of host transferrin and haptoglobin‐hemoglobin respectively. The receptors are exposed to host antibodies but this does not lead to clearance of the infection. Here we discuss how the trypanosome avoids this fate in the context of (...) recent findings on the structure and cell biology of the receptors. (shrink)

The public health benefits of herd immunity are often used as the justification for coercive vaccine policies. Yet, ‘herd immunity’ as a term has multiple referents, which can result in ambiguity, including regarding its role in ethical arguments. The term ‘herd immunity’ can refer to (1) the herd immunity threshold, at which models predict the decline of an epidemic; (2) the percentage of a population with immunity, whether it exceeds a given threshold or not; and/or (3) the indirect benefit afforded (...) by collective immunity to those who are less immune. Moreover, the accumulation of immune individuals in a population can lead to two different outcomes: elimination (for measles, smallpox, etc) or endemic equilibrium (for COVID-19, influenza, etc). We argue that the strength of a moral obligation for individuals to contribute to herd immunity through vaccination, and by extension the acceptability of coercion, will depend on how ‘herd immunity’ is interpreted as well as facts about a given disease or vaccine. Among other things, not all uses of ‘herd immunity’ are equally valid for all pathogens. The optimal conditions for herd immunity threshold effects, as illustrated by measles, notably do not apply to the many pathogens for which reinfections are ubiquitous (due to waning immunity and/or antigenic variation). For such pathogens, including SARS-CoV-2, mass vaccination can only be expected to delay rather than prevent new infections, in which case the obligation to contribute to herd immunity is much weaker, and coercive policies less justifiable. (shrink)

Authors frequently refer to gene-based selection in biological evolution, the reaction of the immune system to antigens, and operant learning as exemplifying selection processes in the same sense of this term. However, as obvious as this claim may seem on the surface, setting out an account of “selection” that is general enough to incorporate all three of these processes without becoming so general as to be vacuous is far from easy. In this target article, we set out such a general (...) account of selection to see how well it accommodates these very different sorts of selection. The three fundamental elements of this account are replication, variation, and environmental interaction. For selection to occur, these three processes must be related in a very specific way. In particular, replication must alternate with environmental interaction so that any changes that occur in replication are passed on differentially because of environmental interaction. One of the main differences among the three sorts of selection that we investigate concerns the role of organisms. In traditional biological evolution, organisms play a central role with respect to environmental interaction. Although environmental interaction can occur at other levels of the organizational hierarchy, organisms are the primary focus of environmental interaction. In the functioning of the immune system, organisms function as containers. The interactions that result in selection of antibodies during a lifetime are between entities (antibodies and antigens) contained within the organism. Resulting changes in the immune system of one organism are not passed on to later organisms. Nor are changes in operant behavior resulting from behavioral selection passed on to later organisms. But operant behavior is not contained in the organism because most of the interactions that lead to differential replication include parts of the world outside the organism. Changes in the organism's nervous system are the effects of those interactions. The role of genes also varies in these three systems. Biological evolution is gene-based (i.e., genes are the primary replicators). Genes play very different roles in operant behavior and the immune system. However, in all three systems, iteration is central. All three selection processes are also incredibly wasteful and inefficient. They can generate complexity and novelty primarily because they are so wasteful and inefficient. Key Words: evolution; immunology; interaction; operant behavior; operant learning; replication; selection; variation. (shrink)

Somatic diversification of antigen receptor genes depends on the activity of enzymes whose homologs participate in a mutagenic DNA repair in unicellular species. Indeed, by engaging error-prone polymerases, gap filling molecules and altered mismatch repair pathways, lymphocytes utilize conserved components of genomic stress response systems, which can already be found in bacteria and archaea. These ancient systems of mutagenesis and repair act to increase phenotypic diversity of microbial cell populations and operate to enhance their ability to produce fit variants during (...) stress. Coopted by lymphocytes, the ancient mutagenic processing systems retained their diversification functions instilling the adaptive immune cells with enhanced evolvability and defensive capacity to resist infection and damage. As reviewed here, the ubiquity and conserved character of specialized variation-generating mechanisms from bacteria to lymphocytes highlight the importance of these mechanisms for evolution of life in general. (shrink)

For a long time, several natural phenomena have been considered unproblematically selection processes in the same sense of “selection.” In our target article we dealt with three of these phenomena: gene-based selection in biological evolution, the reaction of the immune system to antigens, and operant learning. We characterize selection in terms of three processes (variation, replication, and environmental interaction) resulting in the evolution of lineages via differential replication. Our commentators were largely supportive with respect to variation and environmental (...) interaction but critical with respect to replication, in particular its appeal to information. With some reservations, our commentators think that our general analysis of selection may fit gene-based selection in biological evolution and the reaction of the immune system but not operant learning. If nothing else, this article shows that the notion of selection is not as straightforward as it may seem. (shrink)

We analyse the effect of the regulatory T cells (Tregs) in the local control of the immune responses by T cells. We obtain an explicit formula for the level of antigenic stimulation of T cells as a function of the concentration of T cells and the parameters of the model. The relation between the concentration of the T cells and the antigenic stimulation of T cells is an hysteresis, that is unfold for some parameter values. We study the (...) appearance of autoimmunity from cross-reactivity between a pathogen and a self antigen or from bystander proliferation. We also study an asymmetry in the death rates. With this asymmetry we show that the antigenic stimulation of the Tregs is able to control locally the population size of Tregs. Other effects of this asymmetry are a faster immune response and an improvement in the simulations of the bystander proliferation. The rate of variation of the levels of antigenic stimulation determines if the outcome is an immune response or if Tregs are able to maintain control due to the presence of a transcritical bifurcation for some tuning between the antigenic stimuli of T cells and Tregs. This behavior is explained by the presence of a transcritical bifurcation. (shrink)

Significant associations have been found between specific human leukocyte antigen (HLA) alleles and organ transplant rejection, autoimmune disease development, and the response to infection. Traditional searches for disease associations have conventionally measured risk associated with the presence of individual HLA alleles. However, given the high level of HLA polymorphism, the pattern of amino acid variability, and the fact that most of the HLA variation occurs at functionally important sites, it may be that a combination of variable amino acid sites (...) shared by several alleles (shared epitopes) are better descriptors of the actual causative genetic variants. Here we describe a novel approach to genetic association analysis in which genes/proteins are broken down into smaller sequence features and then variant types defined for each feature, allowing for independent analysis of disease association with each sequence feature variant type. We have used this approach to analyze a cohort of systemic sclerosis patients and show that a sequence feature composed of specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk for systemic sclerosis. (shrink)

Vaccines represent preventative interventions amenable to immunogenetic prediction of how human variability will influence their safety and efficacy. The genetic polymorphism among individuals within any population can render possible that the immunity elicited by a vaccine is variable in length and strength. The same immune challenge (virus and/or vaccine) could provoke partial, complete or even failed protection for some individuals treated under the same conditions. We review genetic variants and mechanistic relationships among chemokines, chemokine receptors, interleukins, interferons, interferon receptors, toll‐like (...) receptors, histocompatibility antigens, various immunoglobulins and major histocompatibility complex antigens. These are the targets for variation among macrophages, dendritic cells, natural killer cells, T‐ and B‐lymphocytes, and complement. The technology platforms (mRNA, viral vectors, proteins) utilized to produce vaccines against SARS‐CoV‐2 infections may each trigger genetically distinct immune reactogenic profiles. With DNA biobanking and immunoprofiling of recipients, global COVID‐19 vaccinations could launch a new era of personalized healthcare. (shrink)

If selection is interpreted as involving repeated cycles of replication, variation, and environmental interaction so structured that environmental interaction causes replication to be differential, then selection in gene-based biological evolution and the reaction of the immune system to antigens are relatively unproblematic examples of selection processes. Operant learning and cultural evolution pose more serious problems. In this response we deal with operant learning as a selection process. Footnotes1 The authors regretfully inform readers that since the publication of our target (...) article in 2001, one of our coauthors, Rod Langman, has died. (shrink)

In reviewing 50 years of personal research on influenza, I have journeyed, literally and figuratively, from an army camp epidemic in Fort Monmouth NJ in 1947 to a (literal and figurative) Valhalla, where I now conduct my research. Having entered the field as a physician, I have always sought practical applications of my work, yet in every instance, such applications have led me to seek further answers in basic research as new questions arose. I entered the area of influenza virus (...) genetics by the back door through an interest in the effects of corticosteroid hormones on viral replication, used the genetic approach in analyzing the morphological variation of the virus and, in so doing, exploited the finding of a linkage of high‐yield growth to spherical morphology. Today, all influenza vaccine viruses are high‐yield genetic reassortants. Subsequent study of reassortant viruses facilitated the identification and isolation of the two major antigens of the virus in antigenic hybrids and showed their differing functions in the induction of immunity. In turn, a new approach to influenza vaccination has been discovered and is presently under clinical investigation. (shrink)

Research on moral psychology has frequently appealed to three, apparently consistent patterns: Males are more likely to engage in transgressions involving harm than females; educated people are likely to be more thorough in their moral deliberations because they have better resources for rationally navigating and evaluating complex information; political affiliations and religious ideologies are an important source of our moral principles. Here, we provide a test of how four factors ‐ gender, education, politics and religion ‐ affect intuitive moral judgments (...) in unfamiliar situations. Using a large-scale sample of participants who voluntarily logged on to the internet-based Moral Sense Test, we analyzed responses to 145 unique moral and conventional scenarios that varied widely in content. Although each demographic or cultural factor sometimes yielded a statistically significant difference in the predicted direction, these differences were consistently associated with extremely small effect sizes. We conclude that gender, education, politics and religion are likely to be relatively insignificant for moral judgments of unfamiliar scenarios. We discuss these results in light of current debates concerning the mechanisms underlying our moral judgments and, especially, the idea that we share a universal moral sense that constrains the range of cross-cultural variation. (shrink)

In general, a given object could have been different in certain respects. For example, the Great Pyramid could have been somewhat shorter or taller; the Mona Lisa could have had a somewhat different pattern of colours; an ordinary table could have been made of a somewhat different quantity of wood. But there seem to be limits. It would be odd to suppose that the Great Pyramid could have been thimble-sized; that the Mona Lisa could have had the pattern of colours (...) that actually characterizes The Scream; or that the table could have been made of the very quantity of wood that in fact made some other table. However, there are puzzling arguments that purport to show that so long as an object is capable of being somewhat different in some respect, it is capable of being radically different in that respect. These arguments rely on two tempting thoughts: first, that an object’s capacity for moderate variation is a non-contingent matter, and second, that what is possibly possible is simply possible. This book systematically investigates competing strategies for resolving these puzzles, and defends one of them. Along the way it engages with foundational questions about the metaphysics of modality. (shrink)

Biologists seems to hold two fundamental beliefs: Organisms are organized into levels and the individuals at these levels differ in their properties. Together these suggest that there will be massive multiple realization, i.e. that many human psychological properties are multiply realized at many neurobiological levels. This paper provides some documentation in support of this suggestion.

Navigation ability varies widely across humans. Prior studies have reported that being younger and a male has an advantage for navigation ability. However, these studies have generally involved small numbers of participants from a handful of western countries. Here, we review findings from our project Sea Hero Quest, which used a video game for mobile and tablet devices to test 3.9 million people on their navigation ability, sampling across every nation-state and from 18 to 99 years of age. Results revealed (...) that the task has good ecological validity and across all countries sufficiently sampled (N = 63), age is linked to a near-linear decline in navigation ability from the early 20s. All countries showed a male advantage, but this varied considerably and could be partly predicted by gender inequality. We found that those who reported growing up in a city were on average worse at navigating than those who grew up outside cities and that navigation performance helped identify those at greater genetic risk of Alzheimer's disease. We discuss the advantages and challenges of using a mobile app to study cognition and the future avenues for understanding individual differences in navigation ability arising from this research. (shrink)

The propensity interpretation of fitness draws on the propensity interpretation of probability, but advocates of the former have not attended sufficiently to problems with the latter. The causal power of C to bring about E is not well-represented by the conditional probability Pr. Since the viability fitness of trait T is the conditional probability Pr, the viability fitness of the trait does not represent the degree to which having the trait causally promotes surviving. The same point holds for fertility fitness. (...) This failure of trait fitness to capture causal role can also be seen in the fact that coextensive traits must have the same fitness values even if one of them promotes survival and the other is neutral or deleterious. Although the fitness of a trait does not represent the trait’s causal power to promote survival and reproduction, variation in fitness in a population causally promotes change in trait frequencies; in this sense, fitness variation is a population-level propensity. (shrink)

The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co-transcriptional and co-translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the biogenesis (...) of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates. These small RNAs can then target the genomic regions from which they initially originate and increase the local mutation rate of the targeted loci. This mechanism is based on molecular pathways involved in anti-parasite genome defence systems, and implies that gene expression-related biophysical constraints represent a driving force of genome evolution. Are randomly generated mutations the only source of genetic variation during evolution? This paper describes the molecular mechanisms by which co-transcriptional and co-translational biophysical constraints trigger genetic variations in targeted-genomic sequences in an RNA-depending manner. This directed-mutational process that drives genome evolution is related to antiparasite genome defence systems. (shrink)

Recent advances in machine learning methods have created opportunities to eliminate unfairness from algorithmic decision making. Multiple computational techniques (i.e., algorithmic fairness criteria) have arisen out of this work. Yet, urgent questions remain about the perceived fairness of these criteria and in which situations organizations should use them. In this paper, we seek to gain insight into these questions by exploring fairness perceptions of five algorithmic criteria. We focus on two key dimensions of fairness evaluations: distributive fairness and procedural fairness. (...) We shed light on variation in the potential for different algorithmic criteria to facilitate distributive fairness. Subsequently, we discuss procedural fairness and provide a framework for understanding how algorithmic criteria relate to essential aspects of this construct, which helps to identify when a specific criterion is suitable. From a practical standpoint, we encourage organizations to recognize that managing fairness in machine learning systems is complex, and that adopting a blind or one-size-fits-all mentality toward algorithmic criteria will surely damage people’s attitudes and trust in automated technology. Instead, firms should carefully consider the subtle yet significant differences between these technical solutions. (shrink)

Individual differences in performance on a variety of selection tasks were examined in three studies employing over 800 participants. Nondeontic tasks were solved disproportionately by individuals of higher cognitive ability. In contrast, responses on two deontic tasks that have shown robust performance facilitationthe Drinking-age Problem and the Sears Problem-were unrelated to cognitive ability. Performance on deontic and nondeontic tasks was consistently associated. Individuals in the correct/correct cell of the bivariate performance matrix were over-represented. That is, individuals giving the modal response (...) on a nondeontic task (P and Q) were significantly less likely to give the modal response on a deontic task (P and not-Q) than were individuals who made the non-modal P and not-Q selection on nondeontic problems. The implications of the results are discussed within the heuristic-analytic framework of Evans (1996; Evans & Over, 1996) and the optimal data selection model of Oaksford and Chater (1994). (shrink)

In their landmark 2010 paper, “The weirdest people in the world?”, Henrich, Heine, and Norenzayan outlined a serious methodological problem for the psychological and behavioural sciences. Most of the studies produced in the field use people from Western, Educated, Industrialised, Rich and Democratic (WEIRD) societies, yet inferences are often drawn to the species as a whole. In drawing such inferences, researchers implicitly assume that either there is little variation across human populations, or that WEIRD populations are generally representative of (...) the species. Yet neither of these assumptions is justified. In many psychological and behavioural domains, cultural variation begets cognitive variation, and WEIRD samples are recurrently shown to be outliers. In the years since the article was published, attention has focused on the implications this has for research on extant human populations. Here we extend those implications to the study of ancient _H. sapiens_, their hominin forebears, and cousin lineages. We assess a range of characteristic arguments and key studies in the cognitive archaeology literature, identifying issues stemming from the problem of sample diversity. We then look at how worrying the problem is, and consider some conditions under which inferences to ancient populations via cognitive models might be provisionally justified. (shrink)

This paper emphasizes the crucial role of variation, at several different levels, for a detailed historical understanding of the development of the biomedical sciences. Going beyond valuable recent studies that focus on model organisms, experimental systems and instruments, we argue that all of these categories can be accommodated within our approach, which pays special attention to organismal and cultural variation. Our empirical examples are drawn in particular from recent historical studies of nineteenth- and early twentieth-century genetics and physiology. (...) Based on the quasi-paradoxical conclusion that biological and cultural variation both constrains and enables innovation in the biomedical sciences, we argue that more attention should be paid to variation as an analytical category in the historiography of the life sciences. (shrink)

The executive hypothesis of self-regulation places cognitive information processing at the center of self-regulatory success/failure. While the hypothesis is well supported by cross-sectional studies, no study has tested its primary prediction, that temporary lapses in executive control underlie moments of self-regulatory failure. Here, we conducted a naturalistic experiment investigating whether short-term variation in executive control is associated with momentary self-regulatory outcomes, indicated by negative affect reactivity to everyday stressors. We assessed working memory capacity (WMC) through ultra-brief, ambulatory assessments on (...) smart phones five times per day in a 7-day ecological momentary assessment (EMA) study involving college-aged adults. We found that participants exhibited more negative affect reactivity to stressor exposures during moments when they exhibited lower than usual WMC. Contrary to previous findings, we found no between-person association between WMC and average stress reactivity. We interpret these findings as reflecting the role of executive control in determining one’s effective capacity to self-regulate. (shrink)

Religion emerged among early humans because both purposive and non-purposive explanations were being employed but understanding was lacking of their precise scope and limits. Given also a context of very limited human power, the resultant foregrounding of agency and purposive explanation expressed itself in religion’s marked tendency towards anthropomorphism and its key role in legitimizing behaviour. The inevitability of death also structures the religious outlook; with ancestors sometimes assigned a role in relation to the living. Subjective elements such as the (...) experience of dreams and the internalization of moral precepts also play their part. Two important sources of variation among religions concern the adoption of a dualist or non-dualist perspective, and whether or not the religion’s early political experience is such as to generate a systematic doctrine subordinating politics to religion. The near ubiquity and endurance of religion are further illuminated by analysis of its functions and ideological role. Religion tends to be socially conservative but has the potential to be revolutionary. (shrink)

The sound system of a language must be able to support a perceptual contrast between different words in order to signal communicatively relevant meaning distinctions. In this paper, we use a simple agent-based exemplar model in which the evolution of sound-category systems is understood as a co-evolutionary process, where the range of variation within sound categories is constrained by functional pressure to keep different words perceptually distinct. We show that this model can reproduce several observed effects on the range (...) of sound variation. We argue that phonological systems can be seen as finding a relative optimum of variation: Efficient communication is sustained while at the same time, hidden category variation provides pathways for future evolution. (shrink)

This is my response as key discussant to papers presented at the workshop on Polarity at this year’s LSA meeting in Anaheim, CA.

Hierbei beruhrt Husserl auch Themen, welche die Grenzen der Methode aufzeigen, z.B. die eidetische Variation meines eigenen Charakters.

Abstract: Chomsky (1986) has claimed that the prima facie incompatibility between descriptive linguistics and semantic externalism proves that an externalist semantics is impossible. Although it is true that a strong form of externalism does not cohere with descriptive linguistics, sociolinguistic theory can unify the two approaches. The resulting two-level theory reconciles descriptivism, mentalism, and externalism by construing community languages as a function of social identification. This approach allows a fresh look at names and definite descriptions while also responding to Chomsky's (...) (1993, 1995) challenge to articulate an externalist theory of meaning that can be used in the scientific investigation of language. (shrink)

I describe a new, comparative, version of the argument from interpersonal variation to subjectivism about color. The comparative version undermines a recent objectivist response to standard versions of that argument (Gómez-Torrente 2014).

People may exhibit two kinds of modifications when demonstrating action for others: modifications to facilitate bottom‐up, or sensory‐based processing; and modifications to facilitate top‐down, or knowledge‐based processing. The current study examined actors' production of such modifications in action demonstrations for audiences that differed in their capacity for intentional reasoning. Actors' demonstrations of complex actions for a non‐anthropomorphic computer system and for people (adult and toddler) were compared. Evidence was found for greater highlighting of top‐down modifications in the demonstrations for the (...) human audiences versus the computer audience. Conversely, participants highlighted simple perceptual modifications for the computer audience, producing more punctuated and wider ranging motions. This study suggests that people consider differences in their audiences when demonstrating action. (shrink)