Complex effects of sequence variants on lipid levels and coronary artery disease.

Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment.

Correlated Neural Activity and Encoding of Behavior across Brains of Socially Interacting Animals.

Social interactions involve complex decision-making tasks that are shaped by dynamic, mutual feedback between participants. An open question is whether and how emergent properties may arise across brains of socially interacting individuals to influence social decisions. By simultaneously performing microendoscopic calcium imaging in pairs of socially interacting mice, we find that animals exhibit interbrain correlations of neural activity in the prefrontal cortex that are dependent on ongoing social interaction. Activity synchrony arises from two neuronal populations that separately encode one's own behaviors and those of the social partner. Strikingly, interbrain correlations predict future social interactions as well as dominance relationships in a competitive context. Together, our study provides conclusive evidence for interbrain synchrony in rodents, uncovers how synchronization arises from activity at the single-cell level, and presents a role for interbrain neural activity coupling as a property of multi-animal systems in coordinating and sustaining social interactions between individuals.

Dominance and multi-locus interaction.

Dominance is usually considered a constant value that describes the relative difference in fitness or phenotype between heterozygotes and the average of homozygotes at a focal polymorphic locus. However, the observed dominance can vary with the genetic background of the focal locus. Here, alleles at other loci modify the observed phenotype through position effects or dominance modifiers that are sometimes associated with pathogen resistance, lineage, sex, or mating type. Theoretical models have illustrated how variable dominance appears in the context of multi-locus interaction (epistasis). Here, we review empirical evidence for variable dominance and how the observed patterns may be captured by proposed epistatic models. We highlight how integrating epistasis and dominance is crucial for comprehensively understanding adaptation and speciation.

Extraordinary preservation of gene collinearity over three hundred million years revealed in homosporous lycophytes.

Homosporous lycophytes (Lycopodiaceae) are a deeply diverged lineage in the plant tree of life, having split from heterosporous lycophytes (Selaginella and Isoetes) ~400 Mya. Compared to the heterosporous lineage, Lycopodiaceae has markedly larger genome sizes and remains the last major plant clade for which no chromosome-level assembly has been available. Here, we present chromosomal genome assemblies for two homosporous lycophyte species, the allotetraploid Huperzia asiatica and the diploid Diphasiastrum complanatum. Remarkably, despite that the two species diverged ~350 Mya, around 30% of the genes are still in syntenic blocks. Furthermore, both genomes had undergone independent whole genome duplications, and the resulting intragenomic syntenies have likewise been preserved relatively well. Such slow genome evolution over deep time is in stark contrast to heterosporous lycophytes and is correlated with a decelerated rate of nucleotide substitution. Together, the genomes of H. asiatica and D. complanatum not only fill a crucial gap in the plant genomic landscape but also highlight a potentially meaningful genomic contrast between homosporous and heterosporous species.

Fluctuating selection and the determinants of genetic variation.

Recent studies of cosmopolitan Drosophila populations have found hundreds to thousands of genetic loci with seasonally fluctuating allele frequencies, bringing temporally fluctuating selection to the forefront of the historical debate surrounding the maintenance of genetic variation in natural populations. Numerous mechanisms have been explored in this longstanding area of research, but these exciting empirical findings have prompted several recent theoretical and experimental studies that seek to better understand the drivers, dynamics, and genome-wide influence of fluctuating selection. In this review, we evaluate the latest evidence for multilocus fluctuating selection in Drosophila and other taxa, highlighting the role of potential genetic and ecological mechanisms in maintaining these loci and their impacts on neutral genetic variation.

Role of genetic architecture in phenotypic plasticity.

Phenotypic plasticity, the ability of an organism to display different phenotypes across environments, is widespread in nature. Plasticity aids survival in novel environments. Herein, we review studies from yeast that allow us to start uncovering the genetic architecture of phenotypic plasticity. Genetic variants and their interactions impact the phenotype in different environments, and distinct environments modulate the impact of genetic variants and their interactions on the phenotype. Because of this, certain hidden genetic variation is expressed in specific genetic and environmental backgrounds. A better understanding of the genetic mechanisms of phenotypic plasticity will help to determine short- and long-term responses to selection and how wide variation in disease manifestation occurs in human populations.

Neural Mechanisms of Social Cognition in Primates.

Activity in a network of areas spanning the superior temporal sulcus, dorsomedial frontal cortex, and anterior cingulate cortex is concerned with how nonhuman primates negotiate the social worlds in which they live. Central aspects of these circuits are retained in humans. Activity in these areas codes for primates' interactions with one another, their attempts to find out about one another, and their attempts to prevent others from finding out too much about themselves. Moreover, important features of the social world, such as dominance status, cooperation, and competition, modulate activity in these areas. We consider the degree to which activity in these regions is simply encoding an individual's own actions and choices or whether this activity is especially and specifically concerned with social cognition. Recent advances in comparative anatomy and computational modeling may help us to gain deeper insights into the nature and boundaries of primate social cognition.

polyGBLUP: a modified genomic best linear unbiased prediction improved the genomic prediction efficiency for autopolyploid species.

Given the universality of autopolyploid species in nature, it is crucial to develop genomic selection methods that consider different allele dosages for autopolyploid breeding. However, no method has been developed to deal with autopolyploid data regardless of the ploidy level. In this study, we developed a modified genomic best linear unbiased prediction (GBLUP) model (polyGBLUP) through constructing additive and dominant genomic relationship matrices based on different allele dosages. polyGBLUP could carry out genomic prediction for autopolyploid species regardless of the ploidy level. Through comprehensive simulations and analysis of real data of autotetraploid blueberry and guinea grass and autohexaploid sweet potato, the results showed that polyGBLUP achieved higher prediction accuracy than GBLUP and its superiority was more obvious when the ploidy level of autopolyploids is high. Furthermore, when the dominant effect was added to polyGBLUP (polyGDBLUP), the greater the dominance degree, the more obvious the advantages of polyGDBLUP over the diploid models in terms of prediction accuracy, bias, mean squared error and mean absolute error. For real data, the superiority of polyGBLUP over GBLUP appeared in blueberry and sweet potato populations and a part of the traits in guinea grass population due to the high correlation coefficients between diploid and polyploidy genomic relationship matrices. In addition, polyGDBLUP did not produce higher prediction accuracy than polyGBLUP for most traits of real data as dominant genetic variance was not captured for these traits. Our study will be a significant promising method for genomic prediction of autopolyploid species.

The lack of negative association between TE load and subgenome dominance in synthesized Brassica allotetraploids.

Polyploidization is important to the evolution of plants. Subgenome dominance is a distinct phenomenon associated with most allopolyploids. A gene on the dominant subgenome tends to express to higher RNA levels in all organs as compared to the expression of its syntenic paralogue (homoeolog). The mechanism that underlies the formation of subgenome dominance remains unknown, but there is evidence for the involvement of transposon/DNA methylation density differences nearby the genes of parents as being causal. The subgenome with lower density of transposon and methylation near genes is positively associated with subgenome dominance. Here, we generated eight generations of allotetraploid progenies from the merging of parental genomes Brassica rapa and Brassica oleracea. We found that transposon/methylation density differ near genes between the parental (rapa:oleracea) existed in the wide hybrid, persisted in the neotetraploids (the synthetic Brassica napus), but these neotetraploids expressed no expected subgenome dominance. This absence of B. rapa vs. B. oleracea subgenome dominance is particularly significant because, while there is no negative relationship between transposon/methylation level and subgenome dominance in the neotetraploids, the more ancient parental subgenomes for all Brassica did show differences in transposon/methylation densities near genes and did express, in the same samples of cells, biased gene expression diagnostic of subgenome dominance. We conclude that subgenome differences in methylated transposon near genes are not sufficient to initiate the biased gene expressions defining subgenome dominance. Our result was unexpected, and we suggest a "nuclear chimera" model to explain our data.

Experience-dependent functional plasticity and visual response selectivity of surviving subplate neurons in the mouse visual cortex.

Subplate neurons are early-born cortical neurons that transiently form neural circuits during perinatal development and guide cortical maturation. Thereafter, most subplate neurons undergo cell death, while some survive and renew their target areas for synaptic connections. However, the functional properties of the surviving subplate neurons remain largely unknown. This study aimed to characterize the visual responses and experience-dependent functional plasticity of layer 6b (L6b) neurons, the remnants of subplate neurons, in the primary visual cortex (V1). Two-photon Ca2+ imaging was performed in V1 of awake juvenile mice. L6b neurons showed broader tunings for orientation, direction, and spatial frequency than did layer 2/3 (L2/3) and L6a neurons. In addition, L6b neurons showed lower matching of preferred orientation between the left and right eyes compared with other layers. Post hoc 3D immunohistochemistry confirmed that the majority of recorded L6b neurons expressed connective tissue growth factor (CTGF), a subplate neuron marker. Moreover, chronic two-photon imaging showed that L6b neurons exhibited ocular dominance (OD) plasticity by monocular deprivation during critical periods. The OD shift to the open eye depended on the response strength to the stimulation of the eye to be deprived before starting monocular deprivation. There were no significant differences in visual response selectivity prior to monocular deprivation between the OD changed and unchanged neuron groups, suggesting that OD plasticity can occur in L6b neurons showing any response features. In conclusion, our results provide strong evidence that surviving subplate neurons exhibit sensory responses and experience-dependent plasticity at a relatively late stage of cortical development.

Cytonuclear Interactions and Subgenome Dominance Shape the Evolution of Organelle-Targeted Genes in the Brassica Triangle of U.

The interaction and coevolution between nuclear and cytoplasmic genomes are one of the fundamental hallmarks of eukaryotic genome evolution and, 2 billion yr later, are still major contributors to the formation of new species. Although many studies have investigated the role of cytonuclear interactions following allopolyploidization, the relative magnitude of the effect of subgenome dominance versus cytonuclear interaction on genome evolution remains unclear. The Brassica triangle of U features 3 diploid species that together have formed 3 separate allotetraploid species on similar evolutionary timescales, providing an ideal system for understanding the contribution of the cytoplasmic donor to hybrid polyploid. Here, we investigated the evolutionary pattern of organelle-targeted genes in Brassica carinata (BBCC) and 2 varieties of Brassica juncea (AABB) at the whole-genome level, with particular focus on cytonuclear enzyme complexes. We found partial evidence that plastid-targeted genes experience selection to match plastid genomes, but no obvious corresponding signal in mitochondria-targeted genes from these 2 separately formed allopolyploids. Interestingly, selection acting on plastid genomes always reduced the retention rate of plastid-targeted genes encoded by the B subgenome, regardless of whether the Brassica nigra (BB) subgenome was contributed by the paternal or maternal progenitor. More broadly, this study illustrates the distinct selective pressures experienced by plastid- and mitochondria-targeted genes, despite a shared pattern of inheritance and natural history. Our study also highlights an important role for subgenome dominance in allopolyploid genome evolution, even in genes whose function depends on separately inherited molecules.

Evolutionary Dynamics of Chromatin Structure and Duplicate Gene Expression in Diploid and Allopolyploid Cotton.

Polyploidy is a prominent mechanism of plant speciation and adaptation, yet the mechanistic understandings of duplicated gene regulation remain elusive. Chromatin structure dynamics are suggested to govern gene regulatory control. Here, we characterized genome-wide nucleosome organization and chromatin accessibility in allotetraploid cotton, Gossypium hirsutum (AADD, 2n = 4X = 52), relative to its two diploid parents (AA or DD genome) and their synthetic diploid hybrid (AD), using DNS-seq. The larger A-genome exhibited wider average nucleosome spacing in diploids, and this intergenomic difference diminished in the allopolyploid but not hybrid. Allopolyploidization also exhibited increased accessibility at promoters genome-wide and synchronized cis-regulatory motifs between subgenomes. A prominent cis-acting control was inferred for chromatin dynamics and demonstrated by transposable element removal from promoters. Linking accessibility to gene expression patterns, we found distinct regulatory effects for hybridization and later allopolyploid stages, including nuanced establishment of homoeolog expression bias and expression level dominance. Histone gene expression and nucleosome organization are coordinated through chromatin accessibility. Our study demonstrates the capability to track high-resolution chromatin structure dynamics and reveals their role in the evolution of cis-regulatory landscapes and duplicate gene expression in polyploids, illuminating regulatory ties to subgenomic asymmetry and dominance.

Biased retention of environment-responsive genes following genome fractionation.

The molecular underpinnings and consequences of cycles of whole-genome duplication (WGD) and subsequent gene loss through subgenome fractionation remain largely elusive. Endogenous drivers, such as transposable elements, have been postulated to shape genome-wide dominance and biased fractionation leading to a conserved least-fractionated (LF) and a degenerated most-fractionated (MF) subgenome. In contrast, the role of exogenous factors, such as those induced by environmental stresses, has been overlooked. A chromosome-scale assembly of the alpine Buckler Mustard (Biscutella laevigata; Brassicaceae) that underwent a WGD event about 11 million years ago is here coupled with transcriptional responses to heat, cold, drought and herbivory to assess how gene expression is associated with differential gene retention across the MF and LF subgenomes. Counteracting the impact of transposable elements in reducing the expression and retention of nearby genes across the MF subgenome, dosage balance is highlighted as a main endogenous promoter of the retention of duplicated gene products under purifying selection. Consistent with the "turn a hobby into a job" model, about one third of environment-responsive duplicates exhibit novel expression patterns, with one copy typically remaining conditionally-expressed, whereas the other copy has evolved constitutive expression, highlighting exogenous factors as a major driver of gene retention. Showing uneven patterns of fractionation, with regions remaining unbiased while others show high bias and significant enrichment in environment-responsive genes, this mesopolyploid genome presents evolutionary signatures consistent with an interplay of endogenous and exogenous factors having driven gene content following WGD-fractionation cycles.

Overcoming constraints on the detection of recessive selection in human genes from population frequency data.

The identification of genes that evolve under recessive natural selection is a long-standing goal of population genetics research that has important applications to the discovery of genes associated with disease. We found that commonly used methods to evaluate selective constraint at the gene level are highly sensitive to genes under heterozygous selection but ubiquitously fail to detect recessively evolving genes. Additionally, more sophisticated likelihood-based methods designed to detect recessivity similarly lack power for a human gene of realistic length from current population sample sizes. However, extensive simulations suggested that recessive genes may be detectable in aggregate. Here, we offer a method informed by population genetics simulations designed to detect recessive purifying selection in gene sets. Applying this to empirical gene sets produced significant enrichments for strong recessive selection in genes previously inferred to be under recessive selection in a consanguineous cohort and in genes involved in autosomal recessive monogenic disorders.

Atypical neural encoding of faces in individuals with autism spectrum disorder.

Individuals with autism spectrum disorder (ASD) experience pervasive difficulties in processing social information from faces. However, the behavioral and neural mechanisms underlying social trait judgments of faces in ASD remain largely unclear. Here, we comprehensively addressed this question by employing functional neuroimaging and parametrically generated faces that vary in facial trustworthiness and dominance. Behaviorally, participants with ASD exhibited reduced specificity but increased inter-rater variability in social trait judgments. Neurally, participants with ASD showed hypo-activation across broad face-processing areas. Multivariate analysis based on trial-by-trial face responses could discriminate participant groups in the majority of the face-processing areas. Encoding social traits in ASD engaged vastly different face-processing areas compared to controls, and encoding different social traits engaged different brain areas. Interestingly, the idiosyncratic brain areas encoding social traits in ASD were still flexible and context-dependent, similar to neurotypicals. Additionally, participants with ASD also showed an altered encoding of facial saliency features in the eyes and mouth. Together, our results provide a comprehensive understanding of the neural mechanisms underlying social trait judgments in ASD.

Dominant negative variants and cotranslational assembly of macromolecular complexes.

Pathogenic variants occurring in protein-coding regions underlie human genetic disease through various mechanisms. They can lead to a loss of function (LOF) such as in recessive conditions or in dominant conditions due to haploinsufficiency. Dominant-negative (DN) effects, counteracting the activity of the normal gene-product, and gain of function (GOF) are also mechanisms driving dominance. Here, I discuss a few papers on these specific mechanisms. In short, there is accumulating evidence pointing to differences between LOF versus non-LOF variants (DN and GOF). The latter are thought to have milder effects on protein structure and, as expected, DN variants are enriched at protein interfaces. This tendency to cluster in 3D space can help improve the ability of computational tools to predict the pathogenicity of DN variants, which is currently a challenging issue. More recent results support the hypothesis whereby cotranslational assembly of macromolecular complexes can buffer deleterious consequences of variants that would otherwise lead to DN effects (DNEs). Indeed, subunits the variants of which are responsible for DNEs tend to elude cotranslational assembly, thus poisoning complexes involving wild-type subunits. The constraints explaining why the buffering of DNEs is not universal require further investigation.

When fertile, women seek status via prestige but not dominance.

Biological predictors of human dominance are hotly contested, with far-reaching implications for psychological sex differences and the placement of men and women in the social hierarchy. Most investigations have focused on dominance in men and testosterone, with diminished attention paid to dominance in women and other biological mechanisms. Investigating biological influences on other routes to status attainment popular among women-such as via prestige in addition to dominance-have also been neglected. Here, I examined whether status seeking via prestige and via dominance covaried with fertility probability in a citizen science project spanning 14 countries and 4 world regions. Across 4,179 observations, participants tracked their menstrual cycle characteristics, motivation for prestige and dominance, dominance contest outcomes, and three domains of self-esteem. Self-esteem is predicted by status within a group and helps individuals navigate social hierarchies. Bayesian mixed models controlling for menstruation indicated that the motivation to obtain status via prestige but not dominance peaked when conception was most likely, as did dominance contest losses and two self-esteem domains. Fertility appears to reorient female psychology toward prestige-based strategies to success, enhancing women's desire for social capital through influence and admiration but not through fear, coercion, or intimidation. These insights fundamentally advance the understanding of the biological correlates of status seeking among women. They further suggest that fertility motivates not only mating competition but gaining rank and positive regard in social hierarchies.

Ca2+ imaging of self and other in medial prefrontal cortex during social dominance interactions in a tube test.

The study of social dominance interactions between animals offers a window onto the decision-making involved in establishing dominance hierarchies and an opportunity to examine changes in social behavior observed in certain neurogenetic disorders. Competitive social interactions, such as in the widely used tube test, reflect this decision-making. Previous studies have focused on the different patterns of behavior seen in the dominant and submissive animal, neural correlates of effortful behavior believed to mediate the outcome of such encounters, and interbrain correlations of neural activity. Using a rigorous mutual information criterion, we now report that neural responses recorded with endoscopic calcium imaging in the prelimbic zone of the medial prefrontal cortex show unique correlations to specific dominance-related behaviors. Interanimal analyses revealed cell/behavior correlations that are primarily with an animal's own behavior or with the other animal's behavior, or the coincident behavior of both animals (such as pushing by one and resisting by the other). The comparison of unique and coincident cells helps to disentangle cell firing that reflects an animal's own or the other's specific behavior from situations reflecting conjoint action. These correlates point to a more cognitive rather than a solely behavioral dimension of social interactions that needs to be considered in the design of neurobiological studies of social behavior. These could prove useful in studies of disorders affecting social recognition and social engagement, and the treatment of disorders of social interaction.

Higher-order effects, continuous species interactions, and trait evolution shape microbial spatial dynamics.

The assembly and maintenance of microbial diversity in natural communities, despite the abundance of toxin-based antagonistic interactions, presents major challenges for biological understanding. A common framework for investigating such antagonistic interactions involves cyclic dominance games with pairwise interactions. The incorporation of higher-order interactions in such models permits increased levels of microbial diversity, especially in communities in which antibiotic-producing, sensitive, and resistant strains coexist. However, most such models involve a small number of discrete species, assume a notion of pure cyclic dominance, and focus on low mutation rate regimes, none of which well represent the highly interlinked, quickly evolving, and continuous nature of microbial phenotypic space. Here, we present an alternative vision of spatial dynamics for microbial communities based on antagonistic interactions-one in which a large number of species interact in continuous phenotypic space, are capable of rapid mutation, and engage in both direct and higher-order interactions mediated by production of and resistance to antibiotics. Focusing on toxin production, vulnerability, and inhibition among species, we observe highly divergent patterns of diversity and spatial community dynamics. We find that species interaction constraints (rather than mobility) best predict spatiotemporal disturbance regimes, whereas community formation time, mobility, and mutation size best explain patterns of diversity. We also report an intriguing relationship among community formation time, spatial disturbance regimes, and diversity dynamics. This relationship, which suggests that both higher-order interactions and rapid evolution are critical for the origin and maintenance of microbial diversity, has broad-ranging links to the maintenance of diversity in other systems.

The nonclassical MHC class I Qa-1 expressed in layer 6 neurons regulates activity-dependent plasticity via microglial CD94/NKG2 in the cortex.

During developmental critical periods, circuits are sculpted by a process of activity-dependent competition. The molecular machinery involved in regulating the complex process of responding to different levels of activity is now beginning to be identified. Here, we show that the nonclassical major histocompatibility class I (MHCI) molecule Qa-1 is expressed in the healthy brain in layer 6 corticothalamic neurons. In the visual cortex, Qa-1 expression begins during the critical period for ocular dominance (OD) plasticity and is regulated by neuronal activity, suggesting a role in regulating activity-dependent competition. Indeed, in mice lacking Qa-1, OD plasticity is perturbed. Moreover, signaling through CD94/NKG2, a known cognate Qa-1 heterodimeric receptor in the immune system, is implicated: selectively targeting this interaction phenocopies the plasticity perturbation observed in Qa-1 knockouts. In the cortex, CD94/NKG2 is expressed by microglial cells, which undergo activity-dependent changes in their morphology in a Qa-1­dependent manner. Our study thus reveals a neuron­microglial interaction dependent upon a nonclassical MHCI molecule expressed in L6 neurons, which regulates plasticity in the visual cortex. These results also point to an unexpected function for the Qa-1/HLA-E (ligand) and CD94/NKG2 (receptor) interaction in the nervous system, in addition to that described in the immune system.