Evolution of diapause in the African turquoise killifish by remodeling the ancient gene regulatory landscape.

Suspended animation states allow organisms to survive extreme environments. The African turquoise killifish has evolved diapause as a form of suspended development to survive a complete drought. However, the mechanisms underlying the evolution of extreme survival states are unknown. To understand diapause evolution, we performed integrative multi-omics (gene expression, chromatin accessibility, and lipidomics) in the embryos of multiple killifish species. We find that diapause evolved by a recent remodeling of regulatory elements at very ancient gene duplicates (paralogs) present in all vertebrates. CRISPR-Cas9-based perturbations identify the transcription factors REST/NRSF and FOXOs as critical for the diapause gene expression program, including genes involved in lipid metabolism. Indeed, diapause shows a distinct lipid profile, with an increase in triglycerides with very-long-chain fatty acids. Our work suggests a mechanism for the evolution of complex adaptations and offers strategies to promote long-term survival by activating suspended animation programs in other species.

Repeat polymorphisms underlie top genetic risk loci for glaucoma and colorectal cancer.

Many regions in the human genome vary in length among individuals due to variable numbers of tandem repeats (VNTRs). To assess the phenotypic impact of VNTRs genome-wide, we applied a statistical imputation approach to estimate the lengths of 9,561 autosomal VNTR loci in 418,136 unrelated UK Biobank participants and 838 GTEx participants. Association and statistical fine-mapping analyses identified 58 VNTRs that appeared to influence a complex trait in UK Biobank, 18 of which also appeared to modulate expression or splicing of a nearby gene. Non-coding VNTRs at TMCO1 and EIF3H appeared to generate the largest known contributions of common human genetic variation to risk of glaucoma and colorectal cancer, respectively. Each of these two VNTRs associated with a >2-fold range of risk across individuals. These results reveal a substantial and previously unappreciated role of non-coding VNTRs in human health and gene regulation.

Incomplete lineage sorting and phenotypic evolution in marsupials.

Incomplete lineage sorting (ILS) makes ancestral genetic polymorphisms persist during rapid speciation events, inducing incongruences between gene trees and species trees. ILS has complicated phylogenetic inference in many lineages, including hominids. However, we lack empirical evidence that ILS leads to incongruent phenotypic variation. Here, we performed phylogenomic analyses to show that the South American monito del monte is the sister lineage of all Australian marsupials, although over 31% of its genome is closer to the Diprotodontia than to other Australian groups due to ILS during ancient radiation. Pervasive conflicting phylogenetic signals across the whole genome are consistent with some of the morphological variation among extant marsupials. We detected hundreds of genes that experienced stochastic fixation during ILS, encoding the same amino acids in non-sister species. Using functional experiments, we confirm how ILS may have directly contributed to hemiplasy in morphological traits that were established during rapid marsupial speciation ca. 60 mya.

Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease.

Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.

Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases.

Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

A Thalamic Orphan Receptor Drives Variability in Short-Term Memory.

Working memory is a form of short-term memory that involves maintaining and updating task-relevant information toward goal-directed pursuits. Classical models posit persistent activity in prefrontal cortex (PFC) as a primary neural correlate, but emerging views suggest additional mechanisms may exist. We screened ∼200 genetically diverse mice on a working memory task and identified a genetic locus on chromosome 5 that contributes to a substantial proportion (17%) of the phenotypic variance. Within the locus, we identified a gene encoding an orphan G-protein-coupled receptor, Gpr12, which is sufficient to drive substantial and bidirectional changes in working memory. Molecular, cellular, and imaging studies revealed that Gpr12 enables high thalamus-PFC synchrony to support memory maintenance and choice accuracy. These findings identify an orphan receptor as a potent modifier of short-term memory and supplement classical PFC-based models with an emerging thalamus-centric framework for the mechanistic understanding of working memory.

Genetic Mapping and Biochemical Basis of Yellow Feather Pigmentation in Budgerigars.

Parrot feathers contain red, orange, and yellow polyene pigments called psittacofulvins. Budgerigars are parrots that have been extensively bred for plumage traits during the last century, but the underlying genes are unknown. Here we use genome-wide association mapping and gene-expression analysis to map the Mendelian blue locus, which abolishes yellow pigmentation in the budgerigar. We find that the blue trait maps to a single amino acid substitution (R644W) in an uncharacterized polyketide synthase (MuPKS). When we expressed MuPKS heterologously in yeast, yellow pigments accumulated. Mass spectrometry confirmed that these yellow pigments match those found in feathers. The R644W substitution abolished MuPKS activity. Furthermore, gene-expression data from feathers of different bird species suggest that parrots acquired their colors through regulatory changes that drive high expression of MuPKS in feather epithelia. Our data also help formulate biochemical models that may explain natural color variation in parrots. VIDEO ABSTRACT.

Histone Acetylome-wide Association Study of Autism Spectrum Disorder.

The association of histone modification changes with autism spectrum disorder (ASD) has not been systematically examined. We conducted a histone acetylome-wide association study (HAWAS) by performing H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) on 257 postmortem samples from ASD and matched control brains. Despite etiological heterogeneity, ≥68% of syndromic and idiopathic ASD cases shared a common acetylome signature at >5,000 cis-regulatory elements in prefrontal and temporal cortex. Similarly, multiple genes associated with rare genetic mutations in ASD showed common "epimutations." Acetylome aberrations in ASD were not attributable to genetic differentiation at cis-SNPs and highlighted genes involved in synaptic transmission, ion transport, epilepsy, behavioral abnormality, chemokinesis, histone deacetylation, and immunity. By correlating histone acetylation with genotype, we discovered >2,000 histone acetylation quantitative trait loci (haQTLs) in human brain regions, including four candidate causal variants for psychiatric diseases. Due to the relative stability of histone modifications postmortem, we anticipate that the HAWAS approach will be applicable to multiple diseases.

Drosophila sechellia: A Genetic Model for Behavioral Evolution and Neuroecology.

Defining the mechanisms by which animals adapt to their ecological niche is an important problem bridging evolution, genetics, and neurobiology. We review the establishment of a powerful genetic model for comparative behavioral analysis and neuroecology, Drosophila sechellia. This island-endemic fly species is closely related to several cosmopolitan generalists, including Drosophila melanogaster, but has evolved extreme specialism, feeding and reproducing exclusively on the noni fruit of the tropical shrub Morinda citrifolia. We first describe the development and use of genetic approaches to facilitate genotype/phenotype associations in these drosophilids. Next, we survey the behavioral, physiological, and morphological adaptations of D. sechellia throughout its life cycle and outline our current understanding of the genetic and cellular basis of these traits. Finally, we discuss the principles this knowledge begins to establish in the context of host specialization, speciation, and the neurobiology of behavioral evolution and consider open questions and challenges in the field.

Shaping immunity: The influence of natural selection on population immune diversity.

Humans exhibit considerable variability in their immune responses to the same immune challenges. Such variation is widespread and affects individual and population-level susceptibility to infectious diseases and immune disorders. Although the factors influencing immune response diversity are partially understood, what mechanisms lead to the wide range of immune traits in healthy individuals remain largely unexplained. Here, we discuss the role that natural selection has played in driving phenotypic differences in immune responses across populations and present-day susceptibility to immune-related disorders. Further, we touch on future directions in the field of immunogenomics, highlighting the value of expanding this work to human populations globally, the utility of modeling the immune response as a dynamic process, and the importance of considering the potential polygenic nature of natural selection. Identifying loci acted upon by evolution may further pinpoint variants critically involved in disease etiology, and designing studies to capture these effects will enrich our understanding of the genetic contributions to immunity and immune dysregulation.

Metamorphic protein folding as evolutionary adaptation.

Metamorphic proteins switch reversibly between multiple distinct, stable structures, often with different functions. It was previously hypothesized that metamorphic proteins arose as intermediates in the evolution of a new fold - rare and transient exceptions to the 'one sequence, one fold' paradigm. However, as described herein, mounting evidence suggests that metamorphic folding is an adaptive feature, preserved and optimized over evolutionary time as exemplified by the NusG family and the chemokine XCL1. Analysis of extant protein families and resurrected protein ancestors demonstrates that large regions of sequence space are compatible with metamorphic folding. As a category that enhances biological fitness, metamorphic proteins are likely to employ fold switching to perform important biological functions and may be more common than previously thought.

Finding genes and pathways that underlie coral adaptation.

Mass coral bleaching is one of the clearest threats of climate change to the persistence of marine biodiversity. Despite the negative impacts of bleaching on coral health and survival, some corals may be able to rapidly adapt to warming ocean temperatures. Thus, a significant focus in coral research is identifying the genes and pathways underlying coral heat adaptation. Here, we review state-of-the-art methods that may enable the discovery of heat-adaptive loci in corals and identify four main knowledge gaps. To fill these gaps, we describe an experimental approach combining seascape genomics with CRISPR/Cas9 gene editing to discover and validate heat-adaptive loci. Finally, we discuss how information on adaptive genotypes could be used in coral reef conservation and management strategies.

Alternative polyadenylation quantitative trait methylation mapping in human cancers provides clues into the molecular mechanisms of APA.

Genetic variants are involved in the orchestration of alternative polyadenylation (APA) events, while the role of DNA methylation in regulating APA remains unclear. We generated a comprehensive atlas of APA quantitative trait methylation sites (apaQTMs) across 21 different types of cancer (1,612 to 60,219 acting in cis and 4,448 to 142,349 in trans). Potential causal apaQTMs in non-cancer samples were also identified. Mechanistically, we observed a strong enrichment of cis-apaQTMs near polyadenylation sites (PASs) and both cis- and trans-apaQTMs in proximity to transcription factor (TF) binding regions. Through the integration of ChIP-signals and RNA-seq data from cell lines, we have identified several regulators of APA events, acting either directly or indirectly, implicating novel functions of some important genes, such as TCF7L2, which is known for its involvement in type 2 diabetes and cancers. Furthermore, we have identified a vast number of QTMs that share the same putative causal CpG sites with five different cancer types, underscoring the roles of QTMs, including apaQTMs, in the process of tumorigenesis. DNA methylation is extensively involved in the regulation of APA events in human cancers. In an attempt to elucidate the potential underlying molecular mechanisms of APA by DNA methylation, our study paves the way for subsequent experimental validations into the intricate biological functions of DNA methylation in APA regulation and the pathogenesis of human cancers. To present a comprehensive catalog of apaQTM patterns, we introduce the Pancan-apaQTM database, available at https://pancan-apaqtm-zju.shinyapps.io/pancanaQTM/.

Genetic Factors in Mammalian Prion Diseases.

Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; kuru; inherited prion disease; sheep scrapie; bovine spongiform encephalopathy; and chronic wasting disease. Prions are composed of misfolded and multimeric forms of the normal cellular prion protein (PrP). Prion diseases require host expression of the prion protein gene (PRNP) and a range of other cellular functions to support their propagation and toxicity. Inherited forms of prion disease are caused by mutation of PRNP, whereas acquired and sporadically occurring mammalian prion diseases are controlled by powerful genetic risk and modifying factors. Whereas some PrP amino acid variants cause the disease, others confer protection, dramatically altered incubation times, or changes in the clinical phenotype. Multiple mechanisms, including interference with homotypic protein interactions and the selection of the permissible prion strains in a host, play a role. Several non-PRNP factors have now been uncovered that provide insights into pathways of disease susceptibility or neurotoxicity.

Impulsivity is a stable, measurable, and predictive psychological trait.

Impulsivity is a personality construct frequently employed to explain and predict important human behaviors. Major inconsistencies in its definition and measurement, however, have led some researchers to call for an outright rejection of impulsivity as a psychological construct. We address this highly unsatisfactory state with a large-scale, preregistered study (N = 1,676) in which each participant completed 48 measures of impulsivity derived from 10 self-report scales and 10 behavioral tasks and reported frequencies of seven impulsivity-related behaviors (e.g., impulsive buying and social media usage); a subsample (N = 196) then completed a retest session 3 mo later. We found that correlations between self-report measures were substantially higher than those between behavioral tasks and between self-report measures and behavioral tasks. Bifactor analysis of these measures exacted one general factor of impulsivity I, akin to the general intelligence factor g, and six specific factors. Factor I was related mainly to self-report measures, had high test-retest reliability, and could predict impulsivity-related behaviors better than existing measures. We further developed a scale named the adjustable impulsivity scale (AIMS) to measure I. AIMS possesses excellent psychometric properties that are largely retained in shorter versions and could predict impulsivity-related behaviors equally well as I. These findings collectively support impulsivity as a stable, measurable, and predictive trait, indicating that it may be too early to reject it as a valid and useful psychological construct. The bifactorial structure of impulsivity and AIMS, meanwhile, significantly advance the conceptualization and measurement of construct impulsivity.

Coadaptation of coexisting plants enhances productivity in an agricultural system.

Growing crops in more diverse crop systems (i.e., intercropping) is one way to produce food more sustainably. Even though intercropping, compared to average monocultures, is generally more productive, the full yield potential of intercropping might not yet have been achieved as modern crop cultivars are bred to be grown in monoculture. Breeding plants for more familiarity in mixtures, i.e., plants that are adapted to more diverse communities (i.e., adaptation) or even to coexist with each other (i.e., coadaptation) might have the potential to sustainably enhance productivity. In this study, the productivity benefits of familiarity through evolutionary adaptation and coevolutionary coadaptation were disentangled in a crop system through an extensive common garden experiment. Furthermore, evolutionary and coevolutionary effects on species-level and community-level productivity were linked to corresponding changes in functional traits. We found evidence for higher productivity and trait convergence with increasing familiarity with the plant communities. Furthermore, our results provide evidence for the coevolution of plants in mixtures leading to higher productivity of coadapted species. However, with the functional traits measured in our study, we could not fully explain the productivity benefits found upon coevolution. Our study investigated coevolution among randomly interacting plants and was able to demonstrate that coadaptation through coevolution of coexisting species in mixtures occurs and promotes ecosystem functioning (i.e., higher productivity). This result is particularly relevant for the diversification of agricultural and forest ecosystems, demonstrating the added value of artificially selecting plants for the communities they are familiar with.

From genome size to trait evolution during angiosperm radiation.

Angiosperm diversity arises from trait flexibility and repeated evolutionary radiations, but the role of genomic characters in these radiations remains unclear. In this opinion article, we discuss how genome size can influence angiosperm diversification via its intricate link with cell size, tissue packing, and physiological processes which, in turn, influence the macroevolution of functional traits. We propose that integrating genome size, functional traits, and phylogenetic data across a wide range of lineages allows us to test whether genome size decrease consistently leads to increased trait flexibility, while genome size increase constrains trait evolution. Combining theories from molecular biology, functional ecology and macroevolution, we provide a framework to better understand the role of genome size in trait evolution, evolutionary radiations, and the global distribution of angiosperms.

Chromatin modules and their implication in genomic organization and gene regulation.

Regulation of gene expression is a complex but highly guided process. While genomic technologies and computational approaches have allowed high-throughput mapping of cis-regulatory elements (CREs) and their interactions in 3D, their precise role in regulating gene expression remains obscure. Recent complementary observations revealed that interactions between CREs frequently result in the formation of small-scale functional modules within topologically associating domains. Such chromatin modules likely emerge from a complex interplay between regulatory machineries assembled at CREs, including site-specific binding of transcription factors. Here, we review the methods that allow identifying chromatin modules, summarize possible mechanisms that steer CRE interactions within these modules, and discuss outstanding challenges to uncover how chromatin modules fit in our current understanding of the functional 3D genome.

Polygenic sex determination in vertebrates - is there any such thing?

Genetic sex determination (SD) in most vertebrates is controlled by a single master sex gene, which ensures a 1:1 sex ratio. However, more complex systems abound, and several have been ascribed to polygenic SD (PSD), in which many genes at different loci interact to produce the sexual phenotype. Here we examine claims for PSD in vertebrates, finding that most constitute transient states during sex chromosome turnover, or aberrant systems in species hybrids. To avoid confusion about terminology, we propose a consistent nomenclature for genetic SD systems.