Genome-wide parallelism underlies contemporary adaptation in urban lizards.

Urbanization drastically transforms landscapes, resulting in fragmentation, degradation, and the loss of local biodiversity. Yet, urban environments also offer opportunities to observe rapid evolutionary change in wild populations that survive and even thrive in these novel habitats. In many ways, cities represent replicated "natural experiments" in which geographically separated populations adaptively respond to similar selection pressures over rapid evolutionary timescales. Little is known, however, about the genetic basis of adaptive phenotypic differentiation in urban populations nor the extent to which phenotypic parallelism is reflected at the genomic level with signatures of parallel selection. Here, we analyzed the genomic underpinnings of parallel urban-associated phenotypic change in Anolis cristatellus, a small-bodied neotropical lizard found abundantly in both urbanized and forested environments. We show that phenotypic parallelism in response to parallel urban environmental change is underlain by genomic parallelism and identify candidate loci across the Anolis genome associated with this adaptive morphological divergence. Our findings point to polygenic selection on standing genetic variation as a key process to effectuate rapid morphological adaptation. Identified candidate loci represent several functions associated with skeletomuscular development, morphology, and human disease. Taken together, these results shed light on the genomic basis of complex morphological adaptations, provide insight into the role of contingency and determinism in adaptation to novel environments, and underscore the value of urban environments to address fundamental evolutionary questions.

Insight into the adaptive role of arachnid genome-wide duplication through chromosome-level genome assembly of the Western black widow spider.

Although spiders are one of the most diverse groups of arthropods, the genetic architecture of their evolutionary adaptations is largely unknown. Specifically, ancient genome-wide duplication occurring during arachnid evolution ~450 mya resulted in a vast assembly of gene families, yet the extent to which selection has shaped this variation is understudied. To aid in comparative genome sequence analyses, we provide a chromosome-level genome of the Western black widow spider (Latrodectus hesperus)-a focus due to its silk properties, venom applications, and as a model for urban adaptation. We used long-read and Hi-C sequencing data, combined with transcriptomes, to assemble 14 chromosomes in a 1.46 Gb genome, with 38,393 genes annotated, and a BUSCO score of 95.3%. Our analyses identified high repetitive gene content and heterozygosity, consistent with other spider genomes, which has led to challenges in genome characterization. Our comparative evolutionary analyses of eight genomes available for species within the Araneoidea group (orb weavers and their descendants) identified 1,827 single-copy orthologs. Of these, 155 exhibit significant positive selection primarily associated with developmental genes, and with traits linked to sensory perception. These results support the hypothesis that several traits unique to spiders emerged from the adaptive evolution of ohnologs-or retained ancestrally duplicated genes-from ancient genome-wide duplication. These comparative spider genome analyses can serve as a model to understand how positive selection continually shapes ancestral duplications in generating novel traits today within and between diverse taxonomic groups.

Relationship between polygenic risk scores and symptom dimensions of schizophrenia and schizotypy in multiplex families with schizophrenia.

BACKGROUND: Psychotic disorders and schizotypal traits aggregate in the relatives of probands with schizophrenia. It is currently unclear how variability in symptom dimensions in schizophrenia probands and their relatives is associated with polygenic liability to psychiatric disorders. AIMS: To investigate whether polygenic risk scores (PRSs) can predict symptom dimensions in members of multiplex families with schizophrenia. METHOD: The largest genome-wide data-sets for schizophrenia, bipolar disorder and major depressive disorder were used to construct PRSs in 861 participants from the Irish Study of High-Density Multiplex Schizophrenia Families. Symptom dimensions were derived using the Operational Criteria Checklist for Psychotic Disorders in participants with a history of a psychotic episode, and the Structured Interview for Schizotypy in participants without a history of a psychotic episode. Mixed-effects linear regression models were used to assess the relationship between PRS and symptom dimensions across the psychosis spectrum. RESULTS: Schizophrenia PRS is significantly associated with the negative/disorganised symptom dimension in participants with a history of a psychotic episode (P = 2.31 × 10-4) and negative dimension in participants without a history of a psychotic episode (P = 1.42 × 10-3). Bipolar disorder PRS is significantly associated with the manic symptom dimension in participants with a history of a psychotic episode (P = 3.70 × 10-4). No association with major depressive disorder PRS was observed. CONCLUSIONS: Polygenic liability to schizophrenia is associated with higher negative/disorganised symptoms in participants with a history of a psychotic episode and negative symptoms in participants without a history of a psychotic episode in multiplex families with schizophrenia. These results provide genetic evidence in support of the spectrum model of schizophrenia, and support the view that negative and disorganised symptoms may have greater genetic basis than positive symptoms, making them better indices of familial liability to schizophrenia.

Genome-wide analysis of schizophrenia and multiple sclerosis identifies shared genomic loci with mixed direction of effects.

Common genetic variants identified in genome-wide association studies (GWAS) show varying degrees of genetic pleiotropy across complex human disorders. Clinical studies of schizophrenia (SCZ) suggest that in addition to neuropsychiatric symptoms, patients with SCZ also show variable immune dysregulation. Epidemiological studies of multiple sclerosis (MS), an autoimmune, neurodegenerative disorder of the central nervous system, suggest that in addition to the manifestation of neuroinflammatory complications, patients with MS may also show co-occurring neuropsychiatric symptoms with disease progression. In this study, we analyzed the largest available GWAS datasets for SCZ (N = 161,405) and MS (N = 41,505) using Gaussian causal mixture modeling (MiXeR) and conditional/conjunctional false discovery rate (condFDR) frameworks to explore and quantify the shared genetic architecture of these two complex disorders at common variant level. Despite detecting only a negligible genetic correlation (rG = 0.057), we observe polygenic overlap between SCZ and MS, and a substantial genetic enrichment in SCZ conditional on associations with MS, and vice versa. By leveraging this cross-disorder enrichment, we identified 36 loci jointly associated with SCZ and MS at conjunctional FDR < 0.05 with mixed direction of effects. Follow-up functional analysis of the shared loci implicates candidate genes and biological processes involved in immune response and B-cell receptor signaling pathways. In conclusion, this study demonstrates the presence of polygenic overlap between SCZ and MS in the absence of a genetic correlation and provides new insights into the shared genetic architecture of these two disorders at the common variant level.

Gene flow and genetic drift in urban environments.

Evidence is growing that human modification of landscapes has dramatically altered evolutionary processes. In urban population genetic studies, urbanization is typically predicted to act as a barrier that isolates populations of species, leading to increased genetic drift within populations and reduced gene flow between populations. However, urbanization may also facilitate dispersal among populations, leading to higher genetic diversity within, and lower differentiation between, urban populations. We reviewed the literature on nonadaptive urban evolution to evaluate the support for each of these urban fragmentation and facilitation models. In a review of the literature with supporting quantitative analyses of 167 published urban population genetics studies, we found a weak signature of reduced within-population genetic diversity and no evidence of consistently increased between-population genetic differentiation associated with urbanization. In addition, we found that urban landscape features act as barriers or conduits to gene flow, depending on the species and city in question. Thus, we speculate that dispersal ability of species and environmental heterogeneity between cities contributes to the variation exhibited in our results. However, >90% of published studies reviewed here showed an association of urbanization with genetic drift or gene flow, highlighting the strong impact of urbanization on nonadaptive evolution. It is clear that species biology and city heterogeneity obscure patterns of genetic drift and gene flow in a quantitative analysis. Thus, we suggest that future research makes comparisons of multiple cities and nonurban habitats, and takes into consideration species' natural history, environmental variation, spatial modelling and marker selection.

Urban hubs of connectivity: contrasting patterns of gene flow within and among cities in the western black widow spider.

As urbanization drastically alters the natural landscape and generates novel habitats within cities, the potential for changes to gene flow for urban-dwelling species increases. The western black widow spider (Latrodectus hesperus) is a medically relevant urban adapter pest species, for which we have previously identified population genetic signatures consistent with urbanization facilitating gene flow, likely due to human-mediated transport. Here, in an analysis of 1.9 million genome-wide SNPs, we contrast broad-scale geographical analyses of 10 urban and 11 non-urban locales with fine-scale within-city analyses including 30 urban locales across the western USA. These hierarchical datasets enable us to test hypotheses of how urbanization impacts multiple urban cities and their genetic connectivity at different spatial scales. Coupled fine-scale and broad-scale analyses reveal contrasting patterns of high and low genetic differentiation among locales within cities as a result of low and high genetic connectivity, respectively, of these cities to the overall population network. We discuss these results as they challenge the use of cities as replicates of urban eco-evolution, and have implications for conservation and human health in a rapidly growing urban habitat.

Urbanization as a facilitator of gene flow in a human health pest.

Urban fragmentation can reduce gene flow that isolates populations, reduces genetic diversity and increases population differentiation, all of which have negative conservation implications. Alternatively, gene flow may actually be increased among urban areas consistent with an urban facilitation model. In fact, urban adapter pests are able to thrive in the urban environment and may be experiencing human-mediated transport. Here, we used social network theory with a population genetic approach to investigate the impact of urbanization on genetic connectivity in the Western black widow spider, as an urban pest model of human health concern. We collected genomewide single nucleotide polymorphism variation from mitochondrial and nuclear double-digest RAD (ddRAD) sequence data sets from 210 individuals sampled from 11 urban and 10 nonurban locales across its distribution of the Western United States. From urban and nonurban contrasts of population, phylogenetic, and network analyses, urban locales have higher within-population genetic diversity, lower between-population genetic differentiation and higher estimates of genetic connectivity. Social network analyses show that urban locales not only have more connections, but can act as hubs that drive connectivity among nonurban locales, which show signatures of historical isolation. These results are consistent with an urban facilitation model of gene flow and demonstrate the importance of sampling multiple cities and markers to identify the role that urbanization has had on larger spatial scales. As the urban landscape continues to grow, this approach will help determine what factors influence the spread and adaptation of pests, like the venomous black widow spider, in building policies for human and biodiversity health.

Predicting childhood effortful control from interactions between early parenting quality and children's dopamine transporter gene haplotypes.

Children's observed effortful control (EC) at 30, 42, and 54 months (n = 145) was predicted from the interaction between mothers' observed parenting with their 30-month-olds and three variants of the solute carrier family C6, member 3 (SLC6A3) dopamine transporter gene (single nucleotide polymorphisms in intron8 and intron13, and a 40 base pair variable number tandem repeat [VNTR] in the 3'-untranslated region [UTR]), as well as haplotypes of these variants. Significant moderating effects were found. Children without the intron8-A/intron13-G, intron8-A/3'-UTR VNTR-10, or intron13-G/3'-UTR VNTR-10 haplotypes (i.e., haplotypes associated with the reduced SLC6A3 gene expression and thus lower dopamine functioning) appeared to demonstrate altered levels of EC as a function of maternal parenting quality, whereas children with these haplotypes demonstrated a similar EC level regardless of the parenting quality. Children with these haplotypes demonstrated a trade-off, such that they showed higher EC, relative to their counterparts without these haplotypes, when exposed to less supportive maternal parenting. The findings revealed a diathesis-stress pattern and suggested that different SLC6A3 haplotypes, but not single variants, might represent different levels of young children's sensitivity/responsivity to early parenting.

Interactions among catechol-O-methyltransferase genotype, parenting, and sex predict children's internalizing symptoms and inhibitory control: Evidence for differential susceptibility.

We used sex, observed parenting quality at 18 months, and three variants of the catechol-O-methyltransferase gene (Val158Met [rs4680], intron1 [rs737865], and 3'-untranslated region [rs165599]) to predict mothers' reports of inhibitory and attentional control (assessed at 42, 54, 72, and 84 months) and internalizing symptoms (assessed at 24, 30, 42, 48, and 54 months) in a sample of 146 children (79 male). Although the pattern for all three variants was very similar, Val158Met explained more variance in both outcomes than did intron1, the 3'-untranslated region, or a haplotype that combined all three catechol-O-methyltransferase variants. In separate models, there were significant three-way interactions among each of the variants, parenting, and sex, predicting the intercepts of inhibitory control and internalizing symptoms. Results suggested that Val158Met indexes plasticity, although this effect was moderated by sex. Parenting was positively associated with inhibitory control for methionine-methionine boys and for valine-valine/valine-methionine girls, and was negatively associated with internalizing symptoms for methionine-methionine boys. Using the "regions of significance" technique, genetic differences in inhibitory control were found for children exposed to high-quality parenting, whereas genetic differences in internalizing were found for children exposed to low-quality parenting. These findings provide evidence in support of testing for differential susceptibility across multiple outcomes.

Online toolkits for collaborative and inclusive global research in urban evolutionary ecology.

Urban evolutionary ecology is inherently interdisciplinary. Moreover, it is a field with global significance. However, bringing researchers and resources together across fields and countries is challenging. Therefore, an online collaborative research hub, where common methods and best practices are shared among scientists from diverse geographic, ethnic, and career backgrounds would make research focused on urban evolutionary ecology more inclusive. Here, we describe a freely available online research hub for toolkits that facilitate global research in urban evolutionary ecology. We provide rationales and descriptions of toolkits for: (1) decolonizing urban evolutionary ecology; (2) identifying and fostering international collaborative partnerships; (3) common methods and freely-available datasets for trait mapping across cities; (4) common methods and freely-available datasets for cross-city evolutionary ecology experiments; and (5) best practices and freely available resources for public outreach and communication of research findings in urban evolutionary ecology. We outline how the toolkits can be accessed, archived, and modified over time in order to sustain long-term global research that will advance our understanding of urban evolutionary ecology.

Effects of urban-induced mutations on ecology, evolution and health.

Increasing evidence suggests that urbanization is associated with higher mutation rates, which can affect the health and evolution of organisms that inhabit cities. Elevated pollution levels in urban areas can induce DNA damage, leading to de novo mutations. Studies on mutations induced by urban pollution are most prevalent in humans and microorganisms, whereas studies of non-human eukaryotes are rare, even though increased mutation rates have the potential to affect organisms and their populations in contemporary time. Our Perspective explores how higher mutation rates in urban environments could impact the fitness, ecology and evolution of populations. Most mutations will be neutral or deleterious, and higher mutation rates associated with elevated pollution in urban populations can increase the risk of cancer in humans and potentially other species. We highlight the potential for urban-driven increased deleterious mutational loads in some organisms, which could lead to a decline in population growth of a wide diversity of organisms. Although beneficial mutations are expected to be rare, we argue that higher mutation rates in urban areas could influence adaptive evolution, especially in organisms with short generation times. Finally, we explore avenues for future research to better understand the effects of urban-induced mutations on the fitness, ecology and evolution of city-dwelling organisms.

Urban evolutionary ecology brings exaptation back into focus.

The contribution of pre-existing phenotypic variation to evolution in novel environments has long been appreciated. Nevertheless, evolutionary ecologists have struggled with communicating these aspects of the adaptive process. In 1982, Gould and Vrba proposed terminology to distinguish character states shaped via natural selection for the roles they currently serve ('adaptations') from those shaped under preceding selective regimes ('exaptations'), with the intention of replacing the inaccurate 'preadaptation'. Forty years later, we revisit Gould and Vrba's ideas which, while often controversial, continue to be widely debated and highly cited. We use the recent emergence of urban evolutionary ecology as a timely opportunity to reintroduce the ideas of Gould and Vrba as an integrated framework to understand contemporary evolution in novel environments.

Comparative vertebrate evolutionary analyses of type I collagen: potential of COL1a1 gene structure and intron variation for common bone-related diseases.

Collagen type I alpha 1 (COL1a1), which encodes the primary subunit of type I collagen, the main structural and most abundant protein in vertebrates, harbors hundreds of mutations linked to human diseases like osteoporosis and osteogenesis imperfecta. Previous studies have attempted to predict the phenotypic severity associated with type I collagen mutations, yet an evolutionary analysis that compares historical and recent selective pressures, including across noncoding regions, has never been conducted. Here, we use a comparative genomic and species evolutionary analysis representing ∼450 My of vertebrate history to investigate functional constraints associated with both exons and introns of the >17-kb COL1a1 gene. We find that although the COL1a1 amino acid sequence is highly conserved, there are both spatial and temporal signatures of varying selective constraint across protein domains. Furthermore, sites of high evolutionary constraint significantly correlate with the location of disease-associated mutations, the latter of which also cluster with respect to specific severity classes typically categorized in clinical studies. Finally, we find that COL1a1 introns are significantly short in length with high GC content, patterns that are shared across highly diverged vertebrates, and which may be a signature of strong stabilizing selection for high COL1a1 gene expression. In conclusion, although previous studies focused on COL1a1 coding regions, the current results implicate introns as areas of high selective constraint and targets of bone-related phenotypic variation. From a broader perspective, our comparative evolutionary approach provides further resolution to models predicting mutations associated with bone-related function and disease severity.

Evolutionary Genetic Signatures of Selection on Bone-Related Variation within Human and Chimpanzee Populations.

Bone strength and the incidence and severity of skeletal disorders vary significantly among human populations, due in part to underlying genetic differentiation. While clinical models predict that this variation is largely deleterious, natural population variation unrelated to disease can go unnoticed, altering our perception of how natural selection has shaped bone morphologies over deep and recent time periods. Here, we conduct the first comparative population-based genetic analysis of the main bone structural protein gene, collagen type I α 1 (COL1A1), in clinical and 1000 Genomes Project datasets in humans, and in natural populations of chimpanzees. Contrary to predictions from clinical studies, we reveal abundant COL1A1 amino acid variation, predicted to have little association with disease in the natural population. We also find signatures of positive selection associated with intron haplotype structure, linkage disequilibrium, and population differentiation in regions of known gene expression regulation in humans and chimpanzees. These results recall how recent and deep evolutionary regimes can be linked, in that bone morphology differences that developed among vertebrates over 450 million years of evolution are the result of positive selection on subtle type I collagen functional variation segregating within populations over time.

Evaluating the role of common risk variation in the recurrence risk of schizophrenia in multiplex schizophrenia families.

Multiplex families have higher recurrence risk of schizophrenia compared to the families of sporadic cases, but the source of this increased recurrence risk is unknown. We used schizophrenia genome-wide association study data (N = 156,509) to construct polygenic risk scores (PRS) in 1005 individuals from 257 multiplex schizophrenia families, 2114 ancestry-matched sporadic cases, and 2205 population controls, to evaluate whether increased PRS can explain the higher recurrence risk of schizophrenia in multiplex families compared to ancestry-matched sporadic cases. Using mixed-effects logistic regression with family structure modeled as a random effect, we show that SCZ PRS in familial cases does not differ significantly from sporadic cases either with, or without family history (FH) of psychotic disorders (All sporadic cases p = 0.90, FH+ cases p = 0.88, FH- cases p = 0.82). These results indicate that increased burden of common schizophrenia risk variation as indexed by current SCZ PRS, is unlikely to account for the higher recurrence risk of schizophrenia in multiplex families. In the absence of elevated PRS, segregation of rare risk variation or environmental influences unique to the families may explain the increased familial recurrence risk. These findings also further validate a genetically influenced psychosis spectrum, as shown by a continuous increase of common SCZ risk variation burden from unaffected relatives to schizophrenia cases in multiplex families. Finally, these results suggest that common risk variation loading are unlikely to be predictive of schizophrenia recurrence risk in the families of index probands, and additional components of genetic risk must be identified and included in order to improve recurrence risk prediction.

Examining the source of increased bipolar disorder and major depressive disorder common risk variation burden in multiplex schizophrenia families.

Psychotic and affective disorders often aggregate in the relatives of probands with schizophrenia, and genetic studies show substantial genetic correlation among schizophrenia, bipolar disorder, and major depressive disorder. In this study, we examined the polygenic risk burden of bipolar disorder and major depressive disorder in 257 multiplex schizophrenia families (N = 1005) from the Irish Study of High-Density Multiplex Schizophrenia Families versus 2205 ancestry-matched controls. Our results indicate that members of multiplex schizophrenia families have an increased polygenic risk for bipolar disorder and major depressive disorder compared to population controls. However, this observation is largely attributable to the part of the genetic risk that bipolar disorder or major depressive disorder share with schizophrenia due to genetic correlation, rather than the affective portion of the genetic risk unique to them. These findings suggest that a complete interpretation of cross-disorder polygenic risks in multiplex families requires an assessment of the relative contribution of shared versus unique genetic factors to account for genetic correlations across psychiatric disorders.

Moving past the challenges and misconceptions in urban adaptation research.

Although the field of urban evolutionary ecology has recently expanded, much progress has been made in identifying adaptations that arise as a result of selective pressures within these unique environments. However, as studies within urban environments have rapidly increased, researchers have recognized that there are challenges and opportunities in characterizing urban adaptation. Some of these challenges are a consequence of increased direct and indirect human influence, which compounds long-recognized issues with research on adaptive evolution more generally. In this perspective, we discuss several common research challenges to urban adaptation related to (1) methodological approaches, (2) trait-environment relationships and the natural history of organisms, (3) agents and targets of selection, and (4) habitat heterogeneity. Ignoring these challenges may lead to misconceptions and further impede our ability to draw conclusions regarding evolutionary and ecological processes in urban environments. Our goal is to first shed light on the conceptual challenges of conducting urban adaptation research to help avoid the propagation of these misconceptions. We further summarize potential strategies to move forward productively to construct a more comprehensive picture of urban adaptation, and discuss how urban environments also offer unique opportunities and applications for adaptation research.

A global horizon scan for urban evolutionary ecology.

Research on the evolutionary ecology of urban areas reveals how human-induced evolutionary changes affect biodiversity and essential ecosystem services. In a rapidly urbanizing world imposing many selective pressures, a time-sensitive goal is to identify the emergent issues and research priorities that affect the ecology and evolution of species within cities. Here, we report the results of a horizon scan of research questions in urban evolutionary ecology submitted by 100 interdisciplinary scholars. We identified 30 top questions organized into six themes that highlight priorities for future research. These research questions will require methodological advances and interdisciplinary collaborations, with continued revision as the field of urban evolutionary ecology expands with the rapid growth of cities.

Haplotype structure and divergence at human and chimpanzee serotonin transporter and receptor genes: implications for behavioral disorder association analyses.

Genetic variation in the human serotonin system has long-been studied because of its functional consequences and links to various behavior-related disorders and it being routinely targeted in research and development for drug therapy. However, aside from clinical studies, little is known about this genetic diversity and how it differs within and between human populations with respect to haplotype structure, which can greatly impact phenotype association studies. In addition, no evolutionary approach among humans and other primates has examined how long- and short-term selective pressures explain existing serotonin variation. Here, we examine DNA sequence variation in natural population samples of 192 human and 40 chimpanzee chromosome sequences for the most commonly implicated approximately 38-kb serotonin transporter (SLC6A4) and approximately 63-kb serotonin 2A receptor (HTR2A) genes. Our comparative population genetic analyses find significant linkage disequilibrium associated with functionally relevant variants in humans, as well as geographic variation for these haplotypes, at both loci. In addition, although amino acid divergence is consistent with purifying selection, promoter and untranslated regions exhibit significantly high divergence in both species lineages. These evolutionary analyses imply that the serotonin system may have accumulated significant regulatory variation over both recent and ancient periods of time in both humans and chimpanzees. We discuss the implications of this variation for disease association studies and for the evolution of behavior-related phenotypes during the divergence of humans and our closest primate relatives.

Evolutionary stability, landscape heterogeneity, and human land-usage shape population genetic connectivity in the Cape Floristic Region biodiversity hotspot.

As human-induced change eliminates natural habitats, it impacts genetic diversity and population connectivity for local biodiversity. The South African Cape Floristic Region (CFR) is the most diverse extratropical area for plant biodiversity, and much of its habitat is protected as a UNESCO World Heritage site. There has long been great interest in explaining the underlying factors driving this unique diversity, especially as much of the CFR is endangered by urbanization and other anthropogenic activity. Here, we use a population and landscape genetic analysis of SNP data from the CFR endemic plant Leucadendron salignum or "common sunshine conebush" as a model to address the evolutionary and environmental factors shaping the vast CFR diversity. We found that high population structure, along with relatively deeper and older genealogies, is characteristic of the southwestern CFR, whereas low population structure and more recent lineage coalescence depict the eastern CFR. Population network analyses show genetic connectivity is facilitated in areas of lower elevation and higher seasonal precipitation. These population genetic signatures corroborate CFR species-level patterns consistent with high Pleistocene biome stability and landscape heterogeneity in the southwest, but with coincident instability in the east. Finally, we also find evidence of human land-usage as a significant gene flow barrier, especially in severely threatened lowlands where genetic connectivity has been historically the highest. These results help identify areas where conservation plans can prioritize protecting high genetic diversity threatened by contemporary human activities within this unique cultural UNESCO site.