Population Differentiation Research Articles

Neural-symbolic hybrid model for myosin complex in cardiac ventriculum decodes structural bases for inheritable heart disease from its genetic encoding.

Human ventriculum myosin (βmys) powers contraction sometimes in complex with myosin binding protein C (MYBPC3). The latter regulates βmys activity and impacts cardiac function. Single residue variants (SRVs) change protein sequence in βmys or MYBPC3 causing inheritable heart diseases by affecting the βmys/MYBPC3 complex. Muscle genetics encode instructions for contraction informing native protein construction, functional integration, and inheritable disease impairment. A digital model decodes these instructions and evolves by processing new information content from diverse data modalities using a human partner-driven virtuous cycle optimization. A general neural-network contraction model characterizes SRV impacts on human health. It rationalizes phenotype and pathogenicity assignment given the SRVs characteristics and, in this sense, decodes βmys/MYBPC3 complex genetics and implicitly captures ventricular muscle functionality. When an SRV modified domain locates to an inter-protein contact in βmys/MYBPC3 it affects complex coordination. Domains involved, one in βmys and the other in MYBPC3, form coordinated domains (co-domains). Bilateral co-domains imply potential for their SRV modification probabilities to respond jointly to a common perturbation revealing location. Human genetic diversity from the serial founder effect is the common systemic perturbation coupling co-domains subsequently mapped by a method called 2-dimensional correlation genetics (2D-CG). Interpreting general neural-network contraction model output involves 2D-CG co-domain mapping providing structural insights with natural language expression. It aligns machine-learned intelligence from the neural network model with human provided structural insight from the 2D-CG map, and other data from the literature, to form a neural-symbolic hybrid model integrating genetic and protein-interaction data into a nascent digital twin. The process forms a template for combining new information content from diverse data modalities into an evolving digital model. This nascent digital twin interprets SRV implications for disease mechanism discovery.

Isolation by environment is more important than isolation by distance along a tropical gradient in direct developing frogs

Abstract Abiotic factors are important for defining population structure and limiting gene flow, especially in ectotherm species. In amphibians, abiotic factors like temperature and precipitation can facilitate or restrict gene flow. The challenge is identifying if these factors can lead to a pattern of isolation by environment. Our study aims to quantify the extent to which divergence is driven by abiotic factors such as temperature, precipitation and elevation. To do so, we used a direct-developing frog species, Craugastor loki that occurs along a steep elevation gradient. Using restriction-site associated DNA sequencing (RADseq) from individuals collected from 100 m to 2250 m of elevation across 13 localities at Sierra Madre de Chiapas in southern Mexico, we described population structure using a variety of model-based clustering and landscape genomics approaches. We found that populations sampled at higher elevation probably correspond to an undescribed new species of Craugastor, and that populations from Craugastor loki between 120 m and 1500 m are clustered in two different genetic groups: a Pacific slope group and a Central Depression slope group. We found signatures of isolation by environment more important than isolation by distance in contributing to genetic divergence in this group of frogs at a fine scale. The environmental variables such as: mean temperature of wettest and warmest quarter, annual mean temperature, and seasonality in temperature and precipitation play an important role on population differentiation. Our results underscore the importance of abiotic factors as drivers of genetic differentiation and highlight the use of different approaches to illuminate fine scale population divergence given the complexity of disentangling the contribution of both patterns of isolation.

A copy number variation detection method based on OCSVM algorithm using multi strategies integration

Copy number variation (CNV) is an important part of human genetic variations, which is associated with various kinds of diseases. To tackle the limitations of traditional CNV detection methods, such as restricted detection types, high error rates, and challenges in precisely identifying the location of variant breakpoints, a new method called MSCNV (copy number variations detection method for multi-strategies integration based on a one-class support vector machine model) is proposed. MSCNV establishes a multi-signal channel that integrates three strategies: read depth, split read, and read pair. First, a one-class support vector machine algorithm is used to detect abnormal signals in read depth and mapping quality values to determine the rough CNV region. Then, the rough CNV region is filtered by using paired read signals to improve the precision of MSCNV method. Finally, MSCNV explores and recognizes tandem duplication regions, interspersed duplication regions, and loss regions. It uses split read signals to determine the precise location of mutation points and to determine the type of variation. Compared with Manta, FREEC, GROM-RD, Rsicnv, and CNVkit, MSCNV significantly improves the sensitivity, precision, F1-score, and overlap density score of CNV detection while reducing the boundary bias of the detection results.

Genetically and chemically intraspecific variations of Ficus hirta provide novel insights into its protection and utilization

BackgroundRadix Fici Hirtae, the dry root of Ficus hirta, is a famous ethnomedicine and food that has been widely used by Yao and Zhuang nationalities in southern China for its potent antitumor, antifungal, and hepatoprotective effects. Recently, owing to over-exploitation and habitat destruction, F. hirta has been pushed to the brink of depletion. In addition, cultivation and breeding have resulted in severe intermixing and degeneration over the past 20 years. However, little is known about the genetic background and medicinal quality of F. hirta across populations, which restricts its protection and utilization. In this study, we conducted an evaluation of the chloroplast DNA (cpDNA) genetic diversity and population structure of F. hirta in southern China, and further evaluated its medicinal quality based on HPLC fingerprinting and the content determination of the active components.ResultsF. hirta presented high overall genetic diversity (Hd = 0.792) for cpDNA but low genetic diversity (Hd = 0.000 ~ 0.467) within populations. All seventeen populations were genetically assigned into two groups, most of which were not geographically clustered together. Mantel test revealed no significant isolation by distance pattern for F. hirta (P = 0.233), which might be related to its habitat fragmentation. High population differentiation (FST = 0.912) was detected in F. hirta, and AMOVA revealed that 91.17% of cpDNA variation occurred between populations. HPLC fingerprint analysis indicated that most F. hirta samples derived from 14 geographic origins had highly similar components (similarity = 0.828 ~ 0.975). Fourteen origins of F. hirta were clustered into three groups by HCA, PCA and OPLS-DA. Psoralen and bergapten were the differentiated quality markers among the groups. The medicinal quality of the populations NN, SD and HZ within southwestern group was much greater than that of the ND and GZ populations within southeastern group, which is consistent with the comprehensive quality scores for each origin (Y = 1.78 ~-0.82). The medicinal quality formation of F. hirta was highly correlated with geographical environment but not with cpDNA genetic variation.ConclusionsF. hirta presented high overall genetic diversity and population differentiation, but without significant isolation by distance, which might relate to its habitat fragmentation. Different geographic origins’ Radix Fici Hirtae were chemically clustered into three groups, which were mainly differentiated by psoralen and bergapten. The medicinal quality of Radix Fici Hirtae exhibited a southwest to southeast variation pattern across southern China, and its quality formation was influenced mostly by geographical environments. Our results provide references for the conservation, core collection construction and improvement of F. hirta.

Monitoring genetic diversity of Torminalis glaberrima for resilient forests in the face of population fragmentation.

Torminalis glaberrima (Gand.) Sennikov & Kurtto is a European tree species currently underutilized in forestry, valued for its high-quality wood and contribution to ecosystem stability. Despite a projected range expansion as climate change progresses, current population fragmentation levels may inhibit the species' ability to migrate and stabilize fragile forest ecosystems. To investigate the relationship between structural and functional connectivity, we surveyed the genetic diversity, spatial genetic structure, and gene flow of T. glaberrima across Austria, to understand which populations should be given conservation priority. Our sampling encompasses 21 natural and planted populations and 910 individuals of T. glaberrima covering the species' distribution in Austria. We estimated genetic diversity indices, the extent of gene dispersal, and conducted SPAGeDi, STRUCTURE, and discriminant analyses of principal components analyses using one chloroplast minisatellite and eight nuclear microsatellite markers. Despite a highly fragmented distribution of T. glaberrima in the southern, western and central part of its range in Austria, we found high genetic diversity, low population differentiation and inbreeding, and estimated higher gene dispersal values than previous studies. Population structure analyses identified two main regions of genetic ancestry in the northwestern and southeastern part of the species' range in Austria and evidence for the usage of foreign genetic material in two planted populations. Only two of the established ex situ plantations and seed orchards appear to well represent the fine-scale population structure present in Austria, and existing in situ gene conservation units (GCUs) are insufficient to conserve the current natural genetic diversity. We suggest the establishment of further in situ GCUs to maximize the conservation of extant forest genetic diversity. Additionally, we encourage corridor plantings between isolated populations, bolstering the genetic connectivity and diversity of populations.

A generalist vector-transmitted parasite exhibits population genetic structure among host genera.

Generalist parasites experience selective pressures from the various host species they infect. However, it is unclear if parasite transmission among host species precludes the establishment of host-specific adaptations and population genetic structure. We assessed the population genetic structure of the vector-transmitted avian haemosporidian parasite Haemoproteus majoris (lineage WW2; n=34 infections) in a single site in southern Sweden among 10 of its host species. The 2 best-sampled host genera were Phylloscopus (2 species, n=15 infections) and Sylvia (4 species, n=15). We designed a sequence capture protocol to isolate 1.13Mbp (ca. 5%) of the parasite genome and identified 1399 variable sites among the sequenced infections. In a principal components analysis, infections of Phylloscopus and Sylvia species mostly separated along the first 2 principal components. Sites with the highest FST values between the genera were found in genes that have mostly not been implicated in infection pathways, but several sites code for amino acid changes. An analysis of molecular variance confirmed significant variation among host genera, but not among host species within genera. The distribution of Tajima's D among sequenced loci was negatively skewed, plausibly reflecting a history of bottleneck followed by population expansion. Tajima's D was lower in infections of Phylloscopus than Sylvia, plausibly because WW2 began infecting Phylloscopus hosts after it was already a parasite of Sylvia hosts. Our results provide evidence of vector-transmitted parasite population differentiation among host species in a single location. Future work should focus on identifying the mechanisms underlying this genetic population structure.

Genome assembly of pomegranate highlights structural variations driving population differentiation and key loci underpinning cold adaption

Genome assembly of pomegranate highlights structural variations driving population differentiation and key loci underpinning cold adaption

Demographic and historical processes influencing Cochliomyia hominivorax (Diptera: Calliphoridae) population structure across South America

BackgroundIn this study, we investigated the genetic variability and population structure of the New World screwworm fly Cochliomyia hominivorax. We tested the hypothesis that the species exhibits a center–periphery distribution of genetic variability, with higher genetic diversity in central populations (e.g., Brazil) and lower diversity in peripheral populations.MethodsUsing microsatellite markers, we analyzed larvae collected from infested livestock across South America. The larvae were collected directly from various wound sites to ensure a broad representation of genetic diversity.ResultsContrary to our initial hypothesis, the results revealed consistent genetic variability across the species’ distribution, low population differentiation, and no evidence of isolation-by-distance patterns among subpopulations. The genetic analysis indicated an excess of homozygotes, potentially due to the Wahlund effect, null alleles, or selection pressure.ConclusionsThese findings suggest a complex metapopulation structure for C. hominivorax, challenging classical population genetics models. This complexity likely arises from the species’ high dispersal capability and frequent local extinctions followed by recolonization. These results have important implications for the design and implementation of control programs, emphasizing the need for coordinated and large-scale actions rather than isolated initiatives.Graphical

Inter‐population variations of saccular otolith of Walton's mudskipper (Periophthalmus waltoni) of the Persian Gulf and Gulf of Oman

AbstractUnderstanding population structure is crucial for predicting species' responses to environmental change and elucidating evolutionary history. This study investigated the population structure of Periophthalmus waltoni in the Persian Gulf and Gulf of Oman using landmark‐based geometric morphometrics (GMM) and discrete wavelet transform (DWT) methods on sagittal otoliths. The objectives were to (i) examine otolith shape variation across different populations and (ii) compare GMM and DWT methods for resolving population differences. Both methods distinguished populations based on general otolith shape, with DWT revealing finer details due to its high accuracy in detecting otolith margins. Interestingly, populations from Sistan‐Baluchestan and Hormozgan, despite geographical separation, showed minimal variation in shape, suggesting environmental factors may influence otolith morphology. Distinct otolith shapes in the Khuzestan population, likely due to geographic isolation, may be influenced by the mangrove forests near Qeshm Island acting as barriers to larval dispersal. This aligns with molecular data and indicates that the relatively young eastern Persian Gulf may also contribute to these differences. Our findings revealed distinct geographical patterns in otolith shape, highlighting the influence of local environmental factors and larval dispersal on population differentiation. These results provide valuable insights into P. waltoni's population structure and evolutionary history, advancing our understanding of its adaptation to the diverse environmental conditions of the Persian Gulf and Oman Sea.

Comparing microsatellites and single nucleotide polymorphisms to evaluate genetic structure and diversity in wolverines (Gulo gulo) across Alaska and western Canada

Abstract The Wolverine (Gulo gulo) is a cold-adapted species of conservation interest because it is sensitive to human development, disturbance, exploitation, and climate warming. Wolverine populations have been studied across much of their distributional range to evaluate patterns of genetic diversity, genetic structure, and gene flow. Little population structure has been detected in northwestern North America with microsatellite loci, but low genomic diversity in wolverines may limit detection of genetic differences in this highly vagile species. Here, we genotyped a relatively large sample of wolverines from across Alaska (US) and adjacent Yukon (Canada) with 12 microsatellite loci (n = 501) and 4,222 single nucleotide polymorphisms (SNPs; n = 201) identified using restriction-site associated DNA sequencing. We compared the relative ability of our microsatellite and SNP datasets to evaluate population genetic structure, genetic diversity, differentiation, and isolation by distance (IBD). We predicted that the SNP dataset would detect a higher degree of genetic structure and provide more significant support for IBD. We found evidence for multiple genetic clusters, including genetic distinctiveness of wolverines in southeast Alaska and on the Kenai Peninsula. The SNP dataset detected additional genetic clusters that align largely with ecoregions, and the SNP dataset showed stronger evidence of IBD, while the 2 datasets were generally consistent in estimates of genetic diversity and differentiation among regional groups. Our results highlight the importance of genomic methods to assess gene flow in wolverines. Identifying population genetic structure allows an assessment of the potential impacts of conservation threats and is an important precursor for designing population monitoring programs.

Genetic Mechanism Analysis Related to Cold Tolerance of Red Swamp Crayfish, Procambarus clarkii.

In China, the red swamp crayfish (Procambarus clarkii), a notorious invasive species, has become an important economic freshwater species. In order to compare the genetic diversity and population structure of crayfish from northern and southern China, we collected 60 crayfish individuals from 4 crayfish populations in northern China and 2 populations in southern China for sequencing using the 2b-RAD technique. Additionally, the whole genome sequence information obtained by 2b-RAD of 90 individuals from 2 populations in northern China and 7 populations in southern China were downloaded from NCBI. After quality control, a total of 25,371 SNPs were detected from approximately 54.22 billion raw reads. Based on these SNPs, high genetic diversity was observed in the 15 crayfish populations in China. The pairwise FST values indicated that there was a large genetic differentiation of crayfish populations in northern and southern China. Despite common genetic backgrounds, due to geographical barriers, genetic divergence has been observed in northern and southern China crayfishes. The principal component analysis in combination with Admixture and Neighbor-Joining tree analysis showed that the crayfish fell into two clusters corresponding to geographical regions. The integrated analysis of whole genome and transcriptome data showed that two genes (CETN4 and CPEB2) might play important roles during crayfish resistance to a cold environment. This study reveals the genetic differentiation of crayfish populations in northern and southern China and provides clues to the genetic mechanism related to cold adaptation.

Environmental Variation Influences Genome Evolution in Hispaniolan Trunk Anoles (Anolis distichus).

Environmental variation often drives evolutionary processes like population differentiation, local adaptation and speciation. We used genome-scale data to investigate the contribution of environmental variation to evolution of the North Caribbean bark anole (Anolis distichus), a widespread common lizard that exhibits impressive phenotypic variation across varying habitats on the island of Hispaniola. We obtained new double-digest restriction-associated DNA sequence data (ddRADseq) from nearly 200 individuals and used 53 GIS data layers representing a range of environmental variables. We first asked how environmental variation has contributed to genome-wide differentiation across Hispaniola. We found that Hispaniola's three major mountain ranges contribute to deep genome-wide divergence and patterns of migration, that some deeply genomically divergent populations occupy significantly different environments, and that environmental variation is broadly capable of explaining more range-wide genomic differentiation than geographic distance alone. We then asked whether specific loci exhibit evidence of local adaptation to environmental variation using genotype-environment association (GEA) methods. We initially identified hundreds of loci broadly distributed across the genome that are significantly correlated with one or more environmental variables, but ultimately found that fewer than 100 of these candidate loci are shared across different GEA methods applied to our entire dataset, and that only 10 candidate loci are shared by independent analyses of two regional subsets of our dataset, suggesting parallel evolution is infrequent. Our study shows that abiotic environmental variation has played a critical role in explaining the evolution and diversity of a widespread and phenotypically diverse Caribbean anole species.

Plastome data provides new insights into population differentiation and evolution of Ginkgo in the Sichuan Basin of China

BackgroundGinkgo biloba L., an iconic living fossil, challenges traditional views of evolutionary stasis. While nuclear genomic studies have revealed population structure across China, the evolutionary patterns reflected in maternally inherited plastomes remain unclear, particularly in the Sichuan Basin - a potential glacial refugium that may have played a crucial role in Ginkgo’s persistence.ResultsAnalysis of 227 complete plastomes, including 81 newly sampled individuals from the Sichuan Basin, revealed three distinct maternal lineages differing from known nuclear genome patterns. We identified 170 sequence variants and extensive RNA editing (235 sites) with a bias toward hydrophobic amino acid conversions, suggesting active molecular evolution. A previously undocumented haplotype (IIA2), predominant in western Sichuan Basin populations, showed close genetic affinity with rare refugial haplotypes. Western populations exhibited higher haplotypic diversity and distinctive genetic structure, supporting the basin’s role as both glacial refugium and corridor for population expansion. Ancient trees (314–784 years) provided evidence for interaction between natural processes and historical human dispersal in shaping current genetic patterns.ConclusionsOur findings demonstrate substantial genetic diversity within Sichuan Basin Ginkgo populations and reveal dynamic molecular evolution through plastome variation and RNA editing patterns, challenging the notion of evolutionary stasis in this living fossil. This study provides crucial genomic resources for understanding Ginkgo’s evolution and informs conservation strategies for this endangered species.

Population Genetics of Haliotis discus hannai in China Inferred Through EST-SSR Markers.

The Pacific abalone Haliotis discus hannai originated in cold waters and is an economically important aquaculture shellfish in China. Our goal was to clarify the current status of the genetic structure of Pacific abalone in China. In this study, eighteen polymorphic EST-SSR loci were successfully developed based on the hemolymph transcriptome data of Pacific abalone, and thirteen highly polymorphic EST-SSR loci were selected for the genetic variation analysis of the six populations collected. The results showed that the average number of observed alleles was 8.0769 (RC)-11.3848 (DQ) in each population. The number of observed alleles in the DQ, NH, and TJ populations was significantly higher than that in the RC population. The cultivated population outside the Changshan Islands has experienced a 22.79% reduction in allele diversity compared to the wild population of DQ. The pairwise Fst values and analysis of molecular variance (AMOVA) revealed significant population differentiation among all populations except DQ and NH populations, with RC and ZZ cultured populations exhibiting the largest population differentiation (Fst = 0.1334). The phylogenetic tree and structural analysis divided the six populations into two groups (group 1: NH, DQ, and ZZ; group 2: DL, TJ, and RC), and there was no relationship between geographical distance and genetic distance. These results may reflect the large-scale culture from different populations in China and the exchange of juveniles between hatcheries. Different breeding conditions have led to a higher degree of genetic differentiation between the RC and ZZ populations. This study enables a better understanding of the genetic diversity and structure of current Pacific abalone populations.

Human longevity and Alzheimer's disease variants act via microglia and oligodendrocyte gene networks.

Ageing underlies functional decline of the brain and is the primary risk factor for several neurodegenerative conditions, including Alzheimer's disease (AD). However, the molecular mechanisms that cause functional decline of the brain during ageing, and how these contribute to AD pathogenesis, are not well understood. The objective of this study was to identify biological processes that are altered during ageing in the hippocampus and that modify Ad risk and lifespan, and then to identify putative gene drivers of these programmes. We integrated common human genetic variation associated with human lifespan or Ad from genome-wide association studies with co-expression transcriptome networks altered with age in the mouse and human hippocampus. Our work confirmed that genetic variation associated with Ad was enriched in gene networks expressed by microglia responding to ageing and revealed that they were also enriched in an oligodendrocytic gene network. Compellingly, longevity-associated genetic variation was enriched in a gene network expressed by homeostatic microglia whose expression declined with age. The genes driving this enrichment include CASP8 and STAT3, highlighting a potential role for these longevity-associated genes in the homeostatic functions of innate immune cells, and these genes might drive 'inflammageing'. Thus, we observed that gene variants contributing to ageing and AD balance different aspects of microglial and oligodendrocytic function. Furthermore, we also highlight putative Ad risk genes, such as LAPTM5, ITGAM and LILRB4, whose association with Ad falls below genome-wide significance but show strong co-expression with known Ad risk genes in these networks. Indeed, five of the putative risk genes highlighted by our analysis, ANKH, GRN, PLEKHA1, SNX1 and UNC5CL, have subsequently been identified as genome-wide significant risk genes in a subsequent genome-wide association study with larger sample size, validating our analysis. This work identifies new genes that influence ageing and AD pathogenesis, and highlights the importance of microglia and oligodendrocytes in the resilience of the brain against ageing and AD pathogenesis. Our findings have implications for developing markers indicating the physiological age of the brain and new targets for therapeutic intervention.

Maternal high-fat diet programs offspring airway hyperinnervation and hyperresponsiveness.

The impact of diet-induced maternal obesity on offspring airway hyperresponsiveness was studied in a diversity outbred mouse model that mirrors human genetic diversity. Female mice were started on high-fat or regular diet 8 weeks before breeding and throughout pregnancy and lactation. After weaning, all offspring were fed a regular diet. By 12 weeks, body weight and fat were increased in offspring of high-fat diet-fed dams, which was accompanied by metabolic dysfunction and hyperinsulinemia. This was followed by increased epithelial sensory innervation and increased bronchoconstriction to inhaled 5-hydroxytryptamine at 16 weeks. Bronchoconstriction was nerve mediated and blocked by vagotomy or atropine. A high-fat diet before pregnancy exerted the most influence on offspring airway physiology. Maternal obesity induced metabolic dysfunction and hyperinsulinemia, resulting in hyperinnervation and subsequent increased reflex-mediated hyperresponsiveness in their offspring. This is relevant to our understanding of asthma inheritance, considering the genetic diversity of humans.

A Post-Mortem Molecular Damage Profile in the Ancient Human Mitochondrial DNA.

Mitochondrial DNA (mtDNA) analysis is crucial for understanding human population structure and genetic diversity. However, post-mortem DNA damage poses challenges, that make analysis difficult. DNA preservation is affected by environmental conditions which, among other factors, complicates the differentiation of endogenous variants from artefacts in ancient mtDNA mix profiles. This study aims to develop a molecular damage profile for ancient mtDNA that can become a useful tool in analysing mtDNA from ancient remains. A dataset of 427 whole genomes or capture of mtDNA sequences from individuals representing different historical periods and climatic regions was compiled from the ENA database. Present-day and UDG-treated ancient samples were also included and used to establish levels of damaged reads. Results indicated that samples from cold regions exhibited the lowest percentage of damaged reads, followed by arid, cold, tropical and temperate regions, with significant differences observed between cold and temperate regions. A global damage profile was generated, identifying 2933 positions (25% of the positions considered) with damage in more than 23.8% of the samples analysed, deemed as damage hotspots. Notably, 2856 of these hotspots had never been reported as damage or mutational hotspots, or heteroplasmic positions. Damage hotspot frequency by position was slightly higher in the non-coding region compared with the coding region. In conclusion, this study provides a molecular damage profile for ancient mtDNA analysis that is expected to be a valuable tool in the interpretation of mtDNA variation in ancient samples.

The Impact of Administrative Districts and Urban Landscape on the Dispersal of Aedes aegypti via Genetic Differentiation.

Mosquito-borne diseases affect millions and cause numerous deaths annually. Effective vector control, which hinges on understanding their dispersal, is vital for reducing infection rates. Given the variability in study results, likely due to environmental and human factors, gathering local dispersal data is critical for targeted disease control. To analyse the spread and differentiation of Aedes aegypti in southern Taiwan, we established a dengue vector monitoring network in Southern Taiwan's cities. This network employed GPS-equipped ovitraps to gather eggs that were subsequently hatched in the laboratory and genotyped using genome-wide SNP markers. From 168 individuals, we identified 757,238 SNPs for detailed analysis. The estimated effective dispersal distance was 154 m (95% CI: 126-180 m), consistent with prior mark-release-recapture (MRR) estimates. We discovered that geographic isolation significantly influences genetic differentiation at larger scales, such as between cities, whereas its correlation with genetic distances is considerably weaker at smaller scales, like within cities. This is likely due to the urban landscape in Taiwan, characterised by narrow roads and densely packed buildings, which facilitates extensive dispersal of Ae. aegypti. In evaluating potential barriers to Ae. aegypti dispersal, we found that roads had no significant impact, whereas administrative districts accounted for 4.8% of the population differentiation (p < 10-4). Surprisingly, this variation aligns with the effects of district-specific mosquito control measures implemented at the municipal level. These findings highlight the complex interplay between urban landscapes, administrative measures and Ae. aegypti dispersal, emphasising the need for implementing targeted control strategies that consider these local dynamics.

Context-specific eQTLs provide deeper insight into causal genes underlying shared genetic architecture of critically ill COVID-19 and idiopathic pulmonary fibrosis.

Most genetic variants identified through genome-wide association studies (GWAS) are suspected to be regulatory in nature, but only a small fraction colocalize with expression quantitative trait loci (eQTLs, variants associated with expression of a gene). Therefore, it is hypothesized but largely untested that integration of disease GWAS with context-specific eQTLs will reveal the underlying genes driving disease associations. We used colocalization and transcriptomic analyses to identify shared genetic variants and likely causal genes associated with critically ill COVID-19 and idiopathic pulmonary fibrosis. We first identified five genome-wide significant variants associated with both diseases. Four of the variants did not demonstrate clear colocalization between GWAS and healthy lung eQTL signals. Instead, two of the four variants colocalized only in cell-type and disease-specific eQTL datasets. These analyses pointed to higher ATP11A expression from the C allele of rs12585036, in monocytes and in lung tissue from primarily smokers, which increased risk of IPF and decreased risk of critically ill COVID-19. We also found lower DPP9 expression (and higher methylation at a specific CpG) from the G allele of rs12610495, acting in fibroblasts and in IPF lungs, and increased risk of IPF and critically ill COVID-19. We further found differential expression of the identified causal genes in diseased lungs when compared to non-diseased lungs, specifically in epithelial and immune cell types. These findings highlight the power of integrating GWAS, context-specific eQTLs, and transcriptomics of diseased tissue to harness human genetic variation to identify causal genes and where they function during multiple diseases.

Genetic diversity leads to differential inflammatory responses to cigarette smoke in mice.

The use of genetically diverse mouse models offers a more accurate reflection of human genetic variability, improving the translatability of findings to heterogeneous human populations. This approach is particularly valuable in understanding diverse immune responses to disease by environmental exposures. This study investigates the inflammatory responses to acute exposures to mainstream cigarette smoke (CS) and environmental tobacco smoke (ETS) in two genetically diverse mouse strains, CC002/UncJ (UNC) & Diversity Outbred (J:DO). The UM-HET3 (HET3) mouse strain, typically used in aging intervention studies, has also been used to evaluate the translatability of this model for age-associated pathologies. The study involves a comprehensive approach, including BALF cytokine analysis, evaluation of lung tissue architecture, assessment of macrophages and its associated proteins (MMP9 & MMP12) abundance. Several cytokines/chemokines were found to be upregulated across three strains. Notably, the UNC strain exclusively showed upregulation of TNF-α, IL-17A, and IL-13, whereas the J:DO showed an upregulation in KC. The number of alveolar macrophages in the lungs of UNC mice was very low at baseline compared to other strains studied in this study, which is indicative of some inherent shift in the pulmonary immune profiles of these inbred mice. In contrast, the J:DO strain, characterized by genetic outbreeding, showed a much more robust lung macrophage response comparable to C57BL/6J. The findings provide valuable insight into how genetic diversity affects immune responses in responseto acute CS/ETS exposure, with implications for understanding diverse human responses to environmental stressors in studying lung pathophysiology.