Allele Frequency Differentiation Research Articles

Quantifying variations associated with dental caries reveals disparity in effect allele frequencies across diverse populations

BackgroundDental caries (DC) is a multifaceted oral condition influenced by genetic and environmental factors. Recent advancements in genotyping and sequencing technologies, such as Genome-Wide Association Studies (GWAS) have helped researchers to identify numerous genetic variants associated with DC, but their prevalence and significance across diverse global populations remain poorly understood as most of the studies were conducted in European populations, and very few were conducted in Asians specifically in Indians.AimThis study aimed to evaluate the genetic affinity of effect alleles associated with DC to understand the genetic relationship between global populations with respect to the Indian context.MethodologyThis present study used an empirical approach in which variants associated with DC susceptibility were selected. These variants were identified and annotated using the GWAS summary. The genetic affinity was evaluated using Fst.ResultsThe effect of allele frequencies among different populations was examined, revealing variations in allele distribution. African populations exhibited higher frequencies of specific risk alleles, whereas East Asian and European populations displayed distinct profiles. South Asian populations showed a unique genetic cluster.ConclusionOur study emphasises the complex genetic landscape of DC and highlights the need for population-specific research as well as validation of GWAS-identified markers in Indians before defining them as established candidate genes.

The gout epidemic in French Polynesia: a modelling study of data from the Ma’i u’u epidemiological survey

Gout is the most common cause of inflammatory arthritis worldwide, particularly in Pacific regions. We aimed to establish the prevalence of gout and hyperuricaemia in French Polynesia, their associations with dietary habits, their comorbidities, the prevalence of the HLA-B*58:01 allele, and current management of the disease. The Ma'i u'u survey was epidemiological, prospective, cross-sectional, and gout-focused and included a random sample of adults from the general adult population of French Polynesia. It was conducted and data were collected between April 13 and Aug 16, 2021. Participants were randomly selected to represent the general adult population of French Polynesia on the basis of housing data collected during the 2017 territorial census. Each selected household was visited by a research nurse from the Ma'i u'u survey who collected data via guided, 1-h interviews with participants. In each household, the participant was the individual older than 18 years with the closest upcoming birthday. To estimate the frequency of HLA-B*58:01, we estimated HLA-B haplotypes on individuals who had whole-genome sequencing to approximately 5× average coverage (mid-pass sequencing). A subset of individuals who self-reported Polynesian ancestry and not European, Chinese, or other ancestry were used to estimate Polynesian-ancestry specific allele frequencies. Bivariate associations were reported for weighted participants; effect sizes were estimated through the odds ratio (OR) of the association calculated on the basis of a logistic model fitted with weighted observations. Among the random sample of 2000 households, 896 participants were included, 140 individuals declined, and 964 households could not be contacted. 22 participants could not be weighted due to missing data, so the final weighted analysis included 874 participants (449 [51·4%] were female and 425 [48·6%] were male) representing the 196 630 adults living in French Polynesia. The estimated prevalence of gout was 14·5% (95% CI 9·9-19·2), representing 28 561 French Polynesian adults, that is 25·5% (18·2-32·8) of male individuals and 3·5% (1·0-6·0) of female individuals. The prevalence of hyperuricaemia was estimated at 71·6% (66·7-76·6), representing 128 687 French Polynesian adults. In multivariable analysis, age (OR 1·5, 95% CI 1·2-1·8 per year), male sex (10·3, 1·8-60·7), serum urate (1·6, 1·3-2·0 per 1 mg/dL), uraturia (0·8, 0·8-0·8 per 100 mg/L), type 2 diabetes (2·1, 1·4-3·1), BMI more than 30 kg/m2 (1·1, 1·0-1·2 per unit), and percentage of visceral fat (1·7, 1·1-2·7 per 1% increase) were associated with gout. There were seven heterozygous HLA-B*58:01 carriers in the full cohort of 833 individuals (seven [0·4%] of 1666 total alleles) and two heterozygous carriers in a subset of 696 individuals of Polynesian ancestry (two [0·1%]). French Polynesia has an estimated high prevalence of gout and hyperuricaemia, with gout affecting almost 15% of adults. Territorial measures that focus on increasing access to effective urate-lowering therapies are warranted to control this major public health problem. Variant Bio, the French Polynesian Health Administration, Lille Catholic University Hospitals, French Society of Rheumatology, and Novartis.

Comparative analysis of ARID1A mutations with mRNA levels and protein expression in gastric carcinoma

The ARID1A gene is pivotal in chromatin remodeling and genomic integrity and is frequently mutated in various cancer types. ARID1A mutation is the second most frequently mutated tumor suppressor gene and has been suggested as a predictor of immunotherapeutic responsiveness in gastric carcinoma (GC). Despite its significance, the relationship among ARID1A somatic mutations, RNA expression levels, and protein expression remains unclear, particularly in GC. For this purpose, we performed comparative study in two cohorts. Cohort 1 used next-generation sequencing (NGS) to identify 112 GC cases with ARID1A mutations. These cases were compared with ARID1A immunohistochemistry (IHC) results. Cohort 2 employed microarray gene expression data to assess ARID1A RNA levels and compare them with ARID1A IHC results. In Cohort 1, 38.4% of ARID1A-mutated GC exhibited a complete loss of ARID1A protein when assessed by IHC, whereas the remaining 61.6% displayed intact ARID1A. Discordance between NGS and IHC results was not associated with specific mutation sites, variant classifications, or variant allele frequencies. In Cohort 2, 24.1% of the patients demonstrated a loss of ARID1A protein, and there was no significant difference in mRNA levels between the ARID1A protein-intact and -loss groups. Our study revealed a substantial discrepancy between ARID1A mutations detected using NGS and protein expression assessed using IHC in GC. Moreover, ARID1A mRNA expression levels did not correlate well with protein expression. These findings highlighted the complexity of ARID1A expression in GC.

Extensive genetic admixture between Tai-Kadai-speaking people and their neighbours in the northeastern region of the Yungui Plateau inferred from genome-wide variations

BackgroundYungui Plateau in Southwest China is characterized by multi-language and multi-ethnic communities and is one of the regions with the wealthiest ethnolinguistic, cultural and genetic diversity in East Asia. There are numerous Tai-Kadai (TK)-speaking populations, but their detailed evolutionary history and biological adaptations are still unclear.ResultsHere, we genotyped genome-wide SNP data of 77 unrelated TK-speaking Zhuang and Dong individuals from the Yungui Plateau and explored their detailed admixture history and adaptive features using clustering patterns, allele frequency differentiation and sharing haplotype patterns. TK-speaking Zhuang and Dong people in Guizhou are closely related to geographically close TK and Hmong-Mien (HM)-speaking populations. Besides, we identified that Guizhou TK-speaking people have a close genetic relationship with Austronesian (AN)-speaking Atayal and Paiwan people, which is supported by the common origin of the ancient Baiyue tribe. We additionally found subtle genetic differences among the newly studied TK people and previously reported Dais via the fine-scale genetic substructure analysis based on the shared haplotype chunks. Finally, we identified specific selection candidate signatures associated with several essential human immune systems and neurological disorders, which could provide evolutionary evidence for the allele frequency distribution pattern of genetic risk loci.ConclusionsOur comprehensive genetic characterization of TK people suggested the strong genetic affinity within TK groups and extensive gene flow with geographically close HM and Han people. We also provided genetic evidence that supported the common origin hypothesis of TK and AN people. The best-fitted admixture models further suggested that ancestral sources from northern millet farmers and southern inland and coastal people contributed to the formation of the gene pool of the Zhuang and Dong people.

Impact of cross-ancestry genetic architecture on GWASs in admixed populations

Genome-wide association studies (GWASs) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWASs in admixed populations, such as the need to correctly adjust for population stratification. In this work we quantify the impact of differences in estimated allelic effect sizes for risk variants between ancestry backgrounds on association statistics. Specifically, while the possibility of estimated allelic effect-size heterogeneity by ancestry (HetLanc) can be modeled when performing a GWAS in admixed populations, the extent of HetLanc needed to overcome the penalty from an additional degree of freedom in the association statistic has not been thoroughly quantified. Using extensive simulations of admixed genotypes and phenotypes, we find that controlling for and conditioning effect sizes on local ancestry can reduce statistical power by up to 72%. This finding is especially pronounced in the presence of allele frequency differentiation. We replicate simulation results using 4,327 African-European admixed genomes from the UK Biobank for 12 traits to find that for most significant SNPs, HetLanc is not large enough for GWASs to benefit from modeling heterogeneity in this way.

Association mapping for protein, total soluble sugars, starch, amylose and chlorophyll content in rice

BackgroundProtein, starch, amylose and total soluble sugars are basic metabolites of seed that influence the eating, cooking and nutritional qualities of rice. Chlorophyll is responsible for the absorption and utilization of the light energy influencing photosynthetic efficiency in rice plant. Mapping of these traits are very important for detection of more number of robust markers for improvement of these traits through molecular breeding approaches.ResultsA representative panel population was developed by including 120 germplasm lines from the initial shortlisted 274 lines for mapping of the six biochemical traits using 136 microsatellite markers through association mapping. A wide genetic variation was detected for the traits, total protein, starch, amylose, total soluble sugars, chlorophyll a, and chlorophyll b content in the population. Specific allele frequency, gene diversity, informative markers and other diversity parameters obtained from the population indicated the effectiveness of utilization of the population and markers for mapping of these traits. The fixation indices values estimated from the population indicated the existence of linkage disequilibrium for the six traits. The population genetic structure at K = 3 showed correspondence with majority of the members in each group for the six traits. The reported QTL, qProt1, qPC6.2, and qPC8.2 for protein content; qTSS8.1 for total soluble sugar; qAC1.2 for amylose content; qCH2 and qSLCHH for chlorophyll a (Chl. a) while qChl5D for chlorophyll b (Chl. b) were validated in this population. The QTL controlling total protein content qPC1.2; qTSS7.1, qTSS8.2 and qTSS12.1 for total soluble sugars; qSC2.1, qSC2.2, qSC6.1 and qSC11.1 for starch content; qAC11.1, qAC11.2 and qAC11.3 for amylose content; qChla8.1 for Chl. a content and qChlb7.1 and qChlb8.1 for Chl. b identified by both Generalized Linear Model and Mixed Linear Model were detected as novel QTL. The chromosomal regions on chromosome 8 at 234 cM for grain protein content and total soluble sugars and at 363 cM for Chl. a and Chl. b along with the position at 48 cM on chromosome 11 for starch and amylose content are genetic hot spots for these traits.ConclusionThe validated, co-localized and the novel QTL detected in this study will be useful for improvement of protein, starch, amylose, total soluble sugars and chlorophyll content in rice.

Species-informative SNP markers for characterising freshwater prawns of genus Macrobrachium in Cameroon.

Single Nucleotide Polymorphisms (SNPs) are now popular for a myriad of applications in animal and plant species including, ancestry assignment, conservation genetics, breeding, and traceability of animal products. The objective of this study was to develop a customized cost-effective SNP panel for genetic characterisation of Macrobrachium species in Cameroon. The SNPs identified in a previous characterization study were screened as viable candidates for the reduced panel. Starting from a full set of 1,814 SNPs, a total of 72 core SNPs were chosen using conventional approaches: allele frequency differentials, minor allele frequency profiles, and Wright’s Fst statistics. The discriminatory power of reduced set of informative SNPs were then tested using the admixture analysis, principal component analysis, and discriminant analysis of principal components. The panel of prioritised SNP markers (i.e., N = 72 SNPs) distinguished Macrobrachium species with 100% accuracy. However, large sample size is needed to identify more informative SNPs for discriminating genetically closely related species, including M. macrobrachion versus M. vollenhovenii and M. sollaudii versus M. dux. Overall, the findings in this study show that we can accurately characterise Macrobrachium using a small set of core SNPs which could be useful for this economically important species in Cameroon. Given the results obtained in this study, a larger independent validation sample set will be needed to confirm the discriminative capacity of this SNP panel for wider commercial and research applications.

Genomic regions and candidate genes selected during the breeding of rice in Vietnam.

Vietnam harnesses a rich diversity of rice landraces adapted to a range of conditions, which constitute a largely untapped source of diversity for the continuous improvement of cultivars. We previously identified a strong population structure in Vietnamese rice, which is captured in five Indica and four Japonica subpopulations, including an outlying Indica‐5 group. Here, we leveraged that strong differentiation and 672 native rice genomes to identify genomic regions and genes putatively selected during the breeding of rice in Vietnam. We identified significant distorted patterns in allele frequency (XP‐CLR) and population differentiation scores (F ST) resulting from differential selective pressures between native subpopulations, and later annotated them with QTLs previously identified by GWAS in the same panel. We particularly focussed on the outlying Indica‐5 subpopulation because of its likely novelty and differential evolution, where we annotated 52 selected regions, which represented 8.1% of the rice genome. We annotated the 4576 genes in these regions and selected 65 candidate genes as promising breeding targets, several of which harboured alleles with nonsynonymous substitutions. Our results highlight genomic differences between traditional Vietnamese landraces, which are likely the product of adaption to multiple environmental conditions and regional culinary preferences in a very diverse country. We also verified the applicability of this genome scanning approach to identify potential regions harbouring novel loci and alleles to breed a new generation of sustainable and resilient rice.

Abstract CT108: Immunogenicity of Poly-ICLC matured dendritic cells as an adjuvant for NY-ESO-1 and Melan-A-MART-1 peptide vaccination compared to Montanide® ISA-51 VG, in study subjects with melanoma in complete clinical remission but at high risk of disease recurrence

Abstract Background: Dendritic cells (DCs) play a critical role in anti-tumor immune response. However, tumor-induced immunosuppression promotes DC dysfunction and T cell exhaustion resulting in evasion of tumor immunity. In this study, we aimed to compare two approaches for engaging DCs and inducing an immune response to tumor antigens in the absence of tumor (melanoma) Methods: This is a Phase II open-label, randomized, two-arm study to compare Arm A: Poly-ICLC-matured DC+PolyICLC to Arm B: Montanide ISA-51-VG+Poly-ICLC, as adjuvants for NY-ESO-1 and Melan-A/MART-1 long peptides in patients with melanoma in complete clinical remission but at high risk of disease recurrence (NCT02334735). Each arm also received helper peptide, keyhole limpet hemocyanin (KLH) with the first vaccine and Poly-ICLC on day 2 of each vaccine. 36 patients were consented and randomized. Of these, 31 subjects received treatment, 16 in Arm A and 15 in Arm B. Immunohistochemistry (IHC) was used to determine expression of NY-ESO-1 and Melan-A/MART-1 and to determine the immune infiltrate landscape in the primary tumors. Humoral responses, TCR clonality, and inflammatory pathways were assessed by ELISA, bulk TCR sequencing, and Olink, respectively. Functional T-cell responses were investigated ex-vivo by interferon (IFN)-g enzyme-linked immunospot assay (ELISPOT) and after expansion by intracellular cytokine staining. Results: Arm B induced a stronger humoral response vs Arm A against both Melan-A/MART-1 and NY-ESO-1. A stronger ex vivo IFN-g response as well as expanded CD4+ T cell response against NY-ESO-1 was also induced in Arm B. However, the response to Melan-A/MART-1, as measured by ex vivo ELISPOT and expanded CD4+T cell assay, was comparable in both arms. Interestingly, while similar proportions of patients in each arm displayed a CD8+ T cell response to NYESO-1, more patients in Arm A vs Arm B responded with a CD8+ T cell response to Melan-A/MART-1 (9/16 responders in Arm A vs 4/14 in Arm B). Melan-A expression was observed in 81% of the patients but did not correlate with antigen specific immune response. TCR sequencing, Olink analysis and evaluation of NY-ESO-1 expression and immune infiltrates in the primary tumors is ongoing. Conclusion: This trial reached the primary endpoint of safety and tolerability. Arm B induced a stronger antibody and CD4+ T cell response, especially to NY-ESO-1, whereas the Arm A vaccine appears to be more efficient at eliciting CD8+ T cell responses against MelanA/MART1. The seemingly enhanced CD8 T cell response in Arm A versus Arm B, could be attributed to frequency of specific HLA-I alleles in either arm or pre-existing immune response in select patients. A deeper investigation into correlation between HLA type and cellular immune response to vaccine is ongoing. Citation Format: Mansi Saxena, Ashleih Burke, Anna Pavlick, Ana Blazquez, Gustavo Gimenez, Marcia Meseck, Michael Donovan, Denise Rodriguez, Mireia Castillo-Martin, Tin Htwe Thin, Rachel Sabado, John Mandeli, Sacha Gnjatic, Philip Friedlander, Nina Bhardwaj. Immunogenicity of Poly-ICLC matured dendritic cells as an adjuvant for NY-ESO-1 and Melan-A-MART-1 peptide vaccination compared to Montanide® ISA-51 VG, in study subjects with melanoma in complete clinical remission but at high risk of disease recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT108.

Abstract LB110: Twist pan-cancer synthetic reference materials for cell-free DNA (cfDNA) assay development

Abstract Liquid biopsies hold great promise in reducing the burden of the disease of cancer on patients. Early detection of cancer via the cell free DNA represents the broadest vision and requires highly specificity. Ongoing disease monitoring is another important application of liquid biopsy and requires high sensitivity. Assay development requires analytical validation, and assays must be monitored for ongoing performance. These assays demand reference materials at specific variant allele frequencies for the assessment of specificity and sensitivity. Previously, obtaining reference materials was a laborious process of finding or engineering mutant cell lines. Here, we describe the design, manufacture, and quality control of a synthetic reference standard: the Twist Pan-Cancer Reference Standards, developed using Twist’s proprietary DNA printing platform to include a wide selection of both common and rare cancer targets for analytical validation. The reference material closely mimics the size distribution and content of cell-free DNA, with a primary peak at 167 bp and a secondary peak at 334 bp. The background cfDNA is derived from a single donor and highly characterized through NGS. The reference standard includes over 400 variant sites across 84 genes, including literature-curated, clinically-relevant variant sites. Additional panel-wide variants were included to aid in troubleshooting capture panels. The variant DNA is synthetically printed at 167 bp ± 5 bp and tiles over the site with extensive overlap, providing diversity of DNA termini relative to the position of the site of variation. Variant sites were printed and quantified independently so they can be pooled uniformly. NGS quality controls are implemented at multiple steps to ensure quality. The final products are available in a variant allele frequency (VAF) dilution series. The dilution series is quality controlled using droplet digital PCR (ddPCR) to ensure precision of variant allele frequencies. The Twist Pan Cancer Reference Standards provide a valuable solution for NGS-based assay developers seeking reference materials for a wide array of cancer variants, advancing adoption of liquid biopsy tests toward routine clinical practice. Citation Format: Patrick D. Cherry. Twist pan-cancer synthetic reference materials for cell-free DNA (cfDNA) assay development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB110.

Demonstration of local adaptation in maize landraces by reciprocal transplantation.

Populations are locally adapted when they exhibit higher fitness than foreign populations in their native habitat. Maize landrace adaptations to highland and lowland conditions are of interest to researchers and breeders. To determine the prevalence and strength of local adaptation in maize landraces, we performed a reciprocal transplant experiment across an elevational gradient in Mexico. We grew 120 landraces, grouped into four populations (Mexican Highland, Mexican Lowland, South American Highland, South American Lowland), in Mexican highland and lowland common gardens and collected phenotypes relevant to fitness and known highland‐adaptive traits such as anthocyanin pigmentation and macrohair density. 67k DArTseq markers were generated from field specimens to allow comparisons between phenotypic patterns and population genetic structure. We found phenotypic patterns consistent with local adaptation, though these patterns differ between the Mexican and South American populations. Quantitative trait differentiation (Q ST) was greater than neutral allele frequency differentiation (F ST) for many traits, signaling directional selection between pairs of populations. All populations exhibited higher fitness metric values when grown at their native elevation, and Mexican landraces had higher fitness than South American landraces when grown in these Mexican sites. As environmental distance between landraces’ native collection sites and common garden sites increased, fitness values dropped, suggesting landraces are adapted to environmental conditions at their natal sites. Correlations between fitness and anthocyanin pigmentation and macrohair traits were stronger in the highland site than the lowland site, supporting their status as highland‐adaptive. These results give substance to the long‐held presumption of local adaptation of New World maize landraces to elevation and other environmental variables across North and South America.

Fine-mapping and candidate gene analysis of a major locus controlling leaf thickness in rice (Oryza sativa L.).

Leaf thickness is an important trait in rice (Oryza sativa L.). It affects both photosynthesis and sink-resource efficiency. However, compared to leaf length and length width, reports seldom focused on leaf thickness due to the complicated measurement and minor difference. To identify the quantitative trait loci (QTL) and explore the genetic mechanism regulating the natural variation of leaf thickness, we crossed a high leaf thickness variety Aixiuzhan (AXZ) to a thin leaf thickness variety Yangdao No.6 (YD 6) and evaluated 585 F2 individuals. We further use bulked sergeant analysis with whole-genome resequencing (BSA-seq) to identify five genomic regions, including chromosomes 1, 6, 9, 10, and 12. These regions represented significant allele frequency differentiation between thick and thin leaf thickness among the mixed pool offspring. Moreover, we conducted a linkage mapping using 276 individuals derived from the F2 population. We fine-mapped and confirmed that chromosome 9 contributed the primary explanation of phenotypic variance. We fine-mapped the candidate regions and confirmed that the chromosome 9 region contributed to flag leaf thickness in rice. We observed the virtual cellular slices and found that the bundle sheath cells in YD 6 flag leaf veins are fewer than AXZ. We analyzed the potential regions on chromosome 9 and narrowed the QTL candidate intervals in the 928-kb region. Candidate genes of this major QTL were listed as potentially controlled leaf thickness. These results provide promising evidence that cloning leaf thickness is associated with yield production in rice.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11032-022-01275-y.

Allele frequency differentiation at height-associated SNPs among continental human populations.

Methods to detect polygenic adaptation have recently been shown to be sensitive to uncorrected stratification in GWAS, thereby casting doubts on whether polygenic adaptation is prevalent among humans. Consistent with a signal of adaptationat human height loci, the mean FST among African, East Asian, and European populations was shown to be significantly higher at height-associated SNPs than that at non-associated SNPs. This conclusion was reached, however, using height-associated SNPs ascertained from a GWAS design impacted by residual confounding due to uncorrected stratification. Specifically, we show here that the estimated effect sizes are significantly correlated with population structure across continents, potentially explaining the elevated differentiation previously reported. We alleviated these concerns of confounding by ascertaining height-associated SNPs from two biobank GWAS (UK Biobank, UKB, and Biobank Japan, BBJ), where measures to control for confounding in GWAS are more effective. Consistent with a global signature of polygenic adaptation, we found that compared to non-associated SNPs, frequencies of height-associated SNPs are indeed significantly more differentiated among continental populations from both the 1000 Genomes Project (p = 0.0012 for UKB and p = 0.0265 for BBJ), and the Human Genome Diversity Project (p = 0.0225 for UKB and p = 0.0032 for BBJ). However, we found no significant difference among continental populations in polygenic height scores. Through simulations, we found that polygenic score-based statistics could lose power in detecting polygenic adaptation in presence of independent converging selections, thereby potentially explaining the inconsistent results based on FST and polygenic scores.

PowerEQTL: an R package and shiny application for sample size and power calculation of bulk tissue and single-cell eQTL analysis.

SummaryGenome-wide association studies (GWAS) have revealed thousands of genetic loci for common diseases. One of the main challenges in the post-GWAS era is to understand the causality of the genetic variants. Expression quantitative trait locus (eQTL) analysis is an effective way to address this question by examining the relationship between gene expression and genetic variation in a sufficiently powered cohort. However, it is frequently a challenge to determine the sample size at which a variant with a specific allele frequency will be detected to associate with gene expression with sufficient power. This is a particularly difficult task for single-cell RNAseq studies. Therefore, a user-friendly tool to estimate statistical power for eQTL analyses in both bulk tissue and single-cell data is needed. Here, we presented an R package called powerEQTL with flexible functions to estimate power, minimal sample size or detectable minor allele frequency for both bulk tissue and single-cell eQTL analysis. A user-friendly, program-free web application is also provided, allowing users to calculate and visualize the parameters interactively.Availability and implementationThe powerEQTL R package source code and online tutorial are freely available at CRAN: https://cran.r-project.org/web/packages/powerEQTL/. The R shiny application is publicly hosted at https://bwhbioinfo.shinyapps.io/powerEQTL/.Supplementary information Supplementary data are available at Bioinformatics online.

A combined BSA-Seq and linkage mapping approach identifies genomic regions associated with Phytophthora root and crown rot resistance in squash

Two QTL mapping approaches were used to identify a total of six QTL associated with Phytophthora root and crown rot resistance in a biparental squash population. Phytophthora root and crown rot, caused by the soilborne oomycete pathogen Phytophthora capsici, leads to severe yield losses in squash (Cucurbita pepo). To identify quantitative trait loci (QTL) involved in resistance to this disease, we crossed a partially resistant squash breeding line with a susceptible zucchini cultivar and evaluated over 13,000 F2 seedlings in a greenhouse screen. Bulked segregant analysis with whole genome resequencing (BSA-Seq) resulted in the identification of five genomic regions-on chromosomes 4, 5, 8, 12, and 16-featuring significant allele frequency differentiation between susceptible and resistant bulks in each of two independent replicates. In addition, we conducted linkage mapping using a population of 176 F3 families derived from individually genotyped F2 individuals. Variation in disease severity among these families was best explained by a four-QTL model, comprising the same loci identified via BSA-Seq on chromosomes 4, 5, and 8 as well as an additional locus on chromosome 19, for a combined total of six QTL identified between both methods. Loci, whether those identified by BSA-Seq or linkage mapping, were of small-to-moderate effect, collectively accounting for 28-35% and individually for 2-10% of the phenotypic variance explained. However, a multiple linear regression model using one marker in each BSA-Seq QTL could predict F2:3 disease severity with only a slight drop in cross-validation accuracy compared to genomic prediction models using genome-wide markers. These results suggest that marker-assisted selection could be a suitable approach for improving Phytophthora crown and root rot resistance in squash.

Comparative analyses of the Pan lineage reveal selection on gene pathways associated with diet and sociality in bonobos.

Chimpanzees (Pan troglodytes) and bonobos (Pan paniscus) diverged into distinct species approximately 1.7 million years ago when the ancestors of modern-day bonobo populations were separated by the Congo River. This geographic boundary separates the two species today and the associated ecological factors, including resource distribution and feeding competition, have likely shaped the divergent social behavior of both species. The most striking behavioral differences pertain to between group interactions in which chimpanzees behave aggressively towards unfamiliar conspecifics, while bonobos display remarkable tolerance. Several hypotheses attempt to explain how different patterns of social behavior have come to exist in the two species, some with specific genetic predictions, likening the evolution of bonobos to a process of domestication. Here, we utilize 73 ape genomes and apply linkage haplotype homozygosity and structure informed allele frequency differentiation methods to identify positively selected regions in bonobos since their split from a common pan ancestor to better understand the environment and processes that resulted in the behavioral differences observed today. We find novel evidence of selection in genetic regions that aid in starch digestion (AMY2) along with support for two genetic predictions related to self-domestication processes hypothesized to have occurred in the bonobo. We also find evidence for selection on neuroendocrine pathways associated with social behavior including the oxytocin, serotonin, and gonadotropin releasing hormone pathways.

Genomic regions influencing aggressive behavior in honey bees are defined by colony allele frequencies

For social animals, the genotypes of group members affect the social environment, and thus individual behavior, often indirectly. We used genome-wide association studies (GWAS) to determine the influence of individual vs. group genotypes on aggression in honey bees. Aggression in honey bees arises from the coordinated actions of colony members, primarily nonreproductive "soldier" bees, and thus, experiences evolutionary selection at the colony level. Here, we show that individual behavior is influenced by colony environment, which in turn, is shaped by allele frequency within colonies. Using a population with a range of aggression, we sequenced individual whole genomes and looked for genotype-behavior associations within colonies in a common environment. There were no significant correlations between individual aggression and specific alleles. By contrast, we found strong correlations between colony aggression and the frequencies of specific alleles within colonies, despite a small number of colonies. Associations at the colony level were highly significant and were very similar among both soldiers and foragers, but they covaried with one another. One strongly significant association peak, containing an ortholog of the Drosophila sensory gene dpr4 on linkage group (chromosome) 7, showed strong signals of both selection and admixture during the evolution of gentleness in a honey bee population. We thus found links between colony genetics and group behavior and also, molecular evidence for group-level selection, acting at the colony level. We conclude that group genetics dominates individual genetics in determining the fatal decision of honey bees to sting.

DCDC2 READ1 regulatory element: how temporal processing differences may shape language.

Classic linguistic theory ascribes language change and diversity to population migrations, conquests, and geographical isolation, with the assumption that human populations have equivalent language processing abilities. We hypothesize that spectral and temporal characteristics make some consonant manners vulnerable to differences in temporal precision associated with specific population allele frequencies. To test this hypothesis, we modelled association between RU1-1 alleles of DCDC2 and manner of articulation in 51 populations spanning five continents, and adjusting for geographical proximity, and genetic and linguistic relatedness. RU1-1 alleles, acting through increased expression of DCDC2, appear to increase auditory processing precision that enhances stop-consonant discrimination, favouring retention in some populations and loss by others. These findings enhance classical linguistic theories by adding a genetic dimension, which until recently, has not been considered to be a significant catalyst for language change.

Whole exome sequencing of a Saudi family and systems biology analysis identifies CPED1 as a putative causative gene to Celiac Disease.

Celiac disease (CD) is a gastrointestinal disorder whose genetic basis is not fully understood. Therefore, we studied a Saudi family with two CD affected siblings to discover the causal genetic defect. Through whole exome sequencing (WES), we identified that both siblings have inherited an extremely rare and deleterious CPED1 genetic variant (c.241 A > G; p.Thr81Ala) segregating as autosomal recessive mutation, suggesting its putative causal role in the CD. Saudi population specific minor allele frequency (MAF) analysis has confirmed its extremely rare prevalence in homozygous condition (MAF is 0.0004). The Sanger sequencing analysis confirmed the absence of this homozygous variant in 100 sporadic Saudi CD cases. Genotype-Tissue Expression (GTEx) data has revealed that CPED1 is abundantly expressed in gastrointestinal mucosa. By using a combination of systems biology approaches like protein 3D modeling, stability analysis and nucleotide sequence conservation analysis, we have further established that this variant is deleterious to the structural and functional aspects of CPED1 protein. To the best of our knowledge, this variant has not been previously reported in CD or any other gastrointestinal disease. The cell culture and animal model studies could provide further insight into the exact role of CPED1 p.Thr81Ala variant in the pathophysiology of CD. In conclusion, by using WES and systems biology analysis, present study for the first-time reports CPED1 as a potential causative gene for CD in a Saudi family with potential implications to both disease diagnosis and genetic counseling.

In the presence of population structure: From genomics to candidate genes underlying local adaptation.

Understanding the genomic signatures, genes, and traits underlying local adaptation of organisms to heterogeneous environments is of central importance to the field evolutionary biology. To identify loci underlying local adaptation, models that combine allelic and environmental variation while controlling for the effects of population structure have emerged as the method of choice. Despite being evaluated in simulation studies, there has not been a thorough investigation of empirical evidence supporting local adaptation across these alleles. To evaluate these methods, we use 875 Arabidopsis thaliana Eurasian accessions and two mixed models (GEMMA and LFMM) to identify candidate SNPs underlying local adaptation to climate. Subsequently, to assess evidence of local adaptation and function among significant SNPs, we examine allele frequency differentiation and recent selection across Eurasian populations, in addition to their distribution along quantitative trait loci (QTL) explaining fitness variation between Italy and Sweden populations and cis‐regulatory/nonsynonymous sites showing significant selective constraint. Our results indicate that significant LFMM/GEMMA SNPs show low allele frequency differentiation and linkage disequilibrium across locally adapted Italy and Sweden populations, in addition to a poor association with fitness QTL peaks (highest logarithm of odds score). Furthermore, when examining derived allele frequencies across the Eurasian range, we find that these SNPs are enriched in low‐frequency variants that show very large climatic differentiation but low levels of linkage disequilibrium. These results suggest that their enrichment along putative functional sites most likely represents deleterious variation that is independent of local adaptation. Among all the genomic signatures examined, only SNPs showing high absolute allele frequency differentiation (AFD) and linkage disequilibrium (LD) between Italy and Sweden populations showed a strong association with fitness QTL peaks and were enriched along selectively constrained cis‐regulatory/nonsynonymous sites. Using these SNPs, we find strong evidence linking flowering time, freezing tolerance, and the abscisic‐acid pathway to local adaptation.