Distinct Genetic Backgrounds Research Articles

All-Optical Electrophysiology in hiPSC-Derived Neurons With Synthetic Voltage Sensors.

Voltage imaging and “all-optical electrophysiology” in human induced pluripotent stem cell (hiPSC)-derived neurons have opened unprecedented opportunities for high-throughput phenotyping of activity in neurons possessing unique genetic backgrounds of individual patients. While prior all-optical electrophysiology studies relied on genetically encoded voltage indicators, here, we demonstrate an alternative protocol using a synthetic voltage sensor and genetically encoded optogenetic actuator that generate robust and reproducible results. We demonstrate the functionality of this method by measuring spontaneous and evoked activity in three independent hiPSC-derived neuronal cell lines with distinct genetic backgrounds.

Transcriptomic Profiling of Skeletal Muscle Reveals Candidate Genes Influencing Muscle Growth and Associated Lipid Composition in Portuguese Local Pig Breeds.

Simple SummaryScreening and interpretation of differentially expressed genes and associated biological pathways was conducted among experimental groups with divergent phenotypes providing valuable information about the metabolic events occurring and identification of candidate genes with major regulation roles. This comparative transcriptomic analysis includes the first RNA-seq analysis of the Longissimus lumborum muscle tissue from two Portuguese autochthonous pig breeds with different genetic backgrounds, Alentejano and Bísaro. Moreover, a complementary candidate gene approach was employed to analyse, by real time qPCR, the expression profile of relevant genes involved in lipid metabolism, and therefore with potential impacts on meat composition. This study contributes to explaining the biological basis of phenotypical differences occurring between breeds, particularly the ones related to meat quality traits that affect consumer interest.Gene expression is one of the main factors to influence meat quality by modulating fatty acid metabolism, composition, and deposition rates in muscle tissue. This study aimed to explore the transcriptomics of the Longissimus lumborum muscle in two local pig breeds with distinct genetic background using next-generation sequencing technology and Real-Time qPCR. RNA-seq yielded 49 differentially expressed genes between breeds, 34 overexpressed in the Alentejano (AL) and 15 in the Bísaro (BI) breed. Specific slow type myosin heavy chain components were associated with AL (MYH7) and BI (MYH3) pigs, while an overexpression of MAP3K14 in AL may be associated with their lower loin proportion, induced insulin resistance, and increased inflammatory response via NFkB activation. Overexpression of RUFY1 in AL pigs may explain the higher intramuscular (IMF) content via higher GLUT4 recruitment and consequently higher glucose uptake that can be stored as fat. Several candidate genes for lipid metabolism, excluded in the RNA-seq analysis due to low counts, such as ACLY, ADIPOQ, ELOVL6, LEP and ME1 were identified by qPCR as main gene factors defining the processes that influence meat composition and quality. These results agree with the fatter profile of the AL pig breed and adiponectin resistance can be postulated as responsible for the overexpression of MAP3K14′s coding product NIK, failing to restore insulin sensitivity.

The identification of a transposon affecting the asexual reproduction of the wheat pathogen Zymoseptoria tritici.

Zymoseptoria tritici, the causal agent of Septoria tritici blotch, is a fungal wheat pathogen that causes significant global yield losses. Within Z. tritici populations, quantitative differences in virulence among different isolates are commonly observed; however, the genetic components that underpin these differences remain elusive. In this study, intraspecific comparative transcriptomic analysis was used to identify candidate genes that contribute to differences in virulence on the wheat cultivar WW2449. This led to the identification of a multicopy gene that was not expressed in the high‐virulence isolate when compared to the medium‐ and low‐virulence isolates. Further investigation suggested this gene resides in a 7.9‐kb transposon. Subsequent long‐read sequencing of the isolates used in the transcriptomic analysis confirmed that this gene did reside in an active Class II transposon, which is composed of four genes named REP9‐1 to ‐4. Silencing and overexpression of REP9‐1 in two distinct genetic backgrounds demonstrated that its expression alone reduces the number of pycnidia produced by Z. tritici during infection. The REP9‐1 gene identified within a Class II transposon is the first discovery of a gene in a transposable element that influences the virulence of Z. tritici. This discovery adds further complexity to genetic loci that contribute to quantitative virulence in this important pathogen.

Genetic Background Influences Endothelium‐dependent Vasomotor Function in Large Arteries

Introduction Endothelial dysfunction is associated with a host of disease states including cardiovascular disease, diabetes, chronic kidney disease, and atherosclerosis. Previous research by our laboratory has shown that vasomotor function, and more specifically endothelium-dependent vasorelaxation responses, differ across large arteries from mice with distinct genetic backgrounds. However, it is unclear how much of the observed variation in endothelium-dependent vasorelaxation is due to nitric oxide (NO) mediated pathways. Objective The purpose of this study was to test the hypothesis that strain-dependent vasorelaxation differences were primarily the result of differences in reliance on NO-mediated pathways. Methods Vasomotor function was assessed in thoracic aorta, abdominal aorta, carotid arteries, and femoral arteries from four inbred strains (SJL/J (SJL), DBA/2J (DBA), NZW/LacJ (NZW) and C57BL/6J (B6)) of mice. Strains were chosen based on previously documented vasomotor variation and susceptibility to clinically significant pathologies. Arteries were dissected, cut into 2mm segments, and mounted in a wire myograph system. Arterial segments were stretched to a resting tension equivalent to a pressure of 90mmHg for all strains based on a passive stretch and relaxation tension-force assessment. Increasing concentrations of the endothelium-dependent vasodilator acetylcholine (ACh, 1x10-9 – 1x10-5M) and endothelium-independent vasodilator sodium nitroprusside (SNP, 1x10-9 – 1x10-5M) were used to assess vasorelaxation responses. To assess reliance on NO, vasorelaxation responses to Ach and SNP were assessed in the presence of a nitric oxide synthase inhibitor (NOS). One arterial segment from each group was treated with the NOS inhibitor N omega-Nitro-L-arginine methyl ester hydrochloride (L-NAME: 10x4 M) for thirty minutes. Results Two way ANOVA revealed a significant main effect of strain in vasorelaxation responses to ACh for all arteries tested (P <.0001) and no significant differences in response to SNP. Maximal relaxation responses to ACh were significantly inhibited in all arterial segments treated with L-NAME, while no differences were detected for L-NAME treated vessels in response to SNP. These findings indicate that large arteries have a strong dependence on NO-mediated, endothelium-dependent pathways to maintain vascular regulation. Furthermore, strain-dependent vasorelaxation differences were abolished in the presence of L-NAME indicating that strain differences were NO-dependent. Conclusion These findings indicate a strong influence of genetic background on endothelial function and suggest that these differences are primarily due to strain related reliance on NO for endothelium-dependent vasodilation.

High resistance to intestinal nematode infection is associated with a strong bias for TFH cell responses, rapid IgG1 class switch and limited Th2 effector cell expansion

Abstract Gastrointestinal nematode infections are highly prevalent in nature, lead to considerable morbidity in infected humans and cause high economical loss in animal husbandry. While it is clear that type 2 responses orchestrated by CD4+GATA-3+ Th2 cells are pivotal for the control of GI nematodes, the basis for differential susceptibility of distinct host genetic backgrounds is less well understood. The high resistance of ‘rapid responder’ SJL mice to infections with the small intestinal nematode H. polygyrus is evident in low parasite egg production and the termination of infection within a few weeks. Comparing the SJL line to slow responder C57BL/6 mice, we found that SJL mice generated relatively few Th2 effector cells, many follicular T helper cells and strong antibody responses in spleen and gut draining lymph nodes. These Th2 effector cells of SJL mice expressed high levels of the gut/mucosal homing markers CCR9/a4b7, resulting in the rapid accumulation of Th2 cells in the infected small intestine. Surprisingly, resistance was further associated with exceptionally high proportions of Treg in the spleen of SJL mice at steady state and the vigorous expansion of Treg in mLN after infection. This coincided with a bias for follicular T helper cells expansion in both mLN and spleen and, consequently, more extensive IgG1 class switching by GL7+ germinal center B cells in both organs. Infection-derived B cells transfer provides protection in SJL mice, not in B6 mice. In conclusion, resistance versus susceptibility to primary H. polygyrus infection appears to be less dependent on the overall magnitude of Th2 responses, but rather seems to depend on rapid Th2 effector homing, follicular T helper cells and the rapid instruction of antibody responses.

Nitrogen Use Efficiency in Sorghum: Exploring Native Variability for Traits Under Variable N-Regimes.

Exploring the natural genetic variability and its exploitation for improved Nitrogen Use Efficiency (NUE) in sorghum is one of the primary goals in the modern crop improvement programs. The integrated strategies include high-throughput phenotyping, next generation sequencing (NGS)-based genotyping technologies, and a priori selected candidate gene studies that help understand the detailed physiological and molecular mechanisms underpinning this complex trait. A set of sixty diverse sorghum genotypes was evaluated for different vegetative, reproductive, and yield traits related to NUE in the field (under three N regimes) for two seasons. Significant variations for different yield and related traits under 0 and 50% N confirmed the availability of native genetic variability in sorghum under low N regimes. Sorghum genotypes with distinct genetic background had interestingly similar NUE associated traits. The Genotyping-By-Sequencing based SNPs (>89 K) were used to study the population structure, and phylogenetic groupings identified three distinct groups. The information of grain N and stalk N content of the individuals covered on the phylogenetic groups indicated randomness in the distribution for adaptation under variable N regimes. This study identified promising sorghum genotypes with consistent performance under varying environments, with buffer capacity for yield under low N conditions. We also report better performing genotypes for varied production use—grain, stover, and dual-purpose sorghum having differential adaptation response to NUE traits. Expression profiling of NUE associated genes in shoot and root tissues of contrasting lines (PVK801 and HDW703) grown in varying N conditions revealed interesting outcomes. Root tissues of contrasting lines exhibited differential expression profiles for transporter genes [ammonium transporter (SbAMT), nitrate transporters (SbNRT)]; primary assimilatory (glutamine synthetase (SbGS), glutamate synthase (SbGOGAT[NADH], SbGOGAT[Fd]), assimilatory genes [nitrite reductase (SbNiR[NADH]3)]; and amino acid biosynthesis associated gene [glutamate dehydrogenase (SbGDH)]. Identification and expression profiling of contrasting sorghum genotypes in varying N dosages will provide new information to understand the response of NUE genes toward adaptation to the differential N regimes in sorghum. High NUE genotypes identified from this study could be potential candidates for in-depth molecular analysis and contribute toward the development of N efficient sorghum cultivars.

Association of XmnI Polymorphism with Fetal Hemoglobin Level in Sudanese Patients with Sickle Cell Disease

Background: Sickle cell disease (SCD) is an inherited blood disorder that affects red blood cells. The studyof various modulating factors, and genetic factors affecting the clinical severity of the SCD is an interestingresearch focus especially in communities with a distinct genetic background. The XmnI polymorphism isa common genetic variation that was reported in previous studies to increase fetal hemoglobin (HbF) level.This was a descriptive cross-sectional study, conducted in El-Obeid city in Northern Kordofan state, westernSudan, during the period from August to November 2016. The Xmn1 polymorphic site was determined bypolymerase chain reaction. Data was analyzed using SPSS software program version 20. P-value of 0.05and below was considered of significance. In present study HbF level among normal individuals AA , shownsignificant difference (p&lt;0.05) between presence of Xmnl +/+ and absence of Xmnl -/- site. in patients withSS , the HbF level was higher in those who had one or two Xmnl sites as compared to those with the siteabsent . In patients with sickle cell trait AS and AA, only the presence of the one and two Xmnl site (+/+)compared to the absence of the site (-/-) was associated with significant increase in the HbF level. There isa close link between the Xmn1 polymorphism site and HbF level. A wide range of HbF level was obtainedboth in the present and absence of this site. Further studies with a large sample size as well as analysis BShaplotypes among the patient with sickle cell anemia population are needed for better understand of possibleassociation .

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Update: Genetic Pathogenesis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by the inflammation of small and medium vessels and presence of proteinase 3-ANCA or myeloperoxidase-ANCA in the circulation. AAV comprises three clinical subtypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA). Although the pathogenesis of AAV is still unclear, genetic and environmental factors and the immune system are thought to be involved. Genetic factors have been confirmed to play an important role in AAV. Genome-wide association studies have identified numerous genetic variants in MHC and non-MHC regions associated with AAV. The strongest evidence of MHC association in AAV is human leukocyte antigen (HLA)-DP. A significant association between AAV and genetic variations in non-MHC regions, such as CTLA-4, FCGR2A, PTPN22, SERPINA1, and TLR9 has also been found. Moreover, different clinical subtypes of AAV have distinct genetic backgrounds. GPA is associated with HLA-DP1, MPA with HLA-DQ, and EGPA with HLA-DRB4. These findings could help elucidate the etiology of AAV and develop new biomarkers for diagnosis and targeted therapy. Herein, we briefly summarize the updates on the genetic pathogenesis and biomarkers of AAV.

Human MUS81: A Fence-Sitter in Cancer.

MUS81 complex, exhibiting endonuclease activity on specific DNA structures, plays an influential part in DNA repair. Research has proved that MUS81 is dispensable for embryonic development and cell viability in mammals. However, an intricate picture has emerged from studies in which discrepant gene mutations completely alter the role of MUS81 in human cancers. Here, we review the recent understanding of how MUS81 functions in tumors with distinct genetic backgrounds and discuss the potential therapeutic strategies targeting MUS81 in cancer.

Eosinophilic Granulomatosis With Polyangiitis: Dissecting the Pathophysiology.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare multisystemic disease classified both amongst hypereosinophilic disorders and ANCA-associated vasculitis. Vessel inflammation and eosinophilic proliferation are the hallmarks of the disease and main effectors of organ damage. Two distinct disease phenotypes have classically been described according to ANCA-status: the ANCA-negative subset with eosinophil-driven manifestation and the ANCA-positive one with vasculitic manifestations. An analogous dichotomization has also been backed by histological findings and a distinct genetic background. EGPA is typically consider a Th2-mediated disease and blood and tissue eosinophilia represent the cornerstone of diagnosis. Besides, ANCA are known for inducing endothelial injury and vascular inflammation by activating the circulating neutrophils. Thus, the pathogenesis of EGPA seems to be mediated by two coexisting mechanisms. However, the verbatim application of this strict dualism cannot always be translated into routine clinical practice. In the present review we describe the current knowledge on the eosinophilic and ANCA-mediated aspects of EGPA pathogenesis. Finally, we review the rationale of the currently proposed EGPA dichotomy and future research perspectives.

ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of SKP2 at Both Transcriptional and Post-Translational Levels.

The objective was to investigate the anti-cancer effects and underlying molecular mechanisms of cytostasis which were activated by an anti-microtubule drug, ABT-751, in two urinary bladder urothelial carcinoma (UBUC)-derived cell lines, BFTC905 and J82, with distinct genetic backgrounds. A series of in vitro assays demonstrated that ABT-751 induced G2/M cell cycle arrest, decreased cell number in the S phase of the cell cycle and suppressed colony formation/independent cell growth, accompanied with alterations of the protein levels of several cell cycle regulators. In addition, ABT-751 treatment significantly hurdled cell migration and invasion along with the regulation of epithelial–mesenchymal transition-related proteins. ABT-751 triggered autophagy and apoptosis, downregulated the mechanistic target of rapamycin kinase (MTOR) and upregulated several pro-apoptotic proteins that are involved in extrinsic and intrinsic apoptotic pathways. Inhibition of autophagosome and autolysosome enhanced apoptosis was also observed. Through the inhibition of the NFκB signaling pathway, ABT-751 suppressed S-phase kinase associated protein 2 (SKP2) transcription and subsequent translation by downregulation of active/phospho-AKT serine/threonine kinase 1 (AKT1), component of inhibitor of nuclear factor kappa B kinase complex (CHUK), NFKB inhibitor alpha (NFKBIA), nuclear RELA proto-oncogene, NFκB subunit (RELA) and maintained a strong interaction between NFKBIA and RELA to prevent RELA nuclear translocation for SKP2 transcription. ABT-751 downregulated stable/phospho-SKP2 including pSKP2(S64) and pSKP2(S72), which targeted cyclin-dependent kinase inhibitors for degradation through the inactivation of AKT. Our results suggested that ABT-751 may act as an anti-cancer drug by inhibiting cell migration, invasion yet inducing cell cycle arrest, autophagy and apoptosis in distinct UBUC-derived cells. Particularly, the upstream molecular mechanism of its anticancer effects was identified as ABT-751-induced cytostasis through the inhibition of SKP2 at both transcriptional and post-translational levels to stabilize cyclin dependent kinase inhibitor 1A (CDKN1A) and CDKN1B proteins.

Exposure to bisphenol A differentially impacts neurodevelopment and behavior in Drosophila melanogaster from distinct genetic backgrounds

Bisphenol A (BPA) is a ubiquitous environmental chemical that has been linked to behavioral differences in children and shown to impact critical neurodevelopmental processes in animal models. Though data is emerging, we still have an incomplete picture of how BPA disrupts neurodevelopment; in particular, how its impacts may vary across different genetic backgrounds. Given the genetic tractability of Drosophila melanogaster, they present a valuable model to address this question. Fruit flies are increasingly being used for assessment of neurotoxicants because of their relatively simple brain structure and variety of measurable behaviors. Here we investigated the neurodevelopmental impacts of BPA across two genetic strains of Drosophila—w1118 (control) and the Fragile X Syndrome (FXS) model—by examining both behavioral and neuronal phenotypes. We show that BPA induces hyperactivity in larvae, increases repetitive grooming behavior in adults, reduces courtship behavior, impairs axon guidance in the mushroom body, and disrupts neural stem cell development in the w1118 genetic strain. Remarkably, for every behavioral and neuronal phenotype examined, the impact of BPA in FXS flies was either insignificant or contrasted with the phenotypes observed in the w1118 strain. This data indicates that the neurodevelopmental impacts of BPA can vary widely depending on genetic background and suggests BPA may elicit a gene-environment interaction with Drosophila fragile X mental retardation 1 (dFmr1)—the ortholog of human FMR1, which causes Fragile X Syndrome and is associated with autism spectrum disorder.

Transcriptomic profiling of diverse mouse strains identifies sex‐specific Alzheimer's‐related pathway modifications

AbstractBackgroundAlzheimer’s disease (AD) is a heterogenous disease that is associated with complex brain changes and major alterations in gene expression. The analysis of correlated transcriptomic variation can help in understanding the biological mechanisms underlying the disease. Having a comprehensive atlas of changes in human brain transcriptome, as in the Accelerating Medicine’s Partnership for AD (AMP‐AD), enables the use of animal models to validate, assess, and compare such changes. Identifying the optimal animal model can further advance the discovery of the early disease characteristics and development of potential drugs.MethodWe performed comprehensive transcriptome profiling of brains from a panel of early‐onset AD mouse models at 8 months of age, including six distinct genetic backgrounds carrying the same APP/PS1 transgenic construct. We identified co‐expression modules in female and male mice, separately. Then, we associated strains that drive each module. Moreover, we determined which mouse modules overlapped with modules derived from the AMP‐AD transcriptome studies. Finally, we identified the altered pathways in which the mouse strain effects mimic disease effects in human modules.ResultThe majority of mouse modules are driven by strain (independent of APP/PS1 genotype). These modules are significantly overlapped with multiple AD‐related processes in AMP‐AD modules including inflammation, microglia, and neuronal systems. Our results suggested that the altered pathways in mice are sex‐specific, where female mouse strain effects are associated more with immune systems and less with neuronal system than male mouse strain effects.ConclusionWe identified the potential mouse strain effects, in each sex, with the potential AD‐related genes that have similar genetic characteristics to human modules. We believe that using diverse mouse strains to model AD in human can facilitate the discovery of progression pattern of AD.

Identification of citrus immune regulators involved in defence against Huanglongbing using a new functional screening system.

SummaryHuanglongbing (HLB) is the most devastating citrus disease in the world. Almost all commercial citrus varieties are susceptible to the causal bacterium, Candidatus Liberibacter asiaticus (CLas), which is transmitted by the Asian citrus psyllid (ACP). Currently, there are no effective management strategies to control HLB. HLB‐tolerant traits have been reported in some citrus relatives and citrus hybrids, which offer a direct pathway for discovering natural defence regulators to combat HLB. Through comparative analysis of small RNA profiles and target gene expression between an HLB‐tolerant citrus hybrid (Poncirus trifoliata × Citrus reticulata) and a susceptible citrus variety, we identified a panel of candidate defence regulators for HLB‐tolerance. These regulators display similar expression patterns in another HLB‐tolerant citrus relative, with a distinct genetic and geographic background, the Sydney hybrid (Microcitrus virgata). Because the functional validation of candidate regulators in tree crops is always challenging, we developed a novel rapid functional screening method, using a C. Liberibacter solanacearum (CLso)/potato psyllid/Nicotiana benthamiana interaction system to mimic the natural transmission and infection circuit of the HLB complex. When combined with efficient virus‐induced gene silencing in N. benthamiana, this innovative and cost‐effective screening method allows for rapid identification and functional characterization of regulators involved in plant immune responses against HLB, such as the positive regulator BRCA1‐Associated Protein, and the negative regulator Vascular Associated Death Protein.

Variation under domestication in animal models: the case of the Mexican axolotl

BackgroundSpecies adaptation to laboratory conditions is a special case of domestication that has modified model organisms phenotypically and genetically. The characterisation of these changes is crucial to understand how this variation can affect the outcome of biological experiments. Yet despite the wide use of laboratory animals in biological research, knowledge of the genetic diversity within and between different strains and populations of some animal models is still scarce. This is particularly the case of the Mexican axolotl, which has been bred in captivity since 1864.ResultsUsing gene expression data from nine different projects, nucleotide sequence variants were characterised, and distinctive genetic background of the experimental specimens was uncovered. This study provides a catalogue of thousands of nucleotide variants along predicted protein-coding genes, while identifying genome-wide differences between pigment phenotypes in laboratory populations.ConclusionsAwareness of the genetic variation could guide a better experimental design while helping to develop molecular tools for monitoring genetic diversity and studying gene functions in laboratory axolotls. Overall, this study highlights the cross-taxa utility that transcriptomic data might have to assess the genetic variation of the experimental specimens, which might help to shorten the journey towards reproducible research.

Abstract 16599: Impact of Race and Ethnicity on Long Term Outcomes Post Percutaneous Coronary Intervention With Drug Eluting Stents

Introduction: Cardiovascular disease is the leading cause of mortality worldwide, irrespective of race/ethnicity. Previous studies reported that minority patients with ACS have distinct clinical, genetic and socioeconomic backgrounds that may affect clinical outcomes. Hypothesis: To investigate post percutaneous coronary intervention (PCI) outcomes according to race/ethnicity in a contemporary ACS population. Methods: We included consecutive patients undergoing drug-eluting stent implantation for STEMI, non-STEMI or unstable angina (UA) between 2012-2017. The study population was stratified into Caucasian, African American, Hispanic and Asian. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE) defined as a composite of death, spontaneous myocardial infarction or stroke at 1 year. Results: Of the 6800 patients included, 3377 (49.7%) were Caucasian, 1408 (20.7%) Hispanic, 1156 (17.0%) Asian and 859 (12.6%) African American. Caucasians were the oldest, Hispanics and Asians had the highest prevalence of diabetes mellitus (DM) and African Americans had more insulin dependent DM and chronic kidney disease. Hispanics and African Americans had the highest STEMI rate, while Asians were more likely to present with UA, have private insurance and be discharged on aspirin and clopidogrel. Compared to Caucasians, Asians had a lower rate of MACCE at 1 year (3.9% vs. 7.1%; p&lt;0.01) whereas Hispanics (6.2% vs. 7.1%; p-value=0.17) and African Americans (8.0% vs. 7.1%; p-value=0.38) had comparable outcomes. Differences were driven by fewer deaths in the Hispanic (2.1% vs. 4.2%; p&lt;0.01) and Asian (1.7% vs. 4.2%; p&lt;0.01) subgroups. Findings remained unchanged after adjusting for potential confounders [Figure]. Conclusions: Among patients undergoing PCI for ACS, Asian race is associated with favorable cardiovascular outcomes compared to Caucasian. No significant differences were observed for Hispanics and African Americans.

Female mating experience and genetic background independently influence male mating success in fruit flies.

When the reproductive interests of males and females conflict, males can evolve traits that are harmful to females, and females can coevolve traits to resist this harm. In the fruit fly, Drosophila melanogaster, there is genetic variation in female resistance traits, which can affect the pre- and post-mating success of males that try to mate with them. However, it is not clear to what extent the expression of these phenotypes can be modified by environmental factors such as sociosexual experience. Here, we tested how the genetic background of a female and her previous mating experience interact to affect the mating success of focal males. In the experience phase, we placed females from 28 distinct genetic backgrounds individually either with a single male (low conflict) or with three males (high conflict) for 48hr. In the subsequent test phase, we measured the mating and post-mating fertilization success of focal males paired individually with each female. We found that focal males paired with females from the high-conflict treatment were less successful at mating, took longer to mate when they were successful, and had a lower proportion of paternity share. Furthermore, we identified significant female genetic variation associated with male mating success. These results indicate that female experience, along with intrinsic genetic factors, can independently influence different fitness components of her subsequent mates and has implications for our understanding of plastic female mating strategies and the evolution of sexually antagonistic traits in males and females.

Modeling epistasis in mice and yeast using the proportion of two or more distinct genetic backgrounds: Evidence for "polygenic epistasis".

BackgroundThe majority of quantitative genetic models used to map complex traits assume that alleles have similar effects across all individuals. Significant evidence suggests, however, that epistatic interactions modulate the impact of many alleles. Nevertheless, identifying epistatic interactions remains computationally and statistically challenging. In this work, we address some of these challenges by developing a statistical test for polygenic epistasis that determines whether the effect of an allele is altered by the global genetic ancestry proportion from distinct progenitors.ResultsWe applied our method to data from mice and yeast. For the mice, we observed 49 significant genotype-by-ancestry interaction associations across 14 phenotypes as well as over 1,400 Bonferroni-corrected genotype-by-ancestry interaction associations for mouse gene expression data. For the yeast, we observed 92 significant genotype-by-ancestry interactions across 38 phenotypes. Given this evidence of epistasis, we test for and observe evidence of rapid selection pressure on ancestry specific polymorphisms within one of the cohorts, consistent with epistatic selection.ConclusionsUnlike our prior work in human populations, we observe widespread evidence of ancestry-modified SNP effects, perhaps reflecting the greater divergence present in crosses using mice and yeast.

Clinical and genetic characteristics of Stargardt disease in a large Western China cohort: Report 1.

Stargardt disease 1 (STGD1) is the most prevalent retinal dystrophy caused by pathogenic biallelic ABCA4 variants. Forty-two unrelated patients mostly originating from Western China were recruited. Comprehensive ophthalmological examinations, including visual acuity measurements (subjective function), fundus autofluorescence (retinal imaging), and full-field electroretinography (objective function), were performed. Next-generation sequencing (target/whole exome) and direct sequencing were conducted. Genotype grouping was performed based on the presence of deleterious variants. The median age of onset/age was 10.0 (5-52)/29.5 (12-72) years, and the median visual acuity in the right/left eye was 1.30 (0.15-2.28)/1.30 (0.15-2.28) in the logarithm of the minimum angle of resolution unit. Ten patients (10/38, 27.0%) showed confined macular dysfunction, and 27 (27/37, 73.7%) had generalized retinal dysfunction. Fifty-eight pathogenic/likely pathogenic ABCA4 variants, including 14 novel variants, were identified. Eight patients (8/35, 22.8%) harbored multiple deleterious variants, and 17 (17/35, 48.6%) had a single deleterious variant. Significant associations were revealed between subjective functional, retinal imaging, and objective functional groups, identifying a significant genotype-phenotype association. This study illustrates a large phenotypic/genotypic spectrum in a large well-characterized STGD1 cohort. A distinct genetic background of the Chinese population from the Caucasian population was identified; meanwhile, a genotype-phenotype association was similarly represented.

Naive Pluripotent Stem Cells Exhibit Phenotypic Variability that Is Driven by Genetic Variation.

SummaryVariability among pluripotent stem cell (PSC) lines is a prevailing issue that hampers not only experimental reproducibility but also large-scale applications and personalized cell-based therapy. This variability could result from epigenetic and genetic factors that influence stem cell behavior. Naive culture conditions minimize epigenetic fluctuation, potentially overcoming differences in PSC line differentiation potential. Here we derived PSCs from distinct mouse strains under naive conditions and show that lines from distinct genetic backgrounds have divergent differentiation capacity, confirming a major role for genetics in PSC phenotypic variability. This is explained in part through inconsistent activity of extra-cellular signaling, including the Wnt pathway, which is modulated by specific genetic variants. Overall, this study shows that genetic background plays a dominant role in driving phenotypic variability of PSCs.