Genetically Research Articles

What Can Really Be Considered a Syndrome? An Insight Based on 16p11.2 Microduplication.

What is the definition of Syndrome? Since the beginning of studies in genetics, certain terminologies have been created and used to define groups of diseases or alterations. With the advancement of knowledge and the emergence of new technologies, the use of basic concepts is being done in a mistaken or often confusing way. Because of this, revisiting and readjusting the old terms becomes imminent. Here, we explore these concepts and their use, through a literature compilation of an already well-defined genetic alteration (16q11.2 microduplication). We bring comparisons in clinical and molecular scope of the alteration itself and its diagnostic methods, to improve the report of cases, rescuing terminologies and their applicability nowadays.

HLA-Cw6 Polymorphism in Autoimmune Blistering Diseases.

Autoimmune blistering diseases of the pemphigus and pemphigoid groups are immune-mediated disorders due to circulating pathogenetic autoantibodies. Multiple human leukocyte antigen (HLA) genes have been associated with predisposition to these disorders. HLA-Cw6 is involved in antigen presentation processes and has been linked to psoriasis. The aim of our study was to investigate the association between the presence of the HLA-Cw6 allele and susceptibility to pemphigus vulgaris and bullous pemphigoid. A genetic study in vitro with a cross-sectional design was performed enrolling forty patients with pemphigus vulgaris and forty patients with bullous pemphigoid. The detection of HLA-Cw6 was performed through the EUROArray test on DNA obtained from whole blood samples. The polymorphism was detected in 3/40 genotypes in the pemphigus vulgaris group and in 4/40 genotypes of patients with bullous pemphigoid, unveiling a non-statistically significant different frequency in pemphigus (p = 0.6368) and in pemphigoid (p = 0.62) compared to the reference frequency from the literature of 0.086. Further research is needed to better investigate the role of HLA-Cw6 in immune-mediated diseases and to identify novel genetic markers associated with susceptibility to autoimmune blistering diseases and with disease severity and response to immunosuppressive therapies.

Causal relationships between dyslexia and the risk of eight dementias

Observational and genetic studies have reported the relationship between dyslexia and Alzheimer’s disease (AD). Until now, the causal effect of dyslexia on AD risk has remained unclear. We conducted a two-sample univariable Mendelian randomization (MR) analysis to determine the causal association between dyslexia and the risk of AD, vascular dementia (VD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) and its four subtypes. First, we selected 42 dyslexia genetic variants from a large-scale genome-wide association studies (GWAS) dataset and extracted their corresponding GWAS summary statistics from AD, VD, LBD, and FTD. Second, we selected four MR methods, including inverse-variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO. Heterogeneity, horizontal pleiotropy, and leave-one-out sensitivity analysis were then used to evaluate the reliability of all causal estimates. We also conducted multivariable MR (MVMR) and mediation analysis to assess the potential mediating role of cognitive performance (CP) or educational achievement (EA) on the causal association between dyslexia and AD. Two MVMR methods, including MV IVW and MV-Egger, and two-step MR were used to perform the analysis. Using IVW, we found a significant causal association between increased dyslexia and increased risk of AD (OR = 1.15, 95% CI: 1.04–1.28, P = 0.006), but not VD, LBD, FTD, or its four subtypes. MR-PRESSO further supported the statistically significant association between dyslexia and AD (OR = 1.15, 95% CI: 1.05–1.27, P = 0.006). All sensitivity analyses confirmed the reliability of causal estimates. Using MV IVW and mediation analysis, we found no causal relationship between dyslexia and AD after adjusting for CP but not EA, CP mediated the total effect of dyslexia on AD with a proportion of 46.32%. We provide genetic evidence to support a causal effect of increased dyslexia on increased risk of AD, which was largely mediated by CP. Reading activity may be a potential intervention strategy for AD by improving cognitive function.

Cross-EHR validation of antidepressant response algorithm and links with genetics of psychiatric traits.

Antidepressants are commonly prescribed medications in the United States, however, factors underlying response are poorly understood. Electronic health records (EHRs) provide a cost-effective way to create and test response algorithms on large, longitudinal cohorts. We describe a new antidepressant response algorithm, validation in two independent EHR databases, and genetic associations with antidepressant response. We deployed the algorithm in EHRs at Vanderbilt University Medical Center (VUMC), the All of Us Research Program, and the Mass General Brigham Healthcare System (MGB) and validated response outcomes with patient health questionnaire (PHQ) scores. In a meta-analysis across all sites, worse antidepressant response associated with higher PHQ-8 scores (beta = 0.20, p-value = 1.09 x 10 -18 ). We used polygenic scores to investigate the relationship between genetic liability of psychiatric disorders and response to first antidepressant trial across VUMC and MGB. After controlling for depression diagnosis, higher polygenic scores for depression, schizophrenia, bipolar, and cross-disorders associated with poorer response to the first antidepressant trial (depression: p-value = 2.84 x 10 -8 , OR = 1.07; schizophrenia: p-value = 5.93 x 10 -4 , OR = 1.05; bipolar: p-value = 1.99 x 10 -3 , OR = 1.04; cross-disorders: p-value = 1.03 x 10 -3 , OR = 1.05). Overall, we demonstrate our antidepressant response algorithm can be deployed across multiple EHR systems to increase sample size of genetic and epidemiologic studies of antidepressant response.

ISOLATION AND ANALYSIS OF NATIVE DNA AND RNA FROM ROOTS OF RUBBER-PRODUCING SPECIES SCORZONERA TAU-SAGHYZ LIPSCH. ET G.G. BOSSE

Scorzonera tau-saghyz Lipsch. et G.G.Bosse, is endemic species, growing in South Kazakhstan and alternative (to Hevea brasilians) source of natural rubber, related to the Asteraceae Family. Natural rubber (NR) is an indispensable raw material for the production of different products for medicine, automotive and aviation industries. The introduction of tau-saghyz into the culture will make it possible to obtain NC not only in Kazakhstan, but also on the territory of the countries of the Northern latitudes. At the growing phases of ontogenesis of tau-saghyz (April-June) latex is actively synthesized in the leaves and transported to the roots. In our experiments it was necessary to conduct molecular genetic studies of the selected forms of tau-saghyz with high rubber concentration. In this regard, it became necessary to isolate and analyze native DNA and RNA from dry roots. Samples with the highest rubber content were used for DNA extraction. The main problem in the isolation of DNA from the dry roots of tau-saghyz is the significant content of natural rubber. In this research the following commercial kits were used: 1) DNeasy Plant Mini Kit (Qiagene); 2) GenElute Plant Genomic DNA Miniprep Kit (Sigma); 3) NucleoSpin® Plant II / Midi / Maxi kit (Macherey-Nagel). Further DNA isolation was carried out in accordance with the kit manufacturer's protocol. Quantitative DNA analysis was performed using both UV spectrophotometry (Nanodrop) and fluorometric analysis (Qubit) method. DNA extracted by the 2 kit (Sigma) was further purified by precipitation with ethanol and demonstrates satisfactory quality. Functional analysis of isolated DNA samples was performed both by restriction analysis and by DNA amplification. It is worth to mention that for reaction primers that are characteristic of gene AACT (ACETOACETYL-COA TRANSFERASE) Cucumis melo were used. This enzyme catalyzes the first reaction of biosynthesis in the mevalonate pathway, which the final product is IDP (isopentenyl diphosphate). The cis-prenyltransferase (CPT) enzyme catalyzes the biosynthesis of rubber by the sequential addition of IDP to the terminal group of the initiating allylic pyrophosphate (APP). As a result of PCR analysis a putative 1200 bp AAST gene for tau-saghyz was identified. In this study two methods of RNA isolation were chosen: 1. A method widely used for plants of the Cucurbitaceae family; 2. A method approved for plants with a high content of polyphenols. The RNA isolation was carried out as described in the relevant protocols with minor modifications (Verwoerd TC, Dekker BMM, Hoekema A (1989) A small-scale procedure for the rapid isolation of plant RNAs. Nucleic Acids Res 17:2362). The final precipitates were dissolved in 50 µl of water pretreated with diethylpyrocarbonate. Quantitative analysis of RNA was carried out using UV spectrophotometry (Nanodrop). Functional analysis of extracted RNA samples was conducted by cDNA synthesis with usage of reverse transcriptase Superscript IV with the following amplification in PCR. In this reaction the primers specific for CPT gene of Taraxacum kok-saghyz were used. The prospective CPT gene was excised from the gel, purified and cloned into the pJET vector. In the further research it is planned to perform its sequencing and comparison with the CPT gene of Taraxacum kok-saghyz and Hevea brasiliensis.

Estimating carrier rates and prevalence of porphyria-associated gene variants in the Chinese population based on genetic databases

Porphyria is a group of rare metabolic disorders caused by mutations in the genes encoding crucial enzymes in the heme biosynthetic pathway. However, the lack of comprehensive genetic analysis of porphyria patients in the Chinese population makes identifying and diagnosing carriers of the condition challenging. Using the ChinaMAP database, we determined the frequencies of P/LP porphyria-associated gene variants according to the ACMG guidelines. We also calculated the carrier rates and prevalence of each type of porphyria in the Chinese population under Hardy–Weinberg equilibrium. Compared with the variants in the gnomAD database, the genetic spectrum of porphyria-related P/LP variants in the Chinese population is distinct. In the ChinaMAP database, we identified 23 variants. We estimated the carrier rates for autosomal dominant porphyrias (AIP, HCP, VP, PCT) in the Chinese population to be 1/1059, 1/1513, 1/10588, and 1/1765, respectively. For autosomal recessive porphyrias (ADP, EPP, HEP, CEP), the estimated carrier rates were 1/5294, 1/2117, 1/1765, and 1/2647, respectively, with predicted prevalence rates of 8.92 × 10−9, 7.51 × 10−5, 8.02 × 10−8, and 3.57 × 10−8, respectively. Notably, 12 of the variants we identified were unique to the Chinese population. The predicted prevalence rate of EPP was the highest among the various types of porphyria in the Chinese population, while the others were moderate to low. This is the first comprehensive genetic study on porphyria in the Chinese population. Clarifying the genetic characteristics of various porphyria types among the Chinese population provides scientifically sound reference data for both research and genetic screening to identify porphyria carriers.

Direct targets of MEF2C are enriched for genes associated with schizophrenia and cognitive function and are involved in neuron development and mitochondrial function.

Myocyte Enhancer Factor 2C (MEF2C) is a transcription factor that plays a crucial role in neurogenesis and synapse development. Genetic studies have identified MEF2C as a gene that influences cognition and risk for neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Here, we investigated the involvement of MEF2C in these phenotypes using human-derived neural stem cells (NSCs) and glutamatergic induced neurons (iNs), which represented early and late neurodevelopmental stages. For these cellular models, MEF2C function had previously been disrupted, either by direct or indirect mutation, and gene expression assayed using RNA-seq. We integrated these RNA-seq data with MEF2C ChIP-seq data to identify dysregulated direct target genes of MEF2C in the NSCs and iNs models. Several MEF2C direct target gene-sets were enriched for SNP-based heritability for intelligence, educational attainment and SCZ, as well as being enriched for genes containing rare de novo mutations reported in ASD and/or developmental disorders. These gene-sets are enriched in both excitatory and inhibitory neurons in the prenatal and adult brain and are involved in a wide range of biological processes including neuron generation, differentiation and development, as well as mitochondrial function and energy production. We observed a trans expression quantitative trait locus (eQTL) effect of a single SNP at MEF2C (rs6893807, which is associated with IQ) on the expression of a target gene, BNIP3L. BNIP3L is a prioritized risk gene from the largest genome-wide association study of SCZ and has a function in mitophagy in mitochondria. Overall, our analysis reveals that either direct or indirect disruption of MEF2C dysregulates sets of genes that contain multiple alleles associated with SCZ risk and cognitive function and implicates neuron development and mitochondrial function in the etiology of these phenotypes.

Development of a haplotype reference panel and analysis of genetic structure in Golden Pompano (Trachinotus ovatus)

Trachinotus ovatus, a valuable marine fish, is primarily farmed in the South China Sea. Intensive aquaculture can lead to genetic uniformity and disease risks. Additionally, the high cost of genome sequencing restricts knowledge of genetic variation, hindering genetic analysis and breeding advancements. This study investigated the genetic diversity and structure of Trachinotus ovatus populations within the South China Sea aquaculture context, with the goal of strengthening sustainability. Additionally, the study also enhanced breeding strategies by developing a high-quality haplotype reference panel and an efficient imputation process. Through high-throughput sequencing (depth＞20X), 173 samples from three key breeding sites (SanYa, Hainan; Zhanjiang, Guangdong; and Beihai, Guangxi) were analyzed, revealing substantial genetic diversity and distinct population structures. Notably, the Beihai (BH) population exhibited significant stratification, suggesting regional genetic uniqueness. Low levels of genomic inbreeding coefficient and the identification of unique SNP loci across populations underscored the genetic richness within these Trachinotus ovatus communities. A major constructed of this work is the creation of the first high-quality haplotype reference panel for the species, demonstrating genotype imputation's viability as a cost-effective alternative for large-scale genetic studies in aquaculture. In particular, a Shapeit reference panel with 5476,550 SNPs was created, excelling in accuracy across various depths, notably achieving up to 95.8 % imputation accuracy at 1X sequencing depth. This high accuracy across populations shows the importance of genetic diversity in the panel. This research not only advances the understanding of Trachinotus ovatus genetic foundations but also provides crucial insights for conservation efforts and genetic analysis. By establishing a robust haplotype reference panel for Trachinotus ovatus helps lower the costs of future genetic research and variation studies, this study lays the foundation for sustainable aquaculture practices and breeding programs.

Genetic links between ovarian ageing, cancer risk and de novo mutation rates

Human genetic studies of common variants have provided substantial insight into the biological mechanisms that govern ovarian ageing1. Here we report analyses of rare protein-coding variants in 106,973 women from the UK Biobank study, implicating genes with effects around five times larger than previously found for common variants (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1). The SAMHD1 association reinforces the link between ovarian ageing and cancer susceptibility1, with damaging germline variants being associated with extended reproductive lifespan and increased all-cause cancer risk in both men and women. Protein-truncating variants in ZNF518A are associated with shorter reproductive lifespan—that is, earlier age at menopause (by 5.61 years) and later age at menarche (by 0.56 years). Finally, using 8,089 sequenced trios from the 100,000 Genomes Project (100kGP), we observe that common genetic variants associated with earlier ovarian ageing associate with an increased rate of maternally derived de novo mutations. Although we were unable to replicate the finding in independent samples from the deCODE study, it is consistent with the expected role of DNA damage response genes in maintaining the genetic integrity of germ cells. This study provides evidence of genetic links between age of menopause and cancer risk.

Moya-Moya Disease in Basal Cortical Areas in a Man with a Family History of Vascular Disorders: A Case Report

Introduction: Moya-Moya disease (MMD) is a rare, chronic, and spontaneous steno-occlusive condition that leads to recurrent strokes due to the occlusion of the terminal internal carotid arteries. This article aims to highlight the significance of familial risk for MMD and other vascular disorders among first-degree relatives in Iran. Case Presentation: We report the case of a 55-year-old male who was admitted to our hospital with complaints of transient ischemic attack, left-sided hemiparesis, and decreased vision that occurred during the night. The initial diagnosis was a brain stem stroke. After undergoing digital subtraction angiography, he was diagnosed with MMD. Moya-Moya disease is a rare cause of cerebral stroke and is seldom reported in Iran. The patient was treated conservatively and had a favorable outcome. His family history was notable, with five of his eight siblings having various cardiovascular diseases. Conclusions: These findings may be useful for guiding future genetic studies and preventive counseling, with a focus on the clinical evaluation of serious adverse events.

High lipoprotein(a) is a risk factor for peripheral artery disease, abdominal aortic aneurysms, and major adverse limb events.

To summarize evidence from recent studies of high lipoprotein(a) as a risk factor for peripheral artery disease (PAD), abdominal aortic aneurysms (AAA), and major adverse limb events (MALE). Additionally, provide clinicians with 10-year absolute risk charts enabling risk prediction of PAD and AAA by lipoprotein(a) levels and conventional risk factors. Numerous studies support high lipoprotein(a) as an independent risk factor for PAD, AAA, and MALE. The strongest evidence is from the Copenhagen General Population Study (CGPS) and the UK Biobank, two large general population-based cohorts. In the CGPS, a 50 mg/dl higher genetically determined lipoprotein(a) associated with hazard ratios of 1.39 (1.24-1.56) for PAD and 1.21 (1.01-1.44) for AAA. Corresponding hazard ratio in the UK Biobank were 1.38 (1.30-1.46) and 1.42 (1.28-1.59). In CGPS participants with levels at least 99th (≥143 mg/dl) vs, less than 50th percentile (≤9 mg/dl), hazard ratios were 2.99 (2.09-4.30) for PAD and 2.22 (1.21-4.07) for AAA, with a corresponding incidence rate ratio for MALE of 3.04 (1.55-5.98) in participants with PAD. Evidence from both observational and genetic studies support high lipoprotein(a) as a causal risk factor for PAD, AAA, and MALE, and highlight the potential of future lipoprotein(a)-lowering therapy to reduce the substantial morbidity and mortality associated with these diseases.

Vein of galen malformations: for patients and caregivers.

Vein of Galen malformations (VOGMs), also known as Vein of Galen Aneurysmal Malformations (VGAMs), are rare and complex cerebrovascular anomalies that pose significant diagnostic and therapeutic challenges. These malformations result from abnormal arteriovenous shunts during embryonic development, leading to a range of severe clinical manifestations, including high-output cardiac failure and hydrocephalus. Advances in prenatal imaging, particularly fetal MRI, have improved early detection, allowing for timely intervention. Endovascular techniques, especially transarterial embolization, have become the primary treatment modality, often preferred over surgical approaches due to their effectiveness and lower risk. However, challenges remain, particularly in managing these malformations in neonates and infants, where the risk of complications is high. Gamma Knife radiosurgery offers a non-invasive alternative for select cases, though its effects are gradual and may carry delayed risks. Despite advancements, the management of VOGMs continues to require a multidisciplinary approach, with ongoing research focused on improving outcomes through a better understanding of the genetic and molecular underpinnings of the disease. Future directions include the integration of genetic studies into clinical practice and the refinement of treatment strategies to optimize outcomes for this complex condition.

Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C

Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system1. Human genetic studies have established a causal role for protein assembly in neurodegeneration2. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in cryo-electron microscopy have enabled the structures of the protein filaments to be determined from the brains of patients1. All neurodegenerative diseases studied to date have been characterized by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) types A and B3,4. Here we used cryo-electron microscopy to determine filament structures from the brains of individuals with FTLD-TDP type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284–N345 and ANXA11 residues L39–Y74 from their respective low-complexity domains. Regions of TDP-43 and ANXA11 that were previously implicated in protein–protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as an approximately 22 kDa N-terminal fragment lacking the annexin core domain. Immunohistochemistry of brain sections showed the colocalization of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP type C. This work establishes a central role for ANXA11 in FTLD-TDP type C. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.

High-nitrogen-induced γ-aminobutyric acid triggers host immunity and pathogen oxidative stress tolerance in tomato and Ralstonia solanacearum interaction.

Soil nitrogen (N) significantly influences the interaction between plants and pathogens, yet its impact on host defenses and pathogen strategies via alterations in plant metabolism remains unclear. Through metabolic and genetic studies, this research demonstrates that high-N-input exacerbates tomato bacterial wilt by altering γ-aminobutyric acid (GABA) metabolism of host plants. Under high-N conditions, the nitrate sensor NIN-like protein 7 (SlNLP7) promotes the glutamate decarboxylase 2/4 (SlGAD2/4) transcription and GABA synthesis by directly binding to the promoters of SlGAD2/4. The tomato plants with enhanced GABA levels showed stronger immune responses but remained susceptible to Ralstonia solanacearum. This led to the discovery that GABA produced by the host actually heightens the pathogen's virulence. We identified the R. solanacearum LysR-type transcriptional regulator OxyR protein, which senses host-derived GABA and, upon interaction, triggers a response involving protein dimerization that enhances the pathogen's oxidative stress tolerance by activating the expression of catalase (katE/katGa). These findings reveal GABA's dual role in activating host immunity and enhancing pathogen tolerance to oxidative stress, highlighting the complex relationship between tomato plants and R. solanacearum, influenced by soil N status.

Causal roles of skin and gut microbiota in skin appendage disorders suggested by genetic study.

There is evidence from observational studies that human microbiota is linked to skin appendage Disorders (SADs). Nevertheless, the causal association between microbiota and SADs is yet to be fully clarified. A comprehensive two-sample Mendelian randomization (MR) was first performed to determine the causal effect of skin and gut microbiota on SADs. A total of 294 skin taxa and 211 gut taxa based on phylum, class, order, family, genus, and ASV level information were identified. Summary data of SADs and eight subtypes (acne vulgaris, hidradenitis suppurativa, alopecia areata, rogenic alopecia, rosacea, rhinophyma, seborrhoeic dermatitis, and pilonidal cyst) were obtained from the FinnGen consortium. We performed bidirectional MR to determine whether the skin and gut microbiota are causally associated with multiple SADs. Furthermore, sensitivity analysis was conducted to examine horizontal pleiotropy and heterogeneity. A total of 65 and 161 causal relationships between genetic liability in the skin and gut microbiota with SADs were identified, respectively. Among these, we separately found 5 and 11 strong causal associations that passed Bonferroni correction in the skin and gut microbiota with SADs. Several skin bacteria, such as Staphylococcus, Streptococcus, and Propionibacterium, were considered associated with multiple SADs. As gut probiotics, Bifidobacteria and Lactobacilli were associated with a protective effect on SAD risk. There was no significant heterogeneity in instrumental variables or horizontal pleiotropy. Our MR analysis unveiled bidirectional causal relationships between SADs and the gut and skin microbiota, and had the potential to offer novel perspectives on the mechanistic of microbiota-facilitated dermatosis.

The evolutionary theory of cancer: challenges and potential solutions.

The clonal evolution model of cancer was developed in the 1950s-1970s and became central to cancer biology in the twenty-first century, largely through studies of cancer genetics. Although it has proven its worth, its structure has been challenged by observations of phenotypic plasticity, non-genetic forms of inheritance, non-genetic determinants of clone fitness and non-tree-like transmission of genes. There is even confusion about the definition of a clone, which we aim to resolve. The performance and value of the clonal evolution model depends on the empirical extent to which evolutionary processes are involved in cancer, and on its theoretical ability to account for those evolutionary processes. Here, we identify limits in the theoretical performance of the clonal evolution model and provide solutions to overcome those limits. Although we do not claim that clonal evolution can explain everything about cancer, we show how many of the complexities that have been identified in the dynamics of cancer can be integrated into the model to improve our current understanding of cancer.

Generation Scotland – Linking all the records we can

ObjectivesGeneration Scotland (GS) is a family-based genetic epidemiology study. Initial recruitment between 2006-11 recruited ~24,000 adults from ~7000 families across Scotland with consent for medical record linkage and re-contact. In 2022 we began recruiting another 20,000, with consent extended to administrative records, with age range now 12+. MethodsOriginal volunteers completed a baseline questionnaire, provided biological samples and underwent clinical assessment. The samples, phenotype and genotype (including methylation) data are linked to routine NHS hospital, maternity, lab test, prescriptions, dentistry, mortality, imaging, cancer screening, GP data records, Covid-19 testing and vaccinations, and follow-up questionnaires. The new wave of recruitment is all online and can be done on a smartphone, with DNA from saliva collected by post. Teenagers aged 12-15 can join with parental consent. ResultsResearchers can find prevalent and incident disease cases and controls, to test research hypotheses on a stratified population. GS is a vanguard cohort testing emerging linkage opportunities in Scotland – including neonatal bloodspots and medical imaging reports. GS has established and validated E-HR linkage with the NHS Scotland CHI Register, overcoming technical and governance issues in the process. We contribute to major international consortia, with collaborators from institutions worldwide, both academic and commercial. ConclusionWe plan to extend the linkage process to include other administrative data from national datasets as and when approvals are obtained. New types of data can also be collected by online questionnaires. The Research Tissue Bank resources are available to academic and commercial researchers through a managed access process.

Generation Scotland Teenage Recruitment – Creating, evaluating and evolving a study sign-up process in collaboration with study participants and young people

ObjectivesGeneration Scotland (GS) is a family-based genetic epidemiology study. Initial recruitment was ~24,000 adult volunteers from across Scotland in 2006-11 with consent for medical record linkage and re-contact. In 2022 we began recruiting another 20,000, with consent extended to administrative records, with age range now 12+. MethodsPeople join the study and complete a questionnaire online, with postal saliva sample collection for DNA. Initially, the consent process required a parent/guardian to join GS, confirm their 12-15 year-old’s capacity for enduring consent and invite their child to join. After launch, parents and young people fed back that the communication and consent methods had a negative effect on the ability of young people to join GS - impacting their autonomy, as they were unable join GS independently of their parents. ResultsThe GS Team designed a new sign-up process for 12–15 year-olds that allowed the teenager to sign up first and request that their parent agree they have capacity to consent. Creating this process was done in collaboration with the new GS YPAG. This new sign-up process was launched in September 2023. We also enabled sign-up using a mobile phone number instead of an email address. ConclusionCo-design of GS recruitment with young people and parents has greatly improved the sign-up process, making GS the first UK longitudinal study where people aged 12-15 can provide enduring consent online with parental confirmation of their capacity. This provides young people with greater ownership over their ability to take part in health research.

The genetics of plant-plant interactions and their cascading effects on agroecosystem - from model plants to application.

Plants are typically surrounded by neighboring individuals in agricultural fields or natural environments. In such circumstances, plant-plant interactions (PPI) are ubiquitous and represent not only important evolutionary forces but also have consequences on (agro-)ecosystem functioning, such as increased productivity and resistance. However, many mechanisms underlying these PPIs remain poorly understood. Recently, new genomic technologies and tools, such as genome-wide association studies, have facilitated genetic approaches to study PPIs, particularly among conspecific individuals. Here, we highlight emerging issues and advances in the field by focusing on three different aspects. First, we overview the current status of genetic mapping studies on PPIs and pinpoint that these studies open a new opportunity that is relevant to agriculture and breeding. Second, we introduce two proof-of-concept studies in Arabidopsis thaliana, in which genetic differences among plants improved the functioning of genotype mixtures. Both studies were able to predict effective mixtures with different experimental designs applied to different outcomes (productivity increase vs. herbivory mitigation). Third, we discuss implications from these case studies about how PPIs have cascading effects that propagate to higher levels of biological organization, such as populations or communities. At the population level, plant yield or resistance can be optimized through breeding that achieves reduced competition or push-pull protection systems, respectively. At the community level, these population-level changes may have further beneficial effects on plant-associated organisms. Overall, we suggest that the increasing availability of genomic resources will improve our understanding of PPIs and thereby contribute to the management of crops or semi-natural ecosystems.

Photoexcited Cryptochrome 1 Interacts With SPCHLESS to Regulate Stomatal Development in Arabidopsis.

Stomata are epidermal openings that facilitate plant-atmosphere gas and water exchange during photosynthesis, respiration and water evaporation. SPEECHLESS (SPCH) is a master basic helix-loop-helix (bHLH) transcription factor that determines the initiation of stomatal development. It is known that blue light promotes stomatal development through the blue light photoreceptor cryptochromes (CRYs, CRY1 and CRY2). Whether CRYs regulate stomatal development through directly modulating SPCH is unknown. Here, we demonstrate by biochemical studies that CRY1 physically interacts with SPCH in a blue light-dependent manner. Genetic studies show that SPCH acts downstream of CRY1 to promote stomatal development in blue light. Furthermore, we show that CRY1 enhances the DNA-binding activity of SPCH and promotes the expression of its target genes in blue light. These results suggest that the mechanism by which CRY1 promotes stomatal development involves positive regulation of the DNA-binding activity of SPCH, which is likely mediated by blue light-induced CRY1-SPCH interaction. The precise regulation of SPCH DNA-binding activity by CRY1 may allow plants to optimize stomatal density and pattern according to ambient light conditions.