Biology subjects

Wright, J.

Publications and source records attributed to Wright, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Hidden rAAV Breakpoints Detected Using Single-Molecule, Modified Base Sequencing

The AAV genome is a single stranded DNA molecule packaged in an icosahedral protein capsid. Vector genomes of plus and minus polarities are packaged and complementary genomic strands hybridize when lysed in vitro. Standard sequencing library methods cause loss of information from individual genomes when mismatches and gaps are repaired. To retain original molecular information, modified bases are used during the repair step which allows pre-existing DNA to be distinguished from DNA added during library preparation. Modified bases introduced during repair are identified using the Sequel II system and used to detect HIDdEN DNA breakpoints (HIDEN-Seq). The most frequent breakpoints in an AAV vector subject to high strand breakage during packaging were linked to adjacent secondary structure, prompting changes in nearby sequences to reduce breakage. This use of modified bases for localizing DNA breaks enables better vector design, resulting in higher quality gene therapy vectors. The same approach can be used in other systems where knowledge of pre-existing sequence and structure is important.

genomics↗

bioRxiv2023

Transcriptional profiling of peripheral blood mononuclear cells identifies inflammatory phenotypes in ataxia telangiectasia

Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy. MethodsParticipants with stable A-T (n=90) were recruited and compared with unaffected controls (n=15). PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features. ResultsPeople with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4+ T cells and CD8+ T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls. ConclusionUsing an unbiased transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy.

immunology↗

bioRxiv2023

Structural and biophysical analysis of a Haemophilus influenzae tripartite ATP-independent periplasmic (TRAP) transporter

Tripartite ATP-independent periplasmic (TRAP) transporters are secondary-active transporters that receive their substrates via a soluble binding protein to move bioorganic acids across bacterial or archaeal cell membranes. Recent cryo-EM structures of TRAP transporters provide a broad framework to understand how they work, but the mechanistic details of transport are not yet defined. Here we report the cryo-EM structure of the Haemophilus influenzae N-acetylneuraminate TRAP transporter (HiSiaQM) at 2.99 [A] resolution (extending to 2.2 [A] at the core), revealing new features. The improved resolution (the previous HiSiaQM structure is 4.7 [A] resolution) permits accurate assignment of two Na+ sites and the architecture of the substrate binding site, consistent with mutagenic and functional data. Moreover, rather than a monomer, the HiSiaQM structure is a homodimer. We observe lipids at the dimer interface, as well as a lipid trapped within the fusion that links the SiaQ and SiaM subunits. We show that the affinity (KD) for the complex between the soluble HiSiaP protein and HiSiaQM is in the micromolar range and that a related SiaP can bind HiSiaQM. This work provides key data that enhances our understanding of the elevator-with-an-operator mechanism of TRAP transporters.

biochemistry↗

bioRxiv2023

Genome-wide assays to characterize rAAV integration into human genomic DNA in vivo

Adeno-associated viral (AAV) vectors are used to treat genetic diseases, expressing therapeutic genes from both extrachromosomal episomes and payloads that integrate into the host genome. Assays were developed to evaluate HR-mediated on-target integration and the potential occurrence of off-target integration. While many studies have addressed elements of these processes, proper characterization requires long-read sequencing to ensure that integrated viral DNA is examined and not the more prevalent episomes. We used Oxford Nanopore to characterize integrated DNA and scan the whole genome for off-target integrations. These assays were applied to cell-based and in vivo models to study vectors that correct phenylketonuria (PKU), caused by loss of phenylalanine hydroxylase (PAH). Administration of the human-specific vector in a humanized-liver mouse xenograft model resulted in stable, nuclease-free integration into PAH. Because detection of rare integration events in a much larger pool of episomal DNA is subject to artifacts, careful assay validation was required. A long-read, genome-wide assay capable of detecting on- and off-target vector integrations showed no evidence of off-target integration. Artifactual false positive events were below the limit of blank. These data support rAAV as an investigational therapeutic for genetic diseases and reinforce the need for characterization of integration assays to avoid artifacts.

genomics↗

bioRxiv2023

Ancient Mongolian aurochs genomes reveal sustained introgression and management in East Asia

Societies in East Asia have utilized domesticated cattle for over 5000 years, but the genetic history of cattle in East Asia remains understudied. Genome-wide analyses of 23 ancient Mongolian cattle reveal that East Asian aurochs and ancient East Asian taurine cattle are closely related, but neither are closely related to any modern East Asian breeds. We observe binary variation in aurochs diet throughout the early Neolithic, and genomic evidence shows millennia of sustained male-dominated introgression. We identify a unique connection between ancient Mongolian aurochs and the European Hereford breed. These results point to the likelihood of human management of aurochs in Northeast Asia prior to and during the initial adoption of taurine cattle pastoralism. One-Sentence SummaryAncient interbreeding of East Asian aurochs and cattle suggests management, but leaves no signature in modern eastern breeds.

genomics↗

bioRxiv2023

Hypoxia delays steroid-induced developmental maturation in Drosophila by suppressing EGF signaling.

Animals often grow and develop in unpredictable environments where factors like food availability, temperature, and oxygen levels can fluctuate dramatically. To ensure proper sexual maturation into adulthood, juvenile animals need to adapt their growth and developmental rates to these fluctuating environmental conditions. Failure to do so can result in impaired maturation and incorrect body size. Here we describe a mechanism by which Drosophila larvae adapt their development in low oxygen (hypoxia). During normal development, larvae grow and increase in mass until they reach critical weight (CW), after which point a neuroendocrine circuit triggers the production of the steroid hormone ecdysone from the prothoracic gland (PG), which promotes maturation to the pupal stage. However, when raised in hypoxia (5% oxygen), larvae slow their growth and delay their maturation to the pupal stage. We find that, although hypoxia delays the attainment of CW, the maturation delay occurs mainly because of hypoxia acting late in development to suppress ecdysone production. This suppression operates through a distinct mechanism from nutrient deprivation, occurs independently of HIF-1 alpha and does not involve modulation of PTTH, the main neuropeptide that initiates ecdysone production in the PG. Instead, we find that hypoxia lowers the expression of the EGF ligand, spitz, and that the delay in maturation occurs due to reduced EGFR/ERK signaling in the PG. Our study sheds light on how animals can adjust their development rate in response to changing oxygen levels in their environment. Given that hypoxia is a feature of both normal physiology and many diseases, our findings have important implications for understanding how low oxygen levels may impact animal development in both normal and pathological situations.

developmental biology↗

bioRxiv2022

The small-bat-in-summer paradigm: energetics and adaptive behavioural routines of bats investigated through a stochastic dynamic model

Strong seasonality at high latitudes represents a major challenge for many endotherms as they must balance survival and reproduction in an environment that varies widely in food availability and temperature. Being heterotherms, bats spend long cold winters in hibernation, avoiding the challenges faced by many animals. To avoid energetic mismatches caused by limited foraging time and stochastic weather conditions, bats can also employ this energy-saving state of torpor during summer to save accumulated energy reserves. However, at high latitudes small-bats-in-summer face a particular challenge: as nocturnal foragers they rely on the darkness of the night to avoid predators and/or interspecific competition, but for many the summer involves short nights of mostly twilight, and even a lack of true night at the northernmost distributions of some bat species. To investigate optimal individual behaviour across diurnal cycles, we constructed a stochastic dynamic model of bats living at high latitudes. Using a detailed parameterized model framework with values that are representative for our study system, we show that individual energetic reserves are a strong driver of day-time use of torpor and night-time foraging behaviour alike, with these linked effects being both temperature and photoperiod dependent. We further used the model framework to predict survival probabilities at five locations across a latitudinal gradient (60.1{degrees}N to 70.9{degrees}N), finding that photoperiod is the main limiting factor to bat species distributions. To verify the accuracy of our model results, we compared predictions for optimal decisions with our own empirical data collected on northern bats (Eptesicus nilssonii) from two latitudes in Norway. The similarities between our predictions and observations provide strong confirmation that this model framework incorporates the most important drivers of diurnal decision-making in bat physiology and behaviour. Our model findings regarding state-dependent decisions in bats should therefore contribute to the understanding of how bats cope with the summer challenges at high latitudes.

ecology↗

bioRxiv2022

CDK4/6 inhibition and dsRNA sensor agonism co-operate to enhance anti-cancer effects through ER stress and immune modulation of tumour cells

Cytoplasmic pattern recognition receptors (PRRs) for double-stranded RNA (RIG-I/MDA5) are key mediators of anti-viral responses. PRR agonists, such as dsRNA oncolytic Reovirus type 3 Dearing (Rt3D), potently activate RNA sensors. We used an unbiased cytotoxicity screen to reveal synergistic drug-virotherapy combinations and found potent effects of Rt3D combined with the CDK4/6 inhibitor, palbociclib. The combination augmented oncolytic virus-induced endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and the expression and activation/signaling of RNA sensors. Combined Rt3D-palbociclib treatment potently increased interferon production and signaling, and knockdown studies implicated key UPR proteins and the RNA sensor, RIG-I, as essential to the phenotype observed. Further experiments, using canonical RIG-I agonists and an ER stress inducer, thapsigargin, confirmed cross-talk between RNA sensing and ER stress pathways that augmented cancer cell death and interferon production. Combined Rt3D-palbociclib also increased innate immune activation within tumour cells and IFN-induced HLA expression. Analysis of the immunopeptidome revealed changes to HLA-captured peptides with Rt3D-palbociclib, including altered expression of peptides from cancer/testis antigens (CTA) and endogenous retroviral elements (ERVs). Our findings highlight cross-talk between UPR signaling and RNA-mediated PRR activation as a means of enhancing anti-cancer efficacy with potential pro-immunogenic consequences. This has implications for future clinical development of PRR agonists and oncolytic viruses, and broadens the therapeutic remit of CDK4/6 inhibitors to include roles as both ER stress and dsRNA PRR sensitizers.

cancer biology↗

bioRxiv2022

NANOGP1, a tandem duplicate of NANOG, exhibits partial functional conservation in human naive pluripotent stem cells

Gene duplication events are important drivers of evolution by providing genetic material for new gene functions. They also create opportunities for diverse developmental strategies to emerge between species. To study the contribution of duplicated genes to human early development, we examined the evolution and function of NANOGP1, a tandem duplicate of the key transcription factor NANOG. We found that NANOGP1 and NANOG have overlapping but distinct expression profiles, with high NANOGP1 expression restricted to early epiblast cells and naive-state pluripotent stem cells. Sequence analysis and epitope-tagging of the endogenous locus revealed that NANOGP1 is protein-coding with an intact homeobox domain. NANOGP1 has been retained only in great apes, whereas Old World monkeys have disabled the gene in different ways including point mutations in the homeodomain. NANOGP1 is a strong inducer of naive pluripotency; however, unlike NANOG, it is not required to maintain the undifferentiated status of human naive pluripotent cells. By retaining expression, sequence and partial functional conservation with its ancestral copy, NANOGP1 exemplifies how gene duplication and subfunctionalisation can contribute to transcription factor activity in human pluripotency and development. Summary statementEstablishing that NANOGP1 has retained partial functional conservation with its ancestral copy NANOG sheds light on the role of gene duplication and subfunctionalisation in human pluripotency and development.

developmental biology↗

bioRxiv2022

Primary Omicron infection elicits weak antibody response but robust cellularimmunity in children

Omicron variants of SARS-CoV-2 are globally dominant and infection rates are very high in children. We determined immune responses following Omicron BA.1/2 infection in children aged 6-14 years and related this to prior and subsequent SARS-CoV-2 infection or vaccination. Primary Omicron infection elicited a weak antibody response with poor functional neutralizing antibodies. Subsequent Omicron reinfection or COVID-19 vaccination elicited increased antibody titres with broad neutralisation of Omicron subvariants. Prior pre-Omicron SARS-CoV-2 virus infection or vaccination primed for robust antibody responses following Omicron infection but these remained primarily focussed against ancestral variants. Primary Omicron infection thus elicits a weak antibody response in children which is boosted after reinfection or vaccination. Cellular responses were robust and broadly equivalent in all groups, providing protection against severe disease irrespective of SARS-CoV-2 variant. Immunological imprinting is likely to act as an important determinant of long-term humoral immunity, the future clinical importance of which is unknown.

immunology↗

bioRxiv2022

Disentangling the genomic complexity of the Fragilariopsis cylindrus (CCMP1102) genome

Fragilariopsis cylindrus CCMP1102 is characterised by a complex genome with significant levels of heterozygosity between haplotypes, > 35% repeats, and an unknown karyotype. This complexity hindered prior assemblies, which show coverage discrepancies indicative of incompleteness. Here, we use a k-mer spectra analysis to reveal the coverage signature for a third haplotype. We applied a novel haplotype-specific assembly method to reconstruct the F. cylindrus CCMP1102 genome, producing 10 fully assembled chromosomes capped by telomeres, and a putative chromosome with a single breakpoint. Our analysis shows triploidy, two cases of aneuploidy, and several truncations. We also present evidence that F. cylindrus reproduces sexually. Taken together, our analytical approach is capable of haplotype-resolved assemblies from structurally complex, poly-ploid genomes, making it suitable for complex genomes of non-model organisms, including those with unknown karyotype.

genomics↗

bioRxiv2022

Proteogenomic characterization of age and sex interactions in cardiac gene expression

The risks of heart diseases are significantly modulated by biological age and sex, but how these factors influence baseline cardiac gene expression remains incompletely understood. Here we characterized young adult and early aging mouse hearts using proteogenomics to identify age and sex dependent gene expression signatures in the mouse heart. RNA sequencing from 4 months old and 20 months old female and male C57BL/6J hearts identified thousands of genes with differential transcript abundances both between sexes (male vs. female) and across age groups (20 mo. vs. 4 mo.). Sex-associated cardiac genes are broadly distributed, functioning in the TCA cycle, mitochondrial translation, autophagy, and other processes. In addition, we found over 800 genes with differential aging response between male and female, which are enriched in calmodulin signaling and cell cycle regulations. Comparison with mass spectrometry data shows a cluster of metabolism genes with up-regulated transcripts but down-regulated protein levels in aging hearts, consistent with an uncoupling of transcriptional regulations in the genetic program with protein compositions. An analysis of sex-adjusted aging cardiac transcriptomes further revealed widespread remodeling of exon usage patterns that is largely independent from differential gene expression, concomitant with upstream changes in RNA-binding protein and splice factor transcripts. To evaluate the potential impact of the splicing events on proteoform composition in the heart, we applied an RNA-guided-proteomics computational pipeline to analyze the mass spectrometry data, and putatively identified hundreds of splice events with the potential to rewire the cardiac proteome through producing detectable splice isoform specific peptides. Taken together, this study contributes to emerging evidences for considerable sexual dimorphism in the cardiac aging process involving sex-biased aging genes and regulatory networks. Aging hearts are associated with a rewiring of RNA splicing programs, including sex- and age-dependent changes in exon usages and splice patterns that have the potential to influence cardiac protein structure and function. These changes represent an under-investigated aspect of cardiac aging that should be considered in the search for disease mechanisms.

physiology↗

bioRxiv2022

Charting functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders

Targeted protein degradation is a new pharmacologic paradigm established by drugs that recruit target proteins to E3 ubiquitin ligases via a ternary ligase-degrader-target complex. Based on the structure of the degrader and the neosubstrate, different E3 ligase interfaces are critically involved in this process, thus forming defined "functional hotspots". Understanding disruptive mutations in functional hotspots informs on the architecture of the underlying assembly, and highlights residues prone to cause drug resistance. Until now, their identification was driven by structural methods with limited scalability. Here, we employ haploid genetics to show that hotspot mutations cluster in the substrate receptors of the hijacked ligases and find that type and frequency of mutations are shaped by the essentiality of the harnessed ligase. Intersection with deep mutational scanning data revealed hotspots that are either conserved, or specific for chemically distinct degraders or recruited neosubstrates. Biophysical and structural validation suggest that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we identified and validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and experimentally widely accessible methodology that empowers the characterization of small-molecule degraders and informs on associated resistance mechanisms.

molecular biology↗

bioRxiv2021

Pre-clinical validation of an RNA-based precision oncology platform for patient-therapy alignment in a diverse set of human malignancies resistant to standard treatments

Predicting tumor sensitivity to antineoplastics remains an elusive challenge, with no methods demonstrating predictive power. Joint analysis of tumors--from patients with distinct malignancies who had progressed on multiple lines of therapy--and drug perturbation transcriptional profiles predicted sensitivity to 28 of 350 drugs, 26 of which (93%) were confirmed in low-passage, patient-derived xenograft (PDX) models. Drugs were prioritized based on their ability to either invert the activity of individual Master Regulator proteins, with available high-affinity inhibitors, or of the modules they comprise (Tumor-Checkpoints), based on de novo mechanism of action analysis. Of 138 PDX mice enrolled in 16 single and 18 multi-protein treatment arms, a disease control rate (DCR) of 68% and 91 %, and an objective response rate (ORR) of 12% and 17%, were achieved respectively, compared to 6% and 0% in the negative controls arm, with multi-protein drugs achieving significantly more durable responses. Thus, these approaches may effectively complement and expand current precision oncology approaches, as also illustrated by a case study.

systems biology↗

bioRxiv2021

A Fully Implantable Wireless Bidirectional Neuromodulation System for Mice

Novel research in the field of bioelectronic medicine requires systems that pair high-performance neurostimulation and bio-signal acquisition hardware with advanced software signal processing and control algorithms. Although mice are the most commonly used animal in medical research, the size, weight, and power requirements of such systems either preclude their use or impose significant constraints on experimental design. Here, we describe a fully-implantable neuromodulation system suitable for use in mice, measuring 2.2 cm3 and weighing 2.8 g. A bidirectional wireless interface allows simultaneous readout of multiple physiological signals and complete control over stimulation parameters, and a wirelessly rechargeable battery provides a lifetime of up to 5 days on a single charge. The device was successfully implanted (N=12) and a functional neural interface (capable of inducing acute bradycardia) is demonstrated with functional lifetimes exceeding to three weeks. The design utilizes only commercially-available components and 3D-printed packaging, with the goal of accelerating discovery and translation of future bioelectronic therapeutics.

bioengineering↗

bioRxiv2021

Multi-tissue integrative analysis of personal epigenomes

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of personal epigenomes, for [~]25 tissues and >10 assays in four donors (>1500 open-access functional genomic and proteomic datasets, in total). Each dataset is mapped to a matched, diploid personal genome, which has long-read phasing and structural variants. The mappings enable us to identify >1 million loci with allele-specific behavior. These loci exhibit coordinated epigenetic activity along haplotypes and less conservation than matched, non-allele-specific loci, in a fashion broadly paralleling tissue-specificity. Surprisingly, they can be accurately modelled just based on local nucleotide-sequence context. Combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci and enables models for transferring known eQTLs to difficult-to-profile tissues. Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

genomics↗

bioRxiv2021

Plasma microbiome in COVID-19 subjects: an indicator of gut barrier defects and dysbiosis

The gut is a well-established route of infection and target for viral damage by SARS-CoV-2. This is supported by the clinical observation that about half of COVID-19 patients exhibit gastrointestinal (GI) symptoms. We asked whether the analysis of plasma could provide insight into gut barrier dysfunction in patients with COVID-19 infection. Plasma samples of COVID-19 patients (n=30) and healthy control (n=16) were collected during hospitalization. Plasma microbiome was analyzed using 16S rRNA sequencing, metatranscriptomic analysis, and gut permeability markers including FABP-2, PGN and LPS in both patient cohorts. Almost 65% (9 out 14) COVID-19 patients showed abnormal presence of gut microbes in their bloodstream. Plasma samples contained predominately Proteobacteria, Firmicutes, and Actinobacteria. The abundance of gram-negative bacteria (Acinetobacter, Nitrospirillum, Cupriavidus, Pseudomonas, Aquabacterium, Burkholderia, Caballeronia, Parabhurkholderia, Bravibacterium, and Sphingomonas) was higher than the gram-positive bacteria (Staphylococcus and Lactobacillus) in COVID-19 subjects. The levels of plasma gut permeability markers FABP2 (1282{+/-}199.6 vs 838.1{+/-}91.33; p=0.0757), PGN (34.64{+/-}3.178 vs 17.53{+/-}2.12; p<0.0001), and LPS (405.5{+/-}48.37 vs 249.6{+/-}17.06; p=0.0049) were higher in COVID-19 patients compared to healthy subjects. These findings support that the intestine may represent a source for bacteremia and may contribute to worsening COVID-19 outcomes. Therapies targeting the gut and prevention of gut barrier defects may represent a strategy to improve outcomes in COVID-19 patients.

microbiology↗

bioRxiv2020

Identification of blood autosomal cis-expression quantitative trait methylation (cis-eQTMs) in children

BackgroundThe identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in childrens blood, using data from 832 children of the Human Early Life Exposome (HELIX) project. MethodsBlood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition. ResultsWe identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGenes TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. 40.4% of eQTMs had at least one genetic variant associated with methylation and expression levels. The overlap of autosomal cis eQTMs in childrens blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants. ConclusionsThis catalogue of autosomal cis eQTMs in childrens blood can help the biological interpretation of EWAS findings and is publicly available at https://helixomics.isglobal.org/. Funding: The study has received funding from the European Communitys Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project); the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project); from the European Unions Horizon 2020 research and innovation programme under grant agreement no 733206 (LIFECYCLE project), and from the European Joint Programming Initiative "A Healthy Diet for a Healthy Life" (JPI HDHL and Instituto de Salud Carlos III) under the grant agreement no AC18/00006 (NutriPROGRAM project). The genotyping was supported by the project PI17/01225, funded by the Instituto de Salud Carlos III and co-funded by European Union (ERDF, "A way to make Europe") and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII).

genomics↗