Biology subjects

Spector, T.

Publications and source records attributed to Spector, T..

10 recordsLinked to original sources

bioRxiv2021

Impacts of dietary exposure to pesticides on faecal microbiome metabolism in adult twins

Concerns have been raised as to whether the consumption of foodstuffs contaminated with pesticides can contribute to the development of chronic human diseases by affecting microbial community function in the gut. We provide the first associations between urinary pesticide excretion and the composition and function of the faecal microbiome in 65 twin pairs in the UK. Biomonitoring of exposure to 186 common insecticide, herbicide, or fungicide residues showed the presence of pyrethroid and/or organophosphorus insecticide residues in all urine samples, while the herbicide glyphosate was found in 45% of individuals. Other pesticides such as DEET, imidacloprid or dithiocarbamate fungicides were less frequently detected. While the geographic location or the rural/urban environment had no influence on pesticide urinary excretion, food frequency questionnaires showed that DMTP levels, a metabolite of organophosphates, was higher with increased consumption of fruit and vegetables. Multivariable association between urinary pesticide excretion and faecal microbial composition and function were determined with shotgun metagenomics and metabolomics. A total of 34 associations between pesticide residues concentrations and faecal metabolite concentrations were detected. Glyphosate excretion was positively associated to an increased bacterial species richness, as well as to fatty acid metabolites and phosphate levels. The insecticide metabolite Br2CA, reflecting deltamethrin exposure, was positively associated with the mammalian phytoestrogens enterodiol and enterolactone, and negatively associated with some N-methyl amino acids. Urine metabolomics performed on a subset of samples did not reveal associations with the excretion of pesticide residues. Our results highlight the need for future interventional studies to understand effects of pesticide exposure on the gut microbiome and possible health consequences.

pharmacology and toxicology↗

bioRxiv2020

Strain-level analysis of Bifidobacterium spp. from gut microbiomes of adults of differing lactase persistence genotypes

One of the strongest associations between human genetics and the gut microbiome is a greater relative abundance of Bifidobacterium in adults with lactase gene (LCT) SNPs associated with lactase-non persistence (GG genotypes), versus lactase persistence (AA/AG genotypes). To gain a finer grained phylogenetic resolution of this association, we interrogated 1,680 16S rRNA libraries and 245 metagenomes from gut microbiomes of adults with varying lactase persistence genotypes. We further employed a novel genome-capture based enrichment of Bifidobacterium DNA from a subset of these metagenomes, including monozygotic (MZ) twin pairs, each sampled 2 or 3 times. B. adolescentis and B. longum were the most abundant Bifidobacterium species regardless of host LCT-genotype. LCT- genotypes could not be discriminated based on relative abundances of Bifidobacterium species or Bifidobacterium community structure. Metagenomic analysis of Bifidobacterium-enriched DNA revealed intra-individual temporal stability of B. longum, B. adolescentis, and B. bifidum strains against the background of a changeable microbiome. We also observed greater strain sharing within MZ twin pairs compared to unrelated individuals, and within GG compared to AA/AG individuals, but no effect of host LCTgenotype on Bifidobacterium strain composition. Our results support a "rising tide lift all boats" model for the dominant Bifidobacteria in the adult gut: their higher abundance in lactase-non persistent compared to lactase-persistent individuals results from an expansion at the genus level. Bifidobacterium species are known to be transmitted from mother to child and stable within individuals in infancy and childhood: our results extend this stability into adulthood. IMPORTANCEWhen human populations domesticated animals to drink their milk they adapted genetically with the ability to digest milk into adulthood (lactase persistence). The gut microbiomes of lactase non-persistent people (LNP) differ from those of lactase-persistent people (LP) by containing more bacteria belonging to the Bifidobacteria. These beneficial gut bacteria, which fall into many species, are known to degrade milk in the baby gut. Here, we asked if adult LP and LNP microbiomes differ in the species of Bifidobacteria present. We studied the gut microbiomes of LP and LNP adults, including twins, sampled at several times. In particular, we used a technique to selectively pull out the DNA belonging to the Bifidobacteria: analysis of these DNA segments allowed us to compare Bifidobacteria at the strain level. Our results show that the LNP enhance the abundance of Bifidobacteria regardless of species. We also noted that a persons specific strains are recoverable several years later, and twins tend to share the same ones. Given that Bifidobacteria are inherited from mother to child, strain stability over time in adulthood suggests long term, multi-generational inheritance.

microbiology↗

bioRxiv2020

Host genetic and environmental factors shape the human gut resistome

BackgroundUnderstanding and controlling the spread of antimicrobial resistance is one of the greatest challenges of modern medicine. To this end many efforts focus on characterising the human resistome or the set of antibiotic resistance determinants within the microbiome of an individual. Aside from antibiotic use, other host environmental and genetic factors that may shape the resistome remain relatively underexplored. MethodsUsing gut metagenome data from 250 TwinsUK female twins, we quantified known antibiotic resistance genes to estimate gut microbiome antibiotic resistance potential for 41 types of antibiotics and resistance mechanisms. Using heritability modelling, we assessed the influence of host genetic and environmental factors on the gut resistome. We then explored links between gut resistome, host health and specific environmental exposures using linear mixed effect models adjusted for age, BMI, alpha diversity and family structure. ResultsWe considered gut microbiome antibiotic resistance to 21 classes of antibiotics, for which resistance genes were detected in over 90% of our population sample. Using twin modelling, we estimated that on average about 25% of resistome variability could be attributed to host genetic influences. Greatest heritability estimates were observed for resistance potential to acriflavine (70%), dalfopristin (51%), clindamycin (48%), aminocoumarin (48%) and the total score summing across all antibiotic resistance genes (38%). As expected, the majority of resistome variability was attributed to host environmental factors specific to an individual. We compared antibiotic resistance profiles to multiple environmental exposures, lifestyle and health factors. The strongest associations were observed with alcohol and vegetable consumption, followed by high cholesterol medication and antibiotic usage. Overall, inter-individual variation in host environment showed modest associations with antibiotic resistance profiles, and host health status had relatively minor signals. ConclusionOur results identify host genetic and environmental influences on the human gut resistome. The findings improve our knowledge of human factors that influence the spread of antibiotic resistance genes and may contribute towards helping to attenuate it.

microbiology↗

bioRxiv2019

Arrhythmic gut microbiome signatures for risk profiling of Type-2 Diabetes

To combat the epidemic increase in Type-2-Diabetes (T2D), risk factors need to be identified. Diet, lifestyle and the gut microbiome are among the most important factors affecting metabolic health. We demonstrate in 1,976 subjects of a prospective population cohort that specific gut microbiota members show diurnal oscillations in their relative abundance and we identified 13 taxa with disrupted rhythmicity in T2D. Prediction models based on this signature classified T2D with an area under the curve of 73%. BMI as microbiota-independent risk marker further improved diagnostic classification of T2D. The validity of this arrhythmic risk signature to predict T2D was confirmed in 699 KORA subjects five years after initial sampling. Shotgun metagenomic analysis linked 26 pathways associated with xenobiotic, amino acid, fatty acid, and taurine metabolism to the diurnal oscillation of gut bacteria. In summary, we determined a cohort-specific risk pattern of arrhythmic taxa which significantly contributes to the classification and prediction of T2D, highlighting the importance of circadian rhythmicity of the microbiome in targeting metabolic human diseases.

microbiology↗

bioRxiv2019

Novel genetic loci affecting facial shape variation in humans

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited despite the relevance for various fields of science and application. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching genome-wide significant association, among which 17 were previously unreported. A multi-ethnic study in additional 7,917 individuals confirmed 13 loci including 8 unreported ones. A global map of polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.

genomics↗

bioRxiv2019

Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels

Saliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the regulation of blood metabolites leading to unprecedented insights into the pathogenesis of complex human diseases, little is known about the impact of host genetics on salivary metabolites. Here we report the first genome-wide association study exploring 476 salivary metabolites in 1,419 subjects of European ancestry from the TwinsUK cohort (discovery phase). A total of 14 salivary metabolites were significantly associated (p<10-10) with genetic variants that mapped to 11 distinct loci, most of which replicated in the Study of Health in Pomerania (SHIP-2) cohort. Interestingly, while only a limited number of the loci that are known to regulate blood metabolites were also associated with salivary metabolites in our study, we identified several novel saliva-specific locus-metabolite associations, including associations for the AGMAT (with the metabolites 4-guanidinobutanoate and beta-guanidinopropanoate), ATP13A5 (with the metabolite creatinine) and DPYS (with the metabolites 3-ureidopropionate and 3-ureidoisobutyrate) loci. Our study suggests that there are biological pathways which are specific to the regulation of the salivary metabolome. In addition, some of our findings may have clinical relevance, such as the utility of the pyrimidine (uracil) degradation metabolites in predicting 5-fluorouracil toxicity and the role of the agmatine pathway metabolites as biomarkers of oral health.

genetics↗

bioRxiv2019

Global variability of the human IgG glycome

Immunoglobulin G (IgG) is the most abundant serum antibody and is a key determinant of the humoral immune response. Its structural characteristics and effector functions are modulated through the attachment of various sugar moieties called glycans. IgG N-glycome patterns change with the age of individual and in different diseases. Variability of IgG glycosylation within a population is well studied and is affected by a combination of genetic and environmental factors. However, global inter-population differences in IgG glycosylation have never been properly addressed. Here we present population-specific N-glycosylation patterns of whole IgG, analysed in 5 different populations totalling 10,482 IgG glycomes, and of IgGs fragment crystallisable region (Fc), analysed in 2,530 samples from 27 populations sampled across the world. We observed that country of residence associates with many N-glycan features and is a strong predictor of monogalactosylation variability. IgG galactosylation also strongly correlated with the development level of a country, defined by United Nations health and socioeconomic development indicators. We found that subjects from developing countries had low IgG galactosylation levels, characteristic for inflammation and ageing. Our results suggest that citizens of developing countries may be exposed to country-specific environmental factors that can cause low-grade chronic inflammation and the apparent increase in biological age.

biochemistry↗

bioRxiv2019

The virome in adult monozygotic twins with concordant or discordant gut microbiomes

The virome is one of the most variable components of the human gut microbiome. Within twin-pairs, viromes have been shown to be similar for infants but not for adults, indicating that as twins age and their environments and microbiomes diverge, so do their viromes. The degree to which the microbiome drives the viromes vast diversity is unclear. Here, we examined the relationship between microbiome diversity and virome diversity in 21 adult monozygotic twin pairs selected for high or low microbiome concordance. Viromes derived from virus-like particles were unique to each subject, dominated by Caudovirales and Microviridae, and exhibited a small core that included crAssphage. Microbiome-discordant twins had more dissimilar viromes compared to microbiome-concordant twins, and the richer the microbiomes, the richer the viromes. These patterns were driven by the bacteriophages, not eukaryotic viruses. These observations support a strong role of the microbiome in patterning the virome.

microbiology↗

bioRxiv2018

Defining the genetic control of human blood plasma N-glycome using genome-wide association study

Glycosylation is a common post-translational modification of proteins. It is known, that glycans are directly involved in the pathophysiology of every major disease. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here, we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people. We discovered and replicated twelve loci. This allowed us to demonstrate a clear overlap in genetic control between total plasma and IgG glycosylation. Majority of loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3, and MGAT5). We, however, also found loci that are likely to reflect other, more complex, aspects of plasma glycosylation process. Functional genomic annotation suggested the role of DERL3, which potentially highlights the role of glycoprotein degradation pathway, and such transcription factor as IKZF1.

genetics↗

bioRxiv2016

Predicting causal variants affecting expression using whole genome sequence and RNA-seq from multiple human tissues.

Genetic association mapping produces statistical links between phenotypes and genomic regions, but identifying the causal variants themselves remains difficult. Complete knowledge of all genetic variants, as provided by whole genome sequence (WGS), will help, but is currently financially prohibitive for well powered GWAS studies. To explore the advantages of WGS in a well powered setting, we performed eQTL mapping using WGS and RNA-seq, and showed that the lead eQTL variants called using WGS are more likely to be causal. We derived properties of the causal variant from simulation studies, and used these to propose a method for implicating likely causal SNPs. This method predicts that 25% - 70% of the causal variants lie in open chromatin regions, depending on tissue and experiment. Finally, we identify a set of high confidence causal variants and show that they are more enriched in GWAS associations than other eQTL. Of these, we find 65 associations with GWAS traits and show examples where the gene implicated by expression has been functionally validated as relevant for complex traits.

genomics↗