Host genetics is one of several factors known to shape human gut microbiome composition, however, the physiological processes underlying the heritability are largely unknown. Inter-individual ...differences in host factors secreted into the gut lumen may lead to variation in microbiome composition. One such factor is the ABO antigen. This molecule is not only expressed on the surface of red blood cells, but is also secreted from mucosal surfaces in individuals containing an intact FUT2 gene (secretors). Previous studies report differences in microbiome composition across ABO and secretor genotypes. However, due to methodological limitations, the specific bacterial taxa involved remain unknown.
Here, we sought to determine the relationship of the microbiota to ABO blood group and secretor status in a large panel of 1503 individuals from a cohort of twins from the United Kingdom. Contrary to previous reports, robust associations between either ABO or secretor phenotypes and gut microbiome composition were not detected. Overall community structure, diversity, and the relative abundances of individual taxa were not significantly associated with ABO or secretor status. Additionally, joint-modeling approaches were unsuccessful in identifying combinations of taxa that were predictive of ABO or secretor status.
Despite previous reports, the taxonomic composition of the microbiota does not appear to be strongly associated with ABO or secretor status in 1503 individuals from the United Kingdom. These results highlight the importance of replicating microbiome-associated traits in large, well-powered cohorts to ensure results are robust.
Interactions between the gut microbiome and immunoglobulin A (IgA) in the gut during infancy are important for future health. IgM and IgG are also present in the gut; however, their interactions with ...the microbiome in the developing infant remain to be characterized. Using stool samples sampled 15 times in infancy from 32 healthy subjects at 4 locations in 3 countries, we characterized patterns of microbiome development in relation to fecal levels of IgA, IgG, and IgM. For 8 infants from a single location, we used fluorescence-activated cell sorting of microbial cells from stool by Ig-coating status over 18 months. We used 16S rRNA gene profiling on full and sorted microbiomes to assess patterns of antibody coating in relation to age and other factors. All antibodies decreased in concentration with age but were augmented by breastmilk feeding regardless of infant age. Levels of IgA correlated with relative abundances of operational taxonomic units (OTUs) belonging to the
and
, which dominated the early microbiome, and IgG levels correlated with
The diversity of Ig-coated microbiota was influenced by breastfeeding and age. IgA and IgM coated the same microbiota, which reflected the overall diversity of the microbiome, while IgG targeted a different subset.
generally evaded antibody coating, while members of the
and
were high in IgA/M. IgA/M displayed similar dynamics, generally coating the microbiome proportionally, and were influenced by breastfeeding status. IgG only coated a small fraction of the commensal microbiota and differed from the proportion targeted by IgA and IgM.
Antibodies are secreted into the gut and attach to roughly half of the trillions of bacterial cells present. When babies are born, the breastmilk supplies these antibodies until the baby's own immune system takes over this task after a few weeks. The vast majority of these antibodies are IgA, but two other types, IgG and IgM, are also present in the gut. Here, we ask if these three different antibody types target different types of bacteria in the infant gut as the infant develops from birth to 18 months old and how patterns of antibody coating of bacteria change with age. In this study of healthy infant samples over time, we found that IgA and IgM coat the same bacteria, which are generally representative of the diversity present, with a few exceptions that were more or less antibody coated than expected. IgG coated a separate suite of bacteria. These results provide a better understanding of how these antibodies interact with the developing infant gut microbiome.
Chronic intake of Western diet has driven an epidemic of obesity and metabolic syndrome, but how it induces mortality remains unclear. Here, we show that chronic intake of a high-fat diet (HFD), not ...a low-fat diet, leads to severe pulmonary damage and mortality in mice deficient in Toll-like receptors 2 and 4 (DKO). Diet-induced pulmonary lesions are blocked by antibiotic treatment and are transmissible to wild-type mice upon either cohousing or fecal transplantation, pointing to the existence of bacterial pathogens. Indeed, diet and innate deficiency exert significant impact on gut microbiota composition. Thus, chronic intake of HFD promotes severe pulmonary damage and mortality in DKO mice in part via gut dysbiosis, a finding that may be important for immunodeficient patients, particularly those on chemotherapy or radiotherapy, where gut-microbiota-caused conditions are often life threatening.
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•TLR2/TLR4-null mice on chronic high-fat diet have lethal pulmonary damage•Mortality is transmissible to WT mice upon cohousing and fecal transplantation•HFD and innate immune deficiency synergistically influence gut microbiota composition•Hyperendotoxemia and increased pulmonary cell death were observed in DKO mice on HFD
Chronic intake of Western diet has driven an epidemic of obesity and metabolic syndrome. Ji et al. now show that chronic intake of a Western diet leads to lethal pulmonary damage in immunodeficient mice. The lethality is mediated in part through gut dysbiosis, given that it is transmissible to wild-type immunocompetent mice upon cohousing or fecal transplantation and blocked by antibiotic treatment.
DNA sample contamination is a major issue in clinical and research applications of whole-genome and -exome sequencing. Even modest levels of contamination can substantially affect the overall quality ...of variant calls and lead to widespread genotyping errors. Currently, popular tools for estimating the contamination level use short-read data (BAM/CRAM files), which are expensive to store and manipulate and often not retained or shared widely. We propose a metric to estimate DNA sample contamination from variant-level whole-genome and -exome sequence data called CHARR, contamination from homozygous alternate reference reads, which leverages the infiltration of reference reads within homozygous alternate variant calls. CHARR uses a small proportion of variant-level genotype information and thus can be computed from single-sample gVCFs or callsets in VCF or BCF formats, as well as efficiently stored variant calls in Hail VariantDataset format. Our results demonstrate that CHARR accurately recapitulates results from existing tools with substantially reduced costs, improving the accuracy and efficiency of downstream analyses of ultra-large whole-genome and exome sequencing datasets.
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Lu et al. develop CHARR, a method for estimating DNA sample contamination from variant call data, which leverages the infiltration of reference reads within homozygous alternate variant calls. CHARR accurately recapitulates results from existing tools with substantially reduced cost and increased efficiency, which facilitates downstream analyses of ultra-large genomic data.
Genome-wide association studies have successfully discovered thousands of common variants associated with human diseases and traits, but the landscape of rare variations in human disease has not been ...explored at scale. Exome-sequencing studies of population biobanks provide an opportunity to systematically evaluate the impact of rare coding variations across a wide range of phenotypes to discover genes and allelic series relevant to human health and disease. Here, we present results from systematic association analyses of 4,529 phenotypes using single-variant and gene tests of 394,841 individuals in the UK Biobank with exome-sequence data. We find that the discovery of genetic associations is tightly linked to frequency and is correlated with metrics of deleteriousness and natural selection. We highlight biological findings elucidated by these data and release the dataset as a public resource alongside the Genebass browser for rapidly exploring rare-variant association results.
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•Public release of gene-based association statistics for 4,529 diseases and traits•Genebass, a browser framework to display rare-variant associations•Tight coupling between frequency, natural selection, and power for genetic discovery•Biological signal between SCRIB and white-matter integrity (from MRI)
Karczewski et al. generated a massive-scale association dataset between rare genetic mutations and thousands of diseases and traits and released these data in the Genebass browser. They quantify the influence of natural selection and gene function on association discovery and highlight an association between SCRIB and a brain-imaging trait.
Inflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases quality of life. Endoplasmic reticulum (ER)-associated degradation (ERAD) is responsible for the ...clearance of misfolded proteins; however, its role in disease pathogenesis remains largely unexplored. Here we show that the expression of SEL1L and HRD1, the most conserved branch of mammalian ERAD, is significantly reduced in ileal Crohn's disease (CD). Consistent with this observation, laboratory mice with enterocyte-specific Sel1L deficiency (Sel1L(ΔIEC)) develop spontaneous enteritis and have increased susceptibility to Toxoplasma gondii-induced ileitis. This is associated with profound defects in Paneth cells and a disproportionate increase of Ruminococcus gnavus, a mucolytic bacterium with known association with CD. Surprisingly, whereas both ER stress sensor IRE1α and effector CHOP are activated in the small intestine of Sel1L(ΔIEC) mice, they are not solely responsible for ERAD deficiency-associated lesions seen in the small intestine. Thus our study points to a constitutive role of Sel1L-Hrd1 ERAD in epithelial cell biology and the pathogenesis of intestinal inflammation in CD.
Advances in genome sequencing have resulted in the identification of the causes for numerous rare diseases. However, many cases remain unsolved with standard molecular analyses. We describe a family ...presenting with a phenotype resembling inherited thrombocytopenia 2 (THC2). THC2 is generally caused by single nucleotide variants that prevent silencing of ANKRD26 expression during hematopoietic differentiation. Short-read whole-exome and genome sequencing approaches were unable to identify a causal variant in this family. Using long-read whole-genome sequencing, a large complex structural variant involving a paired-duplication inversion was identified. Through functional studies, we show that this structural variant results in a pathogenic gain-of-function WAC-ANKRD26 fusion transcript. Our findings illustrate how complex structural variants that may be missed by conventional genome sequencing approaches can cause human disease.
JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international ...cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.
Commonly prescribed antibiotics are known to alter human microbiota. We hypothesized that triclosan and triclocarban, components of many household and personal care products (HPCPs), may alter the ...oral and gut microbiota, with potential consequences for metabolic function and weight. In a double-blind, randomized, crossover study, participants were given triclosan- and triclocarban (TCS)-containing or non-triclosan/triclocarban (nTCS)-containing HPCPs for 4 months and then switched to the other products for an additional 4 months. Blood, stool, gingival plaque, and urine samples and weight data were obtained at baseline and at regular intervals throughout the study period. Blood samples were analyzed for metabolic and endocrine markers and urine samples for triclosan. The microbiome in stool and oral samples was then analyzed. Although there was a significant difference in the amount of triclosan in the urine between the TCS and nTCS phases, no differences were found in microbiome composition, metabolic or endocrine markers, or weight. Though this study was limited by the small sample size and imprecise administration of HPCPs, triclosan at physiologic levels from exposure to HPCPs does not appear to have a significant or important impact on human oral or gut microbiome structure or on a panel of metabolic markers. IMPORTANCE Triclosan and triclocarban are commonly used commercial microbicides found in toothpastes and soaps. It is unknown what effects these chemicals have on the human microbiome or on endocrine function. From this randomized crossover study, it appears that routine personal care use of triclosan and triclocarban neither exerts a major influence on microbial communities in the gut and mouth nor alters markers of endocrine function in humans.
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