Showing papers by "George M. Weinstock published in 2016"

The real cost of sequencing: scaling computation to keep pace with data generation.

Abstract: As the cost of sequencing continues to decrease and the amount of sequence data generated grows, new paradigms for data storage and analysis are increasingly important. The relative scaling behavior of these evolving technologies will impact genomics research moving forward.

ATP-dependent renaturation of DNA catalyzed by the recA protein of Escherichia coli (ATPase/single-stranded DNA/lexB30 and tif-l mutants/cold-sensitive mutation/recombination intermediate)

Abstract: The product of the recA gene of Escherichia coli has been purified to near-homogeneity by a simple three- step procedure. Incubation of the recA protein with comple- mentary single strands of DNA, Mg2e+ and ATP results in the rapid formation of large DNA aggregates containing many branched structures. As judged by resistance to SI nuclease and by electron microscopy, these aggregates contain both duplex and single-stranded regions. The renaturation and aggregation of DNA catalyzed by the recA protein is coupled to the hydrol- ysis of ATP. The recA protein purified from a cold-sensitive recA mutant does not catalyze DNA renaturation or aggregation at 28?C, but does so at 37?C, a finding which correlates with the recombination defect observed in vivo and indicates that this activity is an intrinsic function of the recA protein. These results suggest that the recA protein plays a specific role in strand transfer during recombination and possibly in postreplication repair of damaged DNA.

NIH working group report—using genomic information to guide weight management: From universal to precision treatment

Abstract: Precision medicine utilizes genomic and other data to optimize and personalize treatment. Although more than 2,500 genetic tests are currently available, largely for extreme and/or rare phenotypes, the question remains whether this approach can be used for the treatment of common, complex conditions like obesity, inflammation, and insulin resistance, which underlie a host of metabolic diseases.

Effect of Advanced HIV Infection on the Respiratory Microbiome

Abstract: Rationale: Previous work found the lung microbiome in healthy subjects infected with HIV was similar to that in uninfected subjects. We hypothesized the lung microbiome from subjects infected with HIV with more advanced disease would differ from that of an uninfected control population.Objectives: To measure the lung microbiome in an HIV-infected population with advanced disease.Methods: 16s RNA gene sequencing was performed on acellular bronchoalveolar lavage (BAL) fluid from 30 subjects infected with HIV with advanced disease (baseline mean CD4 count, 262 cells/mm3) before and up to 3 years after starting highly active antiretroviral therapy (HAART) and compared with 22 uninfected control subjects.Measurements and Main Results: The lung microbiome in subjects infected with HIV with advanced disease demonstrated decreased alpha diversity (richness and diversity) and greater beta diversity compared with uninfected BAL. Differences improved with HAART, but still persisted up to 3 years after starting thera...

Metagenomic Approach for Identification of the Pathogens Associated with Diarrhea in Stool Specimens

Abstract: The potential to rapidly capture the entire microbial community structure and/or gene content makes metagenomic sequencing an attractive tool for pathogen identification and the detection of resistance/virulence genes in clinical settings. Here, we assessed the consistency between PCR from a diagnostic laboratory, quantitative PCR (qPCR) from a research laboratory, 16S rRNA gene sequencing, and metagenomic shotgun sequencing (MSS) for Clostridium difficile identification in diarrhea stool samples. Twenty-two C. difficile-positive diarrhea samples identified by PCR and qPCR and five C. difficile-negative diarrhea controls were studied. C. difficile was detected in 90.9% of C. difficile-positive samples using 16S rRNA gene sequencing, and C. difficile was detected in 86.3% of C. difficile-positive samples using MSS. CFU inferred from qPCR analysis were positively correlated with the relative abundance of C. difficile from 16S rRNA gene sequencing (r(2) = -0.60) and MSS (r(2) = -0.55). C. difficile was codetected with Clostridium perfringens, norovirus, sapovirus, parechovirus, and anellovirus in 3.7% to 27.3% of the samples. A high load of Candida spp. was found in a symptomatic control sample in which no causative agents for diarrhea were identified in routine clinical testing. Beta-lactamase and tetracycline resistance genes were the most prevalent (25.9%) antibiotic resistance genes in these samples. In summary, the proof-of-concept study demonstrated that next-generation sequencing (NGS) in pathogen detection is moderately correlated with laboratory testing and is advantageous in detecting pathogens without a priori knowledge.

Characterization of the bacterial and fungal microbiome in indoor dust and outdoor air samples: a pilot study

Abstract: Environmental microbes have been associated with both protective and adverse health effects in children and adults. Epidemiological studies often rely on broad biomarkers of microbial exposure (i.e. endotoxin, 1 → 3-beta-d-glucan), but fail to identify the taxonomic composition of the microbial community. Our aim was to characterize the bacterial and fungal microbiome in different types of environmental samples collected in studies of human health effects. We determined the composition of microbial communities present in home, school and outdoor air samples by amplifying and sequencing regions of rRNA genes from bacteria (16S) and fungi (18S and ITS). Samples for this pilot study included indoor settled dust (from both a Boston area birth cohort study on Home Allergens and Asthma (HAA) (n = 12) and a study of school exposures and asthma symptoms (SICAS) (n = 1)), as well as fine and coarse concentrated outdoor ambient particulate (CAP) samples (n = 9). Sequencing of amplified 16S, 18S, and ITS regions was performed on the Roche-454 Life Sciences Titanium pyrosequencing platform. Indoor dust samples were dominated by Gram-positive bacteria (Firmicutes and Actinobacteria); the most abundant bacterial genera were those related to human flora (Streptococcus, Staphylococcus, Corynebacterium and Lactobacillus). Outdoor CAPs were dominated by Gram-negative Proteobacteria from water and soil sources, in particular the genera Acidovorax, and Brevundimonas (which were present at very low levels or entirely absent in indoor dust). Phylum-level fungal distributions identified by 18S or ITS regions showed very similar findings: a predominance of Ascomycota in indoor dust and Basidiomycota in outdoor CAPs. ITS sequencing of fungal genera in indoor dust showed significant proportions of Aureobasidium and Leptosphaerulina along with some contribution from Cryptococcus, Epicoccum, Aspergillus and the human commensal Malassezia. ITS sequencing detected more than 70 fungal genera in indoor dust not observed by culture. Microbiome sequencing is feasible for different types of archived environmental samples (indoor dust, and low biomass air particulate samples), and offers the potential to study how whole communities of microbes (including unculturable taxa) influence human health.

Longitudinal Prediction of the Infant Gut Microbiome with Dynamic Bayesian Networks

Abstract: Sequencing of the 16S rRNA gene allows comprehensive assessment of bacterial community composition from human body sites. Previously published and publicly accessible data on 58 preterm infants in the Neonatal Intensive Care Unit who underwent frequent stool collection was used. We constructed Dynamic Bayesian Networks from the data and analyzed predictive performance and network characteristics. We constructed a DBN model of the infant gut microbial ecosystem, which explicitly captured specific relationships and general trends in the data: increasing amounts of Clostridia, residual amounts of Bacilli, and increasing amounts of Gammaproteobacteria that then give way to Clostridia. Prediction performance of DBNs with fewer edges were overall more accurate, although less so on harder-to-predict subjects (p = 0.045). DBNs provided quantitative likelihood estimates for rare abruptions events. Iterative prediction was less accurate (p < 0.001), but showed remarkable insensitivity to initial conditions and predicted convergence to a mix of Clostridia, Gammaproteobacteria, and Bacilli. DBNs were able to identify important relationships between microbiome taxa and predict future changes in microbiome composition from measured or synthetic initial conditions. DBNs also provided likelihood estimates for sudden, dramatic shifts in microbiome composition, which may be useful in guiding further analysis of those samples.

R2d2 drives selfish sweeps in the house mouse

Abstract: A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2(HC)) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2(HC) rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2(HC) is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution.

Household air pollution and the lung microbiome of healthy adults in Malawi: a cross-sectional study

Abstract: Domestic combustion of biomass fuels, such as wood, charcoal, crop residue and dung causes Household Air Pollution (HAP). These inhaled particulates affect more than half of the world’s population, causing respiratory problems such as infection and inflammatory lung disease. We examined whether the presence of black carbon in alveolar macrophages was associated with alterations in the lung microbiome in a Malawi population. Bronchoalveolar lavage samples from 44 healthy adults were sequenced using 16S rDNA amplification to assess microbial diversity, richness and relative taxa abundance. Individuals were classified as high or low particulate exposure as determined by questionnaire and the percentage of black carbon within their alveolar macrophages. Subjects in the low and high particulate groups did not differ in terms of source of fuels used for cooking or lighting. There was no difference in alpha or beta diversity by particulate group. Neisseria and Streptococcus were significantly more abundant in samples from high particulate exposed individuals, and Tropheryma was found less abundant. Petrobacter abundance was higher in people using biomass fuel for household cooking and lighting, compared with exclusive use of electricity. Healthy adults in Malawi exposed to higher levels of particulates have higher abundances of potentially pathogenic bacteria (Streptococcus, Neisseria) within their lung microbiome. Domestic biomass fuel use was associated with an uncommon environmental bacterium (Petrobacter) associated with oil-rich niches.

Symbiotic Burkholderia Species Show Diverse Arrangements of nif/fix and nod Genes and Lack Typical High-Affinity Cytochrome cbb3 Oxidase Genes.

Abstract: Genome analysis of fourteen mimosoid and four papilionoid beta-rhizobia together with fourteen reference alpha-rhizobia for both nodulation (nod) and nitrogen-fixing (nif/fix) genes has shown phylogenetic congruence between 16S rRNA/MLSA (combined 16S rRNA gene sequencing and multilocus sequence analysis) and nif/fix genes, indicating a free-living diazotrophic ancestry of the beta-rhizobia. However, deeper genomic analysis revealed a complex symbiosis acquisition history in the beta-rhizobia that clearly separates the mimosoid and papilionoid nodulating groups. Mimosoid-nodulating beta-rhizobia have nod genes tightly clustered in the nodBCIJHASU operon, whereas papilionoid-nodulating Burkholderia have nodUSDABC and nodIJ genes, although their arrangement is not canonical because the nod genes are subdivided by the insertion of nif and other genes. Furthermore, the papilionoid Burkholderia spp. contain duplications of several nod and nif genes. The Burkholderia nifHDKEN and fixABC genes are very closely related to those found in free-living diazotrophs. In contrast, nifA is highly divergent between both groups, but the papilionoid species nifA is more similar to alpha-rhizobia nifA than to other groups. Surprisingly, for all Burkholderia, the fixNOQP and fixGHIS genes required for cbb3 cytochrome oxidase production and assembly are missing. In contrast, symbiotic Cupriavidus strains have fixNOQPGHIS genes, revealing a divergence in the evolution of two distinct electron transport chains required for nitrogen fixation within the beta-rhizobia.

Effects of Walnut Consumption on Colon Carcinogenesis and Microbial Community Structure

Abstract: Walnuts are composed of a complex array of biologically active constituents with individual cancer-protective properties. Here, we assessed the potential benefit of whole walnut consumption in a mouse tumor bioassay using azoxymethane. In study 1, a modest reduction (1.3-fold) in tumor numbers was observed in mice fed a standard diet (AIN-76A) containing 9.4% walnuts (15% of total fat). In study 2, the effects of walnut supplementation was tested in the Total Western Diet (TWD). There was a significant reduction (2.3-fold; P < 0.02) in tumor numbers in male mice fed TWD containing 7% walnuts (10.5% of total fat). Higher concentrations of walnuts lacked inhibitory effects, particularly in female mice, indicating there may be optimal levels of dietary walnut intake for cancer prevention. Since components of the Mediterranean diet have been shown to affect the gut microbiome, the effects of walnuts were therefore tested in fecal samples using 16S rRNA gene sequencing. Carcinogen treatment reduced the diversity and richness of the gut microbiome, especially in male mice, which exhibited lower variability and greater sensitivity to environmental changes. Analysis of individual operational taxonomic units (OTU) identified specific groups of bacteria associated with carcinogen exposure, walnut consumption, and/or both variables. Correlation analysis also identified specific OTU clades that were strongly associated with the presence and number of tumors. Taken together, our results indicate that walnuts afford partial protection to the colon against a potent carcinogenic insult, and this may be due, in part, to walnut-induced changes to the gut microbiome. Cancer Prev Res; 9(8); 692-703. ©2016 AACR.

Transmission of Staphylococcus aureus from humans to green monkeys in The Gambia as revealed by whole-genome sequencing

Abstract: R01 OD010980 - NIH HHS; MR/L015080/1 - Medical Research Council; R01 RR016300 - NCRR NIH HHS; MC_UP_A900_1122 - Medical Research Council; MC_U190081991 - Medical Research Council; G1000803 - Medical Research Council

Role of Clinicogenomics in Infectious Disease Diagnostics and Public Health Microbiology

Abstract: Clinicogenomics is the exploitation of genome sequence data for diagnostic, therapeutic, and public health purposes. Central to this field is the high-throughput DNA sequencing of genomes and metagenomes. The role of clinicogenomics in infectious disease diagnostics and public health microbiology was the topic of discussion during a recent symposium (session 161) presented at the 115th general meeting of the American Society for Microbiology that was held in New Orleans, LA. What follows is a collection of the most salient and promising aspects from each presentation at the symposium.

Effect of Advanced HIV Infection on the Respiratory Microbiome

Abstract: Rationale: Previous work found the lung microbiome in healthy subjects infected with HIV was similar to that in uninfected subjects. We hypothesized the lung microbiome from subjects infected with HIV with more advanced disease would differ from that of an uninfected control population.Objectives: To measure the lung microbiome in an HIV-infected population with advanced disease.Methods: 16s RNA gene sequencing was performed on acellular bronchoalveolar lavage (BAL) fluid from 30 subjects infected with HIV with advanced disease (baseline mean CD4 count, 262 cells/mm3) before and up to 3 years after starting highly active antiretroviral therapy (HAART) and compared with 22 uninfected control subjects.Measurements and Main Results: The lung microbiome in subjects infected with HIV with advanced disease demonstrated decreased alpha diversity (richness and diversity) and greater beta diversity compared with uninfected BAL. Differences improved with HAART, but still persisted up to 3 years after starting thera...

Household air pollution and the lung microbiome of healthy adults in Malawi: a cross-sectional study

Abstract: Domestic combustion of biomass fuels, such as wood, charcoal, crop residue and dung causes Household Air Pollution (HAP). These inhaled particulates affect more than half of the world’s population, causing respiratory problems such as infection and inflammatory lung disease. We examined whether the presence of black carbon in alveolar macrophages was associated with alterations in the lung microbiome in a Malawi population. Bronchoalveolar lavage samples from 44 healthy adults were sequenced using 16S rDNA amplification to assess microbial diversity, richness and relative taxa abundance. Individuals were classified as high or low particulate exposure as determined by questionnaire and the percentage of black carbon within their alveolar macrophages. Subjects in the low and high particulate groups did not differ in terms of source of fuels used for cooking or lighting. There was no difference in alpha or beta diversity by particulate group. Neisseria and Streptococcus were significantly more abundant in samples from high particulate exposed individuals, and Tropheryma was found less abundant. Petrobacter abundance was higher in people using biomass fuel for household cooking and lighting, compared with exclusive use of electricity. Healthy adults in Malawi exposed to higher levels of particulates have higher abundances of potentially pathogenic bacteria (Streptococcus, Neisseria) within their lung microbiome. Domestic biomass fuel use was associated with an uncommon environmental bacterium (Petrobacter) associated with oil-rich niches.

Ancient hybridization and strong adaptation to viruses across African vervet monkey populations

Abstract: Vervet monkeys (genus Chlorocebus , also known as African green monkeys), are highly abundant in savannahs and riverine forests throughout sub-Saharan Africa. They are amongst the most widely distributed nonhuman primates, show considerable phenotypic diversity, and have long been an important biomedical model for a variety of human diseases and in vaccine research. They are particularly interesting for HIV/AIDS research as they are the most abundant natural hosts of simian immunodeficiency virus (SIV), a close relative of HIV. Here we present the first genome-wide survey of polymorphism in vervets, using sequencing data from 163 individuals sampled from across Africa and the Caribbean islands where vervets were introduced during the colonial era. We find high diversity, within and between taxa, and clear evidence that taxonomic divergence was reticulate rather than following a simple branching pattern. A scan for diversifying selection across vervet taxa yields gene enrichments much stronger than in similar studies on humans. In particular, we report strong and highly polygenic selection signals affecting viral processes --- in line with recent evidence that proposes a driving role for viruses in protein evolution in mammals. Furthermore, selection scores are highly elevated in genes whose human orthologs interact with HIV, and in genes that show a response to experimental SIV infection in vervet monkeys but not in rhesus macaques, suggesting that part of the signal reflects taxon-specific adaptation to SIV. Intriguingly, rather than affecting genes with antiviral and inflammatory-related functions, selection in vervets appears to have primarily targeted genes involved in the transcriptional regulation of viruses, and in particular those that are harmful only under immunodeficiency, suggesting adaptation to living with SIV rather than defense against infection.

Erratum to: The real cost of sequencing: scaling computation to keep pace with data generation

Abstract: After the publication of this work [1], the authors noticed an error in Fig. 4. The error occurred on the y-axis, instead of running from 0 to 20 it just has 20 at each point. The publisher apologises for the error and any inconvenience caused. The corrected figure is given below: Fig. 4 The number of faculty position hires at 51 US universities in 3-year bins. The recent increase in hiring coincides with the explosion in sequencing data. Data were obtained from http://jeffhuang.com/computer_science_professors.html

Genome Sequences of 15 Gardnerella vaginalis Strains Isolated from the Vaginas of Women with and without Bacterial Vaginosis

Abstract: Gardnerella vaginalis is a predominant species in bacterial vaginosis, a dysbiosis of the vagina that is associated with adverse health outcomes, including preterm birth. Here, we present the draft genome sequences of 15 Gardnerella vaginalis strains (now available through BEI Resources) isolated from women with and without bacterial vaginosis.

Identification of a Novel Gene on 10q22.1 Causing Autosomal Dominant Retinitis Pigmentosa (adRP).

Abstract: Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widely-expressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites.

Genetic variation and gene expression across multiple tissues and developmental stages in a non-human primate

Abstract: By analyzing multi-tissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalogue of expression quantitative trait loci (eQTLs) in a non-human primate model. This catalogue contains more genome-wide significant eQTLs, per sample, than comparable human resources, and reveals sex and age-related expression patterns. Findings include a master regulatory locus that likely plays a role in immune function, and a locus regulating hippocampal long non-coding RNAs (lncRNAs) whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

A Glimpse of Microbial Power in Preventive Medicine.

Abstract: with an astounding number of diseases and characteristics of human health. The promise of deciphering these microbe-host relationships are new diagnostics, therapies, and preventive measures. Despite these efforts, this is still an immature field, and there have been very few ground-breaking advances. Many of the association studies are of unclear statistical power and are often based on small cohorts. The fecal microbiota transplant technique to treat Clostridium difficile– associated diarrhea is the most publicized of the successes. Yet it is a treatment that was known before the current microbiome era and is less an outcome of current research than the type of medical innovation that arises out of strong need. But the era of host-microbe research continues to mature, and in this issue JAMA Pediatrics is a longitudinal, multinational study by Uusitalo et al, for the TEDDY Study Group, 1 in which the effect of probiotics on children with genetically increased risk for type 1 diabetes mellitus (T1DM) is described. The authors observed a reduction in risk of islet autoimmunity (IA) in the children who had received dietary supplements of probiotics at or before age 27 days compared with those who first received probiotics after 27 days of life. Moreover, early probiotic exposure was associated with a 60% decrease in the risk of IA among children with the DR3/4 genotype but not other genotypes. Thus, early exposure to supplemental probiotics may decrease the risk of IA among children at elevated risk of T1DM. This protective association between early probiotic use and T1DM-related IA awaits further randomized clinical trials.

R2d2 drives selfish sweeps in the house mouse

Abstract: A selective sweep is the result of strong positive selection rapidly driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population or species. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little empirical evidence addresses whether "selfish" genes are capable of fixation -- thereby leaving signatures identical to classical selective sweeps -- despite being neutral or deleterious to organismal fitness. We previously reported the discovery of R2d2, a large copy-number variant that causes non-random segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a "selfish" sweep driven by alleles of R2d2 with high copy number (R2d2HC) in natural populations of mice. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2HC rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2HC is also associated with significantly reduced litter sizes in heterozygosity, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution.

Erratum: NIH Working Group Report - Using Genomic Information to Guide Weight Management: From Universal to Precision Treatment (Obesity (2016) 24 (14-22) DOI: 10.1002/oby.21381)

Abstract: Molly S. Bray, Ruth J.F. Loos, Jeanne M. McCaffery, Charlotte Ling, Paul W. Franks, George M. Weinstock, Michael P. Snyder, Jason L. Vassy, Tanya Agurs-Collins, and The Conference Working Group Obesity (2016) 24:14-22. doi: 10.1002/oby.21381 After publication of the above article, it was pointed out that the functional work establishing the link between FTO and IRX3/IRX5 (as given by reference 19, Rask-Andersen M et al.) was performed by Claussnitzer M and Kellis M et al. Therefore, the following reference should have been included in the paper: Claussnitzer M, Dankel SN, Kim K-H, et al. FTO obesity variant circuitry and adipocyte browning in humans. N Eng J Med 2015;373:895907. The authors apologize for any confusion caused by this error.