Biology subjects

Pollard, K.

Publications and source records attributed to Pollard, K..

6 recordsLinked to original sources

bioRxiv2018

A Metagenomic Meta-Analysis Reveals Functional Signatures of Health and Disease in the Human Gut Microbiome

While recent research indicates that human health depends, in part, upon the symbiotic relationship between gut microbes and their host, the specific interactions between host and microbe that define health are poorly resolved. Metagenomic clinical studies clarify this definition by revealing gut microbial taxa and functions that stratify healthy and diseased individuals. However, the typical single-disease focus of microbiome studies limits insight into which microbiome features robustly associate with health, indicate general deviations from health, or predict specific diseases. Additionally, the focus on taxonomy may limit our understanding of how the microbiome relates to health given observations that different taxonomic members can fulfill similar functional roles. To improve our understanding of the association between the gut microbiome and health, we integrated about 2,000 gut metagenomes obtained from eight clinical studies in a statistical meta-analysis. We identify characteristics of the gut microbiome that associate generally with disease, including functional alpha-diversity, beta-diversity, and beta-dispersion. Moreover, we resolve microbiome modules that stratify diseased individuals from controls in a manner independent of study-specific effects. Many of the differentially abundant functions overlap multiple diseases suggesting a role in host health, while others are specific to a single disease and may associate with disease-specific etiologies. Our results clarify potential microbiome-mediated mechanisms of disease and reveal features of the microbiome that may be useful for the development of microbiome-based diagnostics. Ultimately, our study clarifies the definition of a healthy microbiome and how perturbations to it associate with disease.

bioinformatics↗

bioRxiv2018

Chromatin features constrain structural variation across evolutionary timescales

The potential impact of structural variants includes not only the duplication or deletion of coding sequences, but also the perturbation of non-coding DNA regulatory elements and structural chromatin features, including topological domains (TADs). Structural variants disrupting TAD boundaries have been implicated both in cancer and developmental disease; this likely occurs via enhancer hijacking, whereby removal of the TAD boundary exposes enhancers to new target transcription start sites (TSSs). With this functional role, we hypothesized that boundaries would display evidence for negative selection. Here we demonstrate that the chromatin landscape constrains structural variation both within healthy humans and across primate evolution. In contrast, in patients with developmental delay, variants occur remarkably uniformly across genomic features, suggesting a potentially broad role for enhancer hijacking in human disease.

genomics↗

bioRxiv2018

Massively parallel dissection of human accelerated regions in human and chimpanzee neural progenitors

Using machine learning (ML), we interrogated the function of all human-chimpanzee variants in 2,645 Human Accelerated Regions (HARs), some of the fastest evolving regions of the human genome. We predicted that 43% of HARs have variants with large opposing effects on chromatin state and 14% on neurodevelopmental enhancer activity. This pattern, consistent with compensatory evolution, was confirmed using massively parallel reporter assays in human and chimpanzee neural progenitor cells. The species-specific enhancer activity of assayed HARs was accurately predicted from the presence and absence of transcription factor footprints in each species. Despite these striking cis effects, activity of a given HAR sequence was nearly identical in human and chimpanzee cells. These findings suggest that HARs did not evolve to compensate for changes in the trans environment but instead altered their ability to bind factors present in both species. Thus, ML prioritized variants with functional effects on human neurodevelopment and revealed an unexpected reason why HARs may have evolved so rapidly.

evolutionary biology↗

bioRxiv2017

Developmental loci harbor clusters of accelerated regions that evolved independently in ape lineages

Some of the fastest evolving regions of the human genome are conserved non-coding elements with many human-specific DNA substitutions. These Human Accelerated Regions (HARs) are enriched nearby regulatory genes, and several HARs function as developmental enhancers. To investigate if this evolutionary signature is unique to humans, we quantified evidence of accelerated substitutions in conserved genomic elements across multiple lineages and applied this approach simultaneously to the genomes of five apes: human, chimpanzee, gorilla, orangutan, and gibbon. We find roughly similar numbers and genomic distributions of lineage-specific accelerated regions (linARs) in all five apes. In particular, apes share an enrichment of linARs in regulatory DNA nearby genes involved in development, especially transcription factors and other regulators. Many developmental loci harbor clusters of nonoverlapping linARs from multiple apes, suggesting that accelerated evolution in each species affected distinct regulatory elements that control a shared set of developmental pathways. Our statistical tests distinguish between GC-biased and unbiased accelerated substitution rates, allowing us to quantify the roles of different evolutionary forces in creating linARs. We find evidence of GC-biased gene conversion in each ape, but unbiased acceleration consistent with positive selection or loss of constraint is more common in all five lineages. It therefore appears that similar evolutionary processes created independent accelerated regions in the genomes of different apes, and that these lineage-specific changes to conserved non-coding sequences may have differentially altered expression of a core set of developmental genes across ape evolution.

evolutionary biology↗

bioRxiv2017

Transcription Factors Recognize DNA Shape Without Nucleotide Recognition

We hypothesized that transcription factors (TFs) recognize DNA shape without nucleotide sequence recognition. Motivating an independent role for shape, many TF binding sites lack a sequence-motif, DNA shape adds specificity to sequence-motifs, and different sequences can encode similar shapes. We therefore asked if binding sites of a TF are enriched for specific patterns of DNA shape-features, e.g., helical twist. We developed ShapeMF, which discovers these shape-motifs de novo without taking sequence information into account. We find that most TFs assayed in ENCODE have shape-motifs and bind regulatory regions recognizing shape-motifs in the absence of sequence-motifs. When shape- and sequence-recognition co-occur, the two types of motifs can be overlapping, flanking, or separated by consistent spacing. Shape-motifs are prevalent in regions co-bound by multiple TFs. Finally, TFs with identical sequence motifs have different shape-motifs, explaining their binding at distinct locations. These results establish shape-motifs as drivers of TF-DNA recognition complementary to sequence-motifs.

systems biology↗

bioRxiv2017

Topical Silver Diamine Fluoride For Dental Caries Arrest In Preschool Children: A Randomized Controlled Trial

ObjectivesThe Stopping Cavities Trial investigated effectiveness and safety of 38% silver diamine fluoride in arresting caries lesions.\n\nMaterials and MethodsDouble-blind randomized placebo-controlled superiority trial with 2 parallel groups. Oregon preschools. 66 preschool children with [≥]1 lesion. 38% silver diamine fluoride or placebo (blue-tinted water), applied topically to the lesion. The primary endpoint was caries arrest (lesion inactivity, Nyvad criteria) 14-21 days post intervention. Dental plaque was collected from all children, and microbial composition was assessed by RNA sequencing from 2 lesions and 1 unaffected surface before treatment and at follow-up for 3 children from each group.\n\nResults and ConclusionMean fraction of arrested caries lesions in the silver diamine fluoride group was higher (0.72; 95% CI; 0.55, 0.84) than in the placebo group (0.05; 95% CI; 0.00, 0.16). Confirmatory analysis using generalized estimating equation log-linear regression, accounting for the number of treated surfaces and length of follow-up, indicated the fraction of arrested caries was significantly higher in the treatment group (relative risk, 17.3; 95% CI: 4.3 to 69.4). No harms were observed. RNA sequencing analysis identified no consistent changes in relative abundance of caries-associated microbes, nor emergence of antibiotic or metal resistance gene expression. Topical 38% silver diamine fluoride was effective and safe in arresting cavities in preschool children. The treatment is applicable to primary care practice and may reduce the burden of untreated tooth decay in the population.\n\nTrial RegistrationClinicalTrials.gov NCT02536040.\n\nClinical SignificanceIn this clinical trial, 72% of caries lesions were arrested by silver diamine fluoride, with no harms. Contrary to the presumed antibacterial mechanism, lesion bacterial composition changed negligibly. This simple topical treatment is applicable to primary care practice and may reduce the burden of untreated tooth decay in the population.

clinical trials↗