Single-cell multi-cohort dissection of the schizophrenia transcriptome

Science · 2024 · 125 citations

• Biology
• Neuroscience
• Genetics

The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation and the development of more effective therapies. Here, we performed single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across 140 individuals in two independent cohorts. Excitatory neurons were the most affected cell group, with transcriptional changes converging on neurodevelopment and synapse-related molecular pathways. Transcriptional alterations included known genetic risk factors, suggesting convergence of rare and common genomic variants on neuronal population-specific alterations in schizophrenia. Based on the magnitude of schizophrenia-associated transcriptional change, we identified two populations of individuals with schizophrenia marked by expression of specific excitatory and inhibitory neuronal cell states. This single-cell atlas links transcriptomic changes to etiological genetic risk factors, contextualizing established knowledge within the human cortical cytoarchitecture and facilitating mechanistic understanding of schizophrenia pathophysiology and heterogeneity.

Evolutionary constraint and innovation across hundreds of placental mammals

Science · 2023 · 263 citations

• Evolutionary biology
• Biology
• Computational biology

Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.

The functional and evolutionary impacts of human-specific deletions in conserved elements

Science · 2023 · 76 citations

• Biology
• Evolutionary biology
• Computational biology

and developmental genes involved in myelination and synaptic function. Our data provide a rich resource to investigate the evolutionary mechanisms driving new traits in humans and other species.

Colorectal Endoscopic Stenting Trial (CReST) for obstructing left-sided colorectal cancer: randomized clinical trial

British journal of surgery · 2022 · 73 citations

• Medicine
• Surgery
• Internal medicine

BACKGROUND: Colorectal cancer often presents with obstruction needing urgent, potentially life-saving decompression. The comparative efficacy and safety of endoluminal stenting versus emergency surgery as initial treatment for such patients is uncertain. METHODS: Patients with left-sided colonic obstruction and radiological features of carcinoma were randomized to endoluminal stenting using a combined endoscopic/fluoroscopic technique followed by elective surgery 1-4 weeks later, or surgical decompression with or without tumour resection. Treatment allocation was via a central randomization service using a minimization procedure stratified by curative intent, primary tumour site, and severity score (Acute Physiology And Chronic Health Evaluation). Co-primary outcome measures were duration of hospital stay and 30-day mortality. Secondary outcomes were stoma formation, stenting completion and complication rates, perioperative morbidity, 6-month survival, 3-year recurrence, resource use, adherence to chemotherapy, and quality of life. Analyses were undertaken by intention to treat. RESULTS: Between 23 April 2009 and 22 December 2014, 245 patients from 39 hospitals were randomized. Stenting was attempted in 119 of 123 allocated patients (96.7 per cent), achieving relief of obstruction in 98 of 119 (82.4 per cent). For the 89 per cent treated with curative intent, there were no significant differences in 30-day postoperative mortality (3.6 per cent (4 of 110) versus 5.6 per cent (6 of 107); P = 0.48), or duration of hospital stay (median 19 (i.q.r. 11-34) versus 18 (10-28) days; P = 0.94) between stenting followed by delayed elective surgery and emergency surgery. Among patients undergoing potentially curative treatment, stoma formation occurred less frequently in those allocated to stenting than those allocated to immediate surgery (47 of 99 (47.5 per cent) versus 72 of 106 (67.9 per cent); P = 0.003). There were no significant differences in perioperative morbidity, critical care use, quality of life, 3-year recurrence or mortality between treatment groups. CONCLUSION: Stenting as a bridge to surgery reduces stoma formation without detrimental effects. Registration number: ISRCTN13846816 (http://www.controlled-trials.com).

Caloric restriction disrupts the microbiota and colonization resistance

Nature · 2021 · 209 citations

• Biology
• Immunology
• Microbiology

A transcriptional switch governs fibroblast activation in heart disease

Nature · 2021 · 221 citations

• Cell biology
• Biology
• Cancer research

Single-cell epigenomics reveals mechanisms of human cortical development

Nature · 2021 · 289 citations

• Biology
• Neuroscience
• Computational biology

. Here, to identify cell-type-specific chromatin accessibility patterns in the developing human brain, we used a single-cell assay for transposase accessibility by sequencing (scATAC-seq) in primary tissue samples from the human forebrain. We applied unbiased analyses to identify genomic loci that undergo extensive cell-type- and brain-region-specific changes in accessibility during neurogenesis, and an integrative analysis to predict cell-type-specific candidate regulatory elements. We found that cerebral organoids recapitulate most putative cell-type-specific enhancer accessibility patterns but lack many cell-type-specific open chromatin regions that are found in vivo. Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.

Human gut bacterial metabolism drives Th17 activation and colitis

Cell Host & Microbe · 2021 · 256 citations

• Biology
• Immunology
• Microbiology

Longitudinal linked-read sequencing reveals ecological and evolutionary responses of a human gut microbiome during antibiotic treatment

Genome Research · 2021 · 106 citations

• Biology
• Evolutionary biology
• Ecology

Gut microbial communities can respond to antibiotic perturbations by rapidly altering their taxonomic and functional composition. However, little is known about the strain-level processes that drive this collective response. Here, we characterize the gut microbiome of a single individual at high temporal and genetic resolution through a period of health, disease, antibiotic treatment, and recovery. We used deep, linked-read metagenomic sequencing to track the longitudinal trajectories of thousands of single nucleotide variants within 36 species, which allowed us to contrast these genetic dynamics with the ecological fluctuations at the species level. We found that antibiotics can drive rapid shifts in the genetic composition of individual species, often involving incomplete genome-wide sweeps of pre-existing variants. These genetic changes were frequently observed in species without obvious changes in species abundance, emphasizing the importance of monitoring diversity below the species level. We also found that many sweeping variants quickly reverted to their baseline levels once antibiotic treatment had concluded, demonstrating that the ecological resilience of the microbiota can sometimes extend all the way down to the genetic level. Our results provide new insights into the population genetic forces that shape individual microbiomes on therapeutically relevant timescales, with potential implications for personalized health and disease.

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

bioRxiv (Cold Spring Harbor Laboratory) · 2020 · 109 citations

• Biology
• Virology
• Evolutionary biology

category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (<0.1%) variants in 10/25 binding sites. In addition, we observed evidence of positive selection in ACE2 in multiple species, including bats. Utilized appropriately, our results may lead to the identification of intermediate host species for SARS-CoV-2, justify the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.