The Microbe, the Infection Enigma, and the Host

Annual Review of Microbiology, Journal Year: 2024, Volume and Issue: 78(1), P. 103 - 124

Published: July 10, 2024

Human infectious diseases are unique in that the discovery of their environmental trigger, microbe, was sufficient to drive development extraordinarily effective principles and tools for prevention or cure. This medical prowess has outpaced, perhaps even hindered, scientific progress equal magnitude biological understanding diseases. Indeed, hope kindled by germ theory disease rapidly subdued infection enigma, need a host solution, when it realized most individuals infected with agents continue do well. The root causes death unhappy few remained unclear. While canonical approaches vitro (cellular microbiology), vivo (animal models), natura (clinical studies) analyzed consequences considered be cause disease, cells, tissues, organisms seen as uniform host, alternative searched preexisting particularly human genetic immunological determinants populations diverse trigger microbe.

Language: Английский

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Mapping the regulatory effects of common and rare non-coding variants across cellular and developmental contexts in the brain and heart

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Abstract Whole genome sequencing has identified over a billion non-coding variants in humans, while GWAS revealed the as significant contributor to disease. However, prioritizing causal common and rare human disease, understanding how selective pressures have shaped genome, remains challenge. Here, we predicted effects of 15 million with deep learning models trained on single-cell ATAC-seq across 132 cellular contexts adult fetal brain heart, producing nearly two context-specific predictions. Using these predictions, distinguish candidate underlying traits diseases their effects. While variant are more cell-type-specific, exert cell-type-shared regulatory effects, particularly targeting affecting neurons. To prioritize de novo mutations extreme developed FLARE, functional genomic model constraint. FLARE outperformed other methods case from autism-affected families near syndromic autism-associated genes; for example, identifying mutation outliers CNTNAP2 that would be missed by alternative approaches. Overall, our findings demonstrate potential integrating maps population genetics learning-based effect prediction elucidate mechanisms development disease–ultimately, supporting notion genetic contributions neurodevelopmental disorders predominantly rare.

Language: Английский

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Evolutionary divergence in CTCF-mediated chromatin topology drives transcriptional innovation in humans

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 26, 2025

Chromatin topology can impact gene regulation, but how evolutionary divergence in chromatin has shaped regulatory landscapes for distinctive human traits remains poorly understood. CTCF sites determine by forming domains and loops. Here, we show CTCF-mediated at the domain loop scales during primate evolution, elucidating distinct mechanisms shaping landscapes. Human-specific divergent lead to a broad rewiring of transcriptional Divergent loops concord with species-specific enhancer activity, influencing connectivity target genes concordant yet constrained manner. Under this mechanism, establish role human-specific isoform diversity, functional implications disease susceptibility. Furthermore, validate function these using forebrain organoids. This study advances our understanding genetic evolution from perspective genome architecture. regulation. Wu et al. that changes structure, particularly loops, drive diversity contributing traits.

Language: Английский

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Defining the genetic and evolutionary architecture of alternative splicing in response to infection

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: April 11, 2019

Abstract Host and environmental factors contribute to variation in human immune responses, yet the genetic evolutionary drivers of alternative splicing response infection remain largely uncharacterised. Leveraging 970 RNA-sequencing profiles resting stimulated monocytes from 200 individuals African- European-descent, we show that activation elicits a marked remodelling isoform repertoire, while increasing levels erroneous splicing. We identify 1,464 loci associated with usage (sQTLs), 9% them being stimulation-specific, which are enriched disease-related loci. Furthermore, detect longstanding increased plasticity gene splicing, positive selection Neanderthal introgression have both contributed diversify landscape populations. Together, these findings suggest differential has been an important substrate innovation long-term evolution responses more recent vehicle population local adaptation.

Language: Английский

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The human genetic determinism of life-threatening infectious diseases: genetic heterogeneity and physiological homogeneity?

Human Genetics, Journal Year: 2020, Volume and Issue: 139(6-7), P. 681 - 694

Published: May 27, 2020

Language: Английский

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