Natural Selection in a Bangladeshi Population from the Cholera-Endemic Ganges River Delta

Karlsson, Elinor K.; Harris, Jason B.; Tabrizi, Shervin; Rahman, Atiqur; Shlyakhter, Ilya; Patterson, Nick; Ó'Dúshláine, Colm; Schaffner, Stephen F.; Gupta, Sameer; Chowdhury, Fahima; Sheikh, Alaullah; Shin, Ok Sarah; Ellis, Crystal N.; Becker, Christine; Stuart, Lynda M.; Calderwood, Stephen B.; Ryan, Edward T.; Qadri, Firdausi; Sabeti, Pardis C.; LaRocque, Regina C.

doi:10.1126/scitranslmed.3006338

Cited by 82 publications

(89 citation statements)

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“…We hypothesize a model of innate immune activation by V. cholerae O1 which incorporates pathways and regulators highlighted by our IPA analysis, immune proteins that we observed to be significantly abundant during the acute stage of cholera, and pathways previously found to be associated with cholera (8,11,12) (Fig. 6).…”

Section: Figmentioning

confidence: 99%

“…Genome-wide association studies also underscore the importance of the innate immune system in influencing the clinical manifestations of V. cholerae O1 infection (8). A recent analysis of signals of natural selection in individuals from the Ganges River Delta in Bangladesh revealed strong selection for a network of coexpressed genes linked to inhibitor of nuclear factor kappa-B kinase subunit gamma (IKBKG, also known as NEMO).…”

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confidence: 99%

“…Caspase-11 (caspase-4 in humans) cleaves caspase-1, which is part of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and is responsible for activating inflammatory cytokines such as interleukin 1␤ (IL-1␤), a potent mediator of cellular apoptosis (11,12). Intriguingly, cholera toxin (CT) also activates the caspase-1-dependent NLRP3 inflammasome in vitro (8). CT is known as a potent immunoadjuvant that stimulates maturation of mouse dendritic cells; this enhances antigen presentation to CD4 ϩ T cells and induces nuclear translocation of NF-B (13).…”

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confidence: 99%

“…A recent analysis of signals of natural selection in individuals from the Ganges River Delta in Bangladesh revealed strong selection for a network of coexpressed genes linked to inhibitor of nuclear factor kappa-B kinase subunit gamma (IKBKG, also known as NEMO). IKBKG is the regulatory component of the IB (IKK) kinase complex, which is required for activation of the nuclear factor kappa-lightchain-enhancer of activated B cells (NF-B) complex (8). The NF-B complex, in turn, is the major transcriptional regulator of genes involved in the innate immune response, with roles that include cytokine and free radical production, as well as the immune response to stress and bacterial antigens (9,10).…”

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confidence: 99%

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Comparative Proteomic Analysis Reveals Activation of Mucosal Innate Immune Signaling Pathways during Cholera

et al. 2015

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i Vibrio cholerae O1 is a major cause of acute watery diarrhea in over 50 countries. Evidence suggests that V. cholerae O1 may activate inflammatory pathways, and a recent study of a Bangladeshi population showed that variants in innate immune genes play a role in mediating susceptibility to cholera. We analyzed human proteins present in the small intestine of patients infected with V. cholerae O1 to characterize the host response to this pathogen. We collected duodenal biopsy specimens from patients with acute cholera after stabilization and again 30 days after initial presentation. Peptides extracted from biopsy specimens were sequenced and quantified using label-free mass spectrometry and SEQUEST. Twenty-seven host proteins were differentially abundant between the acute and convalescent stages of infection; the majority of these have known roles in innate defense, cytokine production, and apoptosis. Immunostaining confirmed that two proteins, WARS and S100A8, were more abundant in lamina propria cells during the acute stage of cholera. Analysis of the differentially abundant proteins revealed the activation of key regulators of inflammation by the innate immune system, including Toll-like receptor 4, nuclear factor kappa-light-chain-enhancer of activated B cells, mitogen-activated protein kinases, and caspase-dependent inflammasomes. Interleukin-12␤ (IL-12␤) was a regulator of several proteins that were activated during cholera, and we confirmed that IL-12␤ was produced by lymphocytes recovered from duodenal biopsy specimens of cholera patients. Our study shows that a broad inflammatory response is generated in the gut early after onset of cholera, which may be critical in the development of long-term mucosal immunity against V. cholerae O1. Vibrio cholerae O1, which causes 3 to 5 million cases of cholera annually, is a noninvasive pathogen that does not penetrate the intestinal mucosa of human hosts (1, 2). Cholera is considered a prototypical, noninflammatory diarrheal illness, and there are no gross changes in the integrity of mucosal tissue during V. cholerae O1 infection (2, 3). However, there is mounting evidence that V. cholerae O1 triggers inflammatory responses in the gut (2, 4, 5). Studies of duodenal tissue extracted from cholera patients indicate that V. cholerae O1 infection causes upregulation of innate host defenses in the intestinal mucosa, including neutrophil-derived antibacterial proteins, proinflammatory cytokines, and BPIFB1 (also known as LPLUNC1), which is an immune-modifying defense protein that may attenuate the host response to bacterial lipopolysaccharide (LPS) (4-6). A candidate gene study showed that a variant in the promoter region of LPLUNC1 is associated with cholera susceptibility in a population in Bangladesh, an area where cholera is an ancient disease (7).Genome-wide association studies also underscore the importance of the innate immune system in influencing the clinical manifestations of V. cholerae O1 infection (8). A recent analysis of signals of natural selection in in...

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Comparative Proteomic Analysis Reveals Activation of Mucosal Innate Immune Signaling Pathways during Cholera

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“…In contrast to SNP-based studies, in which the object of replication is the significant SNP (or variants in high linkage disequilibrium), the object of replication in gene set-based studies is the significant gene set. Across different samples, replicated gene sets typically are composed of different tagging SNPs (32,33), a phenomenon related to the allelic and locus heterogeneity of complex traits (22,34). In our study we did not observe substantial tagging SNP overlap between replicated gene sets across samples (Tables S5 and S6).…”

Section: Discussionmentioning

confidence: 51%

Computational dissection of human episodic memory reveals mental process-specific genetic profiles

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Fastenrath

Coynel

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Episodic memory performance is the result of distinct mental processes, such as learning, memory maintenance, and emotional modulation of memory strength. Such processes can be effectively dissociated using computational models. Here we performed gene set enrichment analyses of model parameters estimated from the episodic memory performance of 1,765 healthy young adults. We report robust and replicated associations of the amine compound SLC (solute-carrier) transporters gene set with the learning rate, of the collagen formation and transmembrane receptor protein tyrosine kinase activity gene sets with the modulation of memory strength by negative emotional arousal, and of the L1 cell adhesion molecule (L1CAM) interactions gene set with the repetition-based memory improvement. Furthermore, in a large functional MRI sample of 795 subjects we found that the association between L1CAM interactions and memory maintenance revealed large clusters of differences in brain activity in frontal cortical areas. Our findings provide converging evidence that distinct genetic profiles underlie specific mental processes of human episodic memory. They also provide empirical support to previous theoretical and neurobiological studies linking specific neuromodulators to the learning rate and linking neural cell adhesion molecules to memory maintenance. Furthermore, our study suggests additional memory-related genetic pathways, which may contribute to a better understanding of the neurobiology of human memory.learning and memory | computational model | gene set enrichment analysis | functional neuroimaging | frontal lobe H uman memory is a highly heritable and complex trait that is the outcome of numerous neurocognitive processes (1, 2). Although many genetic variations associated with human memory performance have been identified (3-9), most were based on general memory scores, such as the number of recalled items. Such scores may serve as good correlates of overall memory ability, but they offer little insight into the genetic underpinnings of specific memory-related mental processes, such as encoding, memory maintenance, modulation by emotional arousal, or guessing strategies. Importantly, neurobiological and molecular profiles of such processes are known to be partly distinct (10-12). Because some of the mental processes involved in memory are not readily amenable to direct observation, computational modeling can be used to make inferences about them (13,14). Modelbased analyses provided insights into neurocomputational mechanisms of reward-based learning and decision making (15-17), related model parameters such as the learning rate to genetic polymorphisms (18,19), and provided a computational explanation for the inverted-U-shaped relation between stress intensity and behavioral performance (20). As a relatively recent development, the model-based analysis approach has largely been missing from studies of human episodic memory and genome-wide association studies (GWAS).GWAS already had identified a number of associations betwee...

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2019

A Companion to Anthropological Genetics

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Natural Selection in a Bangladeshi Population from the Cholera-Endemic Ganges River Delta

Cited by 82 publications

References 86 publications

Comparative Proteomic Analysis Reveals Activation of Mucosal Innate Immune Signaling Pathways during Cholera

Comparative Proteomic Analysis Reveals Activation of Mucosal Innate Immune Signaling Pathways during Cholera

Computational dissection of human episodic memory reveals mental process-specific genetic profiles

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