scholarly journals Conflicts with diarrheal pathogens trigger rapid evolution of an intestinal signaling axis

2020 ◽  
Author(s):  
Clayton M. Carey ◽  
Sarah E. Apple ◽  
Zoё A. Hilbert ◽  
Michael S. Kay ◽  
Nels C. Elde
Keyword(s):  
Positive Selection ◽  
Rapid Evolution ◽  
Genetic Conflict ◽  
Selective Pressures ◽  
Heat Stable ◽  
Guanylate Cyclase C ◽  
Signaling Axis ◽  
History Of ◽  
Water Secretion

AbstractThe pathogenesis of infectious diarrheal diseases is largely attributed to enterotoxin proteins that disrupt intestinal water absorption, causing severe dehydration. Despite profound health consequences, the impacts of diarrhea-causing microbes on the evolutionary history of host species are largely unknown. We investigated patterns of genetic variation in mammalian Guanylate Cyclase-C (GC-C), an intestinal receptor frequently targeted by bacterial enterotoxins, to determine how hosts might adapt in response to diarrheal infections. Under normal conditions, GC-C interacts with endogenous guanylin peptides to promote water secretion in the intestine, but signaling can be hijacked by bacterially-encoded heat-stable enterotoxins (STa) during infection, which leads to overstimulation of GC-C and diarrhea. Phylogenetic analysis in mammals revealed evidence of recurrent positive selection in the GC-C ligand-binding domain in primates and bats, consistent with selective pressures to evade interactions with STa. Using in vitro assays and transgenic intestinal organoids to model STa-mediated diarrhea, we show that GC-C diversification in these lineages results in substantial variation in toxin susceptibility. In bats, we observe a unique pattern of compensatory coevolution in the endogenous GC-C ligand uroguanylin, reflecting intense bouts of positive selection at the receptor-ligand interface. These findings demonstrate control of water physiology as a previously unrecognized interface for genetic conflict and reveal diarrheal pathogens as a source of selective pressure among diverse mammals.

A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion

2004 ◽  
Vol 286 (1) ◽  
pp. G95-G101 ◽  
Author(s):  
S. P. Rao ◽  
Z. Sellers ◽  
D. L. Crombie ◽  
D. L. Hogan ◽  
E. A. Mann ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Mek Inhibitor ◽  
Acid Exposure ◽  
Wild Type ◽  
Heat Stable ◽  
Guanylate Cyclase C ◽  
Perfusion Studies ◽  
Erk Phosphorylation

Luminal acidification provides the strongest physiological stimulus for duodenal [Formula: see text] secretion. Various neurohumoral mechanisms are believed to play a role in acid-stimulated [Formula: see text] secretion. Previous studies in the rat and human duodenum have shown that guanylin and Escherichia coli heat-stable toxin, both ligands of the transmembrane guanylyl cyclase receptor [guanylate cyclase C (GC-C)], are potent stimulators for duodenal [Formula: see text] secretion. We postulated that the GC-C receptor plays an important role in acid-stimulated [Formula: see text] secretion. In vivo perfusion studies performed in wild-type (WT) and GC-C knockout (KO) mice indicated that acid-stimulated duodenal [Formula: see text] secretion was significantly decreased in the GC-C KO animals compared with the WT counterparts. Pretreatment with PD-98059, an MEK inhibitor, resulted in attenuation of duodenal [Formula: see text] secretion in response to acid stimulation in the WT mice with no further effect in the KO mice. In vitro cGMP generation studies demonstrated a significant and comparable increase in cGMP levels on acid exposure in the duodenum of both WT and KO mice. In addition, a rapid, time-dependent phosphorylation of ERK was observed with acid exposure in the duodenum of WT mice, whereas a marked attenuation in ERK phosphorylation was observed in the KO animals despite equivalent levels of ERK in both groups of animals. On the basis of these studies, we conclude that transmembrane GC-C is a key mediator of acid-stimulated duodenal [Formula: see text] secretion. Furthermore, ERK phosphorylation may be an important intracellular mediator of duodenal [Formula: see text] secretion.

β-Defensin evolution: selection complexity and clues for residues of functional importance

2006 ◽  
Vol 34 (2) ◽  
pp. 257-262 ◽  
Author(s):  
C.A.M. Semple ◽  
K. Taylor ◽  
H. Eastwood ◽  
P.E. Barran ◽  
J.R. Dorin
Keyword(s):  
Positive Selection ◽  
Evolutionary History ◽  
Mammalian Genome ◽  
Functional Importance ◽  
Selective Pressures ◽  
History Of ◽  
Orthologous Loci ◽  
Window Approach ◽  
First Time ◽  
Evolutionary Lineages

We have examined the evolution of the genes at the major human β-defensin locus and the orthologous loci in a range of other primates and mammals. For the first time, these data allow us to examine selective episodes in the more recent evolutionary history of this locus as well as in the ancient past. We have used a combination of maximum-likelihood-based tests and a maximum-parsimony-based sliding window approach to give a detailed view of the varying modes of selection operating at this locus. We provide evidence for strong positive selection soon after the duplication of these genes within an ancestral mammalian genome. During the divergence of primates, however, variable selective pressures have acted on β-defensin genes in different evolutionary lineages, with episodes of both negative and, more rarely, positive selection. Positive selection appears to have been more common in the rodent lineage, accompanying the birth of novel rodent-specific β-defensin gene clades. Sites in the second exon have been subject to positive selection and, by implication, are important in functional diversity. A small number of sites in the mature human peptides were found to have undergone repeated episodes of selection in different primate lineages. Particular sites were consistently implicated by multiple methods at positions throughout the mature peptides. These sites are clustered at positions that are predicted to be important for the function of β-defensins.

Diarrheal pathogens trigger rapid evolution of the guanylate cyclase-C signaling axis in bats

2021 ◽  
Author(s):  
Clayton M. Carey ◽  
Sarah E. Apple ◽  
Zoë A. Hilbert ◽  
Michael S. Kay ◽  
Nels C. Elde
Keyword(s):  
Guanylate Cyclase ◽  
Rapid Evolution ◽  
Guanylate Cyclase C ◽  
Signaling Axis

scholarly journals Rapid evolution and biogeographic spread in a colorectal cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Joao M. Alves ◽  
Sonia Prado-López ◽  
José Manuel Cameselle-Teijeiro ◽  
David Posada
Keyword(s):  
Colorectal Cancer ◽  
Lymph Nodes ◽  
Positive Selection ◽  
Rapid Evolution ◽  
Population Expansion ◽  
Metastatic Colonization ◽  
Biogeographic History ◽  
History Of ◽  
Tumoral Cells ◽  
Over Time

Abstract How and when tumoral clones start spreading to surrounding and distant tissues is currently unclear. Here we leveraged a model-based evolutionary framework to investigate the demographic and biogeographic history of a colorectal cancer. Our analyses strongly support an early monoclonal metastatic colonization, followed by a rapid population expansion at both primary and secondary sites. Moreover, we infer a hematogenous metastatic spread under positive selection, plus the return of some tumoral cells from the liver back to the colon lymph nodes. This study illustrates how sophisticated techniques typical of organismal evolution can provide a detailed, quantitative picture of the complex tumoral dynamics over time and space.

scholarly journals Effect of Recombination on the Accuracy of the Likelihood Method for Detecting Positive Selection at Amino Acid Sites

Genetics ◽  
2003 ◽  
Vol 164 (3) ◽  
pp. 1229-1236 ◽  
Author(s):  
Maria Anisimova ◽  
Rasmus Nielsen ◽  
Ziheng Yang
Keyword(s):  
Positive Selection ◽  
Dna Sequences ◽  
Empirical Bayes ◽  
Null Model ◽  
Likelihood Method ◽  
Ratio Test ◽  
Type I ◽  
Selective Pressures ◽  
Codon Substitution ◽  
History Of

AbstractMaximum-likelihood methods based on models of codon substitution accounting for heterogeneous selective pressures across sites have proved to be powerful in detecting positive selection in protein-coding DNA sequences. Those methods are phylogeny based and do not account for the effects of recombination. When recombination occurs, such as in population data, no unique tree topology can describe the evolutionary history of the whole sequence. This violation of assumptions raises serious concerns about the likelihood method for detecting positive selection. Here we use computer simulation to evaluate the reliability of the likelihood-ratio test (LRT) for positive selection in the presence of recombination. We examine three tests based on different models of variable selective pressures among sites. Sequences are simulated using a coalescent model with recombination and analyzed using codon-based likelihood models ignoring recombination. We find that the LRT is robust to low levels of recombination (with fewer than three recombination events in the history of a sample of 10 sequences). However, at higher levels of recombination, the type I error rate can be as high as 90%, especially when the null model in the LRT is unrealistic, and the test often mistakes recombination as evidence for positive selection. The test that compares the more realistic models M7 (β) against M8 (β and ω) is more robust to recombination, where the null model M7 allows the positive selection pressure to vary between 0 and 1 (and so does not account for positive selection), and the alternative model M8 allows an additional discrete class with ω= dN/dS that could be estimated to be >1 (and thus accounts for positive selection). Identification of sites under positive selection by the empirical Bayes method appears to be less affected than the LRT by recombination.

scholarly journals Intestinal Enteroids Model Guanylate Cyclase C-Dependent Secretion Induced by Heat-Stable Enterotoxins

2016 ◽  
Vol 84 (10) ◽  
pp. 3083-3091 ◽  
Author(s):  
Amanda M. Pattison ◽  
Erik S. Blomain ◽  
Dante J. Merlino ◽  
Fang Wang ◽  
Mary Ann S. Crissey ◽  
...  
Keyword(s):  
High Throughput ◽  
Guanylate Cyclase ◽  
High Throughput Screening ◽  
Molecular Mechanisms ◽  
Diarrheal Disease ◽  
Intestinal Secretion ◽  
Fluid Secretion ◽  
Heat Stable ◽  
Guanylate Cyclase C ◽  
Signaling Axis

EnterotoxigenicEscherichia coli(ETEC) causes ∼20% of the acute infectious diarrhea (AID) episodes worldwide, often by producing heat-stable enterotoxins (STs), which are peptides structurally homologous to paracrine hormones of the intestinal guanylate cyclase C (GUCY2C) receptor. While molecular mechanisms mediating ST-induced intestinal secretion have been defined, advancements in therapeutics have been hampered for decades by the paucity of disease models that integrate molecular and functional endpoints amenable to high-throughput screening. Here, we reveal that mouse and human intestinal enteroids in three-dimensionalex vivocultures express the components of the GUCY2C secretory signaling axis. ST and its structural analog, linaclotide, an FDA-approved oral secretagog, induced fluid accumulation quantified simultaneously in scores of enteroid lumens, recapitulating ETEC-induced intestinal secretion. Enteroid secretion depended on canonical molecular signaling events responsible for ETEC-induced diarrhea, including cyclic GMP (cGMP) produced by GUCY2C, activation of cGMP-dependent protein kinase (PKG), and opening of the cystic fibrosis transmembrane conductance regulator (CFTR). Importantly, pharmacological inhibition of CFTR abrogated enteroid fluid secretion, providing proof of concept for the utility of this model to screen antidiarrheal agents. Intestinal enteroids offer a unique model, integrating the GUCY2C signaling axis and luminal fluid secretion, to explore the pathophysiology of, and develop platforms for, high-throughput drug screening to identify novel compounds to prevent and treat ETEC diarrheal disease.

Genetic conflicts during meiosis and the evolutionary origins of centromere complexity

2006 ◽  
Vol 34 (4) ◽  
pp. 569-573 ◽  
Author(s):  
H.S. Malik ◽  
J.J. Bayes
Keyword(s):  
Positive Selection ◽  
Dna Sequence ◽  
Rapid Evolution ◽  
Genetic Conflict ◽  
Centromeric Dna ◽  
Preferential Transmission ◽  
Evolutionary Origins ◽  
Genetic Conflicts ◽  
Centromere Drive

Centromeric DNA evolves rapidly, ranging in size and complexity over several orders of magnitude. Traditional attempts at studying centromeres have left unexplained the causes underlying this complexity and rapid evolution. Instead of directly studying centromeric DNA sequence, our approach has been to study the proteins that epigenetically determine centromere identity. We have discovered that centromeric histones (CenH3s) have evolved under positive selection in multiple lineages, suggesting an involvement in recurrent genetic conflict. Our hypothesis is that ‘centromere-drive’ is the source of this conflict. Under this model, centromeres compete via microtubule attachments for preferential transmission in female meioses occurring in animals and plants. Since only one of four meiotic products will become the egg, this competition confers a selfish advantage to chromosomes that can make more microtubule attachments, resulting in runaway expansions of centromeric satellites. While beneficial to the ‘driving’ chromosome, these expansions can have deleterious effects on the fitness of an organism and of the species. CenH3s as well as other heterochromatin proteins have evolved under positive selection to suppress the deleterious consequences of ‘centromere-drive’ by restoring meiotic parity.

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