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Ancient and recent selective pressures shaped genetic diversity at AIM2-like nucleic acid sensors.

ABSTRACT: AIM2-like receptors (ALRs) are a family of nucleic acid sensors essential for innate immune responses against viruses and bacteria. We performed an evolutionary analysis of ALR genes (MNDA, PYHIN1, IFI16, and AIM2) by analyzing inter- and intraspecies diversity. Maximum-likelihood analyses indicated that IFI16 and AIM2 evolved adaptively in primates, with branch-specific selection at the catarrhini lineage for IFI16. Application of a population genetics-phylogenetics approach also allowed identification of positive selection events in the human lineage. Positive selection in primates targeted sites located at the DNA-binding interface in both IFI16 and AIM2. In IFI16, several sites positively selected in primates and in the human lineage were located in the PYD domain, which is involved in protein-protein interaction and is bound by a human cytomegalovirus immune evasion protein. Finally, positive selection was found to target nuclear localization signals in IFI16 and the spacer region separating the two HIN domains. Population genetic analysis in humans revealed that an IFI16 genic region has been a target of long-standing balancing selection, possibly acting on two nonsynonymous polymorphisms located in the spacer region. Data herein indicate that ALRs have been repeatedly targeted by natural selection. The balancing selection region in IFI16 carries a variant with opposite risk effect for distinct autoimmune diseases, suggesting antagonistic pleiotropy. We propose that the underlying scenario is the result of an ancestral and still ongoing host-pathogen arms race and that the maintenance of susceptibility alleles for autoimmune diseases at IFI16 represents an evolutionary trade-off.

SUBMITTER: Cagliani R

PROVIDER: S-EPMC4007548 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Ancient and recent selective pressures shaped genetic diversity at AIM2-like nucleic acid sensors.

Cagliani Rachele R Forni Diego D Biasin Mara M Comabella Manuel M Guerini Franca R FR Riva Stefania S Pozzoli Uberto U Agliardi Cristina C Caputo Domenico D Malhotra Sunny S Montalban Xavier X Bresolin Nereo N Clerici Mario M Sironi Manuela M

Genome biology and evolution 20140401 4

AIM2-like receptors (ALRs) are a family of nucleic acid sensors essential for innate immune responses against viruses and bacteria. We performed an evolutionary analysis of ALR genes (MNDA, PYHIN1, IFI16, and AIM2) by analyzing inter- and intraspecies diversity. Maximum-likelihood analyses indicated that IFI16 and AIM2 evolved adaptively in primates, with branch-specific selection at the catarrhini lineage for IFI16. Application of a population genetics-phylogenetics approach also allowed identi ...[more]

PMID: 24682156

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Project description:Nucleic acid-based electrochemical sensors (NBEs) can support continuous and highly selective molecular monitoring in biological fluids, both in vitro and in vivo, via affinity-based interactions. Such interactions afford a sensing versatility that is not supported by strategies that depend on target-specific reactivity. Thus, NBEs have significantly expanded the scope of molecules that can be monitored continuously in biological systems. However, the technology is limited by the lability of the thiol-based monolayers employed for sensor fabrication. Seeking to understand the main drivers of monolayer degradation, we studied four possible mechanisms of NBE decay: (i) passive desorption of monolayer elements in undisturbed sensors, (ii) voltage-induced desorption under continuous voltammetric interrogation, (iii) competitive displacement by thiolated molecules naturally present in biofluids like serum, and (iv) protein binding. Our results indicate that voltage-induced desorption of monolayer elements is the main mechanism by which NBEs decay in phosphate-buffered saline. This degradation can be overcome by using a voltage window contained between -0.2 and 0.2 V vs Ag|AgCl, reported for the first time in this work, where electrochemical oxygen reduction and surface gold oxidation cannot occur. This result underscores the need for chemically stable redox reporters with more positive reduction potentials than the benchmark methylene blue and the ability to cycle thousands of times between redox states to support continuous sensing for long periods. Additionally, in biofluids, the rate of sensor decay is further accelerated by the presence of thiolated small molecules like cysteine and glutathione, which can competitively displace monolayer elements even in the absence of voltage-induced damage. We hope that this work will serve as a framework to inspire future development of novel sensor interfaces aiming to eliminate the mechanisms of signal decay in NBEs.

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Ancient and recent selective pressures shaped genetic diversity at AIM2-like nucleic acid sensors.

Publications

Ancient and recent selective pressures shaped genetic diversity at AIM2-like nucleic acid sensors.

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