Genetic Variation in Neurotransmitter Receptors Generates Behavioral Diversity

Variation in behavior among individuals is both remarkable and of great significance to society. People differ in locomotor skills, in sleep patterns, in their willingness to take risks, and in how they relate to other people. Whereas diversity enriches society, extreme behavioral deviations can be pathological, so it is important to identify the causes of behavioral variability. It is clear that both the environment and genetics contribute to behavioral diversity in all animals, but the nature of the specific genes involved is only beginning to emerge. The nematode worm Caenorhabditis elegans is a good animal model to study the genetic and neuronal bases of behavioral variation, as there are large differences in behavior between naturally-occurring strains, and powerful tools exist to characterize these differences. One example of the behavioral diversity of C. elegans is the existence of different thresholds for exploration–exploitation tradeoffs: some strains decide to exploit resources more thoroughly, while others decide to abandon resources earlier and explore other options. Using quantitative genetic tools I have found that genetic variation in the adrenergic receptor tyra-3 affects this exploration– exploitation decision. tyra-3 responds to the neurotransmitter tyramine, which is related to vertebrate adrenaline and noradrenaline. tyra-3 modifies the activity of sensory neurons that detect food cues and that regulate the decision to abandon depleting food resources. In strains that are more prone to exploration tyra-3 is expressed at lower levels, and this altered expression modifies the response of the sensory neurons to food. Variation in a gene that affects the response to the environment helps explain how nature and nurture interact to produce behavioral outcomes. In addition to variation in exploratory behavior, C. elegans strains also differ in social behaviors. In most strains animals aggregate with each other, whereas a few strains have evolved a solitary life-style. Variation in the neuropeptide Y receptor homologue npr-1 contributes to social behavior variation, but I found that other genes are also involved in this behavior. Through quantitative genetic analysis I identified polymorphisms in the GABA-gated cation channel exp-1 that generate variation in social behavior. Based on existing behavioral diversity in C. elegans, I discovered genetic variation in two neurotransmitter receptors and characterized the way in which this variation modifies the neuronal circuits that generate behavior. Consistent with findings in other systems, my results suggest that genetic variation in neurotransmitter receptors is a common way of generating behavioral diversity in animals

The Key-Stone to the Arch : Unlocking Section 13\u27s Original Meaning

The Supreme Court of Pennsylvania holds that Section 13 of the State’s constitution, which prohibits all “cruel punishments,” is coextensive with the Eighth Amendment, which prohibits only punishments that are both “cruel and unusual.” Rather than analyze the state provision independently, the court defers to the U.S. Supreme Court’s interpretation of the Eighth Amendment. This, says the court, is because Pennsylvania history does not provide evidence that the Commonwealth’s prohibition differs from the federal one. And without that historical basis, the court believes it is bound by federal precedent. This is mistaken. History reveals that Pennsylvanians had a distinct, original understanding of “cruelty.” The U.S. Supreme Court has said that the original meaning of the federal provision parroted English criminal prohibitions, permitted retributive justifications, and proscribed only pain superadded beyond death through methods left in the past. This understanding is irreconcilable with the original meaning of Section 13. The Commonwealth’s provision, by contrast, parroted Enlightenment criminal philosophy, permitted only deterrence and rehabilitative justifications, and prohibited the addition of any severity contemporary science deemed unnecessary for those ends. The historical record should thus provide, not prevent, a distinctly Pennsylvanian definition of cruelty. This article provides that historical account. It reviews the influence of Montesquieu and Beccaria’s writings on the speeches, pamphlets, and debates of founding Pennsylvanians. It also traverses the text, legislative history, and early Supreme Court of Pennsylvania interpretation of the first penal laws in the Independent State. This penal code, which circumscribed capital punishment and augured the age of the penitentiary, distilled the distinctly Pennsylvania conception of “cruelty” into law. This was the philosophy Pennsylvanians encapsulated in their prohibition on cruel punishments. Section 13 jurisprudence should therefore build—independently—from the original meaning Pennsylvania’s history supplies

Parent‐offspring inference in inbred populations

Genealogical relationships are fundamental components of genetic studies. However, it is often challenging to infer correct and complete pedigrees even when genome-wide information is available. For example, inbreeding can obscure genetic differences between individuals, making it difficult to even distinguish first-degree relatives such as parent-offspring from full siblings. Similarly, genotyping errors can interfere with the detection of genetic similarity between parents and their offspring. Inbreeding is common in natural, domesticated, and experimental populations and genotyping of these populations often has more errors than in human data sets, so efficient methods for building pedigrees under these conditions are necessary. Here, we present a new method for parent-offspring inference in inbred pedigrees called specific parent-offspring relationship estimation (spore). spore is vastly superior to existing pedigree-inference methods at detecting parent-offspring relationships, in particular when inbreeding is high or in the presence of genotyping errors, or both. spore therefore fills an important void in the arsenal of pedigree inference tools

Natural polymorphisms in C. elegans HECW-1 E3 ligase affect pathogen avoidance behaviour

available in PMC 2012 June 22.Heritable variation in behavioural traits generally has a complex genetic basis1, and thus naturally occurring polymorphisms that influence behaviour have been defined in only rare instances2,3. The isolation of wild strains of Caenorhabditis elegans has facilitated the study of natural genetic variation in this species4 and provided insights into its diverse microbial ecology5. C. elegans responds to bacterial infection with conserved innate immune responses6-8 and, while lacking the immunological memory of vertebrate adaptive immunity, exhibits an aversive learning response to pathogenic bacteria9. Here, we report the molecular characterization of naturally occurring coding polymorphisms in a C. elegans gene encoding a conserved HECT domain-containing E3 ubiquitin ligase, HECW-1. We show that two distinct polymorphisms in neighbouring residues of HECW-1 each affect C. elegans behavioural avoidance of a lawn of Pseudomonas aeruginosa. Neuronspecific rescue and ablation experiments, and genetic interaction analysis suggest that HECW-1 functions in a pair of sensory neurons to inhibit P. aeruginosa lawn avoidance behaviour through inhibition of the neuropeptide receptor NPR-110, which we have previously shown promotes P. aeruginosa lawn avoidance behaviour11. Our data establish a molecular basis for natural variation in a C. elegans behaviour that may undergo adaptive changes in response to microbial pathogens.National Institutes of Health (U.S.) (NIH Grant GM084477

Nitroimidazole Action in Entamoeba histolytica: A Central Role for Thioredoxin Reductase

Metronidazole, a 5-nitroimidazole drug, has been the gold standard for several decades in the treatment of infections with microaerophilic protist parasites, including Entamoeba histolytica. For activation, the drug must be chemically reduced, but little is known about the targets of the active metabolites. Applying two-dimensional gel electrophoresis and mass spectrometry, we searched for protein targets in E. histolytica. Of all proteins visualized, only five were found to form adducts with metronidazole metabolites: thioredoxin, thioredoxin reductase, superoxide dismutase, purine nucleoside phosphorylase, and a previously unknown protein. Recombinant thioredoxin reductase carrying the modification displayed reduced enzymatic activity. In treated cells, essential non-protein thiols such as free cysteine were also affected by covalent adduct formation, their levels being drastically reduced. Accordingly, addition of cysteine allowed E. histolytica to survive in the presence of otherwise lethal metronidazole concentrations and reduced protein adduct formation. Finally, we discovered that thioredoxin reductase reduces metronidazole and other nitro compounds, suggesting a new model of metronidazole activation in E. histolytica with a central role for thioredoxin reductase. By reducing metronidazole, the enzyme renders itself and associated thiol-containing proteins vulnerable to adduct formation. Because thioredoxin reductase is a ubiquitous enzyme, similar processes could occur in other eukaryotic or prokaryotic organisms

Drug-microbiota interactions and treatment response: Relevance to rheumatoid arthritis

Knowledge about associations between changes in the structure and/or function of intestinal microbes (the microbiota) and the pathogenesis of various diseases is expanding. However, interactions between the intestinal microbiota and different pharmaceuticals and the impact of these on responses to treatment are less well studied. Several mechanisms are known by which drug-microbiota interactions can influence drug bioavailability, efficacy, and/or toxicity. This includes direct activation or inactivation of drugs by microbial enzymes which can enhance or reduce drug effectiveness. The extensive metabolic capabilities of the intestinal microbiota make it a hotspot for drug modification. However, drugs can also influence the microbiota profoundly and change the outcome of interactions with the host. Additionally, individual microbiota signatures are unique, leading to substantial variation in host responses to particular drugs. In this review, we describe several known and emerging examples of how drug-microbiota interactions influence the responses of patients to treatment for various diseases, including inflammatory bowel disease, type 2 diabetes and cancer. Focussing on rheumatoid arthritis (RA), a chronic inflammatory disease of the joints which has been linked with microbial dysbiosis, we propose mechanisms by which the intestinal microbiota may affect responses to treatment with methotrexate which are highly variable. Furthering our knowledge of this subject will eventually lead to the adoption of new treatment strategies incorporating microbiota signatures to predict or improve treatment outcomes

Analysis of Tp53 Codon 72 Polymorphisms, Tp53 Mutations, and HPV Infection in Cutaneous Squamous Cell Carcinomas

Non-melanoma skin cancers are one of the most common human malignancies accounting for 2-3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas.We studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism).We found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R.These studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations