Medicina darwiniana y psoriasis / Darwinian Medicine and Psoriasis

La medicina evolutiva o darwiniana entiende algunos procesos patológicos como intentos del organismo por solucionar un problema o generar mecanismos de defensa. Algunas enfermedades pueden haber representado una ventaja en ciertos estadios de la evolución humana. La psoriasis es una enfermedad poligénica con alta penetrancia y una prevalencia de hasta el 3% en las poblaciones de origen caucásico. Se ha descrito que las lesiones de psoriasis generan una mayor capacidad para la curación de las heridas, y de lucha contra la infección. Se ha postulado que, en ciertas poblaciones, los genes promotores de psoriasis han sido seleccionados ante la presión ambiental de ciertas infecciones como la lepra, el sida y la tuberculosis. La tendencia de los enfermos con psoriasis grave al desarrollo de síndrome metabólico puede representar un intento de reacción ante presiones ambientales y señales de alarma que desencadenan resistencia insulínica y ahorro de grasa

Darwinian medicine, or evolutionary medicine, regards some pathological conditions as attempts by the organism to solve a problem or develop defense mechanisms. At certain stages of human evolution, some diseases may have conferred a selective advantage. Psoriasis is a high-penetrance multigenic disorder with prevalence among whites of up to 3%. Psoriatic lesions have been linked with enhanced wound-healing qualities and greater capacity to fight infection. Leprosy, tuberculosis, and infections caused by viruses similar to human immunodeficiency virus have been postulated as environmental stressors that may have selected for psoriasis-promoting genes in some human populations. The tendency of patients with severe psoriasis to develop metabolic syndrome may reflect the body’s attempt to react to environmental stresses and warning signs by triggering insulin resistance and fat storage

Darwinian medicine and psoriasis.

Darwinian medicine, or evolutionary medicine, regards some pathological conditions as attempts by the organism to solve a problem or develop defense mechanisms. At certain stages of human evolution, some diseases may have conferred a selective advantage. Psoriasis is a high-penetrance multigenic disorder with prevalence among whites of up to 3%. Psoriatic lesions have been linked with enhanced wound-healing qualities and greater capacity to fight infection. Leprosy, tuberculosis, and infections caused by viruses similar to human immunodeficiency virus have been postulated as environmental stressors that may have selected for psoriasis-promoting genes in some human populations. The tendency of patients with severe psoriasis to develop metabolic syndrome may reflect the body's attempt to react to environmental stresses and warning signs by triggering insulin resistance and fat storage.

Haplotype structure and positive selection at TLR1.

Toll-like receptor 1, when dimerized with Toll-like receptor 2, is a cell surface receptor that, upon recognition of bacterial lipoproteins, activates the innate immune system. Variants in TLR1 associate with the risk of a variety of medical conditions and diseases, including sepsis, leprosy, tuberculosis, and others. The foremost of these is rs5743618 c.2079T>G(p.(Ile602Ser)), the derived allele of which is associated with reduced risk of sepsis, leprosy, and other diseases. Interestingly, 602Ser, which shows signatures of selection, inhibits TLR1 surface trafficking and subsequent activation of NFκB upon recognition of a ligand. This suggests that reduced TLR1 activity may be beneficial for human health. To better understand TLR1 variation and its link to human health, we have typed all 7 high-frequency missense variants (>5% in at least one population) along with 17 other variants in and around TLR1 in 2548 individuals from 56 populations from around the globe. We have also found additional signatures of selection on missense variants not associated with rs5743618, suggesting that there may be multiple functional alleles under positive selection in this gene.

Contrasted evolutionary constraints on secreted and non-secreted proteomes of selected Actinobacteria.

BACKGROUND: Actinobacteria have adapted to contrasted ecological niches such as the soil, and among others to plants or animals as pathogens or symbionts. Mycobacterium genus contains mostly pathogens that cause a variety of mammalian diseases, among which the well-known leprosy and tuberculosis, it also has saprophytic relatives. Streptomyces genus is mostly a soil microbe known for its secondary metabolites, it contains also plant pathogens, animal pathogens and symbionts. Frankia, a nitrogen-fixing actinobacterium establishes a root symbiosis with dicotyledonous pionneer plants. Pathogens and symbionts live inside eukaryotic cells and tissues and interact with their cellular environment through secreted proteins and effectors transported through transmembrane systems; nevertheless they also need to avoid triggering host defense reactions. A comparative genome analysis of the secretomes of symbionts and pathogens allows a thorough investigation of selective pressures shaping their evolution. In the present study, the rates of silent mutations to non-silent mutations in secretory proteins were assessed in different strains of Frankia, Streptomyces and Mycobacterium, of which several genomes have recently become publicly available. RESULTS: It was found that secreted proteins as a whole have a stronger purifying evolutionary rate (non-synonymous to synonymous substitutions or Ka/Ks ratio) than the non-secretory proteins in most of the studied genomes. This difference becomes statistically significant in cases involving obligate symbionts and pathogens. Amongst the Frankia, secretomes of symbiotic strains were found to have undergone evolutionary trends different from those of the mainly saprophytic strains. Even within the secretory proteins, the signal peptide part has a higher Ka/Ks ratio than the mature part. Two contrasting trends were noticed amongst the Frankia genomes regarding the relation between selection strength (i.e. Ka/Ks ratio) and the codon adaptation index (CAI), a predictor of the expression rate, in all the genes belonging to the core genome as well as the core secretory protein genes. The genomes of pathogenic Mycobacterium and Streptomyces also had reduced secretomes relative to saprophytes, as well as in general significant pairwise Ka/Ks ratios in their secretomes. CONCLUSION: In marginally free-living facultative symbionts or pathogenic organisms under consideration, secretory protein genes as a whole evolve at a faster rate than the rest and this process may be an adaptive life-strategy to counter the host selection pressure. The higher evolutionary rate of signal peptide part compared to mature protein provides an indication that signal peptide parts may be under relaxed purifying selection, indicative of the signal peptides not being secreted into host cells. Codon usage analysis suggests that in actinobacterial strains under host selection pressure such as symbiotic Frankia, ACN, FD and the pathogenic Mycobacterium, codon usage bias was negatively correlated to the selective pressure exerted on the secretory protein genes.

Albinism and disease causing pathogens in Tanzania: are alleles that are associated with OCA2 being maintained by balancing selection?

Oculocutaneous albinism type 2 (OCA2) is present at significantly higher frequencies in sub-Saharan African populations compared to populations in other regions of the world. In Tanzania and other sub-Saharan countries, most OCA2 is associated with a common 2.7kb deletion allele. Leprosy is also in high prevalence in sub-Saharan African populations. The infectious agent of leprosy, Mycobacterium leprae, contains a gene, 38L, that is similar to OCA2. Hypopigmented patches of skin are early symptoms that present with infection of leprosy. In consideration of both the genetic similarity of OCA2 and the 38L gene of M. leprae and the involvement of pigmentation in both disorders, we hypothesized that the high rates of OCA2 may be due to heterozygote advantage. Hence, we hypothesized that carriers of the 2.7kb deletion allele of OCA2 may provide a protective advantage from infection with leprosy. We tested this hypothesis by determining the carrier frequency of the 2.7kb deletion allele from a sample of 240 individuals with leprosy from Tanzania. The results were inconclusive due to the small sample size; however, they enabled us to rule out a large protective effect, but perhaps not a small advantage. Mycobacterium tuberculosis is another infectious organism prevalent in sub-Saharan Africa that contains a gene, arsenic-transport integral membrane protein that is also similar to OCA2. Interestingly, chromosomal region 15q11-13, which also contains OCA2, was reported to be linked to tuberculosis susceptibility. Although variants within OCA2 were tested for association, the 2.7kb deletion allele of OCA2 was not tested. This led us to hypothesize that the deletion allele may confer resistance to susceptibility. Confirmation of our hypothesis would enable development of novel pharmocogenetic therapies for the treatment of tuberculosis, which in turn, may enable development of drugs that target other pathogens that utilize a similar infection mechanism as M. tuberculosis. From an evolutionary perspective, confirmation of our hypothesis may provide another example of heterozygote advantage.

Genetic and immunological evidence implicates interleukin 6 as a susceptibility gene for leprosy type 2 reaction.

In leprosy, type 1 reaction (T1R) and type 2 reaction (T2R) are major causes of nerve injury and permanent disabilities. A previous study on plasma levels of 27 cytokines in patients with T1R or T2R and controls with nonreactional leprosy identified the gene for interleukin 6 (IL-6) as a candidate for genetic analysis. Two nested case-control studies were built from a cohort of 409 patients with leprosy from central Brazil, monitored for T1R and T2R. There was evidence for association between T2R and IL-6 tag single-nucleotide polymorphisms rs2069832 (P = .002), rs2069840 (P = .03), and rs2069845 (P = .04), with information on the entire IL-6 locus, as well as functional IL-6 variant rs1800795 (P = .005). Moreover, IL-6 plasma levels in patients with T2R correlated with IL-6 genotypes (P = .04). No association was found between IL-6 variants and T1R. Identifying genetic predictive factors for leprosy reactions may have a major impact on preventive strategies.

Insights from genomic comparisons of genetically monomorphic bacterial pathogens.

Some of the most deadly bacterial diseases, including leprosy, anthrax and plague, are caused by bacterial lineages with extremely low levels of genetic diversity, the so-called 'genetically monomorphic bacteria'. It has only become possible to analyse the population genetics of such bacteria since the recent advent of high-throughput comparative genomics. The genomes of genetically monomorphic lineages contain very few polymorphic sites, which often reflect unambiguous clonal genealogies. Some genetically monomorphic lineages have evolved in the last decades, e.g. antibiotic-resistant Staphylococcus aureus, whereas others have evolved over several millennia, e.g. the cause of plague, Yersinia pestis. Based on recent results, it is now possible to reconstruct the sources and the history of pandemic waves of plague by a combined analysis of phylogeographic signals in Y. pestis plus polymorphisms found in ancient DNA. Different from historical accounts based exclusively on human disease, Y. pestis evolved in China, or the vicinity, and has spread globally on multiple occasions. These routes of transmission can be reconstructed from the genealogy, most precisely for the most recent pandemic that was spread from Hong Kong in multiple independent waves in 1894.

Leprosy and the natural selection for psoriasis.

Psoriasis is a genetically determined, almost worldwide-distributed inflammatory skin disease with overall higher prevalence among people of northern European ancestry. Since enhanced innate immunity is an important feature of the pathophysiology of this disease, it has been proposed that differences in the prevalence of psoriasis in different populations mainly result from differences in natural selection for gene polymorphisms associated with more vigorous immunity against infectious agents. However the infectious agent(s) that could have acted upon human population as selection pressure for psoriasis is still obscure. Based on the remarkable clinical observation that psoriasis and leprosy are almost mutually exclusive, a fact that is further supported by divergent HLA patterns in patients with psoriasis and leprosy we propose that "resisting leprosy" may have been the evolutionary advantage that favoured the expansion of some psoriasis-associated genotypes especially in the progenitors of modern Europeans. Moreover, we suggest that the spreading out of a certain genetic resistance trait may offer a supplementary explanation for the better understanding of the relatively rapid decline of leprosy in the late medieval epoch in Europe. Both genetic and paleoepidemiologic methods could be employed in order to challenge the present hypothesis.

Leprosy epidemics during history increased protective allele frequency of PARK2/PACRG genes in the population of the Mljet Island, Croatia.

INTRODUCTION: Two regulatory polymorphisms (rs1040079 and rs9356058) shared by PARK2 and PACRG genes were identified as major risk variants for leprosy susceptibility. The aim of this study was to investigate if allele frequencies of these polymorphisms in the isolated population of the island of Mljet, which served as a quarantine for leprosy patients during past centuries, were different to allele frequencies in two control populations with no history of leprosy. SUBJECTS AND METHODS: This study included 88 unrelated Caucasian individuals from the island of Mljet while two control groups included 93 individuals from the island of Rab and 160 individuals from the region of Split. Genotyping for rs1040079 and rs9356058 was performed by "real-time" PCR analysis. We also compared the allele frequency of the rs9356058 polymorphism from the population of Mljet with allele frequencies derived from the existing genome wide association scans in two additional island populations, Vis (924 subjects) and Korcula (909 subjects). RESULTS: We found a significant increase in the frequency of rs9356058 allele C in the population of Mljet when compared to both control groups. We also observed a significant increase in the frequency of rs1040079 allele A in the population of Mljet when compared with the population of Rab, however this increase was not significant when compared with the population of Split. Allele frequencies of both examined polymorphisms did not differ between the two control populations. Protective haplotype rs9356058-rs1040079 CA was also more frequent in the population of Mljet compared with the Rab and Split populations. In addition, an increase of frequency of rs9356058 allele C was also observed in the population of Mljet when compared with the frequency in the Korcula population. CONCLUSION: The results of our study show the association of polymorphisms rs9356058 and rs1040079 in gene PARK2/PACRG with leprosy. The results of our study indicate that exposure to leprosy and mortality in the population caused by leprosy on Mljet resulted in the selection of rs9356058 "protective" C allele in the PARK2 gene, while this was not observed in the two control groups. This is the first study to assess the genetic susceptibility to leprosy in a European population.

Resistance to rifampicin: at the crossroads between ecological, genomic and medical concerns.

The first antibiotic of the ansamycin family, rifampicin (RIF), was isolated in 1959 and was introduced into therapy in 1962; it is still a first-line agent in the treatment of diseases such as tuberculosis, leprosy and various biofilm-related infections. The antimicrobial activity of RIF is due to its inhibition of bacterial RNA polymerase (RNAP). Most frequently, bacteria become resistant to RIF through mutation of the target; however, this mechanism is not unique. Other mechanisms of resistance have been reported, such as duplication of the target, action of RNAP-binding proteins, modification of RIF and modification of cell permeability. We suggest that several of these alternative resistance strategies could reflect the ecological function of RIF, such as autoregulation and/or signalling to surrounding microorganisms. Very often, resistance mechanisms found in the clinic have an environmental origin. One may ask whether the introduction of the RIF analogues rifaximin, rifalazil, rifapentine and rifabutin in the therapeutic arsenal, together with the diversification of the pathologies treated by these molecules, will diversify the resistance mechanisms of human pathogens against ansamycins.

Estimates of the effect of natural selection on protein-coding content.

Analysis of natural selection is key to understanding many core biological processes, including the emergence of competition, cooperation, and complexity, and has important applications in the targeted development of vaccines. Selection is hard to observe directly but can be inferred from molecular sequence variation. For protein-coding nucleotide sequences, the ratio of nonsynonymous to synonymous substitutions (omega) distinguishes neutrally evolving sequences (omega = 1) from those subjected to purifying (omega < 1) or positive Darwinian (omega > 1) selection. We show that current models used to estimate omega are substantially biased by naturally occurring sequence compositions. We present a novel model that weights substitutions by conditional nucleotide frequencies and which escapes these artifacts. Applying it to the genomes of pathogens causing malaria, leprosy, tuberculosis, and Lyme disease gave significant discrepancies in estimates with approximately 10-30% of genes affected. Our work has substantial implications for how vaccine targets are chosen and for studying the molecular basis of adaptive evolution.

Ten years of varying lake level and selection on size-at-maturity in sockeye salmon.

Despite the ubiquity of studies quantifying the strength and form of selection in nature, rarely is the ecological context for contemporary selection understood. Here we report a case where lake level is a selective factor acting on sockeye salmon body size-at-maturity because low lake levels cause large salmon to strand and die rather than reach the breeding grounds. As a result of a semelparous life history, death for salmon at this stage results in a lifetime fitness of zero. We combined information on the level of Lake Aleknagik (southwestern Alaska, USA) from 1952 through 2006 with a detailed comparison of the body size of mature salmon that died at the mouth of Hansen Creek vs. individuals that successfully ascended to the spawning grounds over 10 breeding seasons (1997-2006). The percentage of salmon stranding at the mouth varied among years: 2-42% in males and < 1-26% in females. Formal selection analyses indicated that the largest individuals were most susceptible to stranding mortality, especially in years when many salmon stranded, and these were years with low lake levels. Taken together, these results suggest that lake level was a strong and consistent selective force acting on this salmon population, acting synergistically with size-selective predation by bears. Salmon breeding in Hansen Creek tend to be smaller, younger, and more streamlined than conspecifics from neighboring populations, suggesting that selection against large individuals could be driving these patterns.

Effects of genetic selection on behavioral profiles of Single Comb White Leghorn hens through two production cycles.

Four layer genetic stocks consisting of 3 Ottawa control strains (5, 7, and 10) and a commercial laying stock (CCS) were utilized to evaluate potential changes in behavioral profiles due to the effects of genetic selection through 2 production cycles. The Ottawa strains were started as random bred strains from the crosses of several popular commercial layers in 1950, 1959, and 1972, and the commercial strain used herein was from calendar year 1993, and its ancestors were involved in the formation of all of the random bred strains. The behavior study utilized 2 replicates from each strain that contained 4 cages, 6 hens/cage, for a total of 192 hens. Behavioral observations were recorded on 2 consecutive days beginning at 22 wk of age and every 28 d thereafter during the first production cycle, the molt period, and the second production cycle through 90 wk of age and periodic feather and Hansen's test scores recorded. Behavior profiles were similar between the control strains and the CCS, indicating that long-term genetic selection by commercial egg-type breeding firms to enhance production parameters has had no impact on laying strain behavior patterns. Appetitive behaviors were not affected by strain. During the molt, hens had reduced (P < 0.05) feeding and drinking frequencies in comparison with those observed during the first and second cycles. The data indicated that hens pecked inedible objects at a greater (P < 0.0001) frequency during the first cycle and molt than during the second cycle. Fearfulness scores were only influenced by production phase with the molt having the highest (P < 0.01) score of 3.46. Strain or production phase did not influence the frequency of aggressive and submissive acts.

Characterization of a Pseudomonas putida rough variant evolved in a mixed-species biofilm with Acinetobacter sp. strain C6.

Genetic differentiation by natural selection is readily observed among microbial populations, but a more comprehensive understanding of evolutionary forces, genetic causes, and resulting phenotypic advantages is not often sought. Recently, a surface population of Pseudomonas putida bacteria was shown to evolve rapidly by natural selection of better-adapted variants in a mixed-species biofilm consortium (S. K. Hansen, P. B. Rainey, J. A. Haagensen, and S. Molin, Nature 445:533-536, 2007). Adaptation was caused by mutations in a wapH homolog (PP4943) involved in core lipopolysaccharide biosynthesis. Here we investigate further the biofilm physiology and the phenotypic characteristics of the selected P. putida rough colony variants. The coexistence of the P. putida population in a mixed-species biofilm with Acinetobacter sp. strain C6 is dependent on the benzoate excreted from Acinetobacter during the catabolism of benzyl alcohol, the sole carbon source. Examination of biofilm development and the dynamics of the wild-type consortium revealed that the biofilm environment became oxygen limited, possibly with low oxygen concentrations around Acinetobacter microcolonies. In contrast to P. putida wild-type cells, which readily dispersed from the mixed-species biofilm in response to oxygen starvation, the rough variant cells displayed a nondispersal phenotype. However, in monospecies biofilms proliferating on benzoate, the rough variant (like the wild-type population) dispersed in response to oxygen starvation. A key factor explaining this conditional, nondispersal phenotype is likely to be the acquired ability of the rough variant to coaggregate specifically with Acinetobacter cells. We further show that the P. putida rough variant displayed enhanced production of a cellulose-like polymer as a consequence of the mutation in wapH. The resulting phenotypic characteristics of the P. putida rough variant explain its enhanced fitness and ability to form tight structural associations with Acinetobacter microcolonies.

Selection for unequal densities of sigma70 promoter-like signals in different regions of large bacterial genomes.

The evolutionary processes operating in the DNA regions that participate in the regulation of gene expression are poorly understood. In Escherichia coli, we have established a sequence pattern that distinguishes regulatory from nonregulatory regions. The density of promoter-like sequences, that could be recognizable by RNA polymerase and may function as potential promoters, is high within regulatory regions, in contrast to coding regions and regions located between convergently transcribed genes. Moreover, functional promoter sites identified experimentally are often found in the subregions of highest density of promoter-like signals, even when individual sites with higher binding affinity for RNA polymerase exist elsewhere within the regulatory region. In order to see the generality of this pattern, we have analyzed 43 additional genomes belonging to most established bacterial phyla. Differential densities between regulatory and nonregulatory regions are detectable in most of the analyzed genomes, with the exception of those that have evolved toward extreme genome reduction. Thus, presence of this pattern follows that of genes and other genomic features that require weak selection to be effective in order to persist. On this basis, we suggest that the loss of differential densities in the reduced genomes of host-restricted pathogens and symbionts is an outcome of the process of genome degradation resulting from the decreased efficiency of purifying selection in highly structured small populations. This implies that the differential distribution of promoter-like signals between regulatory and nonregulatory regions detected in large bacterial genomes confers a significant, although small, fitness advantage. This study paves the way for further identification of the specific types of selective constraints that affect the organization of regulatory regions and the overall distribution of promoter-like signals through more detailed comparative analyses among closely related bacterial genomes.

Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients.

In many human infections, hosts and pathogens coexist for years or decades. Important examples include HIV, herpes viruses, tuberculosis, leprosy, and malaria. With the exception of intensively studied viral infections such as HIV/AIDs, little is known about the extent to which the clonal expansion that occurs during long-term infection by pathogens involves important genetic adaptations. We report here a detailed, whole-genome analysis of one such infection, that of a cystic fibrosis (CF) patient by the opportunistic bacterial pathogen Pseudomonas aeruginosa. The bacteria underwent numerous genetic adaptations during 8 years of infection, as evidenced by a positive-selection signal across the genome and an overwhelming signal in specific genes, several of which are mutated during the course of most CF infections. Of particular interest is our finding that virulence factors that are required for the initiation of acute infections are often selected against during chronic infections. It is apparent that the genotypes of the P. aeruginosa strains present in advanced CF infections differ systematically from those of "wild-type" P. aeruginosa and that these differences may offer new opportunities for treatment of this chronic disease.

Molecular and immunological characterization of the highly conserved antigen 84 from Mycobacterium tuberculosis and Mycobacterium leprae.

Crossed immunoelectrophoresis (CIE) has been used to develop a reference system for classifying mycobacterial antigens. The subsequent use of specific antibodies allowed further determination of antigens by molecular weight. The monoclonal antibody F126-2, originally raised against a 34-kDa antigen of Mycobacterium kansasii, reacted with antigen 84 (Ag84) in the CIE reference system for Mycobacterium bovis BCG and Mycobacterium tuberculosis. To characterize Ag84, we screened a lambda gt11 gene library from M. tuberculosis with antibody F126-2 and identified the encoding gene. The corresponding Mycobacterium leprae Ag84 gene was subsequently selected from a cosmid library, using the M. tuberculosis gene as a probe. Both genes were expressed as 34-kDa proteins in Escherichia coli, and the recombinant proteins indeed corresponded to Ag84 in the CIE reference system. The derived amino acid sequences of the M. tuberculosis and M. leprae proteins showed 85% identity, which indicates that Ag84 constitutes a group of highly conserved mycobacterial antigens. Antibodies of almost 60% of lepromatous leprosy patients responded to Ag84, indicating that the protein is highly immunogenic following infection in multibacillary leprosy.

[Genetic study of plasmid integration into yeast chromosomes. III. Selection for a phenotype of Saccharomyces cerevisiae (Meyen ex Hansen) clones which lost the 2-micron DNA and their genetic testing]. / Geneticheskoe izuchenie integratsii plazmid v drozhzhevye khromosomy. Soobshchenie III. Otbor po fenotipu klonov drozhzhei Saccharomyces cerevisiae (Meyen ex Hansen), poteriavshikh 2-mkm DNK, i ikh geneticheskoe testirovanie.

We used the coloured adeI (cir+) haploid strain containing an episomal plasmid integrated into the chromosome I for visual detection and genetic testing of Saccharomyces cerevisiae clones having lost 2 microns DNA. During incubation, colonies of this strain were covered with numerous papillae of the same genotype. Stable clones which did not generate such papillae were isolated. Hybrids of these clones with (cir0) partner were not shown to exhibit destabilization of the chimeric chromosome. The stable clones isolated proved to lack 2 microns DNA, as shown by colony hybridization technique. We conclude therefore that the loss of the cryptic yeast plasmid may be phenotypically detected.