Continuous and Discontinuous Phase Transitions in the evolution of a polygenic trait under stabilizing selective pressure

The presence of phenomena analogous to phase transition in Statistical Mechanics, has been suggested in the evolution of a polygenic trait under stabilizing selection, mutation and genetic drift. By using numerical simulations of a model system, we analyze the evolution of a population of $N$ diploid hermaphrodites in random mating regime. The population evolves under the effect of drift, selective pressure in form of viability on an additive polygenic trait, and mutation. The analysis allows to determine a phase diagram in the plane of mutation rate and strength of selection. The involved pattern of phase transitions is characterized by a line of critical points for weak selective pressure (smaller than a threshold), whereas discontinuous phase transitions, characterized by metastable hysteresis, are observed for strong selective pressure. A finite size scaling analysis suggests the analogy between our system and the mean field Ising model for selective pressure approaching the threshold from weaker values. In this framework, the mutation rate, which allows the system to explore the accessible microscopic states, is the parameter controlling the transition from large heterozygosity (disordered phase) to small heterozygosity (ordered one).Comment: 8 pages, 7 figures, 1 tabl

Analysis of DTC nutrigenetic services in Italy: state of the art, agreement to the ESHG statement and future outlooks

Background: In both USA and Europe operate companies selling Direct-to-consumer genetic tests (DTC). These tests are offered to healthy people aiming to identify predispositions to complex diseases and to take preventive measures. Several DTC-nutrigenetic tests (DNTs) are available on the market. They propose the definition of a personalized diet, on the basis of the investigated genetic variants, which would reduce the risk of developing those diseases which have been associated to specific genetic markers. However, the risk/benefit balance of exposing unselected population to genetic testing without any medical surveillance is far from be established. Furthermore, it lacks an accepted procedure to select which genetic markers needs to be investigated, to evaluate their specific role and, as consequence, to define a personalized diet. Within this context, the European Society of Human Genetics (ESHG) released a statement regarding the DTC tests that has been ratified by several national societies including the Italian one. 
In the present study we analyzed the DNT offered in Italy, the state of the art and the abidance with the ESHG statement. 
Methods: We queried web search engine for the DNT offered to italian population, portraying a non-specialized customer. We examined the DNTs vendor websites and/or directly contacted the companies to collect information on: 1) genetic marker essayed, 2) diseases and phenotypes considered and 3) kind of dietary advices provided. Finally, we evaluated the abidance to the ESHG statement. The study was conducted between November, 2010 and May, 2011.
Results: Six companies operate in Italy with a total of seven different DNTs offered. Both studied phenotypes and investigated genetic markers were very different among companies, with a relative higher level of agreement for phenotype than for genes. None of the companies described the methods used to select markers and to define diet advices. None of the companies showed a complete agreement to the statement of the ESHG. 
Conclusion: Although DNT companies' efforts are worthy, a standardization of methods and a more strictly agreement with ESHG statement should be encouraged

Schizophrenia and vitamin D related genes could have been subject to latitude-driven adaptation

<p>Abstract</p> <p>Background</p> <p>Many natural phenomena are directly or indirectly related to latitude. Living at different latitudes, indeed, has its consequences with being exposed to different climates, diets, light/dark cycles, etc. In humans, one of the best known examples of genetic traits following a latitudinal gradient is skin pigmentation. Nevertheless, also several diseases show latitudinal clinals such as hypertension, cancer, dismetabolic conditions, schizophrenia, Parkinson's disease and many more.</p> <p>Results</p> <p>We investigated, for the first time on a wide genomic scale, the latitude-driven adaptation phenomena. In particular, we selected a set of genes showing signs of latitude-dependent population differentiation. The biological characterization of these genes showed enrichment for neural-related processes. In light of this, we investigated whether genes associated to neuropsychiatric diseases were enriched by Latitude-Related Genes (LRGs). We found a strong enrichment of LRGs in the set of genes associated to schizophrenia. In an attempt to try to explain this possible link between latitude and schizophrenia, we investigated their associations with vitamin D. We found in a set of vitamin D related genes a significant enrichment of both LRGs and of genes involved in schizophrenia.</p> <p>Conclusions</p> <p>Our results suggest a latitude-driven adaptation for both schizophrenia and vitamin D related genes. In addition we confirm, at a molecular level, the link between schizophrenia and vitamin D. Finally, we discuss a model in which schizophrenia is, at least partly, a maladaptive by-product of latitude dependent adaptive changes in vitamin D metabolism.</p

Genome-Wide Scan for Signatures of Human Population Differentiation and Their Relationship with Natural Selection, Functional Pathways and Diseases

Genetic differences both between individuals and populations are studied for their evolutionary relevance and for their potential medical applications. Most of the genetic differentiation among populations are caused by random drift that should affect all loci across the genome in a similar manner. When a locus shows extraordinary high or low levels of population differentiation, this may be interpreted as evidence for natural selection. The most used measure of population differentiation was devised by Wright and is known as fixation index, or FST. We performed a genome-wide estimation of FST on about 4 millions of SNPs from HapMap project data. We demonstrated a heterogeneous distribution of FST values between autosomes and heterochromosomes. When we compared the FST values obtained in this study with another evolutionary measure obtained by comparative interspecific approach, we found that genes under positive selection appeared to show low levels of population differentiation. We applied a gene set approach, widely used for microarray data analysis, to detect functional pathways under selection. We found that one pathway related to antigen processing and presentation showed low levels of FST, while several pathways related to cell signalling, growth and morphogenesis showed high FST values. Finally, we detected a signature of selection within genes associated with human complex diseases. These results can help to identify which process occurred during human evolution and adaptation to different environments. They also support the hypothesis that common diseases could have a genetic background shaped by human evolution

The PPARγ2 Pro12Ala variant is protective against progression of nephropathy in people with type 2 diabetes

Cross-sectional studies suggest the association between diabetic nephropathy and the PPARγ2 Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 (PPARγ2). Prospective data are limited to microalbuminuria and no information on renal function is available to date. The present study evaluates the association between the Pro12Ala polymorphism of PPARγ2 and the progression of albuminuria and decay in glomerular filtration rate (GFR) in type 2 diabetes

Uncoupling protein 2 G(-866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients C-reactive protein in type 2 diabetic patients

<p>Abstract</p> <p>Background</p> <p>This study evaluated the relationship between the G(-866)A polymorphism of the uncoupling protein 2 (UCP2) gene and high-sensitivity C reactive protein (hs-CRP) plasma levels in diabetic patients.</p> <p>Methods</p> <p>We studied 383 unrelated people with type 2 diabetes aged 40-70 years. Anthropometry, fasting lipids, glucose, HbA1c, and hs-CRP were measured. Participants were genotyped for the G (-866)A polymorphism of the uncoupling protein 2 gene.</p> <p>Results</p> <p>Hs-CRP (mg/L) increased progressively across the three genotype groups AA, AG, or GG, being respectively 3.0 ± 3.2, 3.6 ± 5.0, and 4.8 ± 5.3 (p for trend = 0.03). Since hs-CRP values were not significantly different between AA and AG genotype, these two groups were pooled for further analyses. Compared to participants with the AA/AG genotypes, homozygotes for the G allele (GG genotype) had significantly higher hs-CRP levels (4.8 ± 5.3 vs 3.5 ± 4.7 mg/L, p = 0.01) and a larger proportion (53.9% vs 46.1%, p = 0.013) of elevated hs-CRP (> 2 mg/L). This was not explained by major confounders such as age, gender, BMI, waist circumference, HbA1c, smoking, or medications use which were comparable in the two genotype groups.</p> <p>Conclusions</p> <p>The study shows for the first time, in type 2 diabetic patients, a significant association of hs-CRP levels with the G(-866)A polymorphism of UCP2 beyond the effect of major confounders.</p

β2-adrenergic receptor and UCP3 variants modulate the relationship between age and type 2 diabetes mellitus

BACKGROUND: It is widely accepted that Type 2 Diabetes Mellitus (T2DM) and other complex diseases are the product of complex interplay between genetic susceptibility and environmental causes. To cope with such a complexity, all the statistical and conceptual strategies available should be used. The working hypothesis of this study was that two well-known T2DM risk factors could have diverse effect in individuals carrying different genotypes. In particular, our effort was to investigate if a well-defined group of genes, involved in peripheral energy expenditure, could modify the impact of two environmental factors like age and obesity on the risk to develop diabetes. To achieve this aim we exploited a multianalytical approach also using dimensionality reduction strategy and conservative significance correction strategies. METHODS: We collected clinical data and characterised five genetic variants and 2 environmental factors of 342 ambulatory T2DM patients and 305 unrelated non-diabetic controls. To take in account the role of one of the major co-morbidity conditions we stratified the whole sample according to the presence of obesity, over and above the 30 Kg/m(2 )BMI threshold. RESULTS: By monofactorial analyses the ADRB2-27 Glu27 homozygotes had a lower frequency of diabetes when compared with Gln27 carriers (Odds Ratio (OR) 0.56, 95% Confidence Interval (CI) 0.36 – 0.91). This difference was even more marked in the obese subsample. Multifactor Dimensionality Reduction method in the non-obese subsample showed an interaction among age, ADRB2-16 and UCP3 polymorphisms. In individuals that were UCP3 T-carriers and ADRB2-16 Arg-carriers the OR increased from 1 in the youngest to 10.84 (95% CI 4.54–25.85) in the oldest. On the contrary, in the ADRB2-16 GlyGly and UCP3 CC double homozygote subjects, the OR for the disease was 1.10 (95% CI 0.53–2.27) in the youngest and 1.61 (95% CI 0.55–4.71) in the oldest. CONCLUSION: Although our results should be confirmed by further studies, our data suggests that, when properly evaluated, it is possible to identify genetic factors that could influence the effect of common risk factors

Ataxia de Friedreich: estudo clínico e molecular de 25 pacientes

INTRODUCTION: Friedreich's ataxia is a neurodegenerative disorder whose clinical diagnostic criteria for typical cases basically include: a) early age of onset (< 20 or 25 years), b) autosomal recessive inheritance, c) progressive ataxia of limbs and gait, and d) absence of lower limb tendon reflexes. METHODS: We studied the frequency and the size of expanded GAA and their influence on neurologic findings, age at onset, and disease progression in 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia - 19 typical and 6 atypical - using a long-range PCR test. RESULTS: Abnormalities in cerebellar signs, in electrocardiography, and pes cavus occurred more frequently in typical cases; however, plantar response and speech were more frequently normal in this group when the both typical and atypical cases were compared. Homozygous GAA expansion repeats were detected in 17 cases (68%) - all typical cases. In 8 patients (32%) (6 atypical and 2 typical), no expansion was observed, ruling out the diagnosis of Friedreich's ataxia. In cases with GAA expansions, foot deformity, cardiac abnormalities, and some neurologic findings occurred more frequently; however, abnormalities in cranial nerves and in tomographic findings were detected less frequently than in patients without GAA expansions. DISCUSSION: Molecular analysis was imperative for the diagnosis of Friedreich's ataxia, not only for typical cases but also for atypical ones. There was no genotype-phenotype correlation. Diagnosis based only on clinical findings is limited; however, it aids in better screening for suspected cases that should be tested. Evaluation for vitamin E deficiency is recommended, especially in cases without GAA expansion.INTRODUÇÃO: A ataxia de Friedreich é uma doença neurodegenerativa e os critérios clínicos diagnósticos para os casos típicos incluem: a) idade de início precoce (< 20 ou 25 anos); b) herança autossômica recessiva; c) ataxia progressiva; e d) abolição dos reflexos tendinosos profundos. MÉTODOS: Estudou-se a freqüência e o tamanho das expansões GAA e a sua influência nos achados neurológicos, idade de início e progressão da doença, em 25 pacientes brasileiros com diagnóstico clínico de ataxia de Friedreich - 19 típicos e 6 atípicos, por PCR. RESULTADOS: Anormalidades sugestivas de comprometimento cerebelar, no ECG e a presença de pés cavos ocorreram com maior freqüência nos casos típicos; contudo, a resposta plantar e a fala mostraram-se mais freqüentemente normal neste grupo, quando comparados casos típicos e atípicos. A expansão GAA em homozigose foi detectada em 17 casos (68%) - todos típicos e, em 8 (32%) (6 atípicos e 2 típicos), não foi observada nenhuma expansão, excluindo-se o diagnóstico de ataxia de Friedreich. Deformidade de pés, anormalidades cardíacas e alguns achados neurológicos ocorreram mais freqüentemente, nos casos com expansão GAA, contudo, sinais de comprometimento dos pares cranianos e alterações dos achados tomográficos foram detectados menos frequentemente do que em pacientes sem expansão. DISCUSSÃO: A análise molecular é imprescindível para o diagnóstico de ataxia de Friedreich, não só para os casos típicos como também para os atípicos. Não há qualquer correlação entre o genótipo e o fenótipo. O diagnóstico baseado apenas nos achados clínicos é limitado, embora facilite a triagem para melhor selecionar os casos suspeitos que merecem ser testados. A dosagem sérica da vitamin E é recomendada , especialmente nos casos sem expansão GAA

CpG Islands Undermethylation in Human Genomic Regions under Selective Pressure

DNA methylation at CpG islands (CGIs) is one of the most intensively studied epigenetic mechanisms. It is fundamental for cellular differentiation and control of transcriptional potential. DNA methylation is involved also in several processes that are central to evolutionary biology, including phenotypic plasticity and evolvability. In this study, we explored the relationship between CpG islands methylation and signatures of selective pressure in Homo Sapiens, using a computational biology approach. By analyzing methylation data of 25 cell lines from the Encyclopedia of DNA Elements (ENCODE) Consortium, we compared the DNA methylation of CpG islands in genomic regions under selective pressure with the methylation of CpG islands in the remaining part of the genome. To define genomic regions under selective pressure, we used three different methods, each oriented to provide distinct information about selective events. Independently of the method and of the cell type used, we found evidences of undermethylation of CGIs in human genomic regions under selective pressure. Additionally, by analyzing SNP frequency in CpG islands, we demonstrated that CpG islands in regions under selective pressure show lower genetic variation. Our findings suggest that the CpG islands in regions under selective pressure seem to be somehow more “protected” from methylation when compared with other regions of the genome