Susceptibility to complex diseases in Sardinian population explained by Runs of Homozygosity and genomic regions under positive selection

Aim: 1)Confirm and detail the homogeneity of the Sardinian population at interregional level based on the analysis "genome-wide" through the use of "Runs of Homozygosity" (RoHS);2) infer the genetic history of the Sardinian population by estimating the level of genetic background of the common ancestry within the island and compare it to the Italian peninsula; 3)Identify indicators of positive selection. Methods: About single nucleotide polymorphisms (SNPs) genotyped in 1077 Sardinian individuals were used to investigate the genetic population structure, as well as to estimate RoH and Extended Haplotype Homozygosity regions. We used four different methods: fixation index, inflaction factor, multi-dimensional scaling and ancestry estimation. we were able to highlight, as expected from a genetic isolate, the high internal homogeneity of the island. Comparing Sardinia to mainland Italy through several classes of RoH. Conclusion: We confirmed the high genetic homogeneity of Sardinia and we have shown that the genome of the Sardinians has mean inbreeding coefficients which are higher than those of mainland Italians. Furthermore, the Sardinian’s genome still preserves traces of the elaborate demographic history of the island. In addition, we observed that some genomic regions showing signs of positive selection

L’universale incompleto. Questione liberale ed emancipazione = L’universel incomplet : la question libérale et l’émancipation = The incomplete universal: the liberal question and emancipation

In defining his particular conception of the philosophy of praxis as absolute historicism, Gramsci intertwines certain fundamental themes of political philosophy, primarily the relationship between civil and political society in the dialectic of freedoms. He conceives the process of human emancipation as a continuation/reversal of the universal values immanent to bourgeois revolutions. According to Gramsci, the transition from liberalism to socialism was historically situated in this passage from incomplete universality to complete emancipation,. The young Sardinian intellectual’s anti-protectionist polemics and his particular way of viewing the Southern Question—understood as a paradigmatic linkage of the organic contradictions inherentin the formation of Italy as a nation—fit into this vision. He did not become aware of the parasitic and regressive function of protectionism in Einaudian academic circles in Turin, but in Sardinia, where this phenomenon occurred at the end of a long historical process of passive modernisation which, in many ways, anticipated the post-unification Southern Question

La dialettica tra 'vecchio e nuovo'. Gramsci e la marcia dell’universalità nelle note di Domenico Losurdo

Losurdo inscrive la transizione di Gramsci dal liberalismo al comunismo critico nella lunga marcia dell’universalità, in quella interminabile dialettica tra vecchio e nuovo all’interno della quale si si-tuano contraddizioni e salti qualitativi immanenti al divenire storico. Le prospettive di trasformazio-ne radicale della società, attorno all’idea di integrale emancipazione umana, sarebbero uno sviluppo del principio di universale dignità dell’uomo (in contrapposizione al particolarismo giuridico aristo-cratico-feudale) al centro dei rivolgimenti politici di fine Settecento e inizio Ottocento. Gramsci non intende fare del socialismo un becchino della società borghese, ma il suo erede. In tal senso si pose in termini dialettici, concependo l’avvento del nuovo ordine come superamento del vecchio, non la sua semplice negazione. Così, anche in una fase storica segnata dalla grave crisi del liberalismo italiano, disposto a mettere da parte le proprie istituzioni e i suoi valori ideali pur di impedire il cambiamento dell’ordine sociale, Gramsci concepisce il socialismo all’interno di un processo ascendente e progressi-vo apertosi con la distruzione del vecchio ordine feudale, trovando in Hegel il filosofo che con maggior sistematicità ha saputo concettualizzare il trapasso dal vecchio Stato patrimoniale per caste chiuse al moderno Stato etico

Lenin e a revolução

The centenary of the October Revolution took place in a cultural and political climate clearly unfavorable to free intellectual confrontation and very unwilling to evaluate reasons and inheritances of an event that, whatever our subjective judgment, represents a radical change in the course of human history, which you cannot ignore. This ended up conditioning any analytical attempt that sought to approach the biography of the Russian revolutionary in a “disinterested” way, making it impossible to evaluate without prejudice the whole of his intellectual and political production. However, placing Lenin in a showcase of teratology ends up hampering a scientific investigation of the importance of his theory; therefore, to understand the how and why of a theory that, in addition to Russian events, opened the doors of distant and peripheral continents to Marxism, enabling revolutionary processes not even imaginable according to the canons of the old Western Marxism, tied to the paradigms of positivism deterministic

A questão judaica: a transição do jovem Marx da crítica filosófica à crítica da economia política

The writing on the Jewish question is of fundamental importance to understand the intellectual formation of the young Marx in the course that led him from philosophical criticism to the critique of political economy. In this work he raises the need to overcome the theological formulation of the Jewish question to reach the heart of the contradiction that determines the alienation of man in modern society. The Jew's emancipation capacity lies in the relation of Judaism to the emancipation of the world today, not to the mere emancipation of the state of religion. In On the Jewish Question, written in the autumn of 1843 and published in the Franco-German Annals of February 1844, Marx argues with Bauer that the complete emancipation of man cannot be limited to political emancipation alone, but also social and productive one. The same is true in the Introduction to the Critique of Hegel’s Philosophy of Right, also written for the Franco-German Annals at the end of 1843 and published in February 1844, where we find the definitive abandonment of simple religious-political critique in the direction to Marxian social criticism. In On the Jewish Question and Introduction, Marx completely emancipates himself from Bauer's influence, so in the passage from 1843 to 1844, these three stages represent essential moments in the formation of the philosophical vision of the young Marx

Mendelian breeding units <i>versus</i> standard sampling strategies: mitochondrial DNA variation in southwest Sardinia

We report a sampling strategy based on Mendelian Breeding Units (MBUs), representing an interbreeding group of individuals sharing a common gene pool. The identification of MBUs is crucial for case-control experimental design in association studies. The aim of this work was to evaluate the possible existence of bias in terms of genetic variability and haplogroup frequencies in the MBU sample, due to severe sample selection. In order to reach this goal, the MBU sampling strategy was compared to a standard selection of individuals according to their surname and place of birth. We analysed mitochondrial DNA variation (first hypervariable segment and coding region) in unrelated healthy subjects from two different areas of Sardinia: the area around the town of Cabras and the western Campidano area. No statistically significant differences were observed when the two sampling methods were compared, indicating that the stringent sample selection needed to establish a MBU does not alter original genetic variability and haplogroup distribution. Therefore, the MBU sampling strategy can be considered a useful tool in association studies of complex traits

A Functional 12T-insertion polymorphism in the <i>ATP1A1</i> promoter confers decreased susceptibility to hypertension in a male Sardinian population

Identification of susceptibility genes for essential hypertension in humans has been a challenge due to its multifactorial pathogenesis complicated by gene-gene and gene-environment interactions, developmental programing and sex specific differences. These concurrent features make identification of causal hypertension susceptibility genes with a single approach difficult, thus requiring multiple lines of evidence involving genetic, biochemical and biological experimentation to establish causal functional mutations. Here we report experimental evidence encompassing genetic, biochemical and in vivo modeling that altogether support ATP1A1 as a hypertension susceptibility gene in males in Sardinia, Italy. ATP1A1 encodes the α1Na,K-ATPase isoform, the sole sodium pump in vascular endothelial and renal tubular epithelial cells. DNA-sequencing detected a 12-nucleotide long thymidine (12T) insertion(ins)/deletion(del) polymorphism within a poly-T sequence (38T vs 26T) in the ATP1A1 5’-regulatory region associated with hypertension in a male Sardinian population. The 12T-insertion allele confers decreased susceptibility to hypertension (P = 0.035; OR = 0.50 [0.28–0.93]) accounting for 12.1 mmHg decrease in systolic BP (P = 0.02) and 6.6 mmHg in diastolic BP (P = 0.046). The ATP1A1 promoter containing the 12T-insertion exhibited decreased transcriptional activity in in vitro reporter-assay systems, indicating decreased α1Na,K-ATPase expression with the 12T-insertion, compared with the 12T-deletion ATP1A1 promoter. To test the effects of decreased α1Na,K-ATPase expression on blood pressure, we measured blood pressure by radiotelemetry in three month-old, highly inbred heterozygous knockout ATP1A1+/− male mice with resultant 58% reduction in ATP1A1 protein levels. Male ATP1A1+/− mice showed significantly lower blood pressure (P &#60; 0.03) than age-matched male wild-type littermate controls. Concordantly, lower ATP1A1 expression is expected to lower Na-reabsorption in the kidney thereby decreasing sodium-associated risk for hypertension and sodium-induced endothelial stiffness and dysfunction. Altogether, data support ATP1A1 as a hypertension susceptibility gene in a male Sardinian population, and mandate further investigation of its involvement in hypertension in the general population

Mendelian breeding units versus standard sampling strategies: Mitochondrial DNA variation in southwest Sardinia

We report a sampling strategy based on Mendelian Breeding Units (MBUs), representing an interbreeding group of individuals sharing a common gene pool. The identification of MBUs is crucial for case-control experimental design in association studies. The aim of this work was to evaluate the possible existence of bias in terms of genetic variability and haplogroup frequencies in the MBU sample, due to severe sample selection. In order to reach this goal, the MBU sampling strategy was compared to a standard selection of individuals according to their surname and place of birth. We analysed mitochondrial DNA variation (first hypervariable segment and coding region) in unrelated healthy subjects from two different areas of Sardinia: the area around the town of Cabras and the western Campidano area. No statistically significant differences were observed when the two sampling methods were compared, indicating that the stringent sample selection needed to establish a MBU does not alter original genetic variability and haplogroup distribution. Therefore, the MBU sampling strategy can be considered a useful tool in association studies of complex traits

Sex-specific effects of NLRP6/AVR and ADM <i>loci</i> on susceptibility to essential hypertension in a Sardinian population

Coronary artery disease, heart failure, fatal arrhythmias, stroke, and renal disease are the most common causes of mortality for humans, and essential hypertension remains a major risk factor. Elucidation of susceptibility loci for essential hypertension has been difficult because of its complex, multifactorial nature involving genetic, environmental, and sex- and age-dependent nature. We investigated whether the 11p15.5 region syntenic to rat chromosome 1 region containing multiple blood pressure quantitative trait loci (QTL) detected in Dahl rat intercrosses harbors polymorphisms that contribute to susceptibility/resistance to essential hypertension in a Sardinian population. Initial testing performed using microsatellite markers spanning 18 Mb of 11p15.5 detected a strong association between D11S1318 (at 2.1 Mb, P = 0.004) and D11S1346 (at 10.6 Mb, P = 0.00000004), suggesting that loci in close proximity to these markers may contribute to susceptibility in our Sardinian cohort. NLR family, pyrin domain containing 6/angiotensin-vasopressin receptor (NLRP6/AVR), and adrenomedullin (ADM) are in close proximity to D11S1318 and D11S1346, respectively; thus we tested single nucleotide polymorphisms (SNPs) within NLRP6/AVR and ADM for their association with hypertension in our Sardinian cohort. Upon sex stratification, we detected one NLRP6/AVR SNP associated with decreased susceptibility to hypertension in males (rs7948797G, P = 0.029; OR = 0.73 [0.57-0.94]). For ADM, sex-specific analysis showed a significant association between rs4444073C, with increased susceptibility to essential hypertension only in the male population (P = 0.006; OR = 1.44 [1.13-1.84]). Our results revealed an association between NLRP6/AVR and ADM loci with male essential hypertension, suggesting the existence of sex-specific NLRP6/AVR and ADM variants affecting male susceptibility to essential hypertension

Sardinians genetic background explained by runs of homozygosity and genomic regions under positive selection

The peculiar position of Sardinia in the Mediterranean sea has rendered its population an interesting biogeographical isolate. The aim of this study was to investigate the genetic population structure, as well as to estimate Runs of Homozygosity and regions under positive selection, using about 1.2 million single nucleotide polymorphisms genotyped in 1077 Sardinian individuals. Using four different methods - fixation index, inflation factor, principal component analysis and ancestry estimation - we were able to highlight, as expected for a genetic isolate, the high internal homogeneity of the island. Sardinians showed a higher percentage of genome covered by RoHs&gt;0.5 Mb (FRoH%0.5) when compared to peninsular Italians, with the only exception of the area surrounding Alghero. We furthermore identified 9 genomic regions showing signs of positive selection and, we re-captured many previously inferred signals. Other regions harbor novel candidate genes for positive selection, like TMEM252, or regions containing long non coding RNA. With the present study we confirmed the high genetic homogeneity of Sardinia that may be explained by the shared ancestry combined with the action of evolutionary forces