465 research outputs found
Effects of the restoration actions to combat desertification on soils: the practice project study site in Pula (Sardinia, Italy)
Land Degradation and Desertification affect much of the worldâs drylands, resulting in a significant loss of biological and economic productivity. Responding to desertification by improving the efficiency of land and resource management represents a crucial step towards social welfare in drylands. However, the evaluation of the actions to combat desertification remains limited. The
PRACTICE EC-FP7 project develops and tests integrated evaluation protocols to assess the effectiveness of restoration practices in a network of study sites distributed among the most LD affected regions of the world
Keratitis-ichthyosis-deafness syndrome, atypical connexin GJB2 genemutation, and peripheral T-cell lymphoma: more than a random association?
Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital disorder characterized by a variety of skin lesionsâ that is, palmoplantar keratoderma, thickening of the skin, and erythematous verrucous lesionsâneurosensorial
hypoacusia, and keratitis with a variable degree of visual
impairment. Both sporadic and familial forms of the
syndrome have been described, the latter usually showing a
dominant pattern of inheritance. The molecular lesion
responsible for the syndrome typically involves the connexin
26 (Cx26) gene (GJB2). Most patients display the heterozygous c.148GâA mutation causing the substitution of an aspartic acid for an asparagine at position 50 (p.Asp50Asn), while a few of them show the c.50CâT mutation, implying the substitution of a serine for a phenylalanine at position 17 (p.Ser17Phe). However, even a mutation in the connexin 30 (Cx30) gene (GJB6) has been found in a typical KID patient, thus suggesting a genetic heterogeneity of the syndrome. As connexins are a large family of small integral membrane proteins which influence tissue cornification by modulating the establishment of direct cell-cell communication through gap junction channels, it is likely that defects involving this class of proteins are at the basis of the wellknown increased incidence of squamous cell carcinoma in KID patients
Learning mutational graphs of individual tumour evolution from single-cell and multi-region sequencing data
Background. A large number of algorithms is being developed to reconstruct
evolutionary models of individual tumours from genome sequencing data. Most
methods can analyze multiple samples collected either through bulk multi-region
sequencing experiments or the sequencing of individual cancer cells. However,
rarely the same method can support both data types.
Results. We introduce TRaIT, a computational framework to infer mutational
graphs that model the accumulation of multiple types of somatic alterations
driving tumour evolution. Compared to other tools, TRaIT supports multi-region
and single-cell sequencing data within the same statistical framework, and
delivers expressive models that capture many complex evolutionary phenomena.
TRaIT improves accuracy, robustness to data-specific errors and computational
complexity compared to competing methods.
Conclusions. We show that the application of TRaIT to single-cell and
multi-region cancer datasets can produce accurate and reliable models of
single-tumour evolution, quantify the extent of intra-tumour heterogeneity and
generate new testable experimental hypotheses
A Novel null homozygous mutation confirms <i>CACNA2D2</i> as a gene mutated in epileptic encephalopathy
Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding α2Ύ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE
is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on
chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and
c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished α2Ύ-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued
in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental
Relative impact of indels versus SNPs on complex disease
It is unclear whether insertions and deletions (indels) are more likely to influence complex traits than abundant singleânucleotide polymorphisms (SNPs). We sought to understand which category of variation is more likely to impact health. Using the SardiNIA study as an exemplar, we characterized 478,876 common indels and 8,246,244 common SNPs in up to 5,949 wellâphenotyped individuals from an isolated valley in Sardinia. We assessed association between 120 traits, resulting in 89 nonoverlappingâassociated loci.We evaluated whether indels were enriched among credible sets of potential causal variants. These credible sets included 1,319 SNPs and 88 indels. We did not find indels to be significantly enriched. Indels were the most likely causal variant in seven loci, including one locus associated with monocyte count where an indel with causality and mechanism previously demonstrated (rs200748895:TGCTG/T) had a 0.999 posterior probability. Overall, our results show a very modest and nonsignificant enrichment for common indels in associated loci.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/1/gepi22175_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/2/gepi22175-sup-0001-Gagliano-Supplementary.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/3/gepi22175.pd
Further Evidence of a Primary, Causal Association of the <i>PTPN22</i> 620W Variant With Type 1 Diabetes
OBJECTIVEâ The minor allele of the nonsynonymous single nucleotide polymorphism (SNP) +1858C>T within the PTPN22 gene is positively associated with type 1 diabetes and other autoimmune diseases. Genetic and functional data underline its causal effect, but some studies suggest that this polymorphism does not entirely explain disease association of the PTPN22 region. The aim of this study was to evaluate type 1 diabetes association within this gene in the Sardinian population.
RESEARCH DESIGN AND METHODSâ We resequenced the exons and potentially relevant portions of PTPN22 and detected 24 polymorphisms (23 SNPs and 1 deletion insertion polymorphism [DIP]), 8 of which were novel. A representative set of 14 SNPs and the DIP were sequentially genotyped and assessed for disease association in 794 families, 490 sporadic patients, and 721 matched control subjects.
RESULTSâ The +1858C>T variant, albeit rare in the general Sardinian population (allele frequency 0.014), was positively associated with type 1 diabetes (Pone tail = 3.7 Ă 10â3). In contrast, the background haplotype in which this mutation occurred was common (haplotype frequency 0.117) and neutrally associated with disease. We did not confirm disease associations reported in other populations for non +1858C>T variants (rs2488457, rs1310182, and rs3811021), although they were present in appreciable frequencies in Sardinia. Additional weak disease associations with rare variants were detected in the Sardinian families but not confirmed in independent case-control sample sets and are most likely spurious.
CONCLUSIONSâ We provide further evidence that the +1858C>T polymorphism is primarily associated with type 1 diabetes and exclude major contributions from other purportedly relevant variants within this gene
Glucose-6-phosphate dehydrogenase deficiency accelerates arterial aging in diabetes
Aims High glucose levels and Glucose-6-Phosphate Dehydrogenase deficiency (G6PDd) have both tissue inflammatory effects. Here we determined whether G6PDd accelerates arterial aging (information linked stiffening) in diabetes.MethodsPlasma glucose, interleukin 6 (IL6), and arterial stiffness (indexed as carotid-femoral Pulse Wave Velocity, PWV) and red blood cell G6PD activity were assessed in a large (4448) Sardinian population.ResultsAlthough high plasma glucose in diabetics, did not differ by G6DP status (178.2 +/- 55.1 vs 169.0 +/- 50.1 mg/dl) in G6DPd versus non-G6PDd subjects, respectively, IL6, and PWV (adjusted for age and glucose) were significantly increased in G6PDd vs non-G6PDd subjects (PWV, 8.0 +/- 0.4 vs 7.2 +/- 0.2 m/sec) and (IL6, 6.9 +/- 5.0 vs 4.2 +/- 3.0 pg/ml). In non-diabetics, neither fasting plasma glucose, nor IL6, nor PWV were impacted by G6PDd.ConclusionG6PDd in diabetics is associated with increased inflammatory markers and accelerated arterial aging
Detection of phylogenetically informative polymorphisms in the entire euchromatic portion of human Y chromosome from a Sardinian sample
Background: Next-Generation Sequencing methods have led to a great increase in phylogenetically useful markers within the male specific portion of the Y chromosome, but previous studies have limited themselves to the study of the X-degenerate regions.
Methods: DNA was extracted from peripheral blood samples of adult males whose paternal grandfathers were born in Sardinia. The DNA samples were sequenced, genotyped and subsequently analysed for variant calling for approximately 23.1 Mbp of the Y chromosome. A phylogenetic tree was built using Network 4.6 software.
Results: From low coverage whole genome sequencing of 1,194 Sardinian males, we extracted 20,155 phylogenetically informative single nucleotide polymorphisms from the whole euchromatic region, including the X-degenerate, X-transposed, and Ampliconic regions, along with variants in other unclassified chromosome intervals and in the readable sequences of the heterochromatic region.
Conclusions: The non X-degenerate classes contain a significant portion of the phylogenetic variation of the whole chromosome and their inclusion in the analysis, almost doubling the number of informative polymorphisms, refining the known molecular phylogeny of the human Y chromosome
HLA Genotyping in Children With Celiac Disease Allows to Establish the Risk of Developing Type 1 Diabetes
Introduction: Celiac disease (CD) and type 1 diabetes (T1D) often co-occur and share genetic components in the human leukocyte antigen (HLA) class II region. We aimed to study the usefulness of HLA genotyping in predicting the risk of developing T1D in patients with CD and the temporal relationship between these diseases. Methods: A cohort of 1,886 Sardinian patients, including 822 with CD, 1,064 with T1D, and 627 controls, underwent HLA class II typing. Seventy-six of 822 patients with CD were also affected by T1D (CD-T1D), and their HLA genotypes were analyzed for specific HLA associations with CD, T1D, and controls. Results: High-risk HLA-DQ genotypes, including HLA-DQ2.5/DQ8, -DQ2.5/DQ2.5, and -DQ2.5/DQ2.3, were strongly associated with CD-T1D with frequencies of 34.5%, 15.9%, and 18.8%, respectively. Conversely, certain HLA genotypes associated with CD seemed to confer protection against T1D development. Therefore, HLA genotyping allows for the identification of those patients with CD who might develop T1D. The frequency of patients with CD preceding T1D is higher in younger children than older ones, with implications for the early childhood approach to diabetes prevention. Discussion: CD is a condition for future T1D development, and specific HLA genotypes can predict this risk. Early screening for celiac autoimmunity and subsequent HLA typing in CD children could help identify those at high risk of T1D, allowing for proactive interventions and immunotherapies to preserve ÎČ-cell function. These findings may support the re-evaluation of HLA typing in children with CD
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