Uberto Pozzoli

Publications (69) View all

• Article: Evolutionary analysis of the contact system indicates that kininogen evolved adaptively in mammals and in human populations.

  Rachele Cagliani, Diego Forni, Stefania Riva, Uberto Pozzoli, Marta Colleoni, Nereo Bresolin, Mario Clerici, Manuela Sironi
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  ABSTRACT: Activation of the contact system leads to the cleavage of kininogen by plasma kallikrein resulting in kinin release, and in the initiation of the intrinsic pathway of coagulation. Proteolysis of kininogen also generates antimicrobial peptides (AMP) and can be induced by diverse pathogens. Thus, the contact system is regarded as a branch of innate immunity. We performed an evolutionary analysis of contact system genes by analyzing both inter- and intra- species diversity. Results indicated that mammalian kininogen genes evolved adaptively. Positively selected sites are located in all protein domains with the exclusion of the bradykinin region and also involve AMP sequences (including the highly effective NAT26 peptide); positively selected sites also occur at alternative cleavage sites for neutrophil-released kinins. Population genetic analysis in humans indicated that a region of the kininogen gene (KNG1) has been a target of long-standing multiallelic balancing selection, and that the coalescence time of the haplotype phylogeny dates back to the split between the humans and chimpanzees. No selection signature was detected in the P. troglodytes KNG1 gene or in human genes encoding other components of the contact system. The selection targets in human KNG1 might be accounted for by variants with transcriptional regulatory activity. Results herein indicate a continuum in selective pressure acting on different timescales and targeting KNG1. This is in line with evidences suggesting a central role for kininogen in modulating of immune response and with its being a target of an extremely diverse array of pathogen species.
  Molecular Biology and Evolution 03/2013; · 5.55 Impact Factor
• Source

  Available from: Shaun Sabico

  Dataset: BMC Med

  Nasser M Al-Daghri, Rachele Cagliani, Diego Forni, Majed S Alokail, Uberto Pozzoli, Khalid M Alkharfy, Shaun Sabico, Mario Clerici, Manuela Sironi
• Source

  Available from: Shaun Sabico

  Article: Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes.

  Nasser M Al-Daghri, Rachele Cagliani, Diego Forni, Majed S Alokail, Uberto Pozzoli, Khalid M Alkharfy, Shaun Sabico, Mario Clerici, Manuela Sironi
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  ABSTRACT: BACKGROUND: The NPC1 gene encodes a protein involved in intracellular lipid trafficking; its second endosomal loop (loop 2) is a receptor for filoviruses. A polymorphism (His215Arg) in NPC1 was associated with obesity in Europeans. Adaptations to diet and pathogens represented powerful selective forces; thus, we analyzed the evolutionary history of the gene and exploited this information for the identification of variants/residues of functional importance in human disease. METHODS: We performed phylogenetic analysis, population genetic tests, and genotype-phenotype analysis in a population from Saudi Arabia. RESULTS: Maximum-likelihood ratio tests indicated the action of positive selection on loop 2 and identified three residues as selection targets; these were confirmed by an independent random effects likelihood (REL) analysis. No selection signature was detected in present-day human populations, but analysis of nonsynonymous polymorphisms showed that a variant (Ile642Met, rs1788799) in the sterol sensing domain affects a highly conserved position. This variant and the previously described His215Arg polymorphism were tested for association with obesity and type 2 diabetes (T2D) in a cohort from Saudi Arabia. Whereas no association with obesity was detected, 642Met allele was found to predispose to T2D. A significant interaction was noted with sex (P = 0.041), and stratification on the basis of gender indicated that the association is driven by men (P = 0.0021, OR = 1.5). Notably, two NPC1 haplotypes were also associated with T2D in men (rs1805081-rs1788799, His-Met: P = 0.0012, OR = 1.54; His-Ile: P = 0.0004, OR = 0.63). CONCLUSIONS: Our data indicate a sex-specific effect of NPC1 variants on T2D risk and describe putative binding sites for filoviruses entry.
  BMC Medicine 11/2012; 10(1):140. · 6.03 Impact Factor
• Source

  Available from: Elena Salvaterra

  Article: Pediatric Biobanking: A Pilot Qualitative Survey of Practices, Rules, and Researcher Opinions in Ten European Countries

  Elena Salvaterra, Roberto Giorda, Maria T Bassi, Renato Borgatti, Lisbeth E Knudsen, Andrea Martinuzzi, Maria Nobile, Uberto Pozzoli, Gian P Ramelli, Gianl L Reni, [......], Maria A Stazi, Sandra Strazzer, Carel Thijs, Virgilia Toccaceli, Antonio Trabacca, Anna C Turconi, Sergio Zanini, Claudio Zucca, Nereo Bresolin, Leonardo Lenzi
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  ABSTRACT: on behalf of the Pediatric Biobank ELSI Working Group { Ethical, legal, and social issues related to the collection, storage, and use of biospecimens and data derived from children raise critical concerns in the international debate. So far, a number of studies have con-sidered a variety of the individual issues crucial to pediatric biobanking such as decision making, privacy protection, minor recontact, and research withdrawal by focusing on theoretical or empirical perspectives. Our research attempted to analyze such issues in a comprehensive manner by exploring practices, rules, and researcher opinions regarding proxy consent, minor assent, specimens and data handling, and return of results as faced in 10 European countries. Because of the lack of comparative analyses of these topics, a pilot study was designed. Following a qualitative methodology, a questionnaire draft mostly including open-ended queries was developed, tested, and sent by e-mail to a selected group of researchers dealing with pediatric biobanking (n = 57). Returned questionnaires (n = 31) highlighted that the collection, storage, distribution, and use of biospecimens and data from children were widely practiced in the contacted laboratories. In most cases, pediatric biobanking was subjected to national or local regulations covering 1
  Biopreservation and Biobanking 01/2012; · 1.29 Impact Factor
• Article: Variants in SNAP25 are targets of natural selection and influence verbal performances in women.

  Rachele Cagliani, Stefania Riva, Cecilia Marino, Matteo Fumagalli, Maria Grazia D'Angelo, Valentina Riva, Giacomo P Comi, Uberto Pozzoli, Diego Forni, Mario Cáceres, Nereo Bresolin, Mario Clerici, Manuela Sironi
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  ABSTRACT: Descriptions of genes that are adaptively evolving in humans and that carry polymorphisms with an effect on cognitive performances have been virtually absent. SNAP25 encodes a presynaptic protein with a role in regulation of neurotransmitter release. We analysed the intra-specific diversity along SNAP25 and identified a region in intron 1 that shows signatures of balancing selection in humans. The estimated TMRCA (time to the most recent common ancestor) of the SNAP25 haplotype phylogeny amounted to 2.08 million years. The balancing selection signature is not secondary to demographic events or to biased gene conversion, and encompasses rs363039. This SNP has previously been associated to cognitive performances with contrasting results in different populations. We analysed this variant in two Italian cohorts in different age ranges and observed a significant genotype effect for rs363039 on verbal performances in females alone. Post hoc analysis revealed that the effect is driven by differences between heterozygotes and both homozygous genotypes. Thus, heterozygote females for rs363039 display higher verbal performances compared to both homozygotes. This finding was replicated in a cohort of Italian subjects suffering from neuromuscular diseases that do not affect cognition. Heterozygote advantage is one of the possible reasons underlying the maintenance of genetic diversity in natural populations. The observation that heterozygotes for rs363039 display higher verbal abilities compared to homozygotes perfectly fits the underlying balancing selection model. Although caution should be used in inferring selective pressures from observed signatures, SNAP25 might represent the first description of an adaptively evolving gene with a role in cognition.
  Cellular and Molecular Life Sciences CMLS 12/2011; 69(10):1705-15. · 6.57 Impact Factor