Computational Biology

Description

Patterns of worldwide genetic variation are consistent with an origin of modern humans in Africa, followed by a series of expansions, migrations, and bottlenecks. Recent data also indicated that, following the out-of-Africa migration, modern humans admixed with archaic hominins. Demographic events have thus played a major role shaping worldwide patterns of human genetic diversity. Nonetheless, during this period of migratory events, humans were exposed to new environments (e.g. different climate conditions, pathogens, and food resources) to which they were forced to adapt, through the action of natural selection. This latter acts on phenotypes and, when these are genetically determined, on the underlying functional genetic variants. Evolutionary analyses can disentangle the distinct contributions to genetic variability and pinpoint functional genetic change with an effect on phenotypes.

Based on these considerations, we have been applying population genetics and evolutionary approaches to identify functional genetic polymorphisms in genes of biomedical interest and to detect variants that affect human phenotypes (e.g. susceptibility to infection, autoimmunity, and verbal skills).

We have also been testing specific hypotheses concerning the role of past selective pressures on the present-day susceptibility to disease. For instance, we have shown that a number of autoimmune risk alleles have increased in frequency in human populations due to pathogen-exerted selective pressures, in line with the hygiene hypothesis. Similarly, we have indicated that a proportion of the susceptibility variants for affective disorders correlate with day-length latitudinal variations at different latitudes.

Likewise, comparison of genetic diversity at the inter-species level (e.g. across mammals or primates) allows identification of sites targeted by natural selection at the single aminoacid resolution and can provide insight into the evolution of genes with an effect on  human phenotypes.

For example, we have studied genes involved with autism spectrum disorder and intellectual disability. We have found several sites under the action of natural selection that could represent candidates for association with neurodevelopmental disorders.

Pathogens have exerted the major selective pressure on human populations, so we have been investigating the evolutionary events acting on human viruses. In particular, our analyses are focused on those pathogens that are responsible of congenital infection that may lead to malformations such microcephaly, intellectual disabilities, or encephalitis. For example, one of our studies highlighted the selective events that have accompanied  the emergence of the lymphocytic choriomeningitis virus, a virus responsible of encephalitis or meningoencephalitis.

As the availability of genetic data is growing on a daily basis, the major research interest of the group remain focused on the comparison of intra- and inter-species diversity to determine the evolutionary history of disease alleles and to detect causal variants for human phenotypes.

Selected publications

• Forni D, Pontremoli C, Pozzoli U, Clerici M, Cagliani R, Sironi M. Ancient Evolution of Mammarenaviruses: Adaptation via Changes in the L Protein and No Evidence for Host-Virus Codivergence. Genome Biol Evol. 2018 Mar 1;10(3):863-874. doi: 10.1093/gbe/evy050.
• Forni D, Cagliani R, Clerici M, Sironi M. Origin and dispersal of Hepatitis E virus. Emerg Microbes Infect. 2018 Feb 7;7(1):11. doi: 10.1038/s41426-017-0009-6.
• Mozzi A, Pontremoli C, Sironi M. Genetic susceptibility to infectious diseases: Current status and future perspectives from genome-wide approaches. Infect Genet Evol. 2017 Sep 22. pii: S1567-1348(17)30334-9. doi:10.1016/j.meegid.2017.09.028.
• Mozzi A, Guerini FR, Forni D, Costa AS, Nemni R, Baglio F, Cabinio M, Riva S, Pontremoli C, Clerici M, Sironi M, Cagliani R. REST, a master regulator of neurogenesis, evolved under strong positive selection in humans and in non human  primates. Sci Rep. 2017 Aug 25;7(1):9530. doi: 10.1038/s41598-017-10245-w.
• Pontremoli C, Forni D, Cagliani R, Pozzoli U, Riva S, Bravo IG, Clerici M, Sironi M. Evolutionary analysis of Old World arenaviruses reveals a major adaptive contribution of the viral polymerase. Mol Ecol. 2017 Aug 5. doi: 10.1111/mec.14282.
• Mozzi A, Forni D, Cagliani R, Pozzoli U, Clerici M, Sironi M. Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders. Sci Rep. 2017 Jul 21;7(1):6116. doi: 10.1038/s41598-017-06440-4.
• Sironi M, Peri AM, Cagliani R, Forni D, Riva S, Biasin M, Clerici M, Gori A. TLR3 Mutations in Adult Patients With Herpes Simplex Virus and Varicella-Zoster Virus Encephalitis. J Infect Dis. 2017 May 1;215(9):1430-1434. doi: 10.1093/infdis/jix166.
• Mozzi A, Riva V, Forni D, Sironi M, Marino C, Molteni M, Riva S, Guerini FR, Clerici M, Cagliani R, Mascheretti S. A common genetic variant in FOXP2 is associated with language-based learning (dis)abilities: Evidence from two Italian independent samples. Am J Med Genet B Neuropsychiatr Genet. 2017 Apr 24. doi: 10.1002/ajmg.b.32546.
• Al-Daghri NM, Pontremoli C, Cagliani R, Forni D, Alokail MS, Al-Attas OS, Sabico S, Riva S, Clerici M, Sironi M. Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection. BMC Evol Biol. 2017 Feb 7;17(1):43. doi:10.1186/s12862-017-0897-z.
• Forni D, Cagliani R, Clerici M, Sironi M. Molecular Evolution of Human Coronavirus Genomes. Trends Microbiol. 2017 Jan;25(1):35-48. doi: 10.1016/j.tim.2016.09.001.
• Pontremoli C, Forni D, Cagliani R, Filippi G, De Gioia L, Pozzoli U, Clerici M, Sironi M. Positive Selection Drives Evolution at the Host-Filovirus Interaction Surface. Mol Biol Evol. 2016 Nov;33(11):2836-2847.
• Sironi M, Forni D, Clerici M, Cagliani R. Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses. PLoS Negl Trop Dis. 2016 Sep 2;10(9):e0004978. doi: 10.1371/journal.pntd.0004978.
• Cagliani R, Forni D, Filippi G, Mozzi A, De Gioia L, Pontremoli C, Pozzoli U, Bresolin N, Clerici M, Sironi M. The mammalian complement system as an epitome of host-pathogen genetic conflicts. Mol Ecol. 2016 Mar;25(6):1324-39. doi:10.1111/mec.13558.
• Mozzi A, Forni D, Clerici M, Pozzoli U, Mascheretti S, Guerini FR, Riva S, Bresolin N, Cagliani R, Sironi M. The evolutionary history of genes involved in spoken and written language: beyond FOXP2. Sci Rep. 2016 Feb 25;6:22157. doi:10.1038/srep22157.
• Montirosso R, Provenzi L, Giorda R, Fumagalli M, Morandi F, Sirgiovanni I, Pozzoli U, Grunau R, Oberlander TF, Mosca F, Borgatti R. SLC6A4 promoter region methylation and socio-emotional stress response in very preterm and full-term infants. Epigenomics. 2016 Jul;8(7):895-907. doi: 10.2217/epi-2016-0010.
• Montirosso R, Provenzi L, Fumagalli M, Sirgiovanni I, Giorda R, Pozzoli U, Beri S, Menozzi G, Tronick E, Morandi F, Mosca F, Borgatti R. Serotonin Transporter Gene (SLC6A4) Methylation Associates With Neonatal Intensive Care Unit Stay and 3-Month-Old Temperament in Preterm Infants. Child Dev. 2016 Jan-Feb;87(1):38-48. doi: 10.1111/cdev.12492.
• Wollscheid HP, Biancospino M, He F, Magistrati E, Molteni E, Lupia M, Soffientini P, Rottner K, Cavallaro U, Pozzoli U, Mapelli M, Walters KJ, Polo S. Diverse functions of myosin VI elucidated by an isoform-specific α-helix domain. Nat Struct Mol Biol. 2016 Apr;23(4):300-308. doi: 10.1038/nsmb.3187.
• Forni D, Cagliani R, Mozzi A, Pozzoli U, Al-Daghri N, Clerici M, Sironi M. Extensive Positive Selection Drives the Evolution of Nonstructural Proteins in Lineage C Betacoronaviruses. J Virol. 2016 Jan 20;90(7):3627-39. doi:10.1128/JVI.02988-15.
• Forni D, Martin D, Abujaber R, Sharp AJ, Sironi M, Hollox EJ. Determining multiallelic complex copy number and sequence variation from high coverage exome sequencing data. BMC Genomics. 2015 Nov 2;16:891. doi: 10.1186/s12864-015-2123-y. PubMed PMID: 26526070; PubMed Central PMCID: PMC4630827.
• Forni D, Filippi G, Cagliani R, De Gioia L, Pozzoli U, Al-Daghri N, Clerici M, Sironi M. The heptad repeat region is a major selection target in MERS-CoV and related coronaviruses. Sci Rep. 2015 Sep 25;5:14480. doi: 10.1038/srep14480.
• Sironi M, Biasin M, Pontremoli C, Cagliani R, Saulle I, Trabattoni D, Vichi F, Lo Caputo S, Mazzotta F, Aguilar-Jimenez W, Rugeles MT, Cedeno S, Sanchez J, Brander C, Clerici M. Variants in the CYP7B1 gene region do not affect natural resistance to HIV-1 infection. Retrovirology. 2015 Sep 24;12:80. doi:10.1186/s12977-015-0206-0.
• Forni D, Pontremoli C, Cagliani R, Pozzoli U, Clerici M, Sironi M. Positive selection underlies the species-specific binding of Plasmodium falciparum RH5 to human basigin. Mol Ecol. 2015 Sep;24(18):4711-22. doi: 10.1111/mec.13354.
• Pontremoli C, Mozzi A, Forni D, Cagliani R, Pozzoli U, Menozzi G, Vertemara J, Bresolin N, Clerici M, Sironi M. Natural Selection at the Brush-Border: Adaptations to Carbohydrate Diets in Humans and Other Mammals. Genome Biol Evol. 2015 Aug 28;7(9):2569-84. doi: 10.1093/gbe/evv166.
• Polley S, Louzada S, Forni D, Sironi M, Balaskas T, Hains DS, Yang F, Hollox EJ. Evolution of the rapidly mutating human salivary agglutinin gene (DMBT1) and population subsistence strategy. Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5105-10. doi: 10.1073/pnas.1416531112.
• Sironi M, Cagliani R, Forni D, Clerici M. Evolutionary insights into host-pathogen interactions from mammalian sequence data. Nat Rev Genet. 2015 Apr;16(4):224-36. doi: 10.1038/nrg3905. Review. PubMed PMID: 25783448.
• Mozzi A, Pontremoli C, Forni D, Clerici M, Pozzoli U, Bresolin N, Cagliani R,Sironi M. OASes and STING: adaptive evolution in concert. Genome Biol Evol. 2015 Mar 9;7(4):1016-32. doi: 10.1093/gbe/evv046.
• Forni D, Mozzi A, Pontremoli C, Vertemara J, Pozzoli U, Biasin M, Bresolin N, Clerici M, Cagliani R, Sironi M. Diverse selective regimes shape genetic diversity at ADAR genes and at their coding targets. RNA Biol. 2015;12(2):149-61. doi: 10.1080/15476286.2015.1017215.
• Provenzi L, Fumagalli M, Sirgiovanni I, Giorda R, Pozzoli U, Morandi F, Beri S, Menozzi G, Mosca F, Borgatti R, Montirosso R. Pain-related stress during the Neonatal Intensive Care Unit stay and SLC6A4 methylation in very preterm infants. Front Behav Neurosci. 2015 Apr 21;9:99. doi: 10.3389/fnbeh.2015.00099.

Partnerships

• Prof. Mario Clerici, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università di Milano, Milano, Italia.
• Dott. Franca Guerini, Fondazione Don C. Gnocchi ONLUS, IRCCS, 20148 Milano, Italia.
• Prof. Mara Biasin, Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università di Milano, Milano, Italia.
• Prof. Andrea Gori, Dipartimento di medicina e chirurgia, Università di Milano-Bicocca, Monza, Italia.
• Dott. Ignacio Bravo, Laboratory MIVEGEC, UMR CNRS 5290, IRD 224, UM, Centre National de la Recherche Scientifique, Montpellier, France.
• Prof. Luca de Gioia, Dipartimento di Biotecnologie e Bioscienze,Università di Milano-Bicocca, Milano, Italia.
• Dott. Edward J Hollox, Department of Genetics, University of Leicester, Leicester, United Kingdom.
• Prof. Santo Landolfo, Dipartimento di Scienze della Sanità Pubblica e Pediatriche, Università degli Studi di Torino, Torino, Italia.