Investigating the role of Copy Number Variants in Specific Language Impairment and identification of new candidate genes

Specific language impairment (SLI) is a complex neurodevelopmental disorder defined as an unexpected failure to develop normal language abilities for no obvious reason. Copy number variants (CNVs) are an important source of variation in the susceptibility to neuropsychiatric disorders. Therefore, a CNV study within SLI families was performed to investigate the role of structural variants in SLI. Among the identified CNVs, we focused on CNVs on chromosome 15q11-q13, recurrently observed in neuropsychiatric conditions, and a homozygous exonic microdeletion in ZNF277. Since this microdeletion falls within the AUTS1 locus, a region linked to autism spectrum disorders (ASD), we investigated a potential role of ZNF277 in SLI and ASD. Frequency data and expression analysis of the ZNF277 microdeletion suggested that this variant may contribute to the risk of language impairments in a complex manner, that is independent of the autism risk previously described in this region. Moreover, we identified an affected individual with a dihydropyrimidine dehydrogenase (DPD) deficiency, caused by compound heterozygosity of two deleterious variants in the gene DPYD. Since DPYD represents a good candidate gene for both SLI and ASD, we investigated its involvement in the susceptibility to these two disorders, focusing on the splicing variant rs3918290, the most common mutation in the DPD deficiency. We observed a higher frequency of rs3918290 in SLI cases (1.2%), compared to controls (~0.6%), while no difference was observed in a large ASD cohort. DPYD mutation screening in 4 SLI and 7 ASD families carrying the splicing variant identified six known missense changes and a novel variant in the promoter region. These data suggest that the combined effect of the mutations identified in affected individuals may lead to an altered DPD activity and that rare variants in DPYD might contribute to a minority of cases, in conjunction with other genetic or non-genetic factors.

Palaeo wind system reconstruction of the last glacial period over Europe, using high resolution proxy data and model-data-comparison

The atmosphere is a global influence on the movement of heat and humidity between the continents, and thus significantly affects climate variability. Information about atmospheric circulation are of major importance for the understanding of different climatic conditions. Dust deposits from maar lakes and dry maars from the Eifel Volcanic Field (Germany) are therefore used as proxy data for the reconstruction of past aeolian dynamics.rnrnIn this thesis past two sediment cores from the Eifel region are examined: the core SM3 from Lake Schalkenmehren and the core DE3 from the Dehner dry maar. Both cores contain the tephra of the Laacher See eruption, which is dated to 12,900 before present. Taken together the cores cover the last 60,000 years: SM3 the Holocene and DE3 the marine isotope stages MIS-3 and MIS-2, respectively. The frequencies of glacial dust storm events and their paleo wind direction are detected by high resolution grain size and provenance analysis of the lake sediments. Therefore two different methods are applied: geochemical measurements of the sediment using µXRF-scanning and the particle analysis method RADIUS (rapid particle analysis of digital images by ultra-high-resolution scanning of thin sections).rnIt is shown that single dust layers in the lake sediment are characterized by an increased content of aeolian transported carbonate particles. The limestone-bearing Eifel-North-South zone is the most likely source for the carbonate rich aeolian dust in the lake sediments of the Dehner dry maar. The dry maar is located on the western side of the Eifel-North-South zone. Thus, carbonate rich aeolian sediment is most likely to be transported towards the Dehner dry maar within easterly winds. A methodology is developed which limits the detection to the aeolian transported carbonate particles in the sediment, the RADIUS-carbonate module.rnrnIn summary, during the marine isotope stage MIS-3 the storm frequency and the east wind frequency are both increased in comparison to MIS-2. These results leads to the suggestion that atmospheric circulation was affected by more turbulent conditions during MIS-3 in comparison to the more stable atmospheric circulation during the full glacial conditions of MIS-2.rnThe results of the investigations of the dust records are finally evaluated in relation a study of atmospheric general circulation models for a comprehensive interpretation. Here, AGCM experiments (ECHAM3 and ECHAM4) with different prescribed SST patterns are used to develop a synoptic interpretation of long-persisting east wind conditions and of east wind storm events, which are suggested to lead to an enhanced accumulation of sediment being transported by easterly winds to the proxy site of the Dehner dry maar.rnrnThe basic observations made on the proxy record are also illustrated in the 10 m-wind vectors in the different model experiments under glacial conditions with different prescribed sea surface temperature patterns. Furthermore, the analysis of long-persisting east wind conditions in the AGCM data shows a stronger seasonality under glacial conditions: all the different experiments are characterized by an increase of the relative importance of the LEWIC during spring and summer. The different glacial experiments consistently show a shift from a long-lasting high over the Baltic Sea towards the NW, directly above the Scandinavian Ice Sheet, together with contemporary enhanced westerly circulation over the North Atlantic.rnrnThis thesis is a comprehensive analysis of atmospheric circulation patterns during the last glacial period. It has been possible to reconstruct important elements of the glacial paleo climate in Central Europe. While the proxy data from sediment cores lead to a binary signal of the wind direction changes (east versus west wind), a synoptic interpretation using atmospheric circulation models is successful. This shows a possible distribution of high and low pressure areas and thus the direction and strength of wind fields which have the capacity to transport dust. In conclusion, the combination of numerical models, to enhance understanding of processes in the climate system, with proxy data from the environmental record is the key to a comprehensive approach to paleo climatic reconstruction.rn

Analysis of the pig genome for the identification of genomic regions affecting production traits

The aim of this work was to identify markers associated with production traits in the pig genome using different approaches. We focused the attention on Italian Large White pig breed using Genome Wide Association Studies (GWAS) and applying a selective genotyping approach to increase the power of the analyses. Furthermore, we searched the pig genome using Next Generation Sequencing (NSG) Ion Torrent Technology to combine selective genotyping approach and deep sequencing for SNP discovery. Other two studies were carried on with a different approach. Allele frequency changes for SNPs affecting candidate genes and at Genome Wide level were analysed to identify selection signatures driven by selection program during the last 20 years. This approach confirmed that a great number of markers may affect production traits and that they are captured by the classical selection programs. GWAS revealed 123 significant or suggestively significant SNP associated with Back Fat Thickenss and 229 associated with Average Daily Gain. 16 Copy Number Variant Regions resulted more frequent in lean or fat pigs and showed that different copies of those region could have a limited impact on fat. These often appear to be involved in food intake and behavior, beside affecting genes involved in metabolic pathways and their expression. By combining NGS sequencing with selective genotyping approach, new variants where discovered and at least 54 are worth to be analysed in association studies. The study of groups of pigs undergone to stringent selection showed that allele frequency of some loci can drastically change if they are close to traits that are interesting for selection schemes. These approaches could be, in future, integrated in genomic selection plans.

Analysis of Copy Number Variants identifies new candidate genes for Autism Spectrum Disorder and Intellectual Disability

Autism spectrum disorder (ASD) and Intellectual Disability (ID) are complex neuropsychiatric disorders characterized by extensive clinical and genetic heterogeneity and with overlapping risk factors. The aim of my project was to further investigate the role of Copy Numbers Variants (CNVs), identified through genome-wide studies performed by the Autism Geome Project (AGP) and the CHERISH consortium in large cohorts of ASD and ID cases, respectively. Specifically, I focused on four rare genic CNVs, selected on the basis of their impact on interesting ASD/ID candidate genes: a) a compound heterozygous deletion involving CTNNA3, predicted to cause the lack of functional protein; b) a 15q13.3 duplication containing CHRNA7; c) a 2q31.1 microdeletion encompassing KLHL23, SSB and METTL5; d) Lastly, I investigated the putative imprinting regulation of the CADPS2 gene, disrupted by a maternal deletion in two siblings with ASD and ID. This study provides further evidence for the role of CTNNA3, CHRNA7, KLHL23 and CADPS2 as ASD and/or ID susceptibility genes, and highlights that rare genetic variation contributes to disease risk in different ways: some rare mutations, such as those impacting CTNNA3, act in a recessive mode of inheritance, while other CNVs, such as those occurring in the 15q13.3 region, are implicated in multiple developmental and/or neurological disorders possibly interacting with other susceptibility variants elsewhere in the genome. On the other hand, the discovery of a tissue-specific monoallelic expression for the CADPS2 gene, implicates the involvement of epigenetic regulatory mechanisms as risk factors conferring susceptibility to ASD/ID.

At last Etta james: Il canto come autobiografia

Questa tesi è un tentativo di analizzare il percorso artistico di Etta James, prendendo in considerazione le varie influenze che hanno contribuito a formare la sua personalità artistica a livello canoro ed interpretativo. Si parte da uno spaccato sull’importanza del gospel come genere propedeutico ad un’interpretazione efficace per l’artista afroamericano. Successivamente si passa all’immagine che Etta James si costruisce per sé e come questa influenza la sua vita, quali sono le canzoni che non le paiono in linea con la sua immagine e come mentre tenta di districarsi attraverso diversi altri generi, come blues, rock, funk. Poi viene analizzata la figura della madre biologica di James e come questa venga collegata indissolubilmente alla figura di Billie Holiday, e come trovare la maturità di affrontare quest’ultima farà in modo che anche il rapporto con la figura materna cambi. Viene analizzato uno dei più grandi successi della cantante, “At Last”, di cui lei è interprete ma non autrice, ma attraverso una grande abilità stilistica riesce a formare quello che sarà uno standard per gli artisti contemporanei. Ed infine si tirano le somme guardando al retaggio artistico che ha lasciato dietro di sé l’artista.

Discovery copy

Programma per il riconoscimento di copie di programmi in linguaggio C

Daily temperature trends in Trentino Alto Adige over the last century

Numerosi lavori apparsi sulla letteratura scientifica negli ultimi decenni hanno evidenziato come, dall’inizio del XX secolo, la temperatura media globale sia aumentata. Tale fenomeno si è fatto più evidente dagli anni ’80, infatti ognuno degli ultimi tre decenni risulta più caldo dei precedenti. L’Europa e l’area mediterranea sono fra le regioni in cui il riscaldamento risulta più marcato, soprattutto per le temperature massime (dal 1951 sono cresciute di +0.39 °C per decennio) che hanno mostrato trend maggiori delle minime. Questo comportamento è stato osservato anche a scala nazionale (+0.25°C/dec per le massime e +0.20°C/dec per le minime). Accanto all’aumento dei valori medi è stato osservato un aumento (diminuzione) degli eventi di caldo (freddo) estremo, studiati attraverso la definizione di alcuni indici basati sui percentili delle distribuzioni. Resta aperto il dibattito su quali siano le cause delle variazioni negli eventi estremi: se le variazioni siano da attribuire unicamente ad un cambiamento nei valori medi, quindi ad uno shift rigido della distribuzione, o se parte del segnale sia dovuto ad una variazione nella forma della stessa, con un conseguente cambiamento nella variabilità. In questo contesto si inserisce la presente tesi con l’obiettivo di studiare l’andamento delle temperature giornaliere sul Trentino-Alto-Adige a partire dal 1926, ricercando cambiamenti nella media e negli eventi estremi in due fasce altimetriche. I valori medi delle temperature massime e minime hanno mostrato un evidente riscaldamento sull’intero periodo specialmente per le massime a bassa quota (`0.13 ̆ 0.03 °C/dec), con valori più alti per la primavera (`0.22 ̆ 0.05 °C/dec) e l’estate (`0.17 ̆ 0.05 °C/dec). Questi trends sono maggiori dopo il 1980 e non significativi in precedenza. L’andamento del numero di giorni con temperature al di sopra e al di sotto delle soglie dei percentili più estremi (stimate sull’intero periodo) indica un chiaro aumento degli estremi caldi, con valori più alti per le massime ad alta quota ( fino a +26.8% per il 99-esimo percentile) e una diminuzione degli estremi freddi (fino a -8.5% per il primo percentile delle minime a bassa quota). Inoltre, stimando anno per anno le soglie di un set di percentili e confrontando i loro trend con quelli della mediana, si è osservato, unicamente per le massime, un trend non uniforme verso temperature più alte, con i percentili più bassi (alti) caratterizzati da trend inferiori (superiori) rispetto a quello della mediana, suggerendo un allargamento della PDF.

Child and adolescent psychiatric genetics

The current status of child and adolescent psychiatric genetics appears promising in light of the initiation of genome-wide association studies (GWAS) for diverse polygenic disorders and the molecular elucidation of monogenic Rett syndrome, for which recent functional studies provide hope for pharmacological treatment strategies. Within the last 50 years, tremendous progress has been made in linking genetic variation to behavioral phenotypes and psychiatric disorders. We summarize the major findings of the Human Genome Project and dwell on largely unsuccessful candidate gene and linkage studies. GWAS for the first time offer the possibility to detect single nucleotide polymorphisms and copy number variants without a priori hypotheses as to their molecular etiology. At the same time it is becoming increasingly clear that very large sample sizes are required in order to enable genome wide significant findings, thus necessitating further large-scaled ascertainment schemes for the successful elucidation of the molecular genetics of childhood and adolescent psychiatric disorders. We conclude by reflecting on different scenarios for future research into the molecular basis of early onset psychiatric disorders. This review represents the introductory article of this special issue of the European Child and Adolescent Psychiatry.