TNFRSF13B Genetic variability an anthropological - evolutionary approach to Biomedical Research

In the recent years TNFRSF13B coding variants have been implicated by clinical genetics studies in Common Variable Immunodeficiency (CVID), the most common clinically relevant primary immunodeficiency in individuals of European ancestry, but their functional effects in relation to the development of the disease have not been entirely established. To examine the potential contribution of such variants to CVID, the more comprehensive perspective of an evolutionary approach was applied in this study, underling the belief that evolutionary genetics methods can play a role in dissecting the origin, causes and diffusion of human diseases, representing a powerful tool also in human health research. For this purpose, TNFRSF13B coding region was sequenced in 451 healthy individuals belonging to 26 worldwide populations, in addition to 96 control, 77 CVID and 38 Selective IgA Deficiency (IgAD) individuals from Italy, leading to the first achievement of a global picture of TNFRSF13B nucleotide diversity and haplotype structure and making suggestion of its evolutionary history possible. A slow rate of evolution, within our species and when compared to the chimpanzee, low levels of genetic diversity geographical structure and the absence of recent population specific selective pressures were observed for the examined genomic region, suggesting that geographical distribution of its variability is more plausibly related to its involvement also in innate immunity rather than in adaptive immunity only. This, together with the extremely subtle disease/healthy samples differences observed, suggests that CVID might be more likely related to still unknown environmental and genetic factors, rather than to the nature of TNFRSF13B variants only.

Conservation genetics of European wildcat (Felis silvestris silvestris): a wide and integrating analysis protocol for admixture inferences and population structure

Introgression of domestic cat genes into European wildcat (Felis silvestris silvestris) populations and reduction of wildcats’ range in Europe, leaded by habitat loss and fragmentation, are considered two of the main conservation problems for this endangered feline. This thesis addressed the questions related with the artificial hybridization and populations’ fragmentation, using a conservation genetics perspective. We combined the use of highly polymorphic loci, Bayesian statistical inferences and landscape analyses tools to investigate the origin of the geographic-genetic substructure of European wildcats (Felis silvestris silvestris) in Italy and Europe. The genetic variability of microsatellites evidenced that European wildcat populations currently distributed in Italy differentiated in, and expanded from two distinct glacial refuges during the Last Glacial Maximum. The genetic and geographic substructure detected between the eastern and western sides of the Apennine ridge, resulted by adaptation to specific ecological conditions of the Mediterranean habitats. European wildcat populations in Europe are strongly structured into 5 geographic-genetic macro clusters corresponding to: the Italian peninsular & Sicily; Balkans & north-eastern Italy; Germany eastern; central Europe; and Iberian Peninsula. Central European population might have differentiated in the extra-Mediterranean Würm ice age refuge areas (Northern Alps, Carpathians, and the Bulgarian mountain systems), while the divergence among and within the southern European populations might have resulted by the Pleistocene bio geographical framework of Europe, with three southern refugia localized in the Balkans, Italian Peninsula and Iberia Peninsula. We further combined the use of most informative autosomal SNPs with uniparental markers (mtDNA and Y-linked) for accurately detecting parental genotypes and levels of introgressive hybridization between European wild and domestic cats. A total of 11 hybrids were identified. The presence of domestic mitochondrial haplotypes shared with some wild individuals led us to hypnotize the possibility that ancient introgressive events might have occurred and that further investigation should be recommended.