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Human Evolutionary Genetics

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. 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.

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.

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.

Splicing Regulation

Most protein encoding genes in metazoans are interrupted by introns; production of functional mRNAs in these organisms is therefore critically dependent upon the accuracy of pre-mRNA splicing, a highly regulated process assuring that introns are removed and an ordered array of exons is maintained in mature transcripts. It is now established that, in mammals, exons (and not introns, as initially speculated) are recognized by the splicing machinery; this notion is referred to as the "exon definition model" and most probably holds true in the great majority of cases. As a consequence, our present understanding of splicing processes in mammals is not far from a finding-needles-in-a-haystack view: the typical situation of most pre-mRNAs envisages relatively small exons embedded in large intronic sequences with short splicing signals to establish which is which. The panorama is even more complicated when alternative splicing events are considered: about 46-60% of human genes encode alternatively spliced transcripts and this mechanism is thought to provide gene expression control and protein functional diversification. Alternative splicing events can be expected to entail additional complexity if compared to constitutive ones since specification of time (developmental stage, cell cycle phase, etc) and space (cell type, organ, tissue) information is often required. Therefore, the major question is where does all this information reside? What factors either cis- or trans-acting regulate both constitutive and alternative exon recognition?

It is now clear that the presence of well-defined cis-elements, namely the 5' and 3' splice sites, the branch point and the poly-pyrimidine tract is necessary but not sufficient to define intron-exon boundaries. The concerted recognition of multiple weak elements located within exons as well as in intronic regions is nowadays thought to provide the necessary splicing information. Sequences having a role in splicing regulation are generally addressed to as either enhances or silencers, depending on the effect they exert.

Intron Evolution

Increase in number and size of intronic sequences is a general feature during the evolution of eukaryotic genomes with introns accounting for about a quarter of genome size in humans. Large intronic sequences have an impact on transcriptional cost and pose an extraordinary task to splicing efficiency, rendering the significance and origin of such expansion a tantalizing question. Recently the notion whereby introns represent mere junk has been confronted with increasing evidences suggesting their functional role in gene regulation and genome architecture.

DNA Recombination

Recombination between DNA sequences sharing little or no homology is referred to as nonhomologous or illegitimate recombination (IR), a process that is involved in many chromosome rearrangements resulting in human genetic diseases. Rejoining of nonhomologous DNA termini (nonhomologous end joining, NHEJ) plays a central role in processes of IR and represents one of the major cellular pathways that is activated in response to DNA double strand breaks (DBS). Analysis of junctions produced by IR in human cells revealed the presence of regions more prone to be involved in the recombination events but failed to detect preferential nucleotide sequences at the joining sites, suggesting that sequence feature alone might not be sufficient and that structure or higher order structures might play a role in the process. Our group has mainly been focusing on NHEJ events within the dystrophin gene (DMD) that lead to deletion/duplication events responsible for Duchenne and Becker Muscular dystrophies (OMIM 300377 and 300376, respectively).