Alessio Boattini

A polymorphism in the chromosome 9p21 ANRIL locus is associated to Philadelphia positive acute lymphoblastic leukemia

Little is known about alterations of cyclin dependent kinase inhibitors p15INK4B, p16INK4A and of MDM2 inhibitor p14ARF due to single nucleotide polymorphisms (SNPs) located within the CDKN2A/B genes and/or neighbouring loci. In order to investigate the potential involvement of such common DNA sequence variants in leukemia susceptibility, an association study was performed by genotyping 23 SNPs spanning the MTAP, CDKN2A/B and CDKN2BAS loci, as well as relative intergenic regions, in a case-control cohort made up of 149 leukemia patients, including Philadelphia positive (Ph(+)) acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples, and 183 healthy controls. rs564398, mapping to the CDKN2BAS locus that encodes for ANRIL antisense non-coding RNA, showed a statistically significant correlation with the ALL phenotype, with a risk pattern that was compatible with an overdominant model of disease susceptibility and a OR of 2 (95% CI, 1.20-3.33; p=7.1×10(-3)). We hypothesized that this association reflects the capability of some ANRIL polymorphisms to contribute to its transcription changes responsible for alterations of CDKN2A/B expression profiles, thus leading to abnormal proliferative boosts and consequent increased ALL susceptibility.

Uniparental markers in Italy reveal a sex-biased genetic structure and different historical strata

Located in the center of the Mediterranean landscape and with an extensive coastal line, the territory of what is today Italy has played an important role in the history of human settlements and movements of Southern Europe and the Mediterranean Basin. Populated since Paleolithic times, the complexity of human movements during the Neolithic, the Metal Ages and the most recent history of the two last millennia (involving the overlapping of different cultural and demic strata) has shaped the pattern of the modern Italian genetic structure. With the aim of disentangling this pattern and understanding which processes more importantly shaped the distribution of diversity, we have analyzed the uniparentally-inherited markers in ∼900 individuals from an extensive sampling across the Italian peninsula, Sardinia and Sicily. Spatial PCAs and DAPCs revealed a sex-biased pattern indicating different demographic histories for males and females. Besides the genetic outlier position of Sardinians, a North West–South East Y-chromosome structure is found in continental Italy. Such structure is in agreement with recent archeological syntheses indicating two independent and parallel processes of Neolithisation. In addition, date estimates pinpoint the importance of the cultural and demographic events during the late Neolithic and Metal Ages. On the other hand, mitochondrial diversity is distributed more homogeneously in agreement with older population events that might be related to the presence of an Italian Refugium during the last glacial period in Europe.

The Family Name as Socio-Cultural Feature and Genetic Metaphor: From Concepts to Methods

Abstract A recent workshop entitled “The Family Name as Socio-Cultural Feature and Genetic Metaphor: From Concepts to Methods” was held in Paris in December 2010, sponsored by the French National Centre for Scientific Research (CNRS) and by the journal Human Biology. This workshop was intended to foster a debate on questions related to the family names and to compare different multidisciplinary approaches involving geneticists, historians, geographers, sociologists and social anthropologists. This collective paper presents a collection of selected communications.

An Ancient Mediterranean Melting Pot: Investigating the Uniparental Genetic Structure and Population History of Sicily and Southern Italy

Due to their strategic geographic location between three different continents, Sicily and Southern Italy have long represented a major Mediterranean crossroad where different peoples and cultures came together over time. However, its multi-layered history of migration pathways and cultural exchanges, has made the reconstruction of its genetic history and population structure extremely controversial and widely debated. To address this debate, we surveyed the genetic variability of 326 accurately selected individuals from 8 different provinces of Sicily and Southern Italy, through a comprehensive evaluation of both Y-chromosome and mtDNA genomes. The main goal was to investigate the structuring of maternal and paternal genetic pools within Sicily and Southern Italy, and to examine their degrees of interaction with other Mediterranean populations. Our findings show high levels of within-population variability, coupled with the lack of significant genetic sub-structures both within Sicily, as well as between Sicily and Southern Italy. When Sicilian and Southern Italian populations were contextualized within the Euro-Mediterranean genetic space, we observed different historical dynamics for maternal and paternal inheritances. Y-chromosome results highlight a significant genetic differentiation between the North-Western and South-Eastern part of the Mediterranean, the Italian Peninsula occupying an intermediate position therein. In particular, Sicily and Southern Italy reveal a shared paternal genetic background with the Balkan Peninsula and the time estimates of main Y-chromosome lineages signal paternal genetic traces of Neolithic and post-Neolithic migration events. On the contrary, despite showing some correspondence with its paternal counterpart, mtDNA reveals a substantially homogeneous genetic landscape, which may reflect older population events or different demographic dynamics between males and females. Overall, both uniparental genetic structures and TMRCA estimates confirm the role of Sicily and Southern Italy as an ancient Mediterranean melting pot for genes and cultures.

Long-Range Comparison between Genes and Languages Based on Syntactic Distances

Objective: To propose a new approach for comparing genetic and linguistic diversity in populations belonging to distantly related groups. Background: Comparisons of linguistic and genetic differences have proved powerful tools to reconstruct human demographic history. Current models assume on both sides that similarities reflect either descent from common ancestry or the balance between isolation and contact. Most linguistic phylogenies are ultimately based on lexical evidence (roughly, words and morphemes with their sounds and meanings). However, measures of lexical divergence are reliable only for closely related languages, thus large-scale comparisons of genetic and linguistic diversity have appeared problematic so far. Methods: Syntax (abstract rules to combine words into sentences) appears more measurable, universally comparable, and stable than the lexicon, and hence certain syntactic similarities might reflect deeper linguistic relationships, such as those between distant language families. In this study, we for the first time compared genetic data to a matrix of syntactic differences among selected populations of three continents. Results: Comparing two databases of microsatellite (Short Tandem Repeat) markers and Single Nucleotides Polymorphisms (SNPs), with a linguistic matrix based on the values of 62 grammatical parameters, we show that there is indeed a correlation of syntactic and genetic distances. We also identified a few outliers and suggest a possible interpretation of the overall pattern. Conclusions: These results strongly support the possibility of better investigating population history by combining genetic data with linguistic information of a new type, provided by a theoretically more sophisticated method to assess the relationships between distantly related languages and language families.

Inbreeding Patterns in La Cabrera, Spain: Dispensations, Multiple Consanguinity Analysis, and Isonymy

Marital structure and inbreeding coefficients were analyzed in La Cabrera, an isolated mountain region in northwestern Spain. A total of 5,714 marriages were celebrated from 1880 to 1989 in the 37 parishes of the area. The total frequency of consanguineous marriages (up to the fourth degree) is 23.05%; multiple consanguineous marriages are remarkably common, reaching 5.43% of the total. The first cousin/second cousin ratio (referred to as kinship-type frequencies) is 0.43. The inbreeding values are the highest recorded in Spain and in Europe: α3 is 4.82x10-3 for the whole period and α4 is 6.78x10-3 for 1880-1919. The temporal trend of inbreeding shows high values (α3>4.5x10-3) for a particularly long period (1900-1959) and a rapid decline from 1960 onward. This historical inbreeding trend is clearly related to changes in population size. The frequencies of multiple consanguineous marriages and the analysis of isonymy show that the inbreeding structure is related to geographic and demographic factors. Comparing the results at two hierarchical levels (La Cabrera as a whole and the 37 parishes individually), we conclude that the inbreeding values are affected by internal geographic subdivision of the population (Wahlund effect). Social and cultural factors, such as avoidance of or preference for consanguineous marriages, are less important but depend on the kinship type involved.

Polymorphic NumtS trace human population relationships

The human genome is constantly subjected to evolutionary forces which shape its architecture. Insertions of mitochondrial DNA sequences into nuclear genome (NumtS) have been described in several eukaryotic species, including Homo sapiens and other primates. The ongoing process of the generation of NumtS has made them valuable markers in primate phylogenetic studies, as well as potentially informative loci for reconstructing the genetic history of modern humans. Here, we report the identification of 53 human-specific NumtS by inspection of the UCSC genome browser, showing that they may be direct insertions of mitochondrial DNA into the human nuclear DNA after the human-chimpanzee split. In silico analyses allowed us to identify 14 NumtS which are polymorphic in terms of their presence/absence within the human genome in individuals of different ancestry. The allele frequencies of these polymorphic NumtS were calculated for 1000 Genomes Project sequence data from 13 populations worldwide, and principal components analysis and hierarchical clustering methods allowed the detection of strong signals of geographical structure related to the genetic diversity of these loci. All identified polymorphic human-specific NumtS together with a tandemly duplicated NumtS have also been validated by PCR amplification on a panel of 60 samples belonging to five native populations worldwide, confirming the expected NumtS variability. On the basis of these findings, we have succeeded in depicting the landscape of variation of a series of NumtS in several ethnic groups, making an advance in their identification as useful markers in the study on human population genetics.

mtDNA variation in East Africa unravels the history of Afro-Asiatic groups.

East Africa (EA) has witnessed pivotal steps in the history of human evolution. Due to its high environmental and cultural variability, and to the long-term human presence there, the genetic structure of modern EA populations is one of the most complicated puzzles in human diversity worldwide. Similarly, the widespread Afro-Asiatic (AA) linguistic phylum reaches its highest levels of internal differentiation in EA. To disentangle this complex ethno-linguistic pattern, we studied mtDNA variability in 1,671 individuals (452 of which were newly typed) from 30 EA populations and compared our data with those from 40 populations (2970 individuals) from Central and Northern Africa and the Levant, affiliated to the AA phylum. The genetic structure of the studied populations--explored using spatial Principal Component Analysis and Model-based clustering--turned out to be composed of four clusters, each with different geographic distribution and/or linguistic affiliation, and signaling different population events in the history of the region. One cluster is widespread in Ethiopia, where it is associated with different AA-speaking populations, and shows shared ancestry with Semitic-speaking groups from Yemen and Egypt and AA-Chadic-speaking groups from Central Africa. Two clusters included populations from Southern Ethiopia, Kenya and Tanzania. Despite high and recent gene-flow (Bantu, Nilo-Saharan pastoralists), one of them is associated with a more ancient AA-Cushitic stratum. Most North-African and Levantine populations (AA-Berber, AA-Semitic) were grouped in a fourth and more differentiated cluster. We therefore conclude that EA genetic variability, although heavily influenced by migration processes, conserves traces of more ancient strata.

Linking Italy and the Balkans. A Y-chromosome perspective from the Arbereshe of Calabria

Background: The Arbereshe are an Albanian-speaking ethno-linguistic minority who settled in Calabria (southern Italy) about five centuries ago. Aim: This study aims to clarify the genetic relationships between Italy and the Balkans through analysis of Y-chromosome variability in a peculiar case study, the Arbereshe. Subject and methods: Founder surnames were used as a means to identify a sample of individuals that might trace back to the Albanians at the time of their establishment in Italy. These results were compared with data of more than 1000 individuals from Italy and the Balkans. Results: The distributions of haplogroups (defined using 31 UEPs) and haplotypes (12 STRs) show that the Italian and Balkan populations are clearly divergent from each other. Within this genetic landscape, the Arbereshe are characterized by two peculiarities: (a) they are a clear outlier in the Italian genetic background, showing a strong genetic affinity with southern Balkans populations; and (b) they retain a high degree of genetic diversity. Conclusion: These results support the hypothesis that the surname-chosen Arbereshe are representative of the Y-chromosome genetic variability of the Albanian founder population. Accordingly, the Arbereshe genetic structure can contribute to the interpretation of the recent biological history of the southern Balkans. Intra-haplogroup analyses suggest that this area may have experienced important changes in the last five centuries, resulting in a marked increase in the frequency of haplogroups I2a and J2.

Traces of medieval migrations in a socially stratified population from Northern Italy. Evidence from uniparental markers and deep-rooted pedigrees.

Social and cultural factors had a critical role in determining the genetic structure of Europe. Therefore, socially stratified populations may help to focus on specific episodes of European demographic history. In this study, we use uniparental markers to analyse the genetic structure of Partecipanza in San Giovanni in Persiceto (Northern Italy), a peculiar institution whose origins date back to the Middle Ages and whose members form the patrilineal descent of a group of founder families. From a maternal point of view (mtDNA), Partecipanza is genetically homogeneous with the rest of the population. However, we observed a significant differentiation for Y-chromosomes. In addition, by comparing 17 Y-STR profiles with deep-rooted paternal pedigrees, we estimated a Y-STR mutation rate equal to 3.90 * 10−3 mutations per STR per generation and an average generation duration time of 33.38 years. When we used these values for tentative dating, we estimated 1300-600 years ago for the origins of the Partecipanza. These results, together with a peculiar Y-chromosomal composition and historical evidence, suggest that Germanic populations (Lombards in particular) settled in the area during the Migration Period (400–800 AD, approximately) and may have had an important role in the foundation of this community.