The History and geography of the Y chromosome SNPs in Europe: an update

The knowledge of the evolution of the human genome is strictly dependent on the availability of appropriate genetic markers and their relative coverage of genetic variation which refine the phylogenetic reconstruction. While autosomal markers are particularly valuable for recognizing correspondence between genetic and geographic distances, markers on mitochondrial DNA (mtDNA) or Non Recombining Portion of Y Chromosome (NRY), because of their unilinear transmission, can effectively trace diachronical patterns of the human peopling. The maximum extent of polymorphism coverage has already been reached for the very small mitochondrial genome (about 16,5 Kbp), whereas the first studies based on RFLPs (Restriction Fragment Length Polymorphisms) (Cann et al., 1987) and on sequencing of the hypervariable regions (Vigliant et al., 1991), were then combined to get higher resolution (Torroni et al., 1996), and finally the complete genome sequencing is now routinely performed (Achilli et al., 2004, Pala et al., 2009), in order to detect the whole mtDNA variation. A similar approach cannot be used yet at population level for the by far larger nuclear genome. However, advances in genotyping technology have dramatically enhanced the resolution of the analysis at genome-wide level, and recent papers significantly improved the knowledge of the relationships among European populations, using 300 to 500 K SNPs (Single Nucleotide Polymorphisms) on microarrays chips (Tian et al., 2008; Novembre et al., 2008). As to the NRY, most of the studies before the year 2000 were performed using Alu insertion (Hammer, 1995) or STRs (Short Tandem Repeats) (De Knijff et al., 1997; Pritchard et al., 1999) with the known limitations due to recurrence and reversion of this kind of polymorphisms. Using D-HPLC (Denaturing High Performance Liquid Chromatography) technology, Underhill and coworkers (1997) discovered 22 new SNP biallelic markers, rapidly raising in number to 167 (Underhill et al., 2000), 242 (YCC, 2002), about 600 (Karafet et al., 2008), up to more than 725 presently listed in the Y-DNA SNP Index 2009, (www.isogg. org), and the knowledge of Y chromosome phylogeny and of the spread worldwide of human populations raised proportionally. The next goal of the research on Y chromosome will be the use of specific microarrays that can genotype a much higher number of SNPs than nowadays routinely performed, and, ultimately, the complete Y chromosome sequencing. Waiting for future developments, this short note reports the state of the art of the phylogenetic (“history”) and phylogeographic (“geography”) research on Y chromosome SNP analyses in Europe, updating the review published in this Journal by Francalacci & Sanna at the beginning of 2008

Surname analysis of the Corsican population reveals an agreement with geographical and linguistic structure

The surname is a cultural trait that is extremely useful for historical and linguistic studies and can effectively be used as a genetic marker. In many human populations the surname is inherited in the paternal lineage, and can therefore be considered a marker for the Y chromosome. In this study, surnames were recorded from the white pages of telephone directories in current use in Corsica in 1993. All surnames present in thirteen villages scattered over the whole island and covering the main historical regions were transcribed. Surname variability was found to be higher in coastal villages, and lower in more isolated communities. The isonymy detected among the thirteen villages allowed the calculation of kinship values, visualized in a tree showing two main clusters, one referring to the northern villages and one encompassing the villages of the south. The pattern reflects the administrative division of the island, with the exception of Vico, which belongs to the southern administrative region but is geographically close to the northern villages, and Ghisoni, which belongs to the northern district but is more similar to the village of Bastelica in the southern district. The data presented here show a structure in the surname distribution that is in substantial agreement with the geographical patterns. The kinship values are consistent with a moderated gene flow among villages producing a surname structure according to the geographic features of the territory

A Comparison of Y-Chromosome variation in Sardinia and Anatolia is more consistent with cultural rather than demic diffusion of agriculture

Two alternative models have been proposed to explain the spread of agriculture in Europe during the Neolithic period. The demic diffusion model postulates the spreading of farmers from the Middle East along a Southeast to Northeast axis. Conversely, the cultural diffusion model assumes transmission of agricultural techniques without substantial movements of people. Support for the demic model derives largely from the observation of frequency gradients among some genetic variants, in particular haplogroups defined by single nucleotide polymorphisms (SNPs) in the Y-chromosome. A recent network analysis of the R-M269 Y chromosome lineage has purportedly corroborated Neolithic expansion from Anatolia, the site of diffusion of agriculture. However, the data are still controversial and the analyses so far performed are prone to a number of biases. In the present study we show that the addition of a single marker, DYSA7.2, dramatically changes the shape of the R-M269 network into a topology showing a clear Western-Eastern dichotomy not consistent with a radial diffusion of people from the Middle East. We have also assessed other Y-chromosome haplogroups proposed to be markers of the Neolithic diffusion of farmers and compared their intra-lineage variation—defined by short tandem repeats (STRs)—in Anatolia and in Sardinia, the only Western population where these lineages are present at appreciable frequencies and where there is substantial archaeological and genetic evidence of pre-Neolithic human occupation. The data indicate that Sardinia does not contain a subset of the variability present in Anatolia and that the shared variability between these populations is best explained by an earlier, pre-Neolithic dispersal of haplogroups from a common ancestral gene pool. Overall, these results are consistent with the cultural diffusion and do not support the demic model of agriculture diffusion

Mendelian breeding units <i>versus</i> standard sampling strategies: mitochondrial DNA variation in southwest Sardinia

We report a sampling strategy based on Mendelian Breeding Units (MBUs), representing an interbreeding group of individuals sharing a common gene pool. The identification of MBUs is crucial for case-control experimental design in association studies. The aim of this work was to evaluate the possible existence of bias in terms of genetic variability and haplogroup frequencies in the MBU sample, due to severe sample selection. In order to reach this goal, the MBU sampling strategy was compared to a standard selection of individuals according to their surname and place of birth. We analysed mitochondrial DNA variation (first hypervariable segment and coding region) in unrelated healthy subjects from two different areas of Sardinia: the area around the town of Cabras and the western Campidano area. No statistically significant differences were observed when the two sampling methods were compared, indicating that the stringent sample selection needed to establish a MBU does not alter original genetic variability and haplogroup distribution. Therefore, the MBU sampling strategy can be considered a useful tool in association studies of complex traits

The Distribution of HLA class II haplotypes reveals that the Sardinian population is genetically differentiated from the other Caucasian populations

In this study we have established the frequencies of the DRB1-DQA1-DQB1 haplotypes in a large cohort of Sardinian new-borns and found that the most frequent haplotypes were detected at frequencies unique to the Sardinians. Other haplotypes, common in other Caucasian populations, are rare or absent across the island. Next, the DRB1-DQA1-DQB1 haplotype frequencies obtained in Sardinians and those reported in other human populations were used to compute genetic distances and construct phylogenetic trees. A clear-cut pattern appeared with a split between the three major human groups: Caucasians, Asians and Blacks. Among the Caucasians there were three major clusters: a group representing the North-Africans, a group including most of the European-derived populations and a group encompassing Bulgaria, Greece and Sardinia. When we increased the resolution of the tree using the genetic distances calculated from both DRB1-DQA1-DQB1 haplotypes and class I HLA A, B, C allelic frequencies, the Sardinians clearly emerged as the major outlier among the various European populations considered in this study. These results indicate that the genetic structure of the present Sardinian population is the result of a fixation of haplotypes, which are very rare elsewhere, and are most likely to have originated from a relatively large group of founders

Frequency distribution of mitochondrial DNA haplogroups in Corsica and Sardinia

Mitochondrial DNA (mtDNA) polymorphisms were analyzed by polymerase chain reaction amplification and haplogroup-specific restriction screening in populations from Corsica and Sardinia. These included 56 individuals from the area of Corte, central Corsica (France), 51 individuals from Gallura, northern Sardinia (Italy), and 45 individuals from Barbagia, central Sardinia. The screening revealed that about 95% of mtDNA could be grouped in 8 of the 9 European haplogroups, including H-K, T-V, and X. Our results confirmed that these haplogroups encompass virtually all the mitochondrial lineages present in Europe and can be detected in both northern and southern European populations. We also discovered 2 restriction sites (-73 Alw441 and +75 SphI) that allow the detection of informative nucleotide changes in the second hyperviariable segment of the control region, which help to detect the haplogroup identity of mtDNAs without requiring further DNA sequencing. Haplogroup H was the most common mtDNA lineage in this sample, reaching frequencies from about 40% in Corsican and Gallurese populations, to about 65% in the Barbagian population. Haplogroup V, possibly originating in the Iberian peninsula, was found only in the central Sardinia sample. Of the 5 Corsican mtDNAs belonging to the haplogroup T, 4 had a restriction fragment length polymorphism found only in this population. It seems that this mutation originated in Corsica and has had time to spread in the area, since the maternal grandmothers of the subjects came from different villages of the island. The sample from central Sardinia shows a remarkable discontinuity with those from the northern part of the island and from Corsica. Gallura and Corsica seem to have undergone a more recent peopling event, possibly related to the arrival of new mitochondrial variability from continental Italy, while Barbagia has apparently maintainded more archaic haplotypes

Archival, demographic and genetic studies define a Sardinian sub-isolate as a suitable model for mapping complex traits

Genetic isolates represent exceptional resources for the mapping of complex traits but not all isolates are similar. We have selected a genetic and cultural isolate, the village of Talana from an isolated area of Sardinia, and propose that this population is suitable for the mapping of complex traits. A wealth of historical and archive data allowed the reconstruction of the demographic and genealogical history of the village. Key features of the population, which has grown slowly with no significant immigration, were defined by using a combination of historical, demographic and genetic studies. The genealogy of each Talana inhabitant was reconstructed and the main maternal and paternal lineages of the village were defined. Haplotype and phylogenetic analyses of the Y chromosome and characterisation of mitochondrial DNA haplogroups were used to determine the number of ancestral village founders. The extent of linkage disequilibrium (LD) was evaluated by the analysis of several microsatellites in chromosomal region Xq13.3, which was previously used to asses the extension of LD. Genealogical reconstructions were confirmed and reinforced by the genetic analyses, since some lineages were found to have merged prior to the beginning of the archival records, suggesting an even smaller number of founders than initially predicted. About 80% of the present-day population appears to derive from eight paternal and eleven maternal ancestral lineages. LD was found to span, on average, a 5-Mb region in Xq13.3. This suggests the possibility of identifying identical-by-descent regions associated with complex traits in a genome-wide search by using a low-density marker map. The present study emphasises the importance of combining genetic studies with genealogical and historical information

Sex-related bias and exclusion mapping of the nonrecombinant portion of chromosome Y in human type 1 diabetes in the isolated founder population of Sardinia

A male excess in Sardinian type 1 diabetic cases has previously been reported and was largely restricted to those patients carrying the HLA-DR3/nonDR4 genotype. In the present study, we have measured the male- to-female (M:F) ratio in a sample set of 542 newly collected, early-onset type 1 diabetic Sardinian patients. This data not only confirm the excess of male type 1 diabetic patients overall (M:F ratio = 1.3, P = 3.9 × 10−3) but also that the bias in male incidence is largely confined to patients with the DR3/nonDR4 genotype (M:F ratio = 1.6, P = 2.0 × 10−4). These sex effects could be due to a role for allelic variation of the Y chromosome in the susceptibility to type 1 diabetes, but to date this chromosome has not been evaluated in type 1 diabetes. We, therefore, established the frequencies of the various chromosome Y lineages and haplotypes in 325 Sardinian male patients, which included 180 cases with the DR3/nonDR4 genotype, and 366 Sardinian male control subjects. Our results do not support a significant involvement of the Y chromosome in DR3/nonDR4 type 1 diabetic cases nor in early-onset type 1 diabetes as a whole. Other explanations, such as X chromosome-linked inheritance, are thus required for the male bias in incidence in type 1 diabetes in Sardinia

The Inter-regional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case–control association studies in complex diseases

We have analysed HLA class II gene-based substructure of the Sardinian population in order to evaluate the possible influence of this parameter in the mapping of common disease loci using association methods. We first examined the distribution of the HLA-DRB1-DQA1-DQB1 haplotypes in 631 newborns from seven different regions of the island, and found that the most frequent haplotypes were uniformly distributed in all regions, but at frequencies unique to Sardinia. Other haplotypes, common in other white European populations, are consistently rare or absent across the whole island. Analysis of molecular variance (AMOVA) showed a very low degree of genetic differentiation between the coastal regions, which have suffered repeated invasions over many years, and the most internal and isolated part of the island. This suggests that there has been little genetic flow from the various populations that have invaded the island during the last 3000 years and that Sardinia is a relatively homogeneous population. The validity of these unrelated control HLA haplotype frequencies and our claim of homogeneity were established by demonstrating the near identity of the affected family-based control (AFBAC) HLA haplotype frequencies in 243 type 1 diabetes and 495 multiple sclerosis families from Sardinia and those of the unrelated controls. These results indicate that robust case–control studies can be carried out in Sardinia offering cost efficiency over certain family-based designs

Peopling of three Mediterranean Islands (Corsica, Sardinia, and Sicily) inferred by Y-chromosome biallelic variability

chromosome variability in a sample from the Mediterranean islands of Corsica and Sicily, and compared with data on Sardinia to gain insights into the ethnogenesis of these island populations. The results were interpreted in a broader Mediterranean context by including in the analysis neighboring populations previously studied with the same methodology. All samples studied were enclosed in the comparable spectrum of European Y-chromosome variability. Pronounced differences were observed between the islands as well as in the percentages of haplotypes previously shown to have distinctive patterns of continental phylogeography. Approximately 60% of the Sicilian haplotypes are also prevalent in Southern Italy and Greece. Conversely, the Corsican sample had elevated levels of alternative haplotypes common in Northern Italy. Sardinia showed a haplotype ratio similar to that observed in Corsica, but with a remarkable difference in the presence of a lineage defined by marker M26, which approaches 35% in Sardinia but seems absent in Corsica. Although geographically adjacent, the data suggest different colonization histories and a minimal amount of recent gene flow between them. Our results identify possible ancestral continental sources of the various island populations and underscore the influence of founder effect and genetic drift. The Y-chromosome data are consistent with comparable mtDNA data at the RFLP haplogroup level of resolution, as well as linguistic and historic knowledge