Y-Chromosome Based Evidence for Pre-Neolithic Origin of the Genetically Homogeneous but Diverse Sardinian Population: Inference for Association Scans

Abstract

The island of Sardinia shows a unique high incidence of several autoimmune diseases with multifactorial inheritance, particularly type 1 diabetes and multiple sclerosis. The prior knowledge of the genetic structure of this population is fundamental to establish the optimal design for association studies in these diseases. Previous work suggested that the Sardinians are a relatively homogenous population, but some reports were contradictory and data were largely based on variants subject to selection. For an unbiased assessment of genetic structure, we studied a combination of neutral Y-chromosome variants, 21 biallelic and 8 short tandem repeats (STRs) in 930 Sardinian males. We found a high degree of interindividual variation but a homogenous distribution of the detected variability in samples from three separate regions of the island. One haplogroup, I-M26, is rare or absent outside Sardinia and is very common (0.37 frequency) throughout the island, consistent with a founder effect. A Bayesian full likelihood analysis (BATWING) indicated that the time from the most recent common ancestor (TMRCA) of I-M26, was 21.0 (16.0–25.5) thousand years ago (KYA) and that the population began to expand 14.0 (7.8–22.0) KYA. These results suggest a largely pre-Neolithic settlement of the island with little subsequent gene flow from outside populations. Consequently, Sardinia is an especially attractive venue for case-control genome wide association scans in common multifactorial diseases. Concomitantly, the high degree of interindividual variation in the current population facilitates fine mapping efforts to pinpoint the aetiologic polymorphisms.

Differential Greek and northern African migrations to Sicily are supported by genetic evidence from the Y chromosome

“…The general heterogeneous composition of Hgs seen in our Sicilian data is consistent with similar patterns observed in other major islands of the Mediterranean, like Sardinia (gene diversity 0.801±0.010 SD on 939 samples using 23 Hgs) 39 and Crete 29,40 (gene diversity 0.926±0.0006 SD on 193 samples using 29 Hgs), 29 possibly reflecting the complex histories of settlements in these islands during the Holocene (Supplementary Table 1). …”

Dissecting the genetic make-up of North-East Sardinia using a large set of haploid and autosomal markers

“…As shown in previous studies, 15,19 Sardinia was clearly separated from nearby Mediterranean populations, with significant Fst estimates that varied from 9% (comparison with Greece) to 23% (comparison with Basques). We included the major Y chromosome haplogroup frequencies based on 373 Sardinian individuals described in Contu et al 15 We did not observe any significant differences between the two Sardinian samples, despite the fact that individuals were sampled from different regions 15 (Table 2a). We also restricted the analysis to individuals from the 'Barbagia' region (Nuoro in Figure 1) and did not observe evidence for differentiation because of place of birth with the Y chromosome markers (data not shown).…”

“…15,19,32 First, we collapsed the subclades into major haplogroups, as not all the markers we used in our analysis were typed in previous publications. Table 2a presents the pairwise Fst as estimated between the Sardinian and other populations.…”

“…14 Still, controversy remains as to whether Sardinia is a homogeneous genetic isolate. Reports based on Y microsatellite markers and a few autosomal loci have shown that Sardinians from different regions of the island cannot be distinguished by their genetic make-up, 15 which implies that pooling individuals from different regions in Sardinia will not lead to substantial population stratification. However, in a recent study, it was shown that even within a single province in Sardinia, there are distinct sub-populations.…”

Evidence for malaria selection of a CR1 haplotype in Sardinia

“…Sardinia is an island that has had a unique history, and recent studies suggest that most Sardinians may have descended from a largely pre-Neolithic settlement with little gene flow from outside populations, despite a complex history of invasions by different European continental populations. [8][9][10] The history of the island is notable for a long history of endemic malaria that plagued the population until the near eradication of mosquitoes shortly after the second World War. Sardinia has been used in classical studies of the effects of malaria on natural selection, including the prevalence of thalassemia.…”