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

Abstract

Sardinia has been used for genetic studies because of its historical isolation, genetic homogeneity and increased prevalence of certain rare diseases. Controversy remains concerning the genetic substructure and the extent of genetic homogeneity, which has implications for the design of genome-wide association studies (GWAS). We revisited this issue by examining the genetic make-up of a sample from North-East Sardinia using a dense set of autosomal, Y chromosome and mitochondrial markers to assess the potential of the sample for GWAS and fine mapping studies. We genotyped individuals for 500K single-nucleotide polymorphisms, Y chromosome markers and sequenced the mitochondrial hypervariable (HVI-HVII) regions. We identified major haplogroups and compared these with other populations. We estimated linkage disequilibrium (LD) and haplotype diversity across autosomal markers, and compared these with other populations. Our results show that within Sardinia there is no major population substructure and thus it can be considered a genetically homogenous population. We did not find substantial differences in the extent of LD in Sardinians compared with other populations. However, we showed that at least 9% of genomic regions in Sardinians differed in LD structure, which is helpful for identifying functional variants using fine mapping. We concluded that Sardinia is a powerful setting for genetic studies including GWAS and other mapping approaches.

Sardinians Genetic Background Explained by Runs of Homozygosity and Genomic Regions under Positive Selection

“…In our knowledge, only one study has previously assessed genome-wide patterns of homozygosity in the Sardinian population [5]. Although the criteria used for the identification of RoHs are slightly different between the present study and that of Pardo and colleagues, the results of the two studies are consistent.…”

“…In general, Sardinia appears characterized by a large internal homogeneity [5], [7], like all isolated populations, even though other investigators suggested the presence of genetically different subpopulations in the island [6], [48]. Recently several genome-wide studies have been performed on Sardinian population taking advantage of the genetic homogeneity of the island using also large cohort of individuals [49], [50], [51], [52], [53].…”

Uniparental Markers in Italy Reveal a Sex-Biased Genetic Structure and Different Historical Strata

“…Previous reconstructions of the genetic structure of Italy agreed on two points: the peculiarity of the population of Sardinia – due to a distinct background and a high degree of isolation [58], [59] – and the clinal pattern of variation in the Italian Peninsula, which has been explained by differential migration patterns [17], [18] although some genetic discontinuity due to local drift and founder effects have been described [16], [19], [20]. This study represents a significant upgrade on the knowledge of the genetic structure of Italy for the following reasons: the wide sampling coverage (coupled to a detailed sampling strategy), the high number of typed markers and the innovative methodological approach.…”

Genetic structure of the Newfoundland and Labrador population: founder effects modulate variability

“…[15][16][17][18] These have revealed distinct genetic structures that can provide guidance on using these populations for mapping the genes for complex diseases. We decided to examine the genetic structure and founder effects within the NL population by comparing genome-wide SNP data with that from Irish, British, Native American and other HapMap3 populations.…”