Not all isolates are equal: linkage disequilibrium analysis on Xq13.3 reveals different patterns in Sardinian sub-populations

Abstract

Recent studies indicate that, whereas the Sardinian population as a whole is comparable to outbred populations for linkage disequilibrium (LD) mapping of common variants, LD in Sardinian sub-isolates is more extended, making these populations particularly suitable for this approach. To evaluate the extent of LD between microsatellite markers, we compared different sub-populations within Sardinia selected on the basis of their geographical position and isolation: two small isolated villages (Talana, Urzulei), two larger but remote areas (Ogliastra, Nuoro province) and a cohort of samples representing the wider Sardinian population. LD analysis was carried out by using six microsatellite markers that are located on Xq13.3 and that have been extensively studied in different populations. We found different extents and patterns of LD in the sub-population samples depending on their degree of isolation and demographic history. All LD measurements and haplotype analyses indicate that there is a decreasing trend from Talana (the most inbred population, LD up to 9.5-11.5 Mb) to the more outbred Sardinian population (LD only for intervals <2 Mb). In one village (Talana), five haplotype classes accounting for 80% of the entire sample perfectly matched five Ogliastra clusters, supporting the origin of the village from the Ogliastra genetic pool. In contrast, the other village (Urzulei) showed a different pattern of haplotypes with a closer relationship to the Nuoro region sub-population. LD analyses therefore show that even neighbouring isolate villages may differ in their genetic background. Here, we highlight the importance of selecting appropriate populations and/or sub-populations for the analysis of complex traits. Isolated sub-populations showing different extents of LD can provide a powerful method for mapping complex traits by LD scanning at relatively low marker density.

Linkage disequilibrium analysis in the genetically isolated Norfolk Island population

“…Average gene diversity estimates for this subset of Norfolk Island individuals indicated that the study population possesses a similar homogeneous genetic architecture when compared to other genetic isolates (Angius et al, 2002a). For comparison purposes, gene diversity values reported in Saami and Finnish samples were included (Laan and Paabo, 1997).…”

“…The pair-wise coefficient of relationship values were interesting since, among the related pairs, most are less than third degree relatives (f 2 ¼ 0.125) (Bellis et al, 2005). However, to avoid upwardly biasing LD results, first and second degree relatives were identified and subsequently removed from the analysis, resulting in a final sample size of 56 men, which is comparable to other population sizes for LD estimates (Angius et al, 2001(Angius et al, , 2002aMarroni et al, 2006). Furthermore, aims of this investigation were to study the descendents of the initial European men and their Tahitian wives and to accurately capture LD patterns within the complex Norfolk Island pedigree.…”

“…To evaluate the extent of LD within the Norfolk isolate we chose six microsatellite markers (DXS983, DXS8092, DXS8082, DXS1225, DXS8037 and DXS986) located in the Xq13.3 region which has been regularly studied for LD estimation in genetic isolates, including in the Finnish, Saami, Sardinina and Brazillian populations (Laan and Paabo, 1997;Kaessmann et al, 1999;Zavattari et al, 2000;Angius et al, 2001Angius et al, , 2002aPereira and Pena, 2006). Primer sequences were obtained from the Genome Database.…”

“…These data were compared to Sardinian isolates from Ogliastra and Talana (Angius et al, 2002a). Allele frequencies were determined by gene counting.…”

“…There are many population isolate studies being investigated-the study populations themselves as diverse as the genetic disorders they are being used to research. European researchers have focused their efforts on historically and culturally distinct populations from Scandinavia including Finland (Peltonen et al, 1999;Varilo et al, 2000Varilo et al, , 2003Wessman et al, 2002) and Iceland (Gulcher and Stefansson, 1998;Helgason et al, 2003), Mediterranean regions of Italy, especially Sardinia (Eaves et al, 2000;Zavattari et al, 2000;Angius et al, 2001Angius et al, , 2002aPugliatti et al, 2003;Falchi et al, 2004;Tenesa et al, 2004) and Corsica, France (Latini et al, 2004). North American isolates have mainly been concerned with large extended pedigrees from, for example, Hutterites (Abney et al, 2000(Abney et al, , 2002Ober et al, 2001;Newman et al, 2003Newman et al, , 2004Weiss et al, 2006), while several remote Polynesian populations are presently involved in disease gene-mapping studies (Redd et al, 1995;Murray-McIntosh et al, 1998;Shmulewitz et al, 2001;Han et al, 2002;Kayser et al, 2003;Wijsman et al, 2003;Tsai et al, 2004;Bonnen et al, 2006).…”