I Evseeva

The Eurasian Heartland: A continental perspective on Y-chromosome diversity

The nonrecombining portion of the human Y chromosome has proven to be a valuable tool for the study of population history. The maintenance of extended haplotypes characteristic of particular geographic regions, despite extensive admixture, allows complex demographic events to be deconstructed. In this study we report the frequencies of 23 Y-chromosome biallelic polymorphism haplotypes in 1,935 men from 49 Eurasian populations, with a particular focus on Central Asia. These haplotypes reveal traces of historical migrations, and provide an insight into the earliest patterns of settlement of anatomically modern humans on the Eurasian continent. Central Asia is revealed to be an important reservoir of genetic diversity, and the source of at least three major waves of migration leading into Europe, the Americas, and India. The genetic results are interpreted in the context of Eurasian linguistic patterns.

People of the British Isles: preliminary analysis of genotypes and surnames in a UK-control population

There is a great deal of interest in a fine-scale population structure in the UK, both as a signature of historical immigration events and because of the effect population structure may have on disease association studies. Although population structure appears to have a minor impact on the current generation of genome-wide association studies, it is likely to have a significant part in the next generation of studies designed to search for rare variants. A powerful way of detecting such structure is to control and document carefully the provenance of the samples involved. In this study, we describe the collection of a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised UK-control population that can be used as a resource by the research community, as well as providing a fine-scale genetic information on the British population. So far, some 4000 samples have been collected, the majority of which fit the criteria of coming from a rural area and having all four grandparents from approximately the same area. Analysis of the first 3865 samples that have been geocoded indicates that 75% have a mean distance between grandparental places of birth of 37.3 km, and that about 70% of grandparental places of birth can be classed as rural. Preliminary genotyping of 1057 samples demonstrates the value of these samples for investigating a fine-scale population structure within the UK, and shows how this can be enhanced by the use of surnames.

Report from the killer immunoglobulin-like receptor (KIR) anthropology component of the 15th International Histocompatibility Workshop: worldwide variation in the KIR loci and further evidence for the co-evolution of KIR and HLA

The killer immunoglobulin-like receptor (KIR) anthropology component of the 15th International Histocompatibility Workshop (IHIWS) sought to explore worldwide population variation in the KIR loci, and to examine the relationship between KIR genes and their human leukocyte antigen (HLA) ligands. Fifteen laboratories submitted KIR genotype and HLA ligand data in 27 populations from six broad ethnic groups. Data were analyzed for correlations between the frequencies of KIR and their known HLA ligands. In addition, allelic typing was performed for KIR2DL2 and 3DL1 in a subset of populations. Strong and significant correlations were observed between KIR2DL2, 2DL3 genotype frequencies and the frequency of their ligand, HLA-C1. In contrast, only weak associations were seen for 3DL1, 3DS1 and the HLA-Bw4 ligand. Although some aspects of the correlations observed here differ from those reported in other populations, these data provide additional evidence of linked evolutionary histories for some KIR and HLA loci. Investigation of allele-level variation for the B haplotype locus KIR 2DL2 showed that two alleles, *001 and *003, predominate in all populations in this study. Much more allelic variation was observed for the A haplotype locus 3DL1, with several alleles observed at moderate frequencies and extensive variation observed between populations.

Linkage disequilibrium and age of HLA region SNPs in relation to classic HLA gene alleles within Europe

The HLA region on chromosome 6 is gene-rich and under selective pressure because of the high proportion of immunity-related genes. Linkage disequilibrium (LD) patterns and allele frequencies in this region are highly differentiated across broad geographical populations, making it a region of interest for population genetics and immunity-related disease studies. We examined LD in this important region of the genome in six European populations using 166 putatively neutral SNPs and the classical HLA-A, -B and -C gene alleles. We found that the pattern of association between classic HLA gene alleles and SNPs implied that most of the SNPs predated the origin of classic HLA gene alleles. The SNPs most strongly associated with HLA gene alleles were in some cases highly predictive of the HLA allele carrier status (misclassification rates ranged from <1 to 27%) in independent populations using five or fewer SNPs, a much smaller number than tagSNP panels previously proposed and often with similar accuracy, showing that our approach may be a viable solution to designing new HLA prediction panels. To describe the LD within this region, we developed a new haplotype clustering method/software based on r2, which may be more appropriate for use within regions of strong LD. Haplotype blocks created using this proposed method, as well as classic HLA gene alleles and SNPs, were predictive of a northern versus southern European population membership (misclassification error rates ranged from 0 to 23%, depending on which independent population was used for prediction), indicating that this region may be a rich source of ancestry informative markers.

Analysis of FMR1 (CGG) n alleles and DXS548-FRAXAC1 haplotypes in three European circumpolar populations: traces of genetic relationship with Asia

Fragile X syndrome, the most common form of inherited mental retardation, is caused by expansion of a (CGG)n repeat located in the FMR1 gene. The molecular factors involved in the mutation process from stable (CGG)n alleles towards unstable alleles are largely unknown, although family transmission studies and population studies have suggested that loss of AGG interruptions in the (CGG)n repeat is essential. We have analysed the AGG interspersion pattern of the FMR1 (CGG)n repeat and the haplotype distribution of closely located microsatellite markers DXS548 and FRAXAC1, in three circumarctic populations: Norwegians, Nenets and Saami. The data confirm the conservation, reported in all human populations studied so far, of an AGG interruption for each 9–10 CGG and support the stabilising effect of AGG interruptions. The data also indicate the existence of chromosomes of Asian origin in the Saami and Nenets population, thereby confirming a genetic relationship between Northern Europe and Asia. DXS548-FRAXAC1 haplotype frequencies were compared between 24 Norwegian fragile X males and 119 normal males. Significant linkage disequilibrium were found between the fragile X mutation and haplotype 6-4 and between normal (CGG)n alleles and haplotype 7-3.