ESHG 2009 abstracts

ESHG 2009 is in two weeks, and there are some very interesting abstracts, including a tantalizing new study on Y-chromosome haplogroup R1b1b2 (R-M269).

Phylogeography of human Y chromosome haplogroup R1b1b2 (R-M269) in Europe

F. Cruciani et al.

The human Y chromosome haplogroup R1b1b2 (R-M269) displays an extremely wide geographic distribution within Europe, with a decreasing frequency cline from Iberia (frequencies up to 90%) towards the Balkans (usually less than 10%). Previous studies have proposed that the observed R1b1b2 frequency cline is due to a population expansion from an Iberian Ice-age refugium after the LGM (Malaspina et al. 1998; Semino et al. 2000).

In this study, we explored the phylogeography of the human Y chromosome haplogroup R1b1b2 by analyzing more than 2,000 males from Europe. The haplogroup-defining marker M269 (Cruciani et al. 2002), and two additional internal markers (U106 and U152, Sims et al 2007) which identify internal branches (R1b1b2g and R1b1b2h) were analyzed. The paragroup R1b1b2*(xR1b1b2g, R1b1b2h) and the haplogroups R1b1b2g and R1b1b2h showed quite different frequency distribution patterns within Europe, with frequency peaks in the Iberian Peninsula, northern Europe and northern Italy/France, respectively. The overall frequency pattern of R1b1b2 haplogroup is suggestive of multiple events of migration and expansion within Europe rather than a single and uniform spread of people from an Iberian Ice-age refugium.

References:

Malaspina et al. (1998) Am J Hum Genet 63:847-860
Semino et al. (2000) Science 290:1155-1159
Cruciani et al. (2002) Am J Hum Genet 70:1197-1214
Sims et al. (2007) Hum Mutat 28:97

Note that in the abstract below, the authors refer to Slavopaionians, not Macedonians.

Y chromosome haplogroup R1a is associated with prostate cancer risk among Macedonian males

D. Plaseska-Karanfilska et al.

Prostate cancer (PC) is one of the most common male-specific cancers. Its incidence varies considerably between populations. Recent surveys suggest that PC is influenced by both genetic and environmental factors, although the etiology of the disease remains unknown in the majority of cases. Certain Y chromosomal lineages have been suggested to predispose individuals to prostate cancer in Japanese population, but no association has been found among Korean and Swedish patients. The aim of this study was to investigate the association between Y chromosomal haplogroups and predisposition to prostate cancer in Macedonian men. We studied 84 PC patients and 126 males from the general population of Macedonian ethnic origin. A total of 28 markers have been studied by multiplex PCR and SNaPshot analysis. Nineteen different Y haplogroups were determined; the most frequent being I1b-P37b, E3b1-M78, R1a-SRY 1532, R1b-P25 and J2b1a-M241. The frequency of R1a was significantly higher in PC patients (20.2%) in comparison with the controls (9.5%) [p=0.027; OR=2.41 (1.09-5.36)]. When stratified according to age, even stronger association was observed between haplogroup R1a and prostate cancer in patients of >65 years of age [p=0.004; OR=3.24 (1.41-7.46)]. Our results suggest that Y chromosome haplogroup R1a is associated with an increased prostate cancer risk in Macedonian men.

The genetic position of Western Brittany (Finistère, France) in the Celtic Y chromosome landscape

K. Rouault et al.

Brittany, a large peninsula located at the western part of France, is of particular interest because of its historical settlement and its relative geographic and cultural isolation. Brittany was invaded by waves of migration from Britain and Ireland between the 4th and 7th centuries and, therefore, belongs to the Brythonic branch of the Insular Celtic language. We have focused our study on the department of Finistère, the most western territorial unit of Brittany, and its administrative and historical areas. To explore the diversity of the Y-chromosome, we analyzed a total of 348 unrelated males using a combination of 23 biallelic markers and 12 microsatellite loci. The molecular analysis revealed that 82.2% of the Y chromosomes fell into haplogroup R1b, placing Finistère within the Western European landscape. Interestingly, at a microgeographical level, differences were detected by the haplogroup R1a* being confined to the south of the department, while haplogroups E3b, F, G, J2, K and R1a1 were found in the north. Nevertheless, geographical distribution of haplogroups and haplotypes suggested territorial homogeneity inside Finistère. Most of the Y-chromosomal gene pool in Finistère is shared with European, especially British, populations, thus corroborating the historical reports of ancient migrations to Brittany. Finally, the results are consistent with those obtained from classic genetic markers and support the Celtic paternal heritage of the Finistère population.

Mitochondrial Genome Diversity in Tungusic-speaking Populations (Even and Evenki) and Resettlement of Arctic Siberia After the Last Glacial Maximum

I. O. Mazunin et al.

The present study includes the Even/Evenki, hunters and reindeer-breeders, sampled from a few localities scattered across their vast geographic range encompassing low Yana-Indigirka-Kolyma in the west and the Sea of Okhotsk coast in the east. The mtDNA data show a very close affinity of the Even/Evenki with the Yukaghir, typical reindeer hunters, dominating in extreme northeastern Siberia until the middle of 18th century but now being on the brink of extinction. We found that the majority of mtDNA diversity in the Tungusic-speaking populations was accounted for by Siberian-East Eurasian lineages C2, C3, D2, D3, D4-D9 and G1. The similarity in the haplogroup C and D mtDNA intrinsic variation between the Even and Yukaghir populations is pronounced and indicates that the Even/Evenki harbor an essential portion of the ancestral Yukaghir pool. The phylogeography of the D4-D9 point to an early Neolithic phase expansion initiated northward to the northern and eastern perimeters of former Beringia. Concerning unique D2* lineage (Volodko et al. 2008), the network analysis encompassing four complete sequences, three of the Yukaghir from the low Indigirka-Kolyma region and one of the Evenk from the upper reaches of the Aldan River would suggest that the founding haplotype (1935-8683-14905) for D2* originated within western part of former Beringia. In the meanwhile, the core of the Even/Evenki mtDNA pool residing in the midst of the Yukaghir ancient territory would represent a recent amalgamation of the remnants of the Yukaghir and northern Tungusic-speakers (Even/Evenki) originated in the mid-Amur region.

X-chromosomal haplotypes in global human populations

V. A. Stepanov, I. Y. Khitrinskaya;

To reconstruct the origin and evolution of X-chromosomal lineages in global human populations we investigated the genetic diversity in 23 population samples (about 1500 individuals totally) using SNP markers in a single linkage disequilibrium region of ZFX gene. About sixty haplotypes belonging to 3 phylogenetic branches (A, B, and F) originated from the single African root were found in the total sample. Branch A includes mostly African haplotypes, whereas four major haplotypes belonging to different sub-branches of B (haplotype E8) and F (haplotypes H4, I3 and I11) were present in Eurasia. Major haplotype of the older branch B (E8) is almost evenly distributed among Eurasian populations. Haplotypes of the younger phylogenetic branches demonstrates clinal distribution with the sharp frequency changes from East to West. Haplotype H4 is presumably “Eastern-Eurasian”. It reaches the highest frequency in Eastern and South-Eastern Asians. Haplotypes I3 and I11 in the contrary show the clear frequency gradient from West to East with the highest frequency in Europeans, moderate frequency in Central Asia, and the minimal frequency in North-East and South-East Asia. The total level of genetic differentiation of global human populations estimated by the analysis of molecular variance of X-chromosomal haplotypes (Fst = 9.1%) is quite high and roughly corresponds to those measured for most other types of genetic markers except Y-chromosomal haplogroups which are characterized by the much higher level of between-population differences.

Dissecting the genetic make-up of Central Eastern Sardinia using a high density set of sex and autosomal markers

L. M. Pardo

Genetic isolates are valuable for identifying genetic variations underlying complex traits. However, prior knowledge of the genetic structure of the isolate is fundamental for carrying-out genome-wide association studies (GWAS) in these populations. The Sardinian population is currently the target of GWAS because of its ancient origin and long-standing isolation. To perform GWAS in Sardinia, we aim to characterize a subpopulation from the archaic area of Central-Eastern Sardinia at the genomic level. We used sex-specific markers (Y-chromosome and mtDNA) to assess the heterogeneity of the founder lineages and the divergence from other populations. In addition, we used a dense set of autosomal markers (SNP 5.0 array, Affymetrix) to investigate genome-wide Linkage Disequilibrium, to construct a Copy Number Variation map and to estimate pair-wise kinship and inbreeding.We first determined Y-chromosome lineages in 256 unrelated Sardinians using biallelic and microsatellite markers. Our analysis showed that the frequency of the major Y haplogroups clearly sets this population apart from other European haplogroups. The analysis of microsatellite markers revealed a high degree of gene diversity. Pairwise kinship and inbreeding were estimated in 113 subjects using 77709 autosomal SNP markers. We found that 16% of the subject pairs shared identical-by descent alleles more often than expected by chance. Furthermore, 60% of the subjects had low inbreeding coefficient values. Our preliminary results confirm that Sardinia is genetically different from other populations, as shown by Y-chromosome markers. The kinship and inbreeding estimates indicate some degree of relatedness among Sardinians, as expected for an isolated population.

Genetic differences between four European populations

V. Moskvina et al.

Population stratification can distort the results of genome-wide association studies (GWAS). One approach to deal with this inflation of the statistic is to estimate the inflation factor and adjust the detection statistic accordingly. However, the evolutionally forces work with different strength in some regions of the human genome, e.g. around the lactase gene (LCT) and the HLA region, making such an adjustment inappropriate.

We examined the population differences in four European populations (Scotland, Ireland, Sweden and Bulgaria) using data from GWAS performed with the Affymetrix 6.0 array at the Broad Institute. We show that there are >20,000 SNPs which are highly (p less than 10-6) significantly stratified between the four populations, after genome wide Bonferroni correction for multiple testing. We then examined the top 20 stratified regions to see what genes might have caused the top differences, using a highly conservative cut-off of p less than 10-40. Some of the loci span genes reported before: hair colour and pigmentation (HERC2, EXOC2), the LCT gene, genes involved in NAD metabolism, and genes involved in immunity (HLA and the Toll-like receptor genes TLR10, TLR 1, TLR 6). Among the top hits were several genes which have not yet been reported as stratified within European populations, indicating that they might also provide a selective advantage. Some involve other immunity genes (CD99, ILT6), but others show no obvious effect on positive selection: several zinc fingers, and most intriguingly, FOXP2, implicated in speech development. Future GWAS should take into consideration any positive associations with these genes.

Genomic runs of homozygosity: population history and disease

R. McQuillan

Runs of homozygosity (ROH), resulting from the inheritance from both parents of identical haplotypes, are abundant in the human genome. ROH length is determined partly by the number of generations since the common ancestor: offspring of cousin matings have long ROH, while the numerous shorter ROH reflect shared ancestry tens and hundreds of generations ago. In studies of European populations we show that Froh, a multipoint estimate of individual autozygosity derived from genomic ROH, distinguishes clearly between subpopulations classified in terms of demographic history and correlates strongly with pedigree-derived inbreeding coefficients. In a global population dataset, analysis of ROH allows categorisation of individuals into four major groups, inferred to have (a) parental relatedness in the last 150 years (many south and west Asians), (b) shared parental ancestry arising hundreds to thousands of years ago through population isolation and restricted effective population size (Ne), but little recent inbreeding (Oceanians, African hunter-gatherers, some European and south Asian isolates), (c) both ancient and recent parental relatedness (Native Americans), and (d) only the background level of shared ancestry relating to continental Ne (east Asians, urban Europeans; African agriculturalists). Long runs of homozygosity are therefore a widespread and underappreciated characteristic of our genomes which record past consanguinity and population isolation and provide a unique record of individual demographic history. Individual ROH measures also allow quantification of the disease risk arising from polygenic recessive effects. We present preliminary data from a survey of the effects of ROH on quantitative disease-related traits and disease risk.

European Lactase Persistence Allele is Associated With Increase in Body Mass Index

J. A. Kettunen et al.

The global prevalence of obesity, usually indexed by body mass index (BMI) cut-offs, has increased significantly in the recent decades, mainly due to positive energy balance. However, the impact of a selection for specific genes cannot be excluded. Here we have tested the association between BMI and one of the best known genetic variants showing strong selective pressure: the functional variant in the cis-regulatory element of the lactase gene. We tested this variant since it is presumed to provide nutritional advantage in specific physical and cultural environments. We found that the variant responsible for lactase persistence among Europeans was also associated with higher BMI in a Nordic population sample (p = 1.3*10-5) of 15 209 individuals, the size of the effect being close to that of FTO. We tested the effect of population stratification and concluded that the association was not due to population substructure.