Serafim Batzoglou (Stanford University): By analyzing polymorphisms in the admixed individual against those seen in representatives from the populations, we can infer the ancestral source of the individual’s haploblocks. In this paper we describe a novel approach for ancestry inference, HAPAA (HMM-based analysis of polymorphisms in admixed ancestries), that models the allelic and haplotypic variation in the populations and captures the signal of correlation due to linkage disequilibrium, resulting in greatly improved accuracy. We also introduce a methodology for evaluating the effect of genetic divergence between ancestral populations and time-to-admixture on inference accuracy. Using HAPAA, we explore the limits of ancestry inference in closely related populations. Software: HAPAA

Lluís Quintana-Murci (Institut Pasteur): To investigate the role of population history and natural selection in shaping NATs variation, we characterized genetic diversity through the resequencing and genotyping of NAT1, NAT2, and the pseudogene NATP in a collection of 13 different populations with distinct ethnic backgrounds and demographic pasts. Our data revealed the reduced diversity observed at NAT1 is consistent with the action of purifying selection, whereas NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular NAT2 haplotype (NAT2*5B) under recent positive selection in western/central Eurasians. This haplotype harbors the mutation 341T→C and encodes the “slowest-acetylator” NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Interestingly, the NAT2*5B haplotype, which seems to have conferred a selective advantage during the past ~6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions.

David Curtis (Royal London Hospital): To determine whether haplotype frequencies differ significantly between cases and controls, the correct approach is to perform a heterogeneity test, in which one calculates whether the overall likelihood is significantly higher if different frequencies are allowed than if the same frequencies apply to both groups. An incorrect approach is to estimate haplotype counts by multiplying the frequencies by twice the sample size and then to treat these counts as if they were actually observed.

Andrew Fry (The Wellcome Trust Centre for Human Genetics): A new allele that arises by mutation will lie on a single haplotype, but, over time, the extensive linkage disequilibrium (LD) between the new allele and other markers on this ancestral haplotype breaks down as a result of recombination. Decay of LD around a target allele is considered to be a stopwatch by which its age can be estimated. Using simulations and empirical data from the International HapMap Project, we show that a simple pairwise metric of haplotype homozygosity gives significantly higher mean values for human single-nucleotide–polymorphism alleles that appear to be derived than for those that appear to be ancestral, as determined by comparison with the chimpanzee genome. Our results support the use of haplotype-based techniques, such as extended haplotypic homozygosity, to assess the age of alleles.

Leena Peltonen (National Public Health Institute, Finland): The T−13910 variant located in the enhancer element of the lactase (LCT) gene correlates perfectly with lactase persistence (LP) in Eurasian populations whereas the variant is almost nonexistent among Sub-Saharan African populations, showing high prevalence of LP. Here, we report identification of two new mutations (T/G−13915 within the −13910 enhancer region and a synonymous SNP in the exon 17 of the MCM6 gene T/C−3712, −3712 bp from the LCT gene) among Saudis, also known for the high prevalence of LP. The European T−13910 and the earlier identified East African G−13907 LP allele share the same ancestral background and most likely the same history, probably related to the same cattle domestication event. In contrast, the compound Arab allele shows a different, highly divergent ancestral haplotype, suggesting that these two major global LP alleles have arisen independently, the latter perhaps in response to camel milk consumption. These results support the convergent evolution of the LP in diverse populations, most probably reflecting different histories of adaptation to milk culture.

Nicholas Schork (University of California at San Diego): We describe a regression method that can be used to relate variation in the measure of genomic dissimilarity (or “distance”) among a set of individuals to variation in their trait values. Weighting factors associated with functional or evolutionary conservation information of the loci can be used in the assessment of similarity. The proposed method is very flexible and is easily extended to complex multilocus-analysis settings involving covariates. In addition, the proposed method actually encompasses both single-locus and haplotype-phylogeny analysis methods, which are two of the most widely used approaches in genetic association analysis.

Pamela Sklar (Massachusetts General Hospital): Using this high-density reference map, we compared the putative disease-associated haplotype from each study and found that the association studies are inconsistent with regard to the identity of the disease-associated haplotype at DTNBP1. Specifically, all five “replication” studies define a positively associated haplotype that is different from the association originally reported. We further demonstrate that, in all six studies, the European-derived populations studied have haplotype patterns and frequencies that are consistent with HapMap CEU samples (and each other). Thus, it is unlikely that population differences are creating the inconsistency of the association studies.

Lin He (Shanghai Jiao Tong University): First, using case-control and transmission/disequilibrium–test (TDT) methodologies, we detected a significant association between schizophrenia and haplotypes within the promoter region of CHI3L1 in two independent cohorts of Chinese individuals. Second, the at-risk CCC haplotype (P=.00058 and .0018 in case-control and TDT studies, respectively) revealed lower transcriptional activity (P=2.2×10-7) and was associated with lower expression (P=3.1×10-5) compared with neutral and protective haplotypes. Third, we found that an allele of SNP4 (rs4950928), the tagging SNP of CCC, impaired the MYC/MAX–regulated transcriptional activation of CHI3L1 by altering the transcriptional-factor consensus sequences, and this may be responsible for the decreased expression of the CCC haplotype. In contrast, the protective TTG haplotype was associated with a high level of CHI3L1 expression.

Richard Sturm (University of Queensland, Australia): Fifty-eight synonymous and nonsynonymous exonic single-nucleotide polymorphisms (SNPs) and tagging SNPs were typed in a collection of 3,839 adolescent twins, their siblings, and their parents. The highest association for blue/nonblue eye color was found with three OCA2 SNPs: rs7495174 T/C, rs6497268 G/T, and rs11855019 T/C (P values of 1.02×10-61, 1.57×10-96, and 4.45×10-54, respectively) in intron 1. These three SNPs are in one major haplotype block, with TGT representing 78.4% of alleles. The TGT/TGT diplotype found in 62.2% of samples was the major genotype seen to modify eye color, with a frequency of 0.905 in blue or green compared with only 0.095 in brown eye color.

Kenneth Kidd (Yale University): Data consisted of 54 single-nucleotide polymorphisms (SNPs) across the ADH clusters in a global sampling of 42 populations. Both the Fst statistic and the long-range haplotype (LRH) test provided positive evidence of selection in several East Asian populations. The ADH1B Arg47His functional polymorphism has the highest Fst of the 54 SNPs in the ADH cluster, and it is significantly above the mean Fst of 382 presumably neutral sites tested on the same 42 population samples. The LRH test that uses cores including that site and extending on both sides also gives significant evidence of positive selection in some East Asian populations for a specific haplotype carrying the ADH1B*47His allele. Interestingly, this haplotype is present at a high frequency in only some East Asian populations, whereas the specific allele also exists in other East Asian populations and in the Near East and Europe but does not show evidence of selection with use of the LRH test.