The distribution and most recent common ancestor of the 17q21 inversion in humans.

The polymorphic inversion on 17q21, sometimes called the microtubular associated protein tau (MAPT) inversion, is an approximately 900 kb inversion found primarily in Europeans and Southwest Asians. We have identified 21 SNPs that act as markers of the inverted, i.e., H2, haplotype. The inversion is found at the highest frequencies in Southwest Asia and Southern Europe (frequencies of approximately 30%); elsewhere in Europe, frequencies vary from < 5%, in Finns, to 28%, in Orcadians. The H2 inversion haplotype also occurs at low frequencies in Africa, Central Asia, East Asia, and the Americas, though the East Asian and Amerindian alleles may be due to recent gene flow from Europe. Molecular evolution analyses indicate that the H2 haplotype originally arose in Africa or Southwest Asia. Though the H2 inversion has many fixed differences across the approximately 900 kb, short tandem repeat polymorphism data indicate a very recent date for the most recent common ancestor, with dates ranging from 13,600 to 108,400 years, depending on assumptions and estimation methods. This estimate range is much more recent than the 3 million year age estimated by Stefansson et al. in 2005.

A global view of the OCA2-HERC2 region and pigmentation.

Mutations in the gene OCA2 are responsible for oculocutaneous albinism type 2, but polymorphisms in and around OCA2 have also been associated with normal pigment variation. In Europeans, three haplotypes in the region have been shown to be associated with eye pigmentation and a missense SNP (rs1800407) has been associated with green/hazel eyes (Branicki et al. in Ann Hum Genet 73:160-170, 2009). In addition, a missense mutation (rs1800414) is a candidate for light skin pigmentation in East Asia (Yuasa et al. in Biochem Genet 45:535-542, 2007; Anno et al. in Int J Biol Sci 4, 2008). We have genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region including those previously associated with eye or skin pigmentation. We report that the blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe; however, one is restricted to Europe and surrounding regions, while the other two are found at moderate to high frequencies throughout the world. We also observed that the derived allele of rs1800414 is essentially limited to East Asia where it is found at high frequencies. Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems but not for the green/hazel eye SNP allele. We also saw evidence of selection at the derived allele of rs1800414 in East Asia. Our data suggest that the haplotype restricted to Europe is the strongest marker for blue eyes globally and add further inferential evidence that the derived allele of rs1800414 is an East Asian skin pigmentation allele.

Pilot study on schizophrenia in Sardinia.

OBJECTIVE: Based on a small sample of cases with schizophrenia and control individuals from an isolated population, a genome-wide association study was undertaken to find variants conferring susceptibility to this disease. METHODS: Standard association tests were employed, followed by newer multilocus association methods (genotype patterns). RESULTS: Individually, no variant produced a significant result. However, the best two variants (rs1360382 on chromosome 9 and rs1303 on chromosome 14) showed significantly different genotype pattern distributions between patients and control individuals. The risk genotype pattern AA-TT is highly predictive of schizophrenia, with estimated sensitivity and specificity of 1 and 0.96, respectively. CONCLUSIONS: These findings support the hypothesis that schizophrenia is partly due to multiple genetic variants, each with a relatively small effect.

A 9.1-kb gap in the genome reference map is shown to be a stable deletion/insertion polymorphism of ancestral origin.

We show a mute 9.1-kb gap in the human genome reference map, unraveled by RDA studies, to be a worldwide deletion/insertion polymorphism of stable type. The molecular and population data presented suggest its origin from a unique ancestral transposition event in chromosomal region 22q11.2, overlapping the IglambdaV genes at about 450 kb from the cluster of the IglambdaJ-C genes. These findings are not meant to be just another report of a polymorphic marker suitable for population studies. Rather, we wish to stress that a large number of inborn mute gaps may be spread all over the genome and that the many RDA-detected microdeletions already available are efficient tools for the discovery of this otherwise hidden category of genetic variation. Apart from their possible impact on expression of structural genes, mute gaps must be filled for the reference map of our genome to be truly completed.