Superimposing Polymorphism: The Case of a Point Mutation within a Polymorphic Alu Insertion

The COL3A1 Alu insertion is a member of the AluY subfamily. It has been found to be absent in non-human primates and polymorphic in worldwide human populations. The integration of the element into the human genome seems to have preceded the initial migration(s) of anatomically modern humans out of the African continent. Although the insertion has been detected in populations from all the continents, its highest frequency values are located within sub-Saharan Africa. The sequence alignment of the COL3A1 insertion from several African individuals revealed a bi-allelic single nucleotide polymorphism (SNP) at the downstream terminus of the element’s poly-A tract. Once discovered, a selective PCR procedure was designed to determine the frequency of both alleles in 19 worldwide populations. The A-allele in this binary SNP experiences a clinal increase in the eastward direction from Africa to Southeast Asia and Mongolia, reaching fixation in the two latter regions. The T variant, on the other hand, exhibits a westward clinal increase outside of Africa, with its lowest frequency in Asia and achieving fixation in northern Europe. The presence of this internal SNP extends the usefulness provided by the polymorphic Alu insertion (PAI). It is possible that superimposing polymorphisms like this one found in the COL3A1 locus may accentuate signals from genetic drift events allowing for visualization of recent dispersal patterns

The BRCA1 Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies

BackgroundWe studied linkage disequilibrium (LD) patterns at the BRCA1 locus, a susceptibility gene for breast and ovarian cancer, using a dense set of 114 single nucleotide polymorphisms in 5 population groups. We focused on Ashkenazi Jews in whom there are known founder mutations, to address the question of whether we would have been able to identify the 185delAG mutation in a case-control association study (should one have been done) using anonymous genetic markers. This mutation is present in approximately 1% of the general Ashkenazi population and 4% of Ashkenazi breast cancer cases. We evaluated LD using pairwise and haplotype-based methods, and assessed correlation of SNPs with the founder mutations using Pearson's correlation coefficient.ResultsBRCA1 is characterized by very high linkage disequilibrium in all populations spanning several hundred kilobases. Overall, haplotype blocks and pair-wise LD bins were highly correlated, with lower LD in African versus non-African populations. The 185delAG and 5382insC founder mutations occur on the two most common haplotypes among Ashkenazim. Because these mutations are rare, even though they are in strong LD with many other SNPs in the region as measured by D-prime, there were no strong associations when assessed by Pearson's correlation coefficient, r (maximum of 0.04 for the 185delAG).ConclusionSince the required sample size is related to the inverse of r, this suggests that it would have been difficult to map BRCA1 in an Ashkenazi case-unrelated control association study using anonymous markers that were linked to the founder mutations

The Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies-1

<p><b>Copyright information:</b></p><p>Taken from "The Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies"</p><p>http://www.biomedcentral.com/1471-2156/8/68</p><p>BMC Genetics 2007;8():68-68.</p><p>Published online 4 Oct 2007</p><p>PMCID:PMC2093936.</p><p></p>wn true size. Anchor lines link to position of the SNP within the region. B-F) LDSelect creates bins of SNPs that have an value of 0.8 or greater with at least one other SNP in the bin. Each vertical line and arrowhead represents a SNP, with dashed lines and shaded background connecting SNPs within the same bin. Down arrowheads indicate Tag SNPs (those with ≥ 0.8 with all other SNPs in a bin). Note that this use of the term Tag-SNP is different from Haploview – with LDSelect, only one Tag-SNP per bin would be required to capture the majority of the nucleotide diversity. Singleton bins (SNPs that did not have ≥ 0.8 with any other SNP) are indicated by solid dots on a single row. SNP number refers to numbering in column 1 of Table 1

The Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies-0

<p><b>Copyright information:</b></p><p>Taken from "The Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies"</p><p>http://www.biomedcentral.com/1471-2156/8/68</p><p>BMC Genetics 2007;8():68-68.</p><p>Published online 4 Oct 2007</p><p>PMCID:PMC2093936.</p><p></p>e indicated by arrowheads; htSNPs in only one population are shown on a yellow background while the single htSNP shared between all populations is shown on a green background