Ascertainment Bias and the Pattern of Nucleotide Diversity at the Human ALDH2 Locus in a Japanese Population
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Many East Asian human populations harbor a high-frequency deficiency allele for the aldehyde dehydrogenase 2 (ALDH2) enzyme, a critical protein involved in the metabolism of ethanol. Here we use resequencing and long-range SNP haplotype data from a Japanese sample to test whether patterns of nucleotide diversity and linkage disequilibrium at this locus are compatible with a standard neutral model of evolution. Examination of the pattern of polymorphism at a locus such as this, where the frequency of a common allele is known a priori, introduces an ascertainment bias that must be corrected for in analyses of the frequency spectrum of polymorphisms. We apply a flexible and generally applicable simulation approach to correct for this bias in our ALDH2 data and, also, to explore the effect of bias on the commonly used summary statistics Tajima’s D, Fu and Li’s D, and Fay and Wu’s H. Our study finds no evidence that the pattern of genetic variation at ALDH2 differs from that expected under a standard neutral model. However, our general examination of ascertainment bias indicates that a priori knowledge of segregating alleles greatly affects the expected distributions of summary statistics. Under many parameter combinations we find that ascertainment bias introduces an elevated rate of false positives when summary statistics are used to test for deviations from a standard neutral model. However, we also show that over a wide range of conditions the power of all summary statistics can be greatly increased by incorporating prior knowledge of segregating alleles.
KeywordsALDH2 Aldehyde dehydrogenase deficiency Ascertainment bias Natural selection Nucleotide diversity
We express our appreciation to M. Hammer, members of the Hammer lab, and A. Stump for useful discussion and D. Garrigan for assistance with data analysis. The manuscript benefited greatly from the comments of two anonymous reviewers. This work was made possible by a Sigma Xi Grant-in-Aid of Research to B.T.B. and a National Science Foundation grant and funds from Williams College to J.A.W.
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