Ascertainment Bias and the Pattern of Nucleotide Diversity at the Human ALDH2 Locus in a Japanese Population |
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Authors: | Benjamin T Brown August Woerner Jason A Wilder |
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Institution: | (1) Department of Biology, Williams College, Williamstown, MA 01267, USA;(2) Division of Biotechnology, University of Arizona, Tucson, AZ 85721, USA |
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Abstract: | 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.
Reviewing Editor: Dr. Martin Kreitman] |
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Keywords: | ALDH2 Aldehyde dehydrogenase deficiency Ascertainment bias Natural selection Nucleotide diversity |
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