Quantitative Analysis of Single Nucleotide Polymorphisms within Copy Number Variation

Soohyun Lee,Charles R Cantor,Zhiping Weng,Simon Kasif,Richard Mayeux

doi:10.1371/journal.pone.0003906

Abstract

BackgroundSingle nucleotide polymorphisms (SNPs) have been used extensively in genetics and epidemiology studies. Traditionally, SNPs that did not pass the Hardy-Weinberg equilibrium (HWE) test were excluded from these analyses. Many investigators have addressed possible causes for departure from HWE, including genotyping errors, population admixture and segmental duplication. Recent large-scale surveys have revealed abundant structural variations in the human genome, including copy number variations (CNVs). This suggests that a significant number of SNPs must be within these regions, which may cause deviation from HWE.ResultsWe performed a Bayesian analysis on the potential effect of copy number variation, segmental duplication and genotyping errors on the behavior of SNPs. Our results suggest that copy number variation is a major factor of HWE violation for SNPs with a small minor allele frequency, when the sample size is large and the genotyping error rate is 0∼1%.ConclusionsOur study provides the posterior probability that a SNP falls in a CNV or a segmental duplication, given the observed allele frequency of the SNP, sample size and the significance level of HWE testing.

Highlights

Assuming that there is no null-allele individual, we propose that a biallelic copy number variations (CNVs) assumption is a good start for quantitative modeling
In order to deal with multiallelic CNVs, more parametric assumptions are required such as how sequence variations are distributed across different copies
Probability that an Hardy-Weinberg equilibrium (HWE)-violating Single nucleotide polymorphism (SNP) is in a CNV Our results suggest that copy number variation can be a major contributor to HWD, even assuming the tendency towards small variant frequencies of CNV, especially at a low observed SNP

Summary

Introduction

1. Single nucleotide polymorphism (SNP) and HardyWeinberg equilibrium (HWE). Single nucleotide polymorphisms (SNPs) are common biallelic variations that are widely used as genetic markers in linkage analyses and association studies[1]. Most human SNPs satisfy the Hardy-Weinberg equilibrium (HWE), the condition of allelic independence, in which allele frequencies and genotype frequencies do not change over generations[2,3]. Many investigators have addressed possible causes for departure from HWE, including genotyping errors, population admixture and segmental duplication. Recent large-scale surveys have revealed abundant structural variations in the human genome, including copy number variations (CNVs). This suggests that a significant number of SNPs must be within these regions, which may cause deviation from HWE

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