Testing neutrality at copy-number-variable loci under the finite-allele and finite-site models

Copy-number variation (CNV) is an important form of DNA structural variation because a certain proportion of genomes in many eukaryotic species can contribute to such variations. Owing to the differences between CNVs and single nucleotide polymorphisms (SNPs) in size, mutation rate and maintaining mechanism, it is more realistic to characterize CNV evolution under the finite-allele and finite-site models. Here, we propose a method to test multiple CNVs neutrality under the finite-allele and finite-site models and the assumption of mutation-drift process. The statistical property of the method is evaluated through Monte Carlo simulations under the effects of the sample size, the scaled mutation rates, the number of CNVs, the population demographic change, and selection. Different from Tajima's D test, a bootstrap or a permutation approach is suggested to conduct a neutrality test. Application of this method is illustrated using the diploid CNV genotypes measured in discrete copy numbers in 11 HapMap phase III populations. The results show that the mutation-drift process can explain the variation of genome-wide CNVs among 1184 individuals (856 CNVs, ∼0.02Mb on average in size), irrespective of the historical demographic changes. Patterns from allele-frequency-spectrum analysis also support the hypothesis of neutral CNVs. Our results suggest that most human chromosomal changes in healthy individuals via unbalanced rearrangements of the segments with certain sizes are neutral.