Population genetics of immune-related multilocus copy number variation in Native Americans

Abstract

While multiallelic copy number variation (mCNV) loci are a major component of genomic variation, quantifying the individual copy number of a locus and defining genotypes is challenging. Few methods exist to study how mCNV genetic diversity is apportioned within and between populations (i.e. to define the population genetic structure of mCNV). These inferences are critical in populations with a small effective size, such as Amerindians, that may not fit the Hardy-Weinberg model due to inbreeding, assortative mating, population subdivision, natural selection or a combination of these evolutionary factors. We propose a likelihood-based method that simultaneously infers mCNV allele frequencies and the population structure parameter , which quantifies the departure of homozygosity from the Hardy-Weinberg expectation. This method is implemented in the freely available software CNVice, which also infers individual genotypes using information from both the population and from trios, if available. We studied the population genetics of five immune-related mCNV loci associated with complex diseases (beta-defensins,, , and ) in 12 traditional Native American populations and found that the population structure parameters inferred for these mCNVs are comparable to but lower than those for single nucleotide polymorphisms studied in the same populations.

FCGR Genetic Variation in Two Populations From Ecuador Highlands—Extensive Copy-Number Variation, Distinctive Distribution of Functional Polymorphisms, and a Novel, Locally Common, Chimeric FCGR3B/A (CD16B/A) Gene

“…Resembling at lower frequency what we saw in individuals from Llano Grande, three and four copies of FCGR3B were found in 35.7% and 7.1% of donors, respectively, all of them estimated to correspond to CNR1/4 duplications in one or both chromosomes ( Figure 3 and Supplementary Tables 1, 2 ). These frequencies are similar to those previously reported in South American and Asian populations and significantly higher than those of Europeans and Africans ( 2 , 4 , 29 , 30 , 40 , 46 , 52 ). In contrast, only five individuals (7.1%) were FCGR3B -hemizygous due to CNR1 deletion, its low frequency being in line with those of populations with diverse backgrounds ( Figure 3 and Supplementary Table 1 ).…”

“…As in other populations (2,4,5,29,30,40,46,52), FCGR3A was scarcely affected by CNV, with low frequencies of both CNR2 deletion and duplication, and absence of CNR3 and CNR5 variations, the latter in sharp contrast to the Llano Grande population. CNR4 deletions were also absent (Figure 3 and Supplementary Table 1).…”

Complement receptor 1 gene (CR1) intragenic duplication and risk of Alzheimer’s disease

“…Previous work has shown, by western blotting of the CR1 protein, that in three out of eight individuals the true genotype was CR1 -A/ CR1 -D not CR1 -B/ CR1 -B, suggesting that a significant proportion of 6 copy individuals may not be homozygous for CR1 -B as we assume (Brouwers et al 2012 ). To assess the validity of our assumption in our population, we estimated the population allele frequencies from the diploid copy number data of the EOAD cohort using the R script CNVice, which simultaneously tests for any departure of the inferred genotype frequencies from Hardy–Weinberg equilibrium (Zuccherato et al 2017 ). The relative probability of a genotype given the individual’s copy number was also calculated from these results.…”

Complement receptor 1 gene (CR1) intragenic duplication and risk of Alzheimer’s disease

“…Previous work has shown, by western blotting of the CR1 protein, that in three out of eight individuals the true genotype was CR1-A/CR1-D not CR1-B/CR1-B, suggesting that a significant proportion of 6 copy individuals may not be homozygous for CR1-B as we assume . In order to assess the validity of our assumption in our population, we estimated the population allele frequencies from the diploid copy number data of the EOAD cohort using the R script CNVice, which simultaneously tests for any departure of the inferred genotype frequencies from Hardy-Weinberg equilibrium (Zuccherato et al 2017). The relative probability of a genotype given the individual's copy number was also calculated from these results.…”