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Hardy-Weinberg equilibrium revisited for inferences on genotypes featuring allele and copy-number variations.

ABSTRACT: Copy number variations represent a substantial source of genetic variation and are associated with a plethora of physiological and pathophysiological conditions. Joint copy number and allelic variations (CNAVs) are difficult to analyze and require new strategies to unravel the properties of genotype distributions. We developed a Bayesian hidden Markov model (HMM) approach that allows dissecting intrinsic properties and metastructures of the distribution of CNAVs within populations, in particular haplotype phases of genes with varying copy numbers. As a key feature, this approach incorporates an extension of the Hardy-Weinberg equilibrium, allowing both a comprehensive and parsimonious model design. We demonstrate the quality of performance and applicability of the HMM approach with a real data set describing the Fc? receptor (Fc?R) gene region. Our concept, using a dynamic process to analyze a static distribution, establishes the basis for a novel understanding of complex genomic data sets.

SUBMITTER: Recke A

PROVIDER: S-EPMC4357990 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Hardy-Weinberg equilibrium revisited for inferences on genotypes featuring allele and copy-number variations.

Recke Andreas A Recke Klaus-Günther KG Ibrahim Saleh S Möller Steffen S Vonthein Reinhard R

Scientific reports 20150313

Copy number variations represent a substantial source of genetic variation and are associated with a plethora of physiological and pathophysiological conditions. Joint copy number and allelic variations (CNAVs) are difficult to analyze and require new strategies to unravel the properties of genotype distributions. We developed a Bayesian hidden Markov model (HMM) approach that allows dissecting intrinsic properties and metastructures of the distribution of CNAVs within populations, in particular ...[more]

PMID: 25765626

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Project description:Objective: Departure from Hardy Weinberg Equilibrium (HWE) may occur due to a variety of causes, including purifying selection, inbreeding, population substructure, copy number variation or genotyping error. We searched for specific characteristics of HWE-departure due to genotyping error. Methods: Genotypes of a random set of genetic variants were obtained from the Exome Aggregation Consortium (ExAC) database. Variants with <80% successful genotypes or with minor allele frequency (MAF) <1% were excluded. HWE-departure (d-HWE) was considered significant at p < 10E-05 and classified as d-HWE with loss of heterozygosity (LoH d-HWE) or d-HWE with excess heterozygosity (gain of heterozygosity: GoH d-HWE). Missing genotypes, variant type (single nucleotide polymorphism (SNP) vs. insertion/deletion); MAF, standard deviation (SD) of MAF across populations (MAF-SD) and copy number variation were evaluated for association with HWE-departure. Results: The study sample comprised 3,204 genotype distributions. HWE-departure was observed in 134 variants: LoH d-HWE in 41 (1.3%), GoH d-HWE in 93 (2.9%) variants. LoH d-HWE was more likely in variants located within deletion polymorphisms (p < 0.001) and in variants with higher MAF-SD (p = 0.0077). GoH d-HWE was associated with low genotyping rate, with variants of insertion/deletion type and with high MAF (all at p < 0.001). In a sub-sample of 2,196 variants with genotyping rate >98%, LoH d-HWE was found in 29 (1.3%) variants, but no GoH d-HWE was detected. The findings of the non-random distribution of HWE-violating SNPs along the chromosome, the association with common deletion polymorphisms and indel-variant type, and the finding of excess heterozygotes in genomic regions that are prone to cross-hybridization were confirmed in a large sample of short variants from the 1,000 Genomes Project. Conclusions: We differentiated between two types of HWE-departure. GoH d-HWE was suggestive for genotyping error. LoH d-HWE, on the contrary, pointed to natural variabilities such as population substructure or common deletion polymorphisms.

Dataset Information

Hardy-Weinberg equilibrium revisited for inferences on genotypes featuring allele and copy-number variations.

Publications

Hardy-Weinberg equilibrium revisited for inferences on genotypes featuring allele and copy-number variations.

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