Reconstructing CNV genotypes using segregation analysis: combining pedigree information with CNV assay

Segregation analysis was used to estimate copy number alleles from assay data on simulated half-sib sheep populations. Copy number variation at the Agouti locus, known to be responsible for the recessive self-colour black phenotype, was used as a model for the simulation and an appropriate penetrance function was derived. The precision with which carriers and non-carriers of the undesirable single copy allele could be identified, was used to evaluate the method for various family sizes, assay strategies and assay accuracies.Using relationship data and segregation analysis, the probabilities of carrying the copy number alleles responsible for black or white fleece were estimated with much greater precision than by analyzing assay results for animals individually. The proportion of lambs correctly identified as non-carriers of the undesirable allele increased from 7% when the lambs were analysed alone to 80% when the lambs were analysed in half-sib families.When a quantitative assay is used to estimate copy number alleles, segregation analysis of related individuals can greatly improve the precision of the estimates. Existing software for segregation analysis would require little if any change to accommodate the penetrance function for copy number assay data.With the increasing resolution at which genomes can be examined has come the recognition that variation in genome structure is common and affects more nucleotides per genome than the sequence variation found in single nucleotide polymorphisms (SNP) [1-3]. Copy number variation (CNV) in DNA, defined as insertions, deletions and duplications larger than 1 kb, is an important component of this structural variation. Recent publications document the contribution of CNV to genetic diversity in humans [2,4-6] and human disease [7-9]. CNV has been shown to contribute to phenotype in model organisms [9-11] and to important production and disease traits in domesticated livestock species [12-15]. Current technologies to assa