Analysis of copy loss and gain variations in Holstein cattle autosomes using BeadChip SNPs.

BACKGROUND: Copy number variation (CNV) has been recently identified in human and other mammalian genomes, and there is a growing awareness of CNV's potential as a major source for heritable variation in complex traits. Genomic selection is a newly developed tool based on the estimation of breeding values for quantitative traits through the use of genome-wide genotyping of SNPs. Over 30,000 Holstein bulls have been genotyped with the Illumina BovineSNP50 BeadChip, which includes 54,001 SNPs (~SNP/50,000 bp), some of which fall within CNV regions. RESULTS: We used the BeadChip data obtained for 912 Israeli bulls to investigate the effects of CNV on SNP calls. For each of the SNPs, we estimated the frequencies of occurrence of loss of heterozygosity (LOH) and of gain, based either on deviation from the expected Hardy-Weinberg equilibrium (HWE) or on signal intensity (SI) using the PennCNV "detect" option. Correlations between LOH/CNV frequencies predicted by the two methods were low (up to r = 0.08). Nevertheless, 418 locations displayed significantly high frequencies by both methods. Efficiency of designating large genomic clusters of olfactory receptors as CNVs was 29%. Frequency values for copy loss were distinguishable in non-autosomal regions, indicating misplacement of a region in the current BTA7 map. Analysis of BTA18 placed major quantitative trait loci affecting net merit in the US Holstein population in regions rich in segmental duplications and CNVs. Enrichment of transporters in CNV loci suggested their potential effect on milk-production traits. CONCLUSIONS: Expansion of HWE and PennCNV analyses allowed estimating LOH/CNV frequencies, and combining the two methods yielded more sensitive detection of inherited CNVs and better estimation of their possible effects on cattle genetics. Although this approach was more effective than methodologies previously applied in cattle, it has severe limitations. Thus the number of CNVs reported here for the Holstein breed may represent as little as one-tenth of inherited common structural variation.

Fine Mapping of a QTL for Fertility on BTA7 and Its Association With a CNV in the Israeli Holsteins.

A quantitative trait locus (QTL) affecting female fertility, scored as the inverse of the number of inseminations to conception, on Bos taurus chromosome 7 was detected by a daughter design analysis of the Israeli Holstein population (P < 0.0003). Sires of five of the 10 families analyzed were heterozygous for the QTL. The 95% confidence interval of the QTL spans 27 cM from the centromere. Seven hundred and four SNP markers on the Illumina BovineSNP50 BeadChip within the QTL confidence interval were tested for concordance. A single SNP, NGS-58779, was heterozygous for all the five QTL heterozygous patriarchs, and homozygous for the remaining five QTL homozygous sires. A significant effect on fertility was associated with this marker in the sample of 900 sires genotyped (P < 10(-6)). Haplotype phase was the same for four of the five segregating sires. Thus concordance was obtained in nine of the ten families. We identified a common haplotype region associated with the rare and economically favorable allele of the SNP, spanning 270 kbp on BTA7 upstream to 4.72 Mbp. Eleven genes found in the common haplotype region should be considered as positional candidates for the identification of the causative quantitative trait nucleotide. Copy number variation was found in one of these genes, KIAA1683. Four gene variants were identified, but only the number of copies of a specific variant (V(1)) was significantly associated with breeding values of sires for fertility.