Multisite haplotype on cattle chromosome 3 is associated with quantitative trait locus effects on lactation traits

Abstract

Multisite haplotype on cattle chromosome 3 is associated with quantitative trait locus effects on lactation traits. Physiol Genomics 43: 1185-1197, 2011. First published September 6, 2011 doi:10.1152/physiolgenomics.00253.2010.-The goal of this study was to identify candidate genes and DNA polymorphisms for quantitative trait loci (QTL) affecting milk yield (MY), fat yield (FY), and protein yield (PY) previously mapped to bovine chromosome 3 (BTA3). To accomplish this, 373 half-siblings sired by three bulls previously shown to be segregating for lactation trait QTL, and 263 additional sires in the U.S. Dairy Bull DNA Repository (DBDR) were genotyped for 2,500 SNPs within a 16.3 Mbp QTL critical region on BTA3. Targeted resequencing of ϳ1.8 Mbp within the QTL critical region of one of the QTL heterozygous sires identified additional polymorphisms useful for association studies. Twentythree single nucleotide polymorphisms (SNPs) within a fine-mapped region were associated with effects on breeding values for MY, FY, or PY in DBDR sires, of which five SNPs were in strong linkage disequilibrium in the population. This multisite haplotype included SNPs located within exons or promoters of four tightly linked genes: RAP1A, ADORA3, OVGP1, and C3H1orf88. An SNP within RAP1A showed strong evidence of a recent selective sweep based on integrated haplotype score and was also associated with breeding value for PY. Because of its known function in alveolar lumen formation in the mammary gland, RAP1A is thus a strong candidate gene for QTL effects on lactation traits. Our results provide a detailed assessment of a QTL region that will be a useful guide for complex traits analysis in humans and other noninbred species.genes; single nucleotide polymorphisms; RAP1A; milk ONE OF THE GRAND CHALLENGES in modern genetics is to identify the molecular genetic basis for complex traits (20). In cattle, the low-to-moderate heritability of quantitative traits under selection and limited sizes of resource populations are largely responsible for mapping most quantitative trait loci (QTL) to large intervals of Ͼ10 cM (http://www.genome.iastate.edu/ cgi-bin/QTLdb/BT/index). The poor genomic resolution of mapped cattle QTL makes identification of the genes and polymorphisms underlying their effects a difficult and expensive endeavor. Despite these limitations, two QTL with large effects on milk, milk fat, and protein yields were resolved at the gene level with high probability (12, 23), thereby demonstrating the strength of available cattle resource populations and genomic tools for complex traits analysis. These findings have been rapidly implemented by the dairy industry for genetic improvement in milk production traits (24). Moreover, these studies have illuminated our general understanding of the genetic control of complex traits and have provided two new model systems for lactation biology. Therefore, genetic dissection of QTL affecting lactation traits is important both as a biomedical model system and for applications in animal breeding...

Determination of quantitative trait nucleotides by concordance analysis between quantitative trait loci and marker genotypes of US Holsteins

“…Except for the effect on BTA15, all effects were chiefly for fat and protein concentration and had been found previously in the Australian Holstein population by Kemper et al (2015). The effect on protein percentage on BTA3 was localized to 23 to 24 Mbp, whereas previous studies found a QTL located between 25 and 45 Mbp (Ashwell et al, 2004;Cohen-Zinder et al, 2011).…”

Variants of the bovine retinoic acid receptor-related orphan receptor C gene are in linkage disequilibrium with QTL for milk production traits on chromosome 3 in a beef × dairy crossbreed population

“…Furthermore, Kolbehdari et al (2009) found an association between MY and LOC511740 (rs43709850), which is 1.2 Mb telomeric to RORC, and an association between the trait PP and the PDZK1 gene (rs41587408) (2.7 Mb telomeric to RORC). Those results are in positional disagreement with a recently published study combining fine mapping and resequencing for the detection of QTL for milk production traits on BTA3 in a Holstein dairy cattle family design by Cohen-Zinder et al (2011). They highlighted four candidate genes (RAP1A, ADORA3, OVGP1 and C3H1orf88) in the region 27.1-36.2 Mb between the microsatellites BL41 and TGLA263 as potentially underlying QTLs found for MY, FY and PY.…”

Osteoporosis genetics: year 2011 in review

“…27 Although RAP1A is a regulator having an important role in the developing mammary gland, 28 not much is known about the mechanism involving this gene with bone metabolism. In their study, Cohen-Zinder et al 26 detected two polymorphisms located in the promoter region of bovine RAP1A and in intron 4 of the gene, which were significantly associated with milk yield and composition traits in dairy Holstein population. Note that, similar to this finding, other lactation genes were previously identified as the top signals for BMD.…”

“…The gene is mapped to a quantitative trait locus located in bovine chromosome 3 (BTA3). 26 Interestingly, an integration of human GWAS and gene expression profiling performed by Hsu et al 27 revealed a locus on 1p13.2 (orthologous to BTA3) associated with osteoporosis-related traits, which harbors the same gene, RAP1A. SNPs within human RAP1A are strongly associated with narrow neck width in women.…”