The increasing evidence of fetal developmental effects on postnatal life, the still unknown fetal growth mechanisms impairing offspring generated by somatic nuclear transfer techniques, and the impact on stillbirth and dystocia in conventional reproduction have generated increasing attention toward mammalian fetal growth. We identified a highly significant quantitative trait locus (QTL) affecting fetal growth on bovine chromosome 6 in a specific resource population, which was set up by consistent use of embryo transfer and foster mothers and, thus, enabled dissection of fetal-specific genetic components of fetal growth. Merging our data with results from other cattle populations differing in historical and geographical origin and with comparative data from human whole-genome association mapping suggests that a nonsynonymous polymorphism in the non-SMC condensin I complex, subunit G (NCAPG) gene, NCAPG c.1326T.G, is the potential cause of the identified QTL resulting in divergent bovine fetal growth. NCAPG gene expression data in fetal placentomes with different NCAPG c.1326T.G genotypes, which are in line with recent results about differential NCAPG expression in placentomes from studies on assisted reproduction techniques, indicate that the NCAPG locus may give valuable information on the specific mechanisms regulating fetal growth in mammals.

Background: Growth-related traits have been mapped on bovine chromosome 6 (BTA 6) in various bovine breed populations. We previously mapped a significant quantitative trait locus (QTL) for carcass and body weight (CW-2) between 38 and 55 cM on BTA 6 using a Japanese Black half-sib family. Additional QTL mapping studies detected four QTL for body or carcass weight that overlapped with CW-2 in Japanese Black and Japanese Brown half-sib families. To map the region in greater detail, we applied cross-breed comparisons of haplotypes that have been shown to be powerful in canine.

Identifying trait-associated genetic variation offers new prospects to reveal novel physiological pathways modulating complex traits. Taking advantage of a unique animal model, we identified the I442M mutation in the non-SMC condensin I complex, subunit G (NCAPG) gene and the Q204X mutation in the growth differentiation factor 8 (GDF8) gene as substantial modulators of pre- and/or postnatal growth in cattle. In a combined metabolomic and genotype association approach, which is the first respective study in livestock, we surveyed the specific physiological background of the effects of both loci on body-mass gain and lipid deposition. Our data provided confirming evidence from two historically and geographically distant cattle populations that the onset of puberty is the key interval of divergent growth. The locus-specific metabolic patterns obtained from monitoring 201 plasma metabolites at puberty mirror the particular NCAPG I442M and GDF8 Q204X effects and represent biosignatures of divergent physiological pathways potentially modulating effects on proportional and disproportional growth, respectively. While the NCAPG I442M mutation affected the arginine metabolism, the 204X allele in the GDF8 gene predominantly raised the carnitine level and had concordant effects on glycerophosphatidylcholines and sphingomyelins. Our study provides a conclusive link between the well-described growth-regulating functions of arginine metabolism and the previously unknown specific physiological role of the NCAPG protein in mammalian metabolism. Owing to the confirmed effect of the NCAPG/LCORL locus on human height in genome-wide association studies, the results obtained for bovine NCAPG might add valuable, comparative information on the physiological background of genetically determined divergent mammalian growth.

Recently, we had located a bovine carcass weight QTL, CW-2, to a 591-kb interval on BTA6 and have identified the SNP c.1326T>G in the NCAPG (non-SMC condensin I complex, subunit G) gene that leads to the amino acid change p.Ile442Met in the NCAPG protein, which is a candidate causative variation. Here, we examined the association of the NCAPG:c.1326T>G locus with linear skeletal measurements of growth-associated traits during adolescence, which is a period of intensive growth, using two historically and geographically distant cattle populations: 792 Japanese Black steers and 161 F(2) bulls of an experimental cross from Charolais and German Holstein. In both populations, the SNP NCAPG:c.1326T>G was associated with each component of body frame size: height, length and width at puberty. The associations of CW-2 with height- and length-associated traits were observed at an earlier growth period compared to the associations with thickness- and width-associated traits, indicating that the primary effect of the CW-2 QTL may possibly be exerted on skeletal growth. The significant associations of the NCAPG:c.1326T>G locus with growth-associated skeletal measurements are similar to the effects of the syntenic region on human chromosome 4 that are associated with adult height in humans, supporting the hypothesis that CW-2 is analogous to the human locus and pointing to a conserved growth-associated locus or chromosomal region present in both species.

The c.1326T>G single nucleotide polymorphism (SNP) in the NCAPG gene, which leads to an amino acid change of Ile442 to Met442, was previously identified as a candidate causative variation for a bovine carcass weight quantitative trait loci (QTL) on chromosome 6, which was associated with linear skeletal measurement gains and daily body weight gain at puberty. Recently, we identified the stature quantitative trait nucleotides (QTNs) in the PLAG1-CHCHD7 intergenic region as the causative variations for another carcass weight QTL on chromosome 14. This study aimed to compare the effects of the two QTL on growth and carcass traits using 768 Japanese Black steers from a progeny testing program and to determine whether a genetic interaction was present between them. The FJX_250879 SNP representing the stature QTL was associated with linear skeletal measurements and average daily body weight gain at early and late periods during adolescence. A genetic interaction between FJX_250879 and NCAPG c.1326T>G was detected only for body and rump lengths. Both were associated with increased carcass weight and Longissimus muscle area, and NCAPG c.1326T>G was also associated with reduced subcutaneous fat thickness and increased carcass yield estimate. These results will provide useful information to improve carcass weight in Japanese Black cattle.