B. E. Harrison

A validated whole-genome association study of efficient food conversion in cattle.

The genetic factors that contribute to efficient food conversion are largely unknown. Several physiological systems are likely to be important, including basal metabolic rate, the generation of ATP, the regulation of growth and development, and the homeostatic control of body mass. Using whole-genome association, we found that DNA variants in or near proteins contributing to the background use of energy of the cell were 10 times as common as those affecting appetite and body-mass homeostasis. In addition, there was a genic contribution from the extracellular matrix and tissue structure, suggesting a trade-off between efficiency and tissue construction. Nevertheless, the largest group consisted of those involved in gene regulation or control of the phenotype. We found that the distribution of micro-RNA motifs was significantly different for the genetic variants associated with residual feed intake than for the genetic variants in total, although the distribution of promoter sequence motifs was not different. This suggests that certain subsets of micro-RNA are more important for the regulation of this trait. Successful validation depended on the sign of the allelic association in different populations rather than on the strength of the initial association or its size of effect.

Accuracy of prediction of genomic breeding values for residual feed intake and carcass and meat quality traits in Bos taurus, Bos indicus, and composite beef cattle

The aim of this study was to assess the accuracy of genomic predictions for 19 traits including feed efficiency, growth, and carcass and meat quality traits in beef cattle. The 10,181 cattle in our study had real or imputed genotypes for 729,068 SNP although not all cattle were measured for all traits. Animals included Bos taurus, Brahman, composite, and crossbred animals. Genomic EBV (GEBV) were calculated using 2 methods of genomic prediction [BayesR and genomic BLUP (GBLUP)] either using a common training dataset for all breeds or using a training dataset comprising only animals of the same breed. Accuracies of GEBV were assessed using 5-fold cross-validation. The accuracy of genomic prediction varied by trait and by method. Traits with a large number of recorded and genotyped animals and with high heritability gave the greatest accuracy of GEBV. Using GBLUP, the average accuracy was 0.27 across traits and breeds, but the accuracies between breeds and between traits varied widely. When the training population was restricted to animals from the same breed as the validation population, GBLUP accuracies declined by an average of 0.04. The greatest decline in accuracy was found for the 4 composite breeds. The BayesR accuracies were greater by an average of 0.03 than GBLUP accuracies, particularly for traits with known genes of moderate to large effect mutations segregating. The accuracies of 0.43 to 0.48 for IGF-I traits were among the greatest in the study. Although accuracies are low compared with those observed in dairy cattle, genomic selection would still be beneficial for traits that are hard to improve by conventional selection, such as tenderness and residual feed intake. BayesR identified many of the same quantitative trait loci as a genomewide association study but appeared to map them more precisely. All traits appear to be highly polygenic with thousands of SNP independently associated with each trait.

A genome-wide association study of meat and carcass traits in Australian cattle

Chromosomal regions containing DNA variation affecting the traits intramuscular fat percentage (IMF), meat tenderness measured as peak force to shear the LM (LLPF), and rump fat measured at the sacro-iliac crest in the chiller (CHILLP8) were identified using a set of 53,798 SNP genotyped on 940 taurine and indicine cattle sampled from a large progeny test experiment. Of these SNP, 87, 64, and 63 were significantly (P < 0.001) associated with the traits IMF, LLPF, and CHILLP8, respectively. A second, nonoverlapping sample of 1,338 taurine and indicine cattle from the same large progeny test experiment genotyped for 335 SNP, including as a positive control the calpastatin (CAST) c.2832A > G SNP, was used to confirm these locations. In total, 37 SNP were significantly (P < 0.05) associated with the same trait and with the same favorable homozygote in both data sets, representing 27 chromosomal regions. For the trait IMF, the effect of SNP in the confirmation data set was predicted from the discovery set by multiplying the estimated allele effect of each SNP in the discovery set by the number of copies of the reference allele of each SNP in the confirmation set. These weighted effects were then summed over all SNP to generate a molecular breeding value (MBV) for each animal in the confirmation data set. Using a bivariate analysis of MBV and IMF phenotypes of animals in the confirmation set, a panel of 14 SNP explained 5.6 and 15.6% of the phenotypic and genetic variance of IMF, respectively, in the confirmation data set. The amount of variation did not increase as more SNP were added to the MBV and instead decreased to 1.2 and 3.8% of the phenotypic and genetic variance of IMF, respectively, when 329 SNP were included in the analysis.

Genome wide signatures of positive selection: The comparison of independent samples and the identification of regions associated to traits

BackgroundThe goal of genome wide analyses of polymorphisms is to achieve a better understanding of the link between genotype and phenotype. Part of that goal is to understand the selective forces that have operated on a population.ResultsIn this study we compared the signals of selection, identified through population divergence in the Bovine HapMap project, to those found in an independent sample of cattle from Australia. Evidence for population differentiation across the genome, as measured by FST, was highly correlated in the two data sets. Nevertheless, 40% of the variance in FST between the two studies was attributed to the differences in breed composition. Seventy six percent of the variance in FST was attributed to differences in SNP composition and density when the same breeds were compared. The difference between FST of adjacent loci increased rapidly with the increase in distance between SNP, reaching an asymptote after 20 kb. Using 129 SNP that have highly divergent FST values in both data sets, we identified 12 regions that had additive effects on the traits residual feed intake, beef yield or intramuscular fatness measured in the Australian sample. Four of these regions had effects on more than one trait. One of these regions includes the R3HDM1 gene, which is under selection in European humans.ConclusionFirstly, many different populations will be necessary for a full description of selective signatures across the genome, not just a small set of highly divergent populations. Secondly, it is necessary to use the same SNP when comparing the signatures of selection from one study to another. Thirdly, useful signatures of selection can be obtained where many of the groups have only minor genetic differences and may not be clearly separated in a principal component analysis. Fourthly, combining analyses of genome wide selection signatures and genome wide associations to traits helps to define the trait under selection or the population group in which the QTL is likely to be segregating. Finally, the FST difference between adjacent loci suggests that 150,000 evenly spaced SNP will be required to study selective signatures in all parts of the bovine genome.

Epistasis Between Calpain 1 and Its Inhibitor Calpastatin Within Breeds of Cattle

The calpain gene family and its inhibitors have diverse effects, many related to protein turnover, which appear to affect a range of phenotypes such as diabetes, exercise-induced muscle injury, and pathological events associated with degenerative neural diseases in humans, fertility, longevity, and postmortem effects on meat tenderness in livestock species. The calpains are inhibited by calpastatin, which binds directly to calpain. Here we report the direct measurement of epistatic interactions of causative mutations for quantitative trait loci (QTL) at calpain 1 (CAPN1), located on chromosome 29, with causative mutations for QTL variation at calpastatin (CAST), located on chromosome 7, in cattle. First we identified potential causative mutations at CAST and then genotyped these along with putative causative mutations at CAPN1 in >1500 cattle of seven breeds. The maximum allele substitution effect on the phenotype of the CAPN1:c.947G>C single nucleotide polymorphism (SNP) was 0.14 σp (P = 0.0003) and of the CAST:c.155C>T SNP was also 0.14 σp (P = 0.0011) when measured across breeds. We found significant epistasis between SNPs at CAPN1 and CAST in both taurine and zebu derived breeds. There were more additive × dominance components of epistasis than additive × additive and dominance × dominance components combined. A minority of breed comparisons did not show epistasis, suggesting that genetic variation at other genes may influence the degree of epistasis found in this system.

Variation at the Calpain 3 gene is associated with meat tenderness in zebu and composite breeds of cattle

BackgroundQuantitative Trait Loci (QTL) affecting meat tenderness have been reported on Bovine chromosome 10. Here we examine variation at the Calpain 3 (CAPN3) gene in cattle, a gene located within the confidence interval of the QTL, and which is a positional candidate gene based on the biochemical activity of the protein.ResultsWe identified single nucleotide polymorphisms (SNP) in the genomic sequence of the CAPN3 gene and tested three of these in a sample of 2189 cattle. Of the three SNP genotyped, the CAPN3:c.1538+225G>T had the largest significant additive effect, with an allele substitution effect in the Brahman of α = -0.144 kg, SE = 0.060, P = 0.016, and the polymorphism explained 1.7% of the residual phenotypic variance in that sample of the breed. Significant haplotype substitution effects were found for all three breeds, the Brahman, the Belmont Red, and the Santa Gertrudis. For the common haplotype, the haplotype substitution effect in the Brahman was α = 0.169 kg, SE = 0.056, P = 0.003. The effect of this gene was compared to Calpastatin in the same sample. The SNP show negligible frequencies in taurine breeds and low to moderate minor allele frequencies in zebu or composite animals.ConclusionThese associations confirm the location of a QTL for meat tenderness in this region of bovine chromosome 10. SNP in or near this gene may be responsible for part of the overall difference between taurine and zebu breeds in meat tenderness, and the greater variability in meat tenderness found in zebu and composite breeds. The evidence provided so far suggests that none of these tested SNP are causative mutations.

A splice site single nucleotide polymorphism of the fatty acid binding protein 4 gene appears to be associated with intramuscular fat deposition in longissimus muscle in Australian cattle

Fatty acid binding protein 4 (FABP4) is a candidate gene affecting fatness traits of mammals. However, its association with fatness traits in cattle and other livestock species is not consistent from one study to another. Here, we sequenced the coding sequence of FABP4 looking for non-synonymous variants. We identified a splice site mutation between the third exon and the third intron of bovine FABP4. We genotyped this SNP, FABP4:g.2502C>G, in 1409 cattle with intramuscular fat measurements from seven breeds. The average allele frequency of the C allele was 0.66 with a range of 0.45 to 0.85. A regression on the number of G alleles shows a statistically significant effect of alpha = 0.11, P = 0.044. This appears to confirm an association between IMF and variation at FABP4, with an effect of 0.3% of the variation in our sample when using this SNP.

A genome-wide association study of tick burden and milk composition in cattle

To study the genetic basis of tick burden and milk production and their interrelationship, we collected a sample of 1961 cattle with multiple tick counts from northern Australia of which 973 had dairy production data in the Australian Dairy Herd Information Service database. We calculated heritabilities, genetic and phenotypic correlations for these traits and showed a negative relationship between tick counts and milk and milk component yield. Tests of polymorphisms of four genes associated with milk yield, ABCG2, DGAT1, GHR and PRLR, showed no statistically significant effect on tick burden but highly significant associations to milk component yield in these data and we confirmed separate effects for GHR and PRLR on bovine chromosome 20. To begin to identify some of the molecular genetic bases for these traits, we genotyped a sample of 189 of these cattle for 7397 single nucleotide polymorphisms in a genome-wide association study. Although the allele effects for adjusted milk fat and protein yield were highly correlated (r = 0.66), the correlations of allele effects of these milk component yields and tick burden were small (|r| <= 0.10). These results agree in general with the phenotypic correlations between tick counts and milk component yield and suggest that selection on markers for tick burden or milk component yield may have no undesirable effect on the other trait.

Variation in the XKR4 gene was significantly associated with subcutaneous rump fat thickness in indicine and composite cattle.

Variation in the XK, Kell blood group complex subunit-related family, member 4 (XKR4) gene on BTA14 was associated with rump fat thickness in a recent genome-wide association study. This region is also of interest because it is known to show evidence of a signature of population genetic selection. In this study, additional variation in this gene was genotyped in a sample of a total of 1283 animals of the Belmont Red (BEL) and Santa Gertrudis (SGT) breeds. The SNP rs41724387 was significantly (P < 0.001) associated with rump fat thickness and explained 5.9% of the genetic variance for the trait in this sample. Using the 4466 genotypes for the SNP rs42646708 from several data sets to estimate effects in seven breeds, this relatively large quantitative trait locus effect appears to be a result of the variation in indicine and taurine-indicine composite cattle. However, the only DNA variant found in Brahman cattle that altered the predicted amino acid sequence of XKR4 was not associated with rump fat thickness. This suggests that causative mutations lie outside the coding sequence of this gene.

Detecting quantitative trait loci affecting beef tenderness on bovine chromosome 7 near calpastatin and lysyl oxidase

From a study of 3 large half-sib families of cattle, we describe linkage between DNA polymorphisms on bovine chromosome 7 and meat tenderness. Quantitative trait loci (QTL) for Longissimus lumborum peak force (LLPF) and Semitendonosis adhesion (STADH) were located to this map of DNA markers, which includes the calpastatin ( CAST) and lysyl oxidase (LOX) genes. The LLPF QTL has a maximum lodscore of 4.9 and allele substitution of approximately 0.80 of a phenotypic standard deviation, and the peak is located over the CAST gene. The STADH QTL has a maximum lodscore of 3.5 and an allele substitution of approximately 0.37 of a phenotypic standard deviation, and the peak is located over the LOX gene. This suggests 2 separate likelihood peaks on the chromosome. Further analyses of meat tenderness measures in the Longissimus lumborum, LLPF and LL compression (LLC), in which outlier individuals or kill groups are removed, demonstrate large shifts in the location of LLPF QTL, as well as confirming that there are indeed 2 QTL on bovine chromosome 7. We found that both QTL are reflected in both LLPF and LLC measurements, suggesting that both these components of tenderness, myofibrillar and connective tissue, are detected by both measurements in this muscle.