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Sequence-based GWAS and post-GWAS analyses reveal a key role of SLC37A1, ANKH, and regulatory regions on bovine milk mineral content.

ABSTRACT: The mineral composition of bovine milk plays an important role in determining its nutritional and cheese-making value. Concentrations of the main minerals predicted from mid-infrared spectra produced during milk recording, combined with cow genotypes, provide a unique opportunity to decipher the genetic determinism of these traits. The present study included 1 million test-day predictions of Ca, Mg, P, K, Na, and citrate content from 126,876 Montbéliarde cows, of which 19,586 had genotype data available. All investigated traits were highly heritable (0.50-0.58), with the exception of Na (0.32). A sequence-based genome-wide association study (GWAS) detected 50 QTL (18 affecting two to five traits) and positional candidate genes and variants, mostly located in non-coding sequences. In silico post-GWAS analyses highlighted 877 variants that could be regulatory SNPs altering transcription factor (TF) binding sites or located in non-coding RNA (mainly lncRNA). Furthermore, we found 47 positional candidate genes and 45 TFs highly expressed in mammary gland compared to 90 other bovine tissues. Among the mammary-specific genes, SLC37A1 and ANKH, encoding proteins involved in ion transport were located in the most significant QTL. This study therefore highlights a comprehensive set of functional candidate genes and variants that affect milk mineral content.

SUBMITTER: Sanchez MP

PROVIDER: S-EPMC8024349 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Milk quality in dairy cattle is routinely assessed via analysis of mid-infrared (MIR) spectra; this approach can also be used to predict the milk's cheese-making properties (CMP) and composition. When this method of high-throughput phenotyping is combined with efficient imputations of whole-genome sequence data from cows' genotyping data, it provides a unique and powerful framework with which to carry out genomic analyses. The goal of this study was to use this approach to identify genes and gene networks associated with milk CMP and composition in the Montbéliarde breed. RESULTS:Milk cheese yields, coagulation traits, milk pH and contents of proteins, fatty acids, minerals, citrate, and lactose were predicted from MIR spectra. Thirty-six phenotypes from primiparous Montbéliarde cows (1,442,371 test-day records from 189,817 cows) were adjusted for non-genetic effects and averaged per cow. 50 K genotypes, which were available for a subset of 19,586 cows, were imputed at the sequence level using Run6 of the 1000 Bull Genomes Project (comprising 2333 animals). The individual effects of 8.5 million variants were evaluated in a genome-wide association study (GWAS) which led to the detection of 59 QTL regions, most of which had highly significant effects on CMP and milk composition. The results of the GWAS were further subjected to an association weight matrix and the partial correlation and information theory approach and we identified a set of 736 co-associated genes. Among these, the well-known caseins, PAEP and DGAT1, together with dozens of other genes such as SLC37A1, ALPL, MGST1, SEL1L3, GPT, BRI3BP, SCD, GPAT4, FASN, and ANKH, explained from 12 to 30% of the phenotypic variance of CMP traits. We were further able to identify metabolic pathways (e.g., phosphate and phospholipid metabolism and inorganic anion transport) and key regulator genes, such as PPARA, ASXL3, and bta-mir-200c that are functionally linked to milk composition. CONCLUSIONS:By using an approach that integrated GWAS with network and pathway analyses at the whole-genome sequence level, we propose candidate variants that explain a substantial proportion of the phenotypic variance of CMP traits and could thus be included in genomic evaluation models to improve milk CMP in Montbéliarde cows.

Dataset Information

Sequence-based GWAS and post-GWAS analyses reveal a key role of SLC37A1, ANKH, and regulatory regions on bovine milk mineral content.

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