Dataset Information

Sequence-based Association Analysis Reveals an MGST1 eQTL with Pleiotropic Effects on Bovine Milk Composition.

ABSTRACT: The mammary gland is a prolific lipogenic organ, synthesising copious amounts of triglycerides for secretion into milk. The fat content of milk varies widely both between and within species, and recent independent genome-wide association studies have highlighted a milk fat percentage quantitative trait locus (QTL) of large effect on bovine chromosome 5. Although both EPS8 and MGST1 have been proposed to underlie these signals, the causative status of these genes has not been functionally confirmed. To investigate this QTL in detail, we report genome sequence-based imputation and association mapping in a population of 64,244 taurine cattle. This analysis reveals a cluster of 17 non-coding variants spanning MGST1 that are highly associated with milk fat percentage, and a range of other milk composition traits. Further, we exploit a high-depth mammary RNA sequence dataset to conduct expression QTL (eQTL) mapping in 375 lactating cows, revealing a strong MGST1 eQTL underpinning these effects. These data demonstrate the utility of DNA and RNA sequence-based association mapping, and implicate MGST1, a gene with no obvious mechanistic relationship to milk composition regulation, as causally involved in these processes.

SUBMITTER: Littlejohn MD

PROVIDER: S-EPMC4857175 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Sequence-based Association Analysis Reveals an MGST1 eQTL with Pleiotropic Effects on Bovine Milk Composition.

Littlejohn Mathew D MD Tiplady Kathryn K Fink Tania A TA Lehnert Klaus K Lopdell Thomas T Johnson Thomas T Couldrey Christine C Keehan Mike M Sherlock Richard G RG Harland Chad C Scott Andrew A Snell Russell G RG Davis Stephen R SR Spelman Richard J RJ

Scientific reports 20160505

The mammary gland is a prolific lipogenic organ, synthesising copious amounts of triglycerides for secretion into milk. The fat content of milk varies widely both between and within species, and recent independent genome-wide association studies have highlighted a milk fat percentage quantitative trait locus (QTL) of large effect on bovine chromosome 5. Although both EPS8 and MGST1 have been proposed to underlie these signals, the causative status of these genes has not been functionally confirm ...[more]

PMID: 27146958

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Project description:BACKGROUND:Human milk oligosaccharides (OS) play a key role in brain and gut microbiota development of the neonate, but the underlying biosynthetic steps of OS in the mammary gland are still largely unknown. As bovine milk contains OS with somewhat similar structures and functionalities there is increased interest in further understanding the genetic basis underlying the OS content of milk for eventual extraction and generation of value-added ingredients for infant formulas and nutraceuticals. The present study is the first to report on genetic parameter estimation as well as on a genome wide association study (GWAS) from the largest bovine milk OS dataset analyzed to date. RESULTS:In total 15 different bovine milk OS were monitored. Heritabilities ranged from 0 to 0.68 in Danish Holstein and from 0 to 0.92 in Danish Jersey. The GWAS identified in total 1770 SNPs (FDR?<?0.10) for five different OS in Danish Holstein and 6913 SNPs (FDR?<?0.10) for 11 OS in Danish Jersey. In Danish Holstein, a major overlapping QTL was identified on BTA1 for LNH and LNT explaining 24% of the variation in these OS. The most significant SNPs were associated with B3GNT5, a gene encoding a glycosyltransferase involved in glycan synthesis. In Danish Jersey, a very strong QTL was detected for the OS with composition 2 Hex 1 HexNAc (isomer 1) on BTA11. The most significant SNP had -log10(P-value) of 52.88 (BOVINEHD1100030300) and was assigned to ABO, a gene encoding ABO blood group glycosyltransferases. This SNP has been reported to be a missense mutation and explains 56% of the OS variation. Other candidate genes of interest identified for milk OS were ALG3, B3GALNT2, LOC520336, PIGV, MAN1C1, ST6GALNAC6, GLT6D1, GALNT14, GALNT17, COLGALT2, LFNG and SIGLEC. CONCLUSION:To our knowledge, this is the first study documenting a solid breeding potential for bovine milk OS and a strong indication of specific candidate genes related to OS synthesis underlying this genetic influence. This new information has the potential to guide breeding strategies to achieve production of milk with higher diversity and concentration of OS and ultimately facilitate large-scale extraction of bovine milk OS.

Project description:Bovine milk is widely regarded as a nutritious food source for humans, although the effects of individual fatty acids on human health is a subject of debate. Based on the assumption that genomic selection offers potential to improve milk fat composition, there is strong interest to understand more about the genetic factors that influence the biosynthesis of bovine milk and the molecular mechanisms that regulate milk fat synthesis and secretion. For this reason, the work reported here aimed at identifying genetic variants that affect milk fatty acid composition in Norwegian Red cattle. Milk fatty acid composition was predicted from the nation-wide recording scheme using Fourier transform infrared spectroscopy data and applied to estimate heritabilities for 36 individual and combined fatty acid traits. The recordings were used to generate daughter yield deviations that were first applied in a genome-wide association (GWAS) study with 17,343 markers to identify quantitative trait loci (QTL) affecting fatty acid composition, and next on high-density and sequence-level datasets to fine-map the most significant QTL on BTA13 (BTA for Bos taurus chromosome).The initial GWAS revealed 200 significant associations, with the strongest signals on BTA1, 13 and 15. The BTA13 QTL highlighted a strong functional candidate gene for de novo synthesis of short- and medium-chained saturated fatty acids; acyl-CoA synthetase short-chain family member 2. However, subsequent fine-mapping using single nucleotide polymorphisms (SNPs) from a high-density chip and variants detected by resequencing showed that the effect was more likely caused by a second nearby gene; nuclear receptor coactivator 6 (NCOA6). These findings were confirmed with results from haplotype studies. NCOA6 is a nuclear receptor that interacts with transcription factors such as PPAR?, which is a major regulator of bovine milk fat synthesis.An initial GWAS revealed a highly significant QTL for de novo-synthesized fatty acids on BTA13 and was followed by fine-mapping of the QTL within NCOA6. The most significant SNPs were either synonymous or situated in introns; more research is needed to uncover the underlying causal DNA variation(s).

Dataset Information

Sequence-based Association Analysis Reveals an MGST1 eQTL with Pleiotropic Effects on Bovine Milk Composition.

Publications

Sequence-based Association Analysis Reveals an MGST1 eQTL with Pleiotropic Effects on Bovine Milk Composition.

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