Phenotypic population screen identifies a new mutation in bovine DGAT1 responsible for unsaturated milk fat

Lehnert, Klaus; Ward, Hamish; Berry, Sarah D.; Ankersmit-Udy, Alex; Burrett, Alayna; Beattie, E. M.; Thomas, Natalie; Harris, B. L.; Ford, Christine A.; Browning, Sharon R.; Rawson, Pisana; Verkerk, G.A.; Does, Yvonne van der; Adams, Lowell; Davis, Stephen R.; Jordan, T. William; MacGibbon, Alastair; Spelman, Richard; Snell, Russell G.

doi:10.1038/srep08484

Cited by 21 publications

(22 citation statements)

References 36 publications

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“…While it is not the first time an expression-based effect of DGAT1 has been proposed as the mechanism by which this gene influences milk composition [14], our study is the first to provide evidence supporting an expression-based effect associated with K232A. Association mapping at the DGAT1 locus using imputed WGS variants showed that DGAT1 K232A retains its status as one of the top ranking variants.…”

Section: Discussionsupporting

confidence: 48%

“…Additionally, the disruption of splicing has recently been reported for a novel DGAT1 mutation in dairy cattle, whereby a non-synonymous A>C transversion in exon 16 disrupts a putative ESE motif and causes the skipping of this exon [14]. This polymorphism results in an enzymatically inactive DGAT1, which in the homozygous state results in a severe phenotype characterised by scouring and slow growth [14].…”

Section: Discussionmentioning

confidence: 99%

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A new mechanism for a familiar mutation – bovineDGAT1K232A modulates gene expression through multi-junction exon splice enhancement

Fink

Lopdell

Tiplady

et al. 2020

Preprint

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The DGAT1 gene encodes an enzyme responsible for catalysing the terminal reaction in mammary triglyceride synthesis, and underpins a well-known pleiotropic quantitative trait locus (QTL) with a large influence on milk composition phenotypes. Since first described over 15 years ago, a protein-coding variant K232A has been assumed as the causative variant underlying these effects, following in-vitro studies that demonstrated differing levels of triglyceride synthesis between the two protein isoforms. In the current study, we used a large RNAseq dataset to re-examine the underlying mechanisms of this large milk production QTL, and hereby report novel expression-based functions of the chr14 g.1802265AA>GC variant that encodes the DGAT1 K232A substitution. Using expression QTL (eQTL) mapping, we demonstrate a highly-significant mammary eQTL for DGAT1, where the K232A mutation appears as one of the top associated variants for this effect. By conducting in vitro expression and splicing experiments in bovine mammary cell culture, we further show modulation of splicing efficiency by this mutation, likely through disruption of an exon splice enhancer as a consequence of the allele encoding the 232A variant. Although the relative contributions of the enzymatic and transcription-based mechanisms now attributed to K232A remain unclear, these results suggest that transcriptional impacts contribute to the diversity of lactation effects observed at this locus.A lysine to alanine amino acid substitution (K232A) encoded by a mutation in the diacylglyercol O-acyltransferase 1 (DGAT1) gene has major impacts on bovine lactation traits, the most substantial being its impact on milk fat percentage [1,2]. This substitution results from an AA to GC dinucleotide substitution in exon eight of DGAT1, and likely constitutes the most widely studied and validated variant in association analyses of bovine milk characteristics (initially described by Grisart et al (2002), with >1000 Google Scholar citations to date). The DGAT1 gene encodes an enzyme responsible for catalysing the terminal reaction in the mammary triglyceride synthesis pathway [3], and the DGAT1 K allele has been shown [4] to synthesise more triglycerides in vitro when compared to the A allele. Aside from the DGAT1 K232A mutation, an additional polymorphism 5′ of the transcription start site of the gene has also been shown to associate with milk fat percentage [5]. This variant, a variable number tandem repeat (VNTR) expansion, was speculated to play a role in bovine milk composition by increasing the number of putative transcription factor binding sites [5]. However, functional testing of the VNTR variant did not show any differences in DGAT1 expression between QTL genotypes in cell culture [6]. This finding largely put the competing, gene expression-based hypothesis of the DGAT1 milk fat effect to rest, with enzymatic differences deriving from the K232A mutation now widely assumed as the underlying mechanism.Since these initial analyses >10 years ago, further functional charact...

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

A new mechanism for a familiar mutation – bovineDGAT1K232A modulates gene expression through multi-junction exon splice enhancement

Fink

Lopdell

Tiplady

et al. 2020

Preprint

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“…18,19 However, in humans only a single family has been reported associated with DGAT1 mutations. Haas et al described a non-consanguineous AshkenaziJewish family in which two of three siblings were homozygous for a splice site mutation leading to exon 8 deletion associated with PLE, hypoalbuminemia, and early-onset diarrhea.…”

Section: Discussionmentioning

confidence: 99%

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

et al. 2016

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Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes.

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“…Development of Saanen goat breeding can not be separated from the selection process of livestock. Conventional selection based on ancestral performance takes a lot of time, so genetic markers underlying commercial phenotype trait as selection mechanism, or known as Marker-Assisted Selection (MAS) was used to abbreviate time and enhance the accurate of selection Lehnert et al, 2015;Muhammed et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Polymorphism identification of Diacylglycerol Acyltransferase1 gene and its correlation with fat content of Saanen goat

Darmoatmodjo

Widodo

Asmara

2018

J. Indonesian Trop. Anim. Agric.

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Gene markers are often usefull for selection process of cattle on commercial certain phenotypes. Saanen goat has predominance in milk production traits. Milk fat content is one of the commercial traits of milk production. Diacylglycerol Acyltransferase1 (DGAT1) gene was involved in the final process of triglyceride synthesis and associated with milk fat content. Single nucleotide subtitution or insertion-deletion in certain sequence of DGAT1 gene could be gene markers for milk fat content. The objective of this study was to identify differences variation in milk fat content among individual Saanen goats, to identify exon 14-16 polymorphism of DGAT1 gene and to examine its correlation between polymorphism and milk fat content on Saanen goats. The methodologies was collection blood and milk samples, DNA isolation from blood, amplification of DGAT1 genes, sequencing, detection of polymorphism of exon 14-16 DGAT1 gene with Polymerase Chain Reaction-Single Strand Conformation Polymorphism (PCR-SSCP), and examination milk quality on three lactation months using Lactoscan. The average of daily milk production from 70 Saanen goat was 2340±709 mL, 1880±632 mL, 1432±536 mL and average of milk fat content was 3.07±0.52%, 2.53±0.55%, 3.00±0.55% for the first, second and third months of lactation, respectively. The amplicon size of exon 14-16 of DGAT1 gene was ± 350 bp and showed monomorphic pattern from PCR-SSCP. Variation of milk fat content on Saanen goats not caused by polymorphism of exon 14-16 DGAT1 gene.

show abstract

Phenotypic population screen identifies a new mutation in bovine DGAT1 responsible for unsaturated milk fat

Cited by 21 publications

References 36 publications

A new mechanism for a familiar mutation – bovineDGAT1K232A modulates gene expression through multi-junction exon splice enhancement

A new mechanism for a familiar mutation – bovineDGAT1K232A modulates gene expression through multi-junction exon splice enhancement

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

Polymorphism identification of Diacylglycerol Acyltransferase1 gene and its correlation with fat content of Saanen goat

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