Functionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle

Littlejohn, Mathew D; Henty, Kristen; Tiplady, Kathryn; Johnson, Thomas; Harland, Chad; Lopdell, Thomas; Sherlock, Richard G.; Li, Wanbo; Lukefahr, S. D.; Shanks, B. C.; Garrick, Dorian J.; Snell, Russell G.; Spelman, Richard; Davis, Stephen R.

doi:10.1038/ncomms6861

Cited by 126 publications

(148 citation statements)

References 33 publications

(43 reference statements)

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…The animals used for the analysis comprised 375 mostly Holstein-Friesian NZ dairy cows, representing a subset of 406 sequenced animals described in detail previously [10,19].…”

Section: Dna Extraction and High Throughput Genotypingmentioning

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…The animals used for the analysis comprised 375 mostly Holstein-Friesian NZ dairy cows, representing a subset of 406 sequenced animals described in detail previously [10,19].…”

Section: Dna Extraction and High Throughput Genotypingmentioning

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Genotypes for 29,350 animals were imputed to WGS resolution in the window of interest using Beagle 4 [15] as described previously [51,9]. Briefly, a reference population of 565 animals, comprising Holstein-Friesians, Jerseys, and cross-bred cattle, was sequenced using the Illumina HiSeq 2000 instrument to yield 100 bp reads.…”

Section: Imputation and Association Analysesmentioning

confidence: 99%

Multiple QTL underlie milk phenotypes at the CSF2RB locus

Lopdell

Tiplady

Couldrey

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Background:Bovine milk provides an important source of nutrition in much of the Western world, forming components of many food products. Over many years, artificial selection has substantially improved milk production by cows. However, the genes underlying milk production quantitative trait loci (QTL) remain relatively poorly characterised. Here, we investigate a previously-reported QTL located at the CSF2RB locus, for several milk production phenotypes, to better understand its underlying genetic and molecular causes.Results: Using a population of 29,350 taurine dairy cattle, we conducted association analyses for milk yield and composition traits, and identified highly significant QTL for milk yield, milk fat concentration, and milk protein concentration. Strikingly, protein concentration and milk yield appear to show co-located yet genetically distinct QTL. To attempt to understand the molecular mechanisms that might be mediating these effects, gene expression data were used to investigate eQTL for eleven genes in the broader interval. This analysis highlighted genetic impacts on CSF2RB and NCF4 expression that share similar association signatures to those observed for lactation QTL, strongly implicating one or both of these genes as the cause of these effects. Using the same gene expression dataset representing 357 lactating cows, we also identified 38 novel RNA editing sites in the 3 UTR of CSF2RB transcripts. The extent to which two of these sites were edited also appears to be genetically co-regulated with lactation QTL, highlighting a further layer of regulatory complexity implicating the CSF2RB gene. Conclusions:This chromosome 5 locus presents a diversity of molecular and lactation QTL, likely representing multiple overlapping effects that, at a minimum, highlight the CSF2RB gene as having a causal role in these processes.

show abstract

“…Dikmen et al (124) indicate that three potential candidate genes are in the region where the slick hair locus resides ( SKP2, SPEF2 , and PRLR ). Littlejohn et al (125) propose mutations in the prolactin receptor ( PRLR ) on chromosome 20 and the prolactin gene ( PRL ) on chromosome 23, as responsible for the slick hair condition. Littlejohn et al (125) indicate that animals with the slick hair condition produced more milk than animals without the condition.…”

Section: Slick Hairmentioning

confidence: 99%

“…Littlejohn et al (125) propose mutations in the prolactin receptor ( PRLR ) on chromosome 20 and the prolactin gene ( PRL ) on chromosome 23, as responsible for the slick hair condition. Littlejohn et al (125) indicate that animals with the slick hair condition produced more milk than animals without the condition. Furthermore, Dikmen et al (124) show that Holstein cattle with the slick hair condition produce more milk than Holstein cattle without the condition.…”

Section: Slick Hairmentioning

confidence: 99%

A Review of Selected Genes with Known Effects on Performance and Health of Cattle

Casas

Kehrli

2016

Front. Vet. Sci.

View full text Add to dashboard Cite

There are genetic conditions that influence production in dairy and beef cattle. The objective of this review was to describe relevant genetic conditions that have been associated with productivity and health in cattle. Genes or genomic regions that have been identified as a candidate for the condition will be included, and the genetic basis of the condition will be defined. Genes and genetic conditions included in this review are bovine leukocyte adhesion deficiency, deficiency of the uridine monophosphate synthase, bovine chronic interstitial nephritis, horn development, myostatin, complex vertebral malformation, leptin, osteopetrosis, apoptosis peptide activating factor 1, chondrodysplastic dwarfism, caseins, calpastatin, umbilical hernia, lactoglobulin, citrullinemia, cholesterol deficiency, prions, thyroglobulin, diacylglycerol acyltransferase, syndactyly, maple syrup urine disease, slick hair, Factor XI deficiency, and μ-Calpain. This review is not meant to be comprehensive, and relevant information is provided to ascertain genetic markers associated with the conditions.

show abstract

Functionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle

Cited by 126 publications

References 33 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

Multiple QTL underlie milk phenotypes at the CSF2RB locus

A Review of Selected Genes with Known Effects on Performance and Health of Cattle

Contact Info

Product

Resources

About