RESUMO
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: The relative contributions of the enzymatic and transcription-based mechanisms now attributed to K232A remain unclear; however, these results suggest that transcriptional impacts contribute to the diversity of lactation effects observed at the DGAT1 locus.
Assuntos
Diacilglicerol O-Aciltransferase , Lactação , Animais , Bovinos , Diacilglicerol O-Aciltransferase/genética , Éxons , Feminino , Expressão Gênica , Leite , MutaçãoRESUMO
A major pleiotropic quantitative trait locus (QTL) located at ~25 Mbp on bovine chromosome 14 affects a myriad of growth and developmental traits in Bos taurus and indicus breeds. These QTL have been attributed to two functional variants in the bidirectional promoter of PLAG1 and CHCHD7. Although PLAG1 is a good candidate for mediating these effects, its role remains uncertain given that these variants are also associated with expression of five additional genes at the broader locus. In the current study, we conducted expression QTL (eQTL) mapping of this region using a large, high depth mammary RNAseq dataset representing 375 lactating cows. Here we show that of the seven previously implicated genes, only PLAG1 and LYN are differentially expressed by QTL genotype, and only PLAG1 bears the same association signature of the growth and body weight QTLs. For the first time, we also report significant association of PLAG1 genotype with milk production traits, including milk fat, volume, and protein yield. Collectively, these data strongly suggest PLAG1 as the causative gene underlying this diverse range of traits, and demonstrate new effects for the locus on lactation phenotypes.
Assuntos
Peso Corporal/genética , Bovinos/genética , Proteínas de Ligação a DNA/genética , Pleiotropia Genética , Leite/química , Animais , Cromossomos de Mamíferos/genética , Indústria de Laticínios , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Característica Quantitativa Herdável , Reprodutibilidade dos TestesRESUMO
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.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Glutationa Transferase/genética , Leite/química , Locos de Características Quantitativas , Animais , Teorema de Bayes , Bovinos , Mapeamento Cromossômico/veterinária , Cromossomos de Mamíferos/genética , Estudo de Associação Genômica Ampla/veterinária , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/veterinária , Análise de Sequência de RNA/veterináriaRESUMO
Adenoid cystic carcinoma (ACC) is a malignant neoplasm most commonly originating in salivary glands of the head and neck area. When ACC presents outside of these locations, the diagnosis may become more challenging. We describe three cases of ACC presenting in extra-salivary gland sites. Two cases were metastatic; in case 1 the initial presentation was widespread bony metastasis of unknown primary origin. The other metastatic case (case 2) was from a patient presenting with a pleural effusion and a history of previously treated metastatic pulmonary ACC. The pleural effusion cytology was unusual in that exfoliated ACC cells were present in the effusion itself, a rare occurrence. Case 3 was a primary bronchial ACC. In conclusion, ACC can present in various body sites and cytologists must consider this neoplasm when presented with a basaloid carcinoma of uncertain origin.
