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1.
Genet Sel Evol ; 51(1): 3, 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30678637

RESUMO

BACKGROUND: Over many years, artificial selection has substantially improved milk production by cows. However, the genes that underlie milk production quantitative trait loci (QTL) remain relatively poorly characterised. Here, we investigate a previously reported QTL located at the CSF2RB locus on chromosome 5, for several milk production phenotypes, to better understand its underlying genetic and molecular causes. RESULTS: Using a population of 29,350 taurine dairy cows, 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 11 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 responsible for 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 that involves the CSF2RB gene. CONCLUSIONS: This 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.


Assuntos
Bovinos/genética , Subunidade beta Comum dos Receptores de Citocinas/genética , Lactação/genética , Fenótipo , Locos de Características Quantitativas , Regiões 3' não Traduzidas , Animais , Subunidade beta Comum dos Receptores de Citocinas/metabolismo , Feminino , Masculino , Leite/metabolismo , Fosfoproteínas/genética
2.
J Dairy Res ; 85(2): 185-192, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29785904

RESUMO

Inflammation of the mammary gland following bacterial infection, commonly known as mastitis, affects all mammalian species. Although the aetiology and epidemiology of mastitis in the dairy cow are well described, the genetic factors mediating resistance to mammary gland infection are not well known, due in part to the difficulty in obtaining robust phenotypic information from sufficiently large numbers of individuals. To address this problem, an experimental mammary gland infection experiment was undertaken, using a Friesian-Jersey cross breed F2 herd. A total of 604 animals received an intramammary infusion of Streptococcus uberis in one gland, and the clinical response over 13 milkings was used for linkage mapping and genome-wide association analysis. A quantitative trait locus (QTL) was detected on bovine chromosome 11 for clinical mastitis status using micro-satellite and Affymetrix 10 K SNP markers, and then exome and genome sequence data used from the six F1 sires of the experimental animals to examine this region in more detail. A total of 485 sequence variants were typed in the QTL interval, and association mapping using these and an additional 37 986 genome-wide markers from the Illumina SNP50 bovine SNP panel revealed association with markers encompassing the interleukin-1 gene cluster locus. This study highlights a region on bovine chromosome 11, consistent with earlier studies, as conferring resistance to experimentally induced mammary gland infection, and newly prioritises the IL1 gene cluster for further analysis in genetic resistance to mastitis.


Assuntos
Mastite Bovina/genética , Mastite Bovina/imunologia , Infecções Estreptocócicas/veterinária , Animais , Bovinos , Mapeamento Cromossômico/veterinária , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/veterinária , Genótipo , Hibridização Genética , Mastite Bovina/microbiologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
3.
BMC Genomics ; 18(1): 968, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-29246110

RESUMO

BACKGROUND: Lactose provides an easily-digested energy source for neonates, and is the primary carbohydrate in milk in most species. Bovine lactose is also a key component of many human food products. However, compared to analyses of other milk components, the genetic control of lactose has been little studied. Here we present the first GWAS focussed on analysis of milk lactose traits. RESULTS: Using a discovery population of 12,000 taurine dairy cattle, we detail 27 QTL for lactose concentration and yield, and subsequently validate the effects of 26 of these loci in a distinct population of 18,000 cows. We next present data implicating causative genes and variants for these QTL. Fine mapping of these regions using imputed, whole genome sequence-resolution genotypes reveals protein-coding candidate causative variants affecting the ABCG2, DGAT1, STAT5B, KCNH4, NPFFR2 and RNF214 genes. Eleven of the remaining QTL appear to be driven by regulatory effects, suggested by the presence of co-locating, co-segregating eQTL discovered using mammary RNA sequence data from a population of 357 lactating cows. Pathway analysis of genes representing all lactose-associated loci shows significant enrichment of genes located in the endoplasmic reticulum, with functions related to ion channel activity mediated through the LRRC8C, P2RX4, KCNJ2 and ANKH genes. A number of the validated QTL are also found to be associated with additional milk volume, fat and protein phenotypes. CONCLUSIONS: Overall, these findings highlight novel candidate genes and variants involved in milk lactose regulation, whose impacts on membrane transport mechanisms reinforce the key osmo-regulatory roles of lactose in milk.


Assuntos
Lactose/metabolismo , Proteínas de Membrana Transportadoras/genética , Leite/metabolismo , Locos de Características Quantitativas , Alelos , Animais , Bovinos , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Transporte de Íons/genética , Lactação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Análise de Sequência de RNA
4.
Sci Rep ; 7: 44793, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28322319

RESUMO

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 Testes
5.
Sci Rep ; 6: 25376, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27146958

RESUMO

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/veterinária
6.
Sci Rep ; 5: 8484, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25719731

RESUMO

Selective breeding has strongly reduced the genetic diversity in livestock species, and contemporary breeding practices exclude potentially beneficial rare genetic variation from the future gene pool. Here we test whether important traits arising by new mutations can be identified and rescued in highly selected populations. We screened milks from 2.5 million cows to identify an exceptional individual which produced milk with reduced saturated fat content, and improved unsaturated and omega-3 fatty acid concentrations. The milk traits were transmitted dominantly to her offspring, and genetic mapping and genome sequencing revealed a new mutation in a previously unknown splice enhancer of the DGAT1 gene. Homozygous carriers show features of human diarrheal disorders, and may be useful for the development of therapeutic strategies. Our study demonstrates that high-throughput phenotypic screening can uncover rich genetic diversity even in inbred populations, and introduces a novel strategy to develop novel milks with improved nutritional properties.


Assuntos
Diacilglicerol O-Aciltransferase/genética , Leite/metabolismo , Mutação de Sentido Incorreto , Animais , Sequência de Bases , Bovinos/genética , Ácidos Graxos/biossíntese , Feminino , Estudos de Associação Genética , Metabolismo dos Lipídeos/genética , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único
7.
Nat Commun ; 5: 5861, 2014 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-25519203

RESUMO

Lactation, hair development and homeothermy are characteristic evolutionary features that define mammals from other vertebrate species. Here we describe the discovery of two autosomal dominant mutations with antagonistic, pleiotropic effects on all three of these biological processes, mediated through the prolactin signalling pathway. Most conspicuously, mutations in prolactin (PRL) and its receptor (PRLR) have an impact on thermoregulation and hair morphology phenotypes, giving prominence to this pathway outside of its classical roles in lactation.


Assuntos
Regulação da Temperatura Corporal/genética , Cabelo/metabolismo , Lactação/genética , Mutação , Prolactina/genética , Transdução de Sinais , Sequência de Aminoácidos , Animais , Sequência de Bases , Temperatura Corporal , Bovinos , Feminino , Expressão Gênica , Pleiotropia Genética , Genótipo , Cabelo/ultraestrutura , Homeostase , Humanos , Dados de Sequência Molecular , Fenótipo , Prolactina/metabolismo , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Pele/anatomia & histologia , Pele/metabolismo
8.
J Dairy Res ; 81(3): 340-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25052435

RESUMO

The objective of this study was to estimate heritability and crossbreeding parameters (breed and heterosis effects) of various fatty acid (FA) concentrations in milk fat of New Zealand dairy cattle. For this purpose, calibration equations to predict concentration of each of the most common FAs were derived with partial least squares (PLS) using mid-infrared (MIR) spectral data from milk samples (n=850) collected in the 2003-04 season from 348 second-parity crossbred cows during peak, mid and late lactation. The milk samples produced both, MIR spectral data and concentration of the most common FAs determined using gas chromatography (GC). The concordance correlation coefficients (CCC) between the concentration of a FA determined by GC and the PLS equation ranged from 0.63 to 0.94, suggesting that some prediction equations can be considered to have substantial predictive ability. The PLS calibration equations were then used to predict the concentration of each of the fatty acids in 26,769 milk samples from 7385 cows that were herd-tested during the 2007-08 season. Data were analysed using a single-trait repeatability animal model. Shorter chain FA (16:0 and below) were significantly higher (P<0.05) in Jersey cows, while longer chain, including unsaturated longer chain FA were higher in Holstein-Friesian cows. The estimates of heritabilities ranged from 0.17 to 0.41 suggesting that selective breeding could be used to ensure milk fat composition stays aligned to consumer, market and manufacturing needs.


Assuntos
Bovinos/genética , Ácidos Graxos/análise , Leite/química , Animais , Cromatografia Gasosa/veterinária , Feminino , Hibridização Genética/genética , Característica Quantitativa Herdável , Espectrofotometria Infravermelho/veterinária
9.
PLoS One ; 9(1): e85757, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24465687

RESUMO

Milk is composed of a complex mixture of lipids, proteins, carbohydrates and various vitamins and minerals as a source of nutrition for young mammals. The composition of milk varies between individuals, with lipid composition in particular being highly heritable. Recent reports have highlighted a region of bovine chromosome 27 harbouring variants affecting milk fat percentage and fatty acid content. We aimed to further investigate this locus in two independent cattle populations, consisting of a Holstein-Friesian x Jersey crossbreed pedigree of 711 F2 cows, and a collection of 32,530 mixed ancestry Bos taurus cows. Bayesian genome-wide association mapping using markers imputed from the Illumina BovineHD chip revealed a large quantitative trait locus (QTL) for milk fat percentage on chromosome 27, present in both populations. We also investigated a range of other milk composition phenotypes, and report additional associations at this locus for fat yield, protein percentage and yield, lactose percentage and yield, milk volume, and the proportions of numerous milk fatty acids. We then used mammary RNA sequence data from 212 lactating cows to assess the transcript abundance of genes located in the milk fat percentage QTL interval. This analysis revealed a strong eQTL for AGPAT6, demonstrating that high milk fat percentage genotype is also additively associated with increased expression of the AGPAT6 gene. Finally, we used whole genome sequence data from six F1 sires to target a panel of novel AGPAT6 locus variants for genotyping in the F2 crossbreed population. Association analysis of 58 of these variants revealed highly significant association for polymorphisms mapping to the 5'UTR exons and intron 1 of AGPAT6. Taken together, these data suggest that variants affecting the expression of AGPAT6 are causally involved in differential milk fat synthesis, with pleiotropic consequences for a diverse range of other milk components.


Assuntos
Bovinos/genética , Variação Genética , Glicerol-3-Fosfato O-Aciltransferase/genética , Lipogênese/genética , Leite/metabolismo , Animais , Sequência de Bases , Cromossomos de Mamíferos/genética , Cruzamentos Genéticos , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Lactação/genética , Lipídeos/genética , Masculino , Glândulas Mamárias Animais/metabolismo , Dados de Sequência Molecular , Fenótipo , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Nat Genet ; 43(5): 405-13, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21516082

RESUMO

We report mapping of a quantitative trait locus (QTL) with a major effect on bovine stature to a ∼780-kb interval using a Hidden Markov Model-based approach that simultaneously exploits linkage and linkage disequilibrium. We re-sequenced the interval in six sires with known QTL genotype and identified 13 clustered candidate quantitative trait nucleotides (QTNs) out of >9,572 discovered variants. We eliminated five candidate QTNs by studying the phenotypic effect of a recombinant haplotype identified in a breed diversity panel. We show that the QTL influences fetal expression of seven of the nine genes mapping to the ∼780-kb interval. We further show that two of the eight candidate QTNs, mapping to the PLAG1-CHCHD7 intergenic region, influence bidirectional promoter strength and affect binding of nuclear factors. By performing expression QTL analyses, we identified a splice site variant in CHCHD7 and exploited this naturally occurring null allele to exclude CHCHD7 as single causative gene.


Assuntos
Bovinos/anatomia & histologia , Bovinos/genética , Variação Genética , Alelos , Animais , Sequência de Bases , Mapeamento Cromossômico , Cruzamentos Genéticos , Primers do DNA/genética , Feminino , Estudo de Associação Genômica Ampla , Haplótipos , Desequilíbrio de Ligação , Masculino , Fases de Leitura Aberta , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Sítios de Splice de RNA , Regulon , Homologia de Sequência do Ácido Nucleico
11.
Science ; 324(5926): 528-32, 2009 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-19390050

RESUMO

The imprints of domestication and breed development on the genomes of livestock likely differ from those of companion animals. A deep draft sequence assembly of shotgun reads from a single Hereford female and comparative sequences sampled from six additional breeds were used to develop probes to interrogate 37,470 single-nucleotide polymorphisms (SNPs) in 497 cattle from 19 geographically and biologically diverse breeds. These data show that cattle have undergone a rapid recent decrease in effective population size from a very large ancestral population, possibly due to bottlenecks associated with domestication, selection, and breed formation. Domestication and artificial selection appear to have left detectable signatures of selection within the cattle genome, yet the current levels of diversity within breeds are at least as great as exists within humans.


Assuntos
Bovinos/genética , Variação Genética , Genoma , Polimorfismo de Nucleotídeo Único , Animais , Cruzamento , Feminino , Frequência do Gene , Masculino , Dados de Sequência Molecular , Mutação , Densidade Demográfica
12.
J Invest Dermatol ; 124(6): 1170-6, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15955091

RESUMO

A mechanobullous skin disorder was identified in the progeny of a 3-y-old Friesian-Jersey crossbred bull. The condition presented as loss of skin and mucosa from contact areas and inflammation. Examination of skin samples under light microscopy revealed separation of the epidermis from the dermis. Electron microscopic analysis refined the site of cleavage to above the basement membrane involving lysis of basal keratinocytes. These observations were consistent with the simplex form of epidermolysis bullosa (EB) in humans. Candidate genes based on human gene mutations were assessed, resulting in keratin 5 being identified as the most likely candidate gene. The sequence of bovine keratin 5 was established and sequencing led to identification of a G to A substitution in all affected animals. This mutation leads to an amino acid change of glutamic acid to lysine in the final E (478) of the KLLEGE motif of the protein. The sire carried a de novo mutation and was mosaic, explaining his asymptomatic status and the less than expected frequency of affected offspring. Remarkably, the same mutation has been previously described in EB simplex in humans.


Assuntos
Doenças dos Bovinos/genética , Epidermólise Bolhosa Simples/veterinária , Queratinas/genética , Mosaicismo , Mutação , Motivos de Aminoácidos , Substituição de Aminoácidos , Animais , Animais Recém-Nascidos , Bovinos , Doenças dos Bovinos/patologia , Doenças dos Bovinos/fisiopatologia , Mapeamento Cromossômico , Feminino , Ácido Glutâmico , Queratina-5 , Lisina , Masculino , Microscopia Eletrônica , Linhagem
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