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Genet Sel Evol ; 51(1): 62, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703548


BACKGROUND: White spotting of the coat is a characteristic trait of various domestic species including cattle and other mammals. It is a hallmark of Holstein-Friesian cattle, and several previous studies have detected genetic loci with major effects for white spotting in animals with Holstein-Friesian ancestry. Here, our aim was to better understand the underlying genetic and molecular mechanisms of white spotting, by conducting the largest mapping study for this trait in cattle, to date. RESULTS: Using imputed whole-genome sequence data, we conducted a genome-wide association analysis in 2973 mixed-breed cows and bulls. Highly significant quantitative trait loci (QTL) were found on chromosomes 6 and 22, highlighting the well-established coat color genes KIT and MITF as likely responsible for these effects. These results are in broad agreement with previous studies, although we also report a third significant QTL on chromosome 2 that appears to be novel. This signal maps immediately adjacent to the PAX3 gene, which encodes a known transcription factor that controls MITF expression and is the causal locus for white spotting in horses. More detailed examination of these loci revealed a candidate causal mutation in PAX3 (p.Thr424Met), and another candidate mutation (rs209784468) within a conserved element in intron 2 of MITF transcripts expressed in the skin. These analyses also revealed a mechanistic ambiguity at the chromosome 6 locus, where highly dispersed association signals suggested multiple or multiallelic QTL involving KIT and/or other genes in this region. CONCLUSIONS: Our findings extend those of previous studies that reported KIT as a likely causal gene for white spotting, and report novel associations between candidate causal mutations in both the MITF and PAX3 genes. The sizes of the effects of these QTL are substantial, and could be used to select animals with darker, or conversely whiter, coats depending on the desired characteristics.

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


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.

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
RNA ; 25(3): 319-335, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30530731


Post-transcriptional RNA editing may regulate transcript expression and diversity in cells, with potential impacts on various aspects of physiology and environmental adaptation. A small number of recent genome-wide studies in Drosophila, mouse, and human have shown that RNA editing can be genetically modulated, highlighting loci that quantitatively impact editing of transcripts. The potential gene expression and physiological consequences of these RNA-editing quantitative trait loci (edQTL), however, are almost entirely unknown. Here, we present analyses of RNA editing in a large domestic mammal (Bos taurus), where we use whole-genome and high-depth RNA sequencing to discover, characterize, and conduct genetic mapping studies of novel transcript edits. Using a discovery population of nine deeply sequenced cows, we identify 2413 edit sites in the mammary transcriptome, the majority of which are adenosine to inosine edits (98.6%). Most sites are predicted to reside in double-stranded secondary structures (85.1%), and quantification of the rates of editing in an additional 355 cows reveals editing is negatively correlated with gene expression in the majority of cases. Genetic analyses of RNA editing and gene expression highlight 152 cis-regulated edQTL, of which 15 appear to cosegregate with expression QTL effects. Trait association analyses in a separate population of 9989 lactating cows also shows 12 of the cis-edQTL coincide with at least one cosegregating lactation QTL. Together, these results enhance our understanding of RNA-editing dynamics in mammals, and suggest mechanistic links by which loci may impact phenotype through RNA editing mediated processes.

Regulação da Expressão Gênica , Mamíferos/genética , Edição de RNA , Animais , Sequência de Bases , Mapeamento Cromossômico , Biologia Computacional/métodos , Sequência Consenso , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Locos de Características Quantitativas , Característica Quantitativa Herdável
Sci Rep ; 5: 8484, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25719731


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.

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
Nat Genet ; 43(5): 405-13, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21516082


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.

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
J Genet Genomics ; 36(11): 661-6, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19932462


Pigmentation traits expressed in animals are visual characteristics that allow us to distinguish between breeds and between strains within breed. The objective of this study was to map quantitative trait loci (QTLs) affecting the pigmentation traits in approximately 800 F(2) grand daughter dairy cattle from a Holstein-Friesian and Jersey cross breed cattle. Traits analyzed included pigmentation phenotypes on the body, teat and hoop. The phenoypes were collected from digital photos or visual inspection of live animals. QTL mapping was implemented using half-sib and line-of-descent inheritance models. Our analysis initially detected a number of significant QTLs on chromosomes: 2, 6, 13, 15, 18 and 22. The significant QTLs were divided into two groups: one group influencing the pigmentation color and the other group affecting the absence or level of pigmentation. The most significant QTL peaks were observed on Bovine taurus autosome 18 (BTA18) close to melanocortin 1 receptor (MC1R) for the color traits, on BTA6 close to the receptor tyrosine kinase (KIT) and BTA22 close to microphthalmia-associated transcription factor (MITF) gene for the spotting traits. Association studies were conducted for candidate regions or genes known to affect pigmentation in dairy cattle.

Bovinos/genética , Genoma , Pigmentação/genética , Característica Quantitativa Herdável , Animais , Bovinos/fisiologia , Mapeamento Cromossômico/veterinária , Cromossomos de Mamíferos/genética , Feminino , Masculino , Locos de Características Quantitativas