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1.
Proc Natl Acad Sci U S A ; 116(39): 19398-19408, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31501319

RESUMO

Many genome variants shaping mammalian phenotype are hypothesized to regulate gene transcription and/or to be under selection. However, most of the evidence to support this hypothesis comes from human studies. Systematic evidence for regulatory and evolutionary signals contributing to complex traits in a different mammalian model is needed. Sequence variants associated with gene expression (expression quantitative trait loci [eQTLs]) and concentration of metabolites (metabolic quantitative trait loci [mQTLs]) and under histone-modification marks in several tissues were discovered from multiomics data of over 400 cattle. Variants under selection and evolutionary constraint were identified using genome databases of multiple species. These analyses defined 30 sets of variants, and for each set, we estimated the genetic variance the set explained across 34 complex traits in 11,923 bulls and 32,347 cows with 17,669,372 imputed variants. The per-variant trait heritability of these sets across traits was highly consistent (r > 0.94) between bulls and cows. Based on the per-variant heritability, conserved sites across 100 vertebrate species and mQTLs ranked the highest, followed by eQTLs, young variants, those under histone-modification marks, and selection signatures. From these results, we defined a Functional-And-Evolutionary Trait Heritability (FAETH) score indicating the functionality and predicted heritability of each variant. In additional 7,551 cattle, the high FAETH-ranking variants had significantly increased genetic variances and genomic prediction accuracies in 3 production traits compared to the low FAETH-ranking variants. The FAETH framework combines the information of gene regulation, evolution, and trait heritability to rank variants, and the publicly available FAETH data provide a set of biological priors for cattle genomic selection worldwide.


Assuntos
Evolução Biológica , Bovinos/genética , Regulação da Expressão Gênica/genética , Herança Multifatorial/genética , Animais , Cruzamento , Bases de Dados Genéticas , Feminino , Variação Genética , Genoma/genética , Estudo de Associação Genômica Ampla , Masculino , Fenótipo , Locos de Características Quantitativas/genética , Seleção Genética
2.
Genetics ; 211(4): 1131-1141, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30967442

RESUMO

In this Review, we focus on the similarity of the concepts underlying prediction of estimated breeding values (EBVs) in livestock and polygenic risk scores (PRS) in humans. Our research spans both fields and so we recognize factors that are very obvious for those in one field, but less so for those in the other. Differences in family size between species is the wedge that drives the different viewpoints and approaches. Large family size achievable in nonhuman species accompanied by selection generates a smaller effective population size, increased linkage disequilibrium and a higher average genetic relationship between individuals within a population. In human genetic analyses, we select individuals unrelated in the classical sense (coefficient of relationship <0.05) to estimate heritability captured by common SNPs. In livestock data, all animals within a breed are to some extent "related," and so it is not possible to select unrelated individuals and retain a data set of sufficient size to analyze. These differences directly or indirectly impact the way data analyses are undertaken. In livestock, genetic segregation variance exposed through samplings of parental genomes within families is directly observable and taken for granted. In humans, this genomic variation is under-recognized for its contribution to variation in polygenic risk of common disease, in both those with and without family history of disease. We explore the equation that predicts the expected proportion of variance explained using PRS, and quantify how GWAS sample size is the key factor for maximizing accuracy of prediction in both humans and livestock. Last, we bring together the concepts discussed to address some frequently asked questions.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Gado/genética , Herança Multifatorial , Característica Quantitativa Herdável , Animais , Big Data , Cruzamento/métodos , Humanos
3.
BMC Genomics ; 19(1): 395, 2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29793448

RESUMO

BACKGROUND: Topological association domains (TADs) are chromosomal domains characterised by frequent internal DNA-DNA interactions. The transcription factor CTCF binds to conserved DNA sequence patterns called CTCF binding motifs to either prohibit or facilitate chromosomal interactions. TADs and CTCF binding motifs control gene expression, but they are not yet well defined in the bovine genome. In this paper, we sought to improve the annotation of bovine TADs and CTCF binding motifs, and assess whether the new annotation can reduce the search space for cis-regulatory variants. RESULTS: We used genomic synteny to map TADs and CTCF binding motifs from humans, mice, dogs and macaques to the bovine genome. We found that our mapped TADs exhibited the same hallmark properties of those sourced from experimental data, such as housekeeping genes, transfer RNA genes, CTCF binding motifs, short interspersed elements, H3K4me3 and H3K27ac. We showed that runs of genes with the same pattern of allele-specific expression (ASE) (either favouring paternal or maternal allele) were often located in the same TAD or between the same conserved CTCF binding motifs. Analyses of variance showed that when averaged across all bovine tissues tested, TADs explained 14% of ASE variation (standard deviation, SD: 0.056), while CTCF explained 27% (SD: 0.078). Furthermore, we showed that the quantitative trait loci (QTLs) associated with gene expression variation (eQTLs) or ASE variation (aseQTLs), which were identified from mRNA transcripts from 141 lactating cows' white blood and milk cells, were highly enriched at putative bovine CTCF binding motifs. The linearly-furthermost, and most-significant aseQTL and eQTL for each genic target were located within the same TAD as the gene more often than expected (Chi-Squared test P-value < 0.001). CONCLUSIONS: Our results suggest that genomic synteny can be used to functionally annotate conserved transcriptional components, and provides a tool to reduce the search space for causative regulatory variants in the bovine genome.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Genômica , Motivos de Nucleotídeos , Animais , Bovinos , Ligação Proteica , Locos de Características Quantitativas/genética
4.
J Dairy Sci ; 101(7): 6220-6231, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29680649

RESUMO

Researching depletions in homozygous genotypes for specific haplotypes among the large cohorts of animals genotyped for genomic selection is a very efficient strategy to map recessive lethal mutations. In this study, by analyzing real or imputed Illumina BovineSNP50 (Illumina Inc., San Diego, CA) genotypes from more than 250,000 Holstein animals, we identified a new locus called HH6 showing significant negative effects on conception rate and nonreturn rate at 56 d in at-risk versus control mating. We fine-mapped this locus in a 1.1-Mb interval and analyzed genome sequence data from 12 carrier and 284 noncarrier Holstein bulls. We report the identification of a strong candidate mutation in the gene encoding SDE2 telomere maintenance homolog (SDE2), a protein essential for genomic stability in eukaryotes. This A-to-G transition changes the initiator ATG (methionine) codon to ACG because the gene is transcribed on the reverse strand. Using RNA sequencing and quantitative reverse-transcription PCR, we demonstrated that this mutation does not significantly affect SDE2 splicing and expression level in heterozygous carriers compared with control animals. Initiation of translation at the closest in-frame methionine codon would truncate the SDE2 precursor by 83 amino acids, including the cleavage site necessary for its activation. Finally, no homozygote for the G allele was observed in a large population of nearly 29,000 individuals genotyped for the mutation. The low frequency (1.3%) of the derived allele in the French population and the availability of a diagnostic test on the Illumina EuroG10K SNP chip routinely used for genomic evaluation will enable rapid and efficient selection against this deleterious mutation.


Assuntos
Bovinos/embriologia , Bovinos/genética , Códon de Iniciação , Mutação , Animais , Genótipo , Haplótipos , Homozigoto , Masculino , Polimorfismo de Nucleotídeo Único
5.
Gigascience ; 7(3): 1-17, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29618048

RESUMO

Genome sequences for hundreds of mammalian species are available, but an understanding of their genomic regulatory regions, which control gene expression, is only beginning. A comprehensive prediction of potential active regulatory regions is necessary to functionally study the roles of the majority of genomic variants in evolution, domestication, and animal production. We developed a computational method to predict regulatory DNA sequences (promoters, enhancers, and transcription factor binding sites) in production animals (cows and pigs) and extended its broad applicability to other mammals. The method utilizes human regulatory features identified from thousands of tissues, cell lines, and experimental assays to find homologous regions that are conserved in sequences and genome organization and are enriched for regulatory elements in the genome sequences of other mammalian species. Importantly, we developed a filtering strategy, including a machine learning classification method, to utilize a very small number of species-specific experimental datasets available to select for the likely active regulatory regions. The method finds the optimal combination of sensitivity and accuracy to unbiasedly predict regulatory regions in mammalian species. Furthermore, we demonstrated the utility of the predicted regulatory datasets in cattle for prioritizing variants associated with multiple production and climate change adaptation traits and identifying potential genome editing targets.


Assuntos
Genoma/genética , Genômica , Transcriptoma/genética , Animais , Bovinos , Mapeamento Cromossômico , Biologia Computacional , Humanos , Mamíferos , Regiões Promotoras Genéticas , Especificidade da Espécie , Suínos/genética
6.
Genet Sel Evol ; 50(1): 10, 2018 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-29571285

RESUMO

BACKGROUND: Genomic prediction and quantitative trait loci (QTL) mapping typically analyze one trait at a time but this may ignore the possibility that one polymorphism affects multiple traits. The aim of this study was to develop a multivariate Bayesian approach that could be used for simultaneously elucidating genetic architecture, QTL mapping, and genomic prediction. Our approach uses information from multiple traits to divide markers into 'unassociated' (no association with any trait) and 'associated' (associated with one or more traits). The effect of associated markers is estimated independently for each trait to avoid the assumption that QTL effects follow a multi-variate normal distribution. RESULTS: Using simulated data, our multivariate method (BayesMV) detected a larger number of true QTL (with a posterior probability > 0.9) and increased the accuracy of genomic prediction compared to an equivalent univariate method (BayesR). With real data, accuracies of genomic prediction in validation sets for milk yield traits with high-density genotypes were approximately equal to those from equivalent single-trait methods. BayesMV tended to select a similar number of single nucleotide polymorphisms (SNPs) per trait for genomic prediction compared to BayesR (i.e. those with non-zero effects), but BayesR selected different sets of SNPs for each trait, whereas BayesMV selected a common set of SNPs across traits. Despite these two dramatically different estimates of genetic architecture (i.e. different SNPs affecting each trait vs. pleiotropic SNPs), both models indicated that 3000 to 4000 SNPs are associated with a trait. The BayesMV approach may be advantageous when the aim is to develop a low-density SNP chip that works well for a number of traits. SNPs for milk yield traits identified by BayesMV and BayesR were also found to be associated with detailed milk composition. CONCLUSIONS: The BayesMV method simultaneously estimates the proportion of SNPs that are associated with a combination of traits. When applied to milk production traits, most of the identified SNPs were associated with all three traits (milk, fat and protein yield). BayesMV aims at exploiting pleiotropic QTL and selects a small number of SNPs that could be used to predict multiple traits.


Assuntos
Mapeamento Cromossômico/veterinária , Genômica/métodos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Algoritmos , Animais , Teorema de Bayes , Bovinos , Simulação por Computador , Feminino , Leite , Modelos Genéticos
8.
Genet Sel Evol ; 49(1): 56, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28683716

RESUMO

BACKGROUND: Enhancers are non-coding DNA sequences, which when they are bound by specific proteins increase the level of gene transcription. Enhancers activate unique gene expression patterns within cells of different types or under different conditions. Enhancers are key contributors to gene regulation, and causative variants that affect quantitative traits in humans and mice have been located in enhancer regions. However, in the bovine genome, enhancers as well as other regulatory elements are not yet well defined. In this paper, we sought to improve the annotation of bovine enhancer regions by using publicly available mammalian enhancer information. To test if the identified putative bovine enhancer regions are enriched with functional variants that affect milk production traits, we performed genome-wide association studies using imputed whole-genome sequence data followed by meta-analysis and enrichment analysis. RESULTS: We produced a library of candidate bovine enhancer regions by using publicly available bovine ChIP-Seq enhancer data in combination with enhancer data that were identified based on sequence homology with human and mouse enhancer databases. We found that imputed whole-genome sequence variants associated with milk production traits in 16,581 dairy cattle were enriched with enhancer regions that were marked by bovine-liver H3K4me3 and H3K27ac histone modifications from both permutation tests and gene set enrichment analysis. Enhancer regions that were identified based on sequence homology with human and mouse enhancer regions were not as strongly enriched with trait-associated sequence variants as the bovine ChIP-Seq candidate enhancer regions. The bovine ChIP-Seq enriched enhancer regions were located near genes and quantitative trait loci that are associated with pregnancy, growth, disease resistance, meat quality and quantity, and milk quality and quantity traits in dairy and beef cattle. CONCLUSIONS: Our results suggest that sequence variants within enhancer regions that are located in bovine non-coding genomic regions contribute to the variation in complex traits. The level of enrichment was higher in bovine-specific enhancer regions that were identified by detecting histone modifications H3K4me3 and H3K27ac in bovine liver tissues than in enhancer regions identified by sequence homology with human and mouse data. These results highlight the need to use bovine-specific experimental data for the identification of enhancer regions.


Assuntos
Bovinos/genética , Elementos Facilitadores Genéticos/genética , Genoma/genética , Animais , Estudo de Associação Genômica Ampla , Humanos , Lactação/genética , Camundongos , Leite , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
9.
J Dairy Sci ; 100(9): 7362-7367, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28711268

RESUMO

Excessive ambient temperature and humidity can impair milk production and fertility of dairy cows. Selection for heat-tolerant animals is one possible option to mitigate the effects of heat stress. To enable selection for this trait, we describe the development of a heat tolerance breeding value for Australian dairy cattle. We estimated the direct genomic values of decline in milk, fat, and protein yield per unit increase of temperature-humidity index (THI) using 46,726 single nucleotide polymorphisms and a reference population of 2,236 sires and 11,853 cows for Holsteins and 506 sires and 4,268 cows for Jerseys. This new direct genomic value is the Australian genomic breeding value for heat tolerance (HT ABVg). The components of the HT ABVg are the decline in milk, fat, and protein per unit increase in THI when THI increases above the threshold of 60. These components are weighted by their respective economic values, assumed to be equivalent to the weights applied to milk, fat, and protein yield in the Australian selection indices. Within each breed, the HT ABVg is then standardized to have a mean of 100 and standard deviation (SD) of 5, which is consistent with the presentation of breeding values for many other traits in Australia. The HT ABVg ranged from -4 to +3 SD in Holsteins and -3 to +4 SD in Jerseys. The mean reliabilities of HT ABVg among validation sires, calculated from the prediction error variance and additive genetic variance, were 38% in both breeds. The range in ABVg and their reliability suggests that HT can be improved using genomic selection. There has been a deterioration in the genetic trend of HT, and to moderate the decline it is suggested that the HT ABVg should be included in a multitrait economic index with other traits that contribute to farm profit.


Assuntos
Cruzamento , Termotolerância/genética , Animais , Austrália , Cruzamento/normas , Bovinos , Feminino , Técnicas Genéticas/veterinária , Umidade , Lactação , Masculino , Leite/metabolismo , Proteínas do Leite/biossíntese , Reprodutibilidade dos Testes , Temperatura , Termotolerância/fisiologia
10.
Plant Genome ; 9(3)2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27902807

RESUMO

Potato ( L.) breeders consider a large number of traits during cultivar development and progress in conventional breeding can be slow. There is accumulating evidence that some of these traits, such as yield, are affected by a large number of genes with small individual effects. Recently, significant efforts have been applied to the development of genomic resources to improve potato breeding, culminating in a draft genome sequence and the identification of a large number of single nucleotide polymorphisms (SNPs). The availability of these genome-wide SNPs is a prerequisite for implementing genomic selection for improvement of polygenic traits such as yield. In this review, we investigate opportunities for the application of genomic selection to potato, including novel breeding program designs. We have considered a number of factors that will influence this process, including the autotetraploid and heterozygous genetic nature of potato, the rate of decay of linkage disequilibrium, the number of required markers, the design of a reference population, and trait heritability. Based on estimates of the effective population size derived from a potato breeding program, we have calculated the expected accuracy of genomic selection for four key traits of varying heritability and propose that it will be reasonably accurate. We compared the expected genetic gain from genomic selection with the expected gain from phenotypic and pedigree selection, and found that genetic gain can be substantially improved by using genomic selection.


Assuntos
Genoma de Planta/genética , Melhoramento Vegetal , Solanum tuberosum/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Seleção Genética
11.
Neurocrit Care ; 25(2): 282-7, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27460062

RESUMO

BACKGROUND: Pneumothorax is an under-recognized complication of apnea testing performed as part of the neurological determination of death. It may result in hemodynamic instability or even cardiac arrest, compromising ability to declare brain death (BD) and viability of organs for transplantation. We report three cases of pneumothorax with apnea testing (PAT) and review the available literature of this phenomenon. METHODS: Series of three cases supplemented with a systematic review of literature (including discussion of apnea testing in major brain death guidelines). RESULTS: Two patients were diagnosed with PAT due to immediate hemodynamic compromise, while the third was diagnosed many hours after BD. An additional nine cases of PAT were found in the literature. Information regarding oxygen cannula diameter was available for nine patients (range 2.3-5.3 mm), and flow rate was available for ten patients (mean 11 L/min). Pneumothorax was treated to resolution in the majority of patients (n = 8), although only six completed apnea testing following diagnosis/treatment of pneumothorax and only three patients became organ donors afterward. Review of major BD guidelines showed that although use of low oxygen flow rate (usually ≤ 6 L/min) during apnea testing is suggested, the risk of PAT was explicitly mentioned in just one. CONCLUSION: Development of PAT may adversely affect the process of BD determination and could limit the opportunity for organ donation. Each institution should have preventive measures in place.


Assuntos
Apneia/diagnóstico , Morte Encefálica/diagnóstico , Pneumotórax/etiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pneumotórax/terapia , Adulto Jovem
12.
J Dairy Sci ; 99(4): 2849-2862, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27037467

RESUMO

Temperature and humidity levels above a certain threshold decrease milk production in dairy cattle, and genetic variation is associated with the amount of lost production. To enable selection for improved heat tolerance, the aim of this study was to develop genomic estimated breeding values (GEBV) for heat tolerance in dairy cattle. Heat tolerance was defined as the rate of decline in production under heat stress. We combined herd test-day recording data from 366,835 Holstein and 76,852 Jersey cows with daily temperature and humidity measurements from weather stations closest to the tested herds for test days between 2003 and 2013. We used daily mean values of temperature-humidity index averaged for the day of test and the 4 previous days as the measure of heat stress. Tolerance to heat stress was estimated for each cow using a random regression model with a common threshold of temperature-humidity index=60 for all cows. The slope solutions for cows from this model were used to define the daughter trait deviations of their sires. Genomic best linear unbiased prediction was used to calculate GEBV for heat tolerance for milk, fat, and protein yield. Two reference populations were used, the first consisted of genotyped sires only (2,300 Holstein and 575 Jersey sires), and the other included genotyped sires and cows (2,189 Holstein and 1,188 Jersey cows). The remainder of the genotyped sires were used as a validation set. All animals had genotypes for 632,003 single nucleotide polymorphisms. When using only genotyped sires in the reference set and only the first parity data, the accuracy of GEBV for heat tolerance in relation to changes in milk, fat, and protein yield were 0.48, 0.50, and 0.49 in the Holstein validation sires and 0.44, 0.61, and 0.53 in the Jersey validation sires, respectively. Some slight improvement in the accuracy of prediction was achieved when cows were included in the reference population for Holsteins. No clear improvements in the accuracy of genomic prediction were observed when data from the second and third parities were included. Correlations of GEBV for heat tolerance with Australian Breeding Values for other traits suggested heat tolerance had a favorable genetic correlation with fertility (0.29-0.39 in Holsteins and 0.15-0.27 in Jerseys), but unfavorable correlations for some production traits. Options to improve heat tolerance with genomic selection in Australian dairy cattle are discussed.


Assuntos
Cruzamento , Bovinos/fisiologia , Temperatura Alta , Seleção Genética , Estresse Fisiológico/genética , Animais , Austrália , Bovinos/genética , Doenças dos Bovinos/genética , Feminino , Fertilidade/genética , Variação Genética , Genótipo , Umidade , Lactação/genética , Masculino , Leite/química , Leite/metabolismo , Paridade/genética , Polimorfismo de Nucleotídeo Único/genética , Gravidez
13.
BMC Genomics ; 16: 993, 2015 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-26596891

RESUMO

BACKGROUND: Allele specific gene expression (ASE), with the paternal allele more expressed than the maternal allele or vice versa, appears to be a common phenomenon in humans and mice. In other species the extent of ASE is unknown, and even in humans and mice there are several outstanding questions. These include; to what extent is ASE tissue specific? how often does the direction of allele expression imbalance reverse between tissues? how often is only one of the two alleles expressed? is there a genome wide bias towards expression of the paternal or maternal allele; and finally do genes that are nearby on a chromosome share the same direction of ASE? Here we use gene expression data (RNASeq) from 18 tissues from a single cow to investigate each of these questions in turn, and then validate some of these findings in two tissues from 20 cows. RESULTS: Between 40 and 100 million sequence reads were generated per tissue across three replicate samples for each of the eighteen tissues from the single cow (the discovery dataset). A bovine gene expression atlas was created (the first from RNASeq data), and differentially expressed genes in each tissue were identified. To analyse ASE, we had access to unambiguously phased genotypes for all heterozygous variants in the cow's whole genome sequence, where these variants were homozygous in the whole genome sequence of her sire, and as a result we were able to map reads to parental genomes, to determine SNP and genes showing ASE in each tissue. In total 25,251 heterozygous SNP within 7985 genes were tested for ASE in at least one tissue. ASE was pervasive, 89 % of genes tested had significant ASE in at least one tissue. This large proportion of genes displaying ASE was confirmed in the two tissues in a validation dataset. For individual tissues the proportion of genes showing significant ASE varied from as low as 8-16 % of those tested in thymus to as high as 71-82 % of those tested in lung. There were a number of cases where the direction of allele expression imbalance reversed between tissues. For example the gene SPTY2D1 showed almost complete paternal allele expression in kidney and thymus, and almost complete maternal allele expression in the brain caudal lobe and brain cerebellum. Mono allelic expression (MAE) was common, with 1349 of 4856 genes (28 %) tested with more than one heterozygous SNP showing MAE. Across all tissues, 54.17 % of all genes with ASE favoured the paternal allele. Genes that are closely linked on the chromosome were more likely to show higher expression of the same allele (paternal or maternal) than expected by chance. We identified several long runs of neighbouring genes that showed either paternal or maternal ASE, one example was five adjacent genes (GIMAP8, GIMAP7 copy1, GIMAP4, GIMAP7 copy 2 and GIMAP5) that showed almost exclusive paternal expression in brain caudal lobe. CONCLUSIONS: Investigating the extent of ASE across 18 bovine tissues in one cow and two tissues in 20 cows demonstrated 1) ASE is pervasive in cattle, 2) the ASE is often MAE but ranges from MAE to slight overexpression of the major allele, 3) the ASE is most often tissue specific and that more than half the time displays divergent allele specific expression patterns across tissues, 4) across all genes there is a slight bias towards expression of the paternal allele and 5) genes expressing the same parental allele are clustered together more than expected by chance, and there are several runs of large numbers of genes expressing the same parental allele.


Assuntos
Animais não Endogâmicos/genética , Expressão Gênica , Polimorfismo de Nucleotídeo Único , Alelos , Animais , Bovinos , Mapeamento Cromossômico , Feminino , Perfilação da Expressão Gênica/métodos , Impressão Genômica , Pulmão/metabolismo , Masculino , Especificidade de Órgãos , Análise de Sequência de RNA/métodos , Timo/metabolismo
14.
Genet Sel Evol ; 47: 29, 2015 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-25887988

RESUMO

BACKGROUND: Genomic selection is increasingly widely practised, particularly in dairy cattle. However, the accuracy of current predictions using GBLUP (genomic best linear unbiased prediction) decays rapidly across generations, and also as selection candidates become less related to the reference population. This is likely caused by the effects of causative mutations being dispersed across many SNPs (single nucleotide polymorphisms) that span large genomic intervals. In this paper, we hypothesise that the use of a nonlinear method (BayesR), combined with a multi-breed (Holstein/Jersey) reference population will map causative mutations with more precision than GBLUP and this, in turn, will increase the accuracy of genomic predictions for selection candidates that are less related to the reference animals. RESULTS: BayesR improved the across-breed prediction accuracy for Australian Red dairy cattle for five milk yield and composition traits by an average of 7% over the GBLUP approach (Australian Red animals were not included in the reference population). Using the multi-breed reference population with BayesR improved accuracy of prediction in Australian Red cattle by 2 - 5% compared to using BayesR with a single breed reference population. Inclusion of 8478 Holstein and 3917 Jersey cows in the reference population improved accuracy of predictions for these breeds by 4 and 5%. However, predictions for Holstein and Jersey cattle were similar using within-breed and multi-breed reference populations. We propose that the improvement in across-breed prediction achieved by BayesR with the multi-breed reference population is due to more precise mapping of quantitative trait loci (QTL), which was demonstrated for several regions. New candidate genes with functional links to milk synthesis were identified using differential gene expression in the mammary gland. CONCLUSIONS: QTL detection and genomic prediction are usually considered independently but persistence of genomic prediction accuracies across breeds requires accurate estimation of QTL effects. We show that accuracy of across-breed genomic predictions was higher with BayesR than with GBLUP and that BayesR mapped QTL more precisely. Further improvements of across-breed accuracy of genomic predictions and QTL mapping could be achieved by increasing the size of the reference population, including more breeds, and possibly by exploiting pleiotropic effects to improve mapping efficiency for QTL with small effects.


Assuntos
Bovinos/genética , Genômica/métodos , Locos de Características Quantitativas , Animais , Teorema de Bayes , Cruzamento , Mapeamento Cromossômico , Fenótipo
15.
Theor Appl Genet ; 127(11): 2279-92, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25186170

RESUMO

KEY MESSAGE: Potatoes are highly heterozygous and the conventional breeding of superior germplasm is challenging, but use of a combination of MAS and EBVs can accelerate genetic gain. Cultivated potatoes are highly heterozygous due to their outbreeding nature, and suffer acute inbreeding depression. Modern potato cultivars also exhibit tetrasomic inheritance. Due to this genetic heterogeneity, the large number of target traits and the specific requirements of commercial cultivars, potato breeding is challenging. A conventional breeding strategy applies phenotypic recurrent selection over a number of generations, a process which can take over 10 years. Recently, major advances in genetics and molecular biology have provided breeders with molecular tools to accelerate gains for some traits. Marker-assisted selection (MAS) can be effectively used for the identification of major genes and quantitative trait loci that exhibit large effects. There are also a number of complex traits of interest, such as yield, that are influenced by a large number of genes of individual small effect where MAS will be difficult to deploy. Progeny testing and the use of pedigree in the analysis can provide effective identification of the superior genetic factors that underpin these complex traits. Recently, it has been shown that estimated breeding values (EBVs) can be developed for complex potato traits. Using a combination of MAS and EBVs for simple and complex traits can lead to a significant reduction in the length of the breeding cycle for the identification of superior germplasm.


Assuntos
Cruzamento , Marcadores Genéticos , Locos de Características Quantitativas , Solanum tuberosum/genética , Mapeamento Cromossômico , Variação Genética , Genoma de Planta , Heterozigoto , Padrões de Herança , Fenótipo , Seleção Genética , Tetraploidia
16.
BMC Public Health ; 14: 645, 2014 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-24965699

RESUMO

BACKGROUND: People who inject drugs (PWID) are at highest risk for hepatitis C virus (HCV) infection, yet many remain unaware of their infection status. New anti-HCV rapid testing has high potential to impact this. METHODS: Young adult (<30 years) active PWID were offered either the rapid OraQuick® or standard anti-HCV test involving phlebotomy, then asked to complete a short questionnaire about testing perceptions and preferences. Sample characteristics, service utilization, and injection risk exposures are assessed with the HCV testing choice as the outcome, testing preferences, and reasons for preference. RESULTS: Of 129 participants: 82.9% (n = 107) chose the rapid test. There were no significant differences between those who chose rapid vs. standard testing. A majority (60.2%) chose the rapid test for quick results; most (60.9%) felt the rapid test was accurate, and less painful (53.3%) than the tests involving venipuncture. CONCLUSIONS: OraQuick® anti-HCV rapid test was widely accepted among young PWID. Our results substantiate the valuable potential of anti-HCV rapid testing for HCV screening in this high risk population.


Assuntos
Técnicas de Laboratório Clínico/métodos , Hepacivirus/isolamento & purificação , Hepatite C/diagnóstico , Aceitação pelo Paciente de Cuidados de Saúde , Preferência do Paciente , Abuso de Substâncias por Via Intravenosa , Adulto , Feminino , Hepatite C/epidemiologia , Hepatite C/transmissão , Humanos , Masculino , Programas de Rastreamento , Inquéritos e Questionários , Adulto Jovem
17.
BMC Genomics ; 15: 246, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24678841

RESUMO

BACKGROUND: Selection signatures aim to identify genomic regions underlying recent adaptations in populations. However, the effects of selection in the genome are difficult to distinguish from random processes, such as genetic drift. Often associations between selection signatures and selected variants for complex traits is assumed even though this is rarely (if ever) tested. In this paper, we use 8 breeds of domestic cattle under strong artificial selection to investigate if selection signatures are co-located in genomic regions which are likely to be under selection. RESULTS: Our approaches to identify selection signatures (haplotype heterozygosity, integrated haplotype score and FST) identified strong and recent selection near many loci with mutations affecting simple traits under strong selection, such as coat colour. However, there was little evidence for a genome-wide association between strong selection signatures and regions affecting complex traits under selection, such as milk yield in dairy cattle. Even identifying selection signatures near some major loci was hindered by factors including allelic heterogeneity, selection for ancestral alleles and interactions with nearby selected loci. CONCLUSIONS: Selection signatures detect loci with large effects under strong selection. However, the methodology is often assumed to also detect loci affecting complex traits where the selection pressure at an individual locus is weak. We present empirical evidence to suggests little discernible 'selection signature' for complex traits in the genome of dairy cattle despite very strong and recent artificial selection.


Assuntos
Herança Multifatorial , Característica Quantitativa Herdável , Seleção Genética , Animais , Cruzamento , Bovinos , Estudos de Associação Genética , Genoma , Estudo de Associação Genômica Ampla , Genômica , Haplótipos , Homozigoto , Leite , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
18.
Theor Appl Genet ; 127(4): 809-20, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24374468

RESUMO

KEY MESSAGE: Best linear unbiased prediction (BLUP), which uses pedigree to estimate breeding values, can result in increased genetic gains for low heritability traits in autotetraploid potato. Conventional potato breeding strategies, based on outcrossing followed by phenotypic recurrent selection over a number of generations, can result in slow but steady improvements of traits with moderate to high heritability. However, faster gains, particularly for low heritability traits, could be made by selection on estimated breeding values (EBVs) calculated using more complete pedigree information in best linear unbiased prediction (BLUP) analysis. One complication in applying BLUP predictions of breeding value to potato breeding programs is the autotetraploid inheritance pattern of this species. Here we have used a large pedigree, dating back to 1908, to estimate heritability for nine key traits for potato breeding, modelling autotetraploid inheritance. We estimate the proportion of double reduction in potatoes from our data, and across traits, to be in the order of 10 %. Estimates of heritability ranged from 0.21 for breeder's visual preference, 0.58 for tuber yield, to 0.83 for plant maturity. Using the accuracies of the EBVs determined by cross generational validation, we model the genetic gain that could be achieved by selection of genotypes for breeding on BLUP EBVs and demonstrate that gains can be greater than in conventional schemes.


Assuntos
Padrões de Herança/genética , Característica Quantitativa Herdável , Solanum tuberosum/genética , Cruzamento , Genótipo , Funções Verossimilhança , Fenótipo , Poliploidia , Seleção Genética , Gravidade Específica
19.
J Proteome Res ; 12(3): 1428-35, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23394630

RESUMO

A detailed understanding of the relationships between the distinct metabolic compartments of blood and milk would be of potential benefit to our understanding of the physiology of lactation, and potentially for development of biomarkers for health and commercially relevant traits in dairy cattle. NMR methods were used to measure metabolic profiles from blood and milk samples from Holstein cows. Data were analyzed using PLS regression to identify quantitative relationships between metabolic profiles and important traits. Statistical Heterospectroscopy (SHY), a powerful approach to recovering latent biological information in NMR spectroscopic data sets from multiple complementary samples, was employed to explore the metabolic relationships between blood and milk from these animals. The study confirms milk is a distinct metabolic compartment with a metabolite composition largely not influenced by plasma composition under normal circumstances. However, several significant relationships were identified, including a high correlation for trimethylamine (TMA) and dimethylsulfone (DMSO(2)) across plasma and milk compartments, and evidence plasma valine levels are linked to differences in amino acid catabolism in the mammary gland. The findings provide insights into the physiological mechanisms underlying lactation and identification of links between key metabolites and milk traits such as the protein and fat content of milk. The approach has the potential to enable measurement of health, metabolic status and other important phenotypes with milk sampling.


Assuntos
Sangue/metabolismo , Indústria de Laticínios , Espectroscopia de Ressonância Magnética/métodos , Leite/metabolismo , Animais , Bovinos , Análise de Componente Principal
20.
BMC Genomics ; 13: 543, 2012 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-23050763

RESUMO

BACKGROUND: The accuracy of genomic prediction is highly dependent on the size of the reference population. For small populations, including information from other populations could improve this accuracy. The usual strategy is to pool data from different populations; however, this has not proven as successful as hoped for with distantly related breeds. BayesRS is a novel approach to share information across populations for genomic predictions. The approach allows information to be captured even where the phase of SNP alleles and casuative mutation alleles are reversed across populations, or the actual casuative mutation is different between the populations but affects the same gene. Proportions of a four-distribution mixture for SNP effects in segments of fixed size along the genome are derived from one population and set as location specific prior proportions of distributions of SNP effects for the target population. The model was tested using dairy cattle populations of different breeds: 540 Australian Jersey bulls, 2297 Australian Holstein bulls and 5214 Nordic Holstein bulls. The traits studied were protein-, fat- and milk yield. Genotypic data was Illumina 777K SNPs, real or imputed. RESULTS: Results showed an increase in accuracy of up to 3.5% for the Jersey population when using BayesRS with a prior derived from Australian Holstein compared to a model without location specific priors. The increase in accuracy was however lower than was achieved when reference populations were combined to estimate SNP effects, except in the case of fat yield. The small size of the Jersey validation set meant that these improvements in accuracy were not significant using a Hotelling-Williams t-test at the 5% level. An increase in accuracy of 1-2% for all traits was observed in the Australian Holstein population when using a prior derived from the Nordic Holstein population compared to using no prior information. These improvements were significant (P<0.05) using the Hotelling Williams t-test for protein- and fat yield. CONCLUSION: For some traits the method might be advantageous compared to pooling of reference data for distantly related populations, but further investigation is needed to confirm the results. For closely related populations the method does not perform better than pooling reference data. However, it does give an increased accuracy compared to analysis based on only one reference population, without an increased computational burden. The approach described here provides a general setup for inclusion of location specific priors: the approach could be used to include biological information in genomic predictions.


Assuntos
Genoma , Modelos Genéticos , Característica Quantitativa Herdável , Alelos , Animais , Cruzamento , Bovinos , Gorduras na Dieta/análise , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Genótipo , Leite/química , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas/análise , Sensibilidade e Especificidade
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