Dataset Information

TALE nickase-mediated SP110 knockin endows cattle with increased resistance to tuberculosis.

ABSTRACT: Transcription activator-like effector nuclease (TALEN)-mediated genome modification has been applied successfully to create transgenic animals in various species, such as mouse, pig, and even monkey. However, transgenic cattle with gene knockin have yet to be created using TALENs. Here, we report site-specific knockin of the transcription activator-like effector (TALE) nickase-mediated SP110 nuclear body protein gene (SP110) via homologous recombination to produce tuberculosis-resistant cattle. In vitro and in vivo challenge and transmission experiments proved that the transgenic cattle are able to control the growth and multiplication of Mycobacterium bovis, turn on the apoptotic pathway of cell death instead of necrosis after infection, and efficiently resist the low dose of M. bovis transmitted from tuberculous cattle in nature. In this study, we developed TALE nickases to modify the genome of Holstein-Friesian cattle, thereby engineering a heritable genome modification that facilitates resistance to tuberculosis.

SUBMITTER: Wu H

PROVIDER: S-EPMC4386332 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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TALE nickase-mediated SP110 knockin endows cattle with increased resistance to tuberculosis.

Wu Haibo H Wang Yongsheng Y Zhang Yan Y Yang Mingqi M Lv Jiaxing J Liu Jun J Zhang Yong Y

Proceedings of the National Academy of Sciences of the United States of America 20150302 13

Transcription activator-like effector nuclease (TALEN)-mediated genome modification has been applied successfully to create transgenic animals in various species, such as mouse, pig, and even monkey. However, transgenic cattle with gene knockin have yet to be created using TALENs. Here, we report site-specific knockin of the transcription activator-like effector (TALE) nickase-mediated SP110 nuclear body protein gene (SP110) via homologous recombination to produce tuberculosis-resistant cattle. ...[more]

PMID: 25733846

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Project description:Bovine tuberculosis (bTB) poses a challenge to animal health and welfare worldwide. Presence of genetic variation in host resistance to Mycobacterium bovis infection makes the trait amenable to improvement with genetic selection. Genetic evaluations for resistance to infection in dairy cattle are currently available in the United Kingdom (UK), enabling genetic selection of more resistant animals. However, the extent to which genetic selection could contribute to bTB eradication is unknown. The objective of this study was to quantify the impact of genetic selection for bTB resistance on cattle-to-cattle disease transmission dynamics and prevalence by developing a stochastic genetic epidemiological model. The model was used to implement genetic selection in a simulated cattle population. The model considered various levels of selection intensity over 20 generations assuming genetic heterogeneity in host resistance to infection. Our model attempted to represent the dairy cattle population structure and current bTB control strategies in the UK, and was informed by genetic and epidemiological parameters inferred from data collected from UK bTB infected dairy herds. The risk of a bTB breakdown was modeled as the percentage of herds where initially infected cows (index cases) generated secondary cases by infecting herd-mates. The model predicted that this risk would be reduced by half after 4, 6, 9, and 15 generations for selection intensities corresponding to genetic selection of the 10, 25, 50, and 70% most resistant sires, respectively. In herds undergoing bTB breakdowns, genetic selection reduced the severity of breakdowns over generations by reducing both the percentage of secondary cases and the duration over which new secondary cases were detected. Selection of the 10, 25, 50, and 70% most resistant sires reduced the percentage of secondary cases to <1% in 4, 5, 7, and 11 generations, respectively. Similarly, the proportion of long breakdowns (breakdowns in which secondary cases were detected for more than 365 days) was reduced by half in 2, 2, 3, and 4 generations, respectively. Collectively, results suggest that genetic selection could be a viable tool that can complement existing management and surveillance methods to control and ultimately eradicate bTB.

Project description:BackgroundThe increasing prevalence of bovine tuberculosis (bTB) in the UK and the limitations of the currently available diagnostic and control methods require the development of complementary approaches to assist in the sustainable control of the disease. One potential approach is the identification of animals that are genetically more resistant to bTB, to enable breeding of animals with enhanced resistance. This paper focuses on prediction of resistance to bTB. We explore estimation of direct genomic estimated breeding values (DGVs) for bTB resistance in UK dairy cattle, using dense SNP chip data, and test these genomic predictions for situations when disease phenotypes are not available on selection candidates.Methodology/principal findingsWe estimated DGVs using genomic best linear unbiased prediction methodology, and assessed their predictive accuracies with a cross validation procedure and receiver operator characteristic (ROC) curves. Furthermore, these results were compared with theoretical expectations for prediction accuracy and area-under-the-ROC-curve (AUC). The dataset comprised 1151 Holstein-Friesian cows (bTB cases or controls). All individuals (592 cases and 559 controls) were genotyped for 727,252 loci (Illumina Bead Chip). The estimated observed heritability of bTB resistance was 0.23±0.06 (0.34 on the liability scale) and five-fold cross validation, replicated six times, provided a prediction accuracy of 0.33 (95% C.I.: 0.26, 0.40). ROC curves, and the resulting AUC, gave a probability of 0.58, averaged across six replicates, of correctly classifying cows as diseased or as healthy based on SNP chip genotype alone using these data.Conclusions/significanceThese results provide a first step in the investigation of the potential feasibility of genomic selection for bTB resistance using SNP data. Specifically, they demonstrate that genomic selection is possible, even in populations with no pedigree data and on animals lacking bTB phenotypes. However, a larger training population will be required to improve prediction accuracies.

Dataset Information

TALE nickase-mediated SP110 knockin endows cattle with increased resistance to tuberculosis.

Publications

TALE nickase-mediated SP110 knockin endows cattle with increased resistance to tuberculosis.

Similar Datasets

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