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. 2009 Feb;37(2):550-6.
doi: 10.1093/nar/gkn963. Epub 2008 Dec 5.

Disease-specific Motifs Can Be Identified in Circulating Nucleic Acids From Live Elk and Cattle Infected With Transmissible Spongiform Encephalopathies

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Disease-specific Motifs Can Be Identified in Circulating Nucleic Acids From Live Elk and Cattle Infected With Transmissible Spongiform Encephalopathies

Paul M K Gordon et al. Nucleic Acids Res. .
Free PMC article

Abstract

To gain insight into the disease progression of transmissible spongiform encephalopathies (TSE), we searched for disease-specific patterns in circulating nucleic acids (CNA) in elk and cattle. In a 25-month time-course experiment, CNAs were isolated from blood samples of 24 elk (Cervus elaphus) orally challenged with chronic wasting disease (CWD) infectious material. In a separate experiment, blood-sample CNAs from 29 experimental cattle (Bos taurus) 40 months post-inoculation with clinical bovine spongiform encephalopathy (BSE) were analyzed according to the same protocol. Next-generation sequencing provided broad elucidation of sample CNAs: we detected infection-specific sequences as early as 11 months in elk (i.e. at least 3 months before the appearance of the first clinical signs) and we established CNA patterns related to BSE in cattle at least 4 months prior to clinical signs. In elk, a progression of CNA sequence patterns was found to precede and correlate with macro-observable disease progression, including delayed CWD progression in elk with PrP genotype LM. Some of the patterns identified contain transcription-factor-binding sites linked to endogenous retroviral integration. These patterns suggest that retroviruses may be connected to the manifestation of TSEs. Our results may become useful for the early diagnosis of TSE in live elk and cattle.

Figures

Figure 1.
Figure 1.
Bioinformatics workflow to design disease-indicator primers for circulating nucleic acids. The list of candidate indicator sequence segments is consecutively filtered based on desired criteria. An initial BLAST search's results are refined for practicality using frequency, sample and length criteria, then a simulated annealing of the candidate primers to the entire dataset is performed to avoid off-target matches. Finally, the candidate primers are placed into infected and uninfected target groups, and co-occurrence criteria (e.g. found in same month's sample from all infected animals) are gradually relaxed (e.g. within a 3-month span in all infected animals) until 100% specificity and 100% selectivity are achieved for a set of primers.

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