Groundbreaking research paves the way for genetic targets to reduce tick-borne diseases

Groundbreaking research paves the way for genetic targets to reduce tick-borne diseases

A University of Maryland-led team of scientists has deciphered the first continuous, complete genome of a parasite responsible for transmitting Lyme disease and other serious infections to hundreds of thousands of Americans each year. With their newly described genome for the black-legged tick, or deer tick, the researchers identified thousands of new genes and new protein functions, including proteins associated with tick immunity, disease transmission, and developmental stages.

This work provides valuable information for the development of interventions for various tick-borne diseases, far surpassing previous efforts to sequence the tick genome, which resulted in partial genomes or genome fragments with gaps and uncertainties.

The study was published on January 19, 2023 in the journal Genetics of Nature and it was possible thanks to the close collaboration between multiple academic institutions, the industry and the federal institutions.

“We’re really excited to have this reference genome now, because there are so many unanswered questions about how these parasites evolved and how they transmit disease,” said Utpal Pal, the study’s lead author and a professor at the Virginia-Maryland College of Veterinary Medicine. in the University Park. “We think there are genetic factors that contribute to making these ticks such good disease vectors, but we can’t really understand it without a genome as good as this.”

Blacklegged ticks (ixodes scapularis) or closely related species are widespread in North America, Europe, North Africa, and Asia. They are the main vectors of a number of diseases, including Lyme disease, which infects nearly half a million Americans each year. However, many aspects of its biology remain unknown.

With a complete genome, scientists can begin to unravel the molecular mechanisms behind many aspects of the parasite’s biology and its interactions with both hosts and the diseases it transmits.

The genome of a blacklegged tick is made up of more than 2 billion discrete pieces of DNA code (expressed as combinations of four nucleotides represented by the letters ATCG). Like the letters that are grouped to form words in a sentence, the DNA codes are grouped into genes that make up the genome.

Previous work to decipher the tick genome used many immature ticks or tick cells that had been grown in laboratories for several generations, introducing errors or combining samples from several individual ticks, resulting in fragmented code packages with many redundant snippets. The researchers had to reassemble the fragments, determining where each gene begins and ends and how they should be arranged.

To overcome these challenges, Pal and his colleagues combined two methods to sequence the genome of a single tick. One method cracked the entire genome at once, creating a complete sequence, but a bit “garbled,” meaning the code was unclear in many places. In the second method, the researchers used a common technique called polymerase chain reaction, or PCR, to “amplify” small segments of the genome so it could be read more clearly. The team then combined the two results, which was a bit like using a large, blurry image as a reference to assemble high-resolution puzzle pieces. Finally, the researchers used a technique called “Hi-C” to join small pieces of DNA into longer, contiguous strands.

The result is a high-quality contiguous genome that is 98% complete. The new genome revealed that 40% of previously described annotations for the blacklegged tick were based on older technology and in need of updating.

The researchers then compared their full genome with fragments of sequenced genomes from 51 wild-caught ticks, showing that the new work could be used as a reference to identify segments of genetic material from other individuals. This also identified unrecognized genetic diversity between groups of ticks from different regions of the US.

Finally, the team analyzed their tick genome to identify thousands of new genes and proteins and describe critical new functions for those genes. For example, in one experiment, they found that some proteins were only present during certain phases of a tick’s life cycle or at specific stages during a tick’s digestion and blood feeding. By knocking out a gene that tells tick cells to make one of those proteins, they were able to disrupt the tick’s feeding and digestion process.

Future work like this could help guide gene-based therapies and vaccines that interrupt a part of the cycle of disease transmission between ticks and humans.

An additional result of the study was that the researchers identified and described a more complete genome for Rickettsia buchnerithe pathogenic bacterium that causes rickettsiosis.

The genomic resources described in the paper are publicly available through major databases and will be useful in advancing tick research and preventive measures.

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