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Key Genes Missing From Christmas Island Rat Genome, Making Resurrection Efforts Difficult

NEW YORK — With current analysis tools, it's unlikely that an animal like the Christmas Island rat could be brought back from extinction, a new analysis has found, because genomic information is missing.

Scientists are currently contemplating three ways to revive animals that have gone extinct: back-breeding, cloning, and genetic engineering. According to researchers from the University of Copenhagen and elsewhere, a genetic engineering approach relying on a combination of ancient DNA sequencing and CRISPR-fueled editing of living cells from related species is likely the method that would be the most applicable to the greatest number of animals. However, they noted that the extent to which a genome from an extinct animal can be reconstructed is unclear.

For a new analysis appearing in Current Biology on Wednesday, the researchers sequenced the genome of the Christmas Island rat (Rattus macleari), which went extinct about 120 years ago, likely due to the introduction of diseases from Europe. They mapped it to other Rattus genomes, finding 95.15 percent coverage of the Norway rat (R. norvegicus) genome. While some of this missed coverage is due to technical issues, much seems to be due to evolutionary divergence between the two species, and genes related to olfaction — which has key roles in foraging and food selection, predator detection, and mate choice in rats — were missing in the Christmas Island rat genome.

"With current technology, it may be completely impossible to ever recover the full sequence, and therefore it is impossible to ever generate a perfect replica of the Christmas Island rat," Tom Gilbert, evolutionary geneticist at the University of Copenhagen, said in a statement.

Using both Illumina and BGI technologies, Gilbert and his colleagues sequenced DNA isolated from two R. macleari samples dating back to the early 1900s that were kept in a museum collection. They mapped the R. macleari reads to R. norvegicus, which the researchers considered a likely animal system for gene editing with the goal of resurrecting R. macleari. After combining the Illumina and BGI reads, coverage of the R. macleari genome reached an average depth of 60.81X, but nevertheless, the R. macleari reads only covered 95.15 percent of the R. norvegicus genome.

While part of this missing coverage was due to 0.81 percent of the bases in the R. norvegicus genome being undetermined, the researchers traced some of the rest to a combination of technical issues stemming from high AT content and evolutionary divergence between the R. macleari and R. norvegicus lineages, which separated about 2.6 million years ago.

The researchers additionally mapped other, publicly available Rattus sequence data to the R. norvegicus reference genome, finding similar coverage rates.

About a quarter of the missing sequences fell within gene regions, suggesting their loss would have functional effects. Further, these regions were enriched for genes involved in immune response and olfaction, which could affect the rats' ability to live in their natural environment.

"It is very, very clear that we are never going to be able to get all the information to create a perfect recovered form of an extinct species," Gilbert said. "There will always be some kind of hybrid."

This analysis, he and his colleagues noted, likely also extends to efforts to resurrect the wooly mammoth by editing the Asian elephant genome, as those animals have a genomic divergence similar to that of R. macleari and R. norvegicus.

Still, Gilbert said that he first plans to edit black rat (R. rattus) genomes to change them into those of a Norway brown rat before trying to revive a version of R. macleari. However, he noted that the process raises ethical concerns. "I think it's a fascinating idea in technology, but one has to wonder if that's the best use of money as opposed to keeping the things alive that are still here," he said.

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