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Genome of Naked Mole Rat Revealed

By Andrea Anderson

NEW YORK (GenomeWeb News) – An international research group reported online today in Nature that it has sequenced and analyzed the genome of the naked mole rat, Heterocephalus glaber, a subterranean rodent with an unusually long life span and ability to resist cancer, among other interesting traits.

Along with their genome sequencing efforts, the team also did transcriptome sequencing to help annotate the genome and to explore gene expression changes associated with aging and adaptation to different oxygen levels.

Using the genome and transcriptome data, the researchers have already started identifying some genes that contribute to characteristic naked mole rat features, such as low oxygen tolerance, longevity, and poor vision. And, they say, the genome sequence and transcript information should serve as resources for future studies of the animal.

"This sequence information provides many leads for future studies," senior author Vadim Gladyshev, a researcher affiliated with the Broad Institute, Brigham and Women's Hospital, and Ewha Womans University in Seoul, told GenomeWeb Daily News. "We hope that the genome and transcriptome will help many other researchers in the field."

The naked mole rat, a small, hairless rodent that resides in underground colonies, has a number of features that have garnered attention from researchers. For example, it is one of just two animal species that are known to have eusociality — a system that includes a single queen capable of breeding and subordinate, non-breeding females.

Along with this uncommon social structure, the naked mole rat also has other rare or unique physiological features, including an exceptionally long life span and an ability to resist some forms of pain and disease.

"It has several unusual traits: it's long-lived, not known to develop cancer, resistant to hypoxia, does not feel certain types of pain, and cannot maintain stable body temperature," Gladyshev noted.

Using whole-genome shotgun sequencing with the Illumina HiSeq 2000, the team sequenced the genome of a male naked mole rat from the University of Illinois at Chicago's captive breeding colony, generating up to 92 times coverage of paired-end libraries. Overall, they got at least 20-fold sequencing depth over nearly 99 percent of the genome.

After assembling the sequence, researchers annotated the genome based on sequence homology and RNA sequence data from seven naked mole rat organs.

During their analyses of the genome, the team tracked down 1.87 million heterozygous SNPs and 22,561 predicted protein-coding genes, including 21,394 genes transcribed in at least one of the organs evaluated by transcriptome sequencing.

Roughly a quarter of the genome was comprised of repeat sequences stemming from transposons, a more modest transposon repeat repertoire than has been detected in mammalian genomes sequenced in the past.

Nevertheless, overall genome features were consistent with those found in other mammals.

Some 93 percent of the naked mole rat genome was syntenic to mouse, rat, or human genome sequences, and the team was able to functionally annotate almost all of the predicted naked mole rat genes detected based on sequence homology to genes in other mammals.

To begin searching for genes that contribute to traits such as such as thermogenesis, hypoxia, melatonin biosynthesis, lack of fur, and so on, the team first focused on some of the genes previously implicated in related processes in mice, humans, and other mammals, Gladyshev explained.

"We see significant overlap, but some genes uniquely changed," he said. "At this point, it's too early to say how general these findings are, because we would need additional mammals to analyze."

When they looked for gene families that seem to have expanded in the naked mole rat lineage compared to other mammals, the researchers found 96 such gene families. Within syntenic regions of the genome, some 320 genes had been lost and 750 gained in the newly sequenced animal's genome.

Another 244 naked mole rat genes appear to have become pseudogenes, including some involved in processes such as olfaction and visual perception — perhaps explaining the animal's poor eyesight.

On the other hand, the team found clues that genes involved in processes such as telomere length regulation have been subjected to positive selection in the naked mole rat genome.

More than three-dozen naked mole rat proteins are predicted to contain amino acid alterations not found in other characterized vertebrates. Among the affected proteins were several cancer-related genes, along with genes involved in cell cycle control, DNA replication and repair, and transcription.

In addition to the genome sequencing and analysis studies, the researchers also did transcriptome sequencing experiments in young and old naked mole rats, comparing the gene expression patterns in newborn, four year-old, and 20 year-old animals. Another experiment was done looking at the transcriptome patterns in naked mole rats grown in low oxygen conditions versus those exposed to atmospheric oxygen levels.

"The extreme traits of the naked mole rat, together with the reported genome and transcriptome information, offer opportunities for understanding aging and advancing other areas of biological and biomedical research," they wrote.

Additional studies are now being done to look at such traits in more detail. The researchers also plan to do studies focused on finding factors that contribute to breeder and non-breeder status in the naked mole rat's eusocial colonies.

Data from the naked mole rat genome sequencing effort has been submitted to sequence databases and will also be available through web portals associated with laboratories involved in the sequencing study.

"[T]his genome and the associated data set offer the research communities working in aging, cancer, eusociality, and many other areas a rich resource that can be mined in numerous ways to uncover the molecular bases for the extraordinary traits of this most unusual mammal," the study authors wrote.

"In turn, this information provides unprecedented opportunities for addressing some of the most challenging questions in biology and medicine," they added, "such as mechanisms of aging, the role of genetic makeup in regulating lifespan, adaptations to extreme environments, hypoxia tolerance, thermogenesis, resistance to cancer, circadian rhythms, sexual development, and hormonal regulation."