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Researchers Report Draft Sequence of Woolly Mammoth Genome

NEW YORK (GenomeWeb News) – Scientists have obtained the draft sequence for the majority of the woolly mammoth’s nuclear genome.
 
An international research team applied metagenomics to preserved woolly mammoth hair taken from two different animals in order to sequence more than three billion bases of mammoth nuclear DNA. The research, appearing online today in Nature, provides information about mammoth evolutionary history and population structure — supporting the notion that more than one group of mammoths roamed Siberia. And, researchers say, it may offer a valuable glimpse into the genetics of extinction.
 
“This study shows that nuclear genome sequencing of extinct species can reveal population differences not evident from the fossil record, and perhaps even discover genetic factors that affect extinction,” senior author Stephan Schuster, a biochemist and molecular biologist at Pennsylvania State University, and his colleagues wrote.
 
Researchers from two independent groups first extracted DNA from preserved mammoth samples in the mid-1990s. Since then, several studies have been done on woolly mammoth mitochondrial DNA, including a paper by Schuster and his colleagues in the Proceedings of the National Academies of Sciences this June. Based on carbon-dating and mitochondrial genome sequence, the team concluded that at least two distinct groups of mammoths lived in Siberia, becoming extinct thousands of years apart.
 
But while mitochondrial genome sequencing of ancient samples is becoming more common, sequencing the nuclear genome has proven challenging since ancient DNA is often damaged or fragmented.
 
To minimize degradation problems, Schuster and his colleagues analyzed DNA extracted from woolly mammoth hair shafts rather than bone. Hair is particularly useful because it can be more easily decontaminated than bone samples, Schuster told GenomeWeb Daily News. And though it’s been debated in the past, he believes hair yields better quality DNA that’s undergone less deamination.
 
Using Roche 454 sequencing, the researchers generated 4.17 billion bases of sequence data from hair samples taken from two animals: a Siberian mammoth specimen called M4 that lived roughly 20,000 years ago and a mammoth specimen dubbed M25 that lived about 59,000 years ago.
 
Of the more than four billion bases, 3.3 billion bases appear to represent mammoth sequence — 2.982 billion bases from M4 and 239 million bases from M25. Overall, about 90 percent of the DNA sequenced from the younger specimen appeared to come from the mammoth, compared with nearly 60 percent from the older sample.
 
The source of the remaining DNA is currently under investigation, Schuster said. Some may belong to the mammoths while some may come from associated bacteria and fungi. That should become clearer as researchers working on the Mammoth Biome Project discern which organisms were associated with mammoth specimens, Schuster noted.
 
The team was shooting for about one-fold coverage of the mammoth genome, which they originally estimated to be about 3.3 billion bases. But they now believe the genome is actually more than four billion base pairs — about the same size estimated for the African elephant genome. That means they likely achieved somewhere around 0.7 to 0.8 times coverage of the genome, Schuster explained.
 
“Only after the genome of the African elephant has been completed will we be able to make a final assessment about how much of the full woolly-mammoth genome we have sequenced,” lead author Webb Miller, a Penn State researcher who spearheaded the bioinformatics portion of the project, said in a statement.
 
The African savanna elephant genome is currently being sequenced by researchers at the Broad Institute, who shared elephant sequence data with those involved in the mammoth project.
 
Although they haven’t yet been able to decipher a great deal of information about protein-coding sequences present in the genome, the researchers discovered that mammoths had distinct amino acid sequences in regions that are very well conserved in the 50 other mammalian genomes — potentially due to the lifestyle or habitat differences, Schuster suggested.
 
The draft genome also appears to confirm the notion — proposed from mitochondrial DNA data — that there were at least two genetically distinct groups of mammoths in Siberia. “We believe that there may have been a sub-species, at least,” Schuster said.
 
In addition, the nuclear sequence corroborated previous divergence times between mammoths and elephants and between mammoth sub-groups. Based on their results, the team concluded that mammoths diverged from African elephants about 7.6 million years ago and from Indian elephants roughly 6.7 million years ago, while the two known mammoths groups diverged from one another between 1.5 and 2 million years ago.
 
The researchers estimated that the M4 mammoth shares about 99.4 percent sequence identity with the African elephant. In general, Schuster said, the rate of divergence in the elephant lineage appears to be about half that described for primates.
 
In an accompanying News and Views article, Max Planck Institute evolutionary anthropologist Michael Hofreiter lauded new sequencing technologies for helping researchers get a handle on ancient genomes.
 
And while he noted that the work leaves unanswered questions, Hofreiter said it opens the door to future research. “[A] draft genome is only the beginning of the story,” he wrote. “The main feature of genome projects is to provide a resource for further research, as vividly shown by the thousands of times the initial human-genome sequencing papers have been cited.”
 
Based on the available woolly mammoth sequence so far, the researchers determined that it will be possible to get high-fidelity, high-coverage data on the mammoth genome once the African elephant genome has been sequenced to between ten and 30-fold coverage. Schuster said the future of the woolly mammoth project will depend on available funding, but he eventually hopes to sequence two complete mammoth genomes to the same level of resolution currently used for living organisms.
 
And though sequencing ancient DNA “seems cool and intriguing,” Schuster emphasized that this sort of research also provides hints about the “biology of extinction and preservation” that could aid living organisms. For instance, the researchers found that mammoths have the same low genetic diversity associated with modern endangered species.
 
Schuster noted that he and his team are currently funded for a Tasmanian devil project comparing the genetics of animals that are sensitive and resistant to the deadly facial tumor disease that’s been devastating Tasmanian devil populations. The researchers have identified resistance markers and developed SNP arrays that collaborators in the “Save the Tasmanian Devil Program” can use to test remaining Tasmanian devil populations and guide conservation efforts, he explained.
 
Information about the Mammoth Genome Sequencing Project is housed in a new web site aimed at providing information to both the research community and the public. “We hope that this will become a portal for mammoth sequencing and research,” Schuster said.

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