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Sequencing Study Uncovers Diversity, Stability in Orangutan Genomes

By Andrea Anderson

NEW YORK (GenomeWeb News) – Orangutan genomes have evolved relatively slowly compared with those of other great apes, a new genome sequencing study suggests.

An international research team led by investigators at Washington University and Baylor College of Medicine used Sanger sequencing to come up with a reference genome for the Sumatran orangutan, Pongo abelii. They then used Illumina short read sequencing to tackle 10 more orangutan genomes — five for P. abelii orangutans and another five representing Bornean orangutans from the P. pygmaeus species.

Along with differences between the two genetically diverse orangutan groups, the team detected genomic features distinguishing orangutans from other primates. In particular, the study, which appears online today in Nature, suggests that the orangutan genome has been far more stable than those of humans and chimpanzees.

"When we look at the genomes of humans and chimps, we see an acceleration of structural changes over the course of evolutionary history," senior author Richard Wilson, director of the Washington University Genome Center. "But for whatever reason, orangutans did not participate in that acceleration, and that was a surprise."

Meanwhile, in an accompanying paper in Genome Research, Danish and American researchers focused on bits of the genome that are more similar between orangutans and humans than between humans and chimpanzees, which are more closely related overall.

Orangutan ancestors diverged from the lineage leading to the other great ape species some 12 million to 16 million years ago, the researchers explained, and have since separated into two genetically distinct groups that are still capable of inter-breeding with one another.

Their numbers have fallen off dramatically in recent years, largely due to habitat loss. The remaining wild orangutans are mainly found in rainforests on the islands of Sumatra and Borneo, which have orangutan populations estimated at around 7,000 and 50,000 individuals, respectively.

For the current study, researchers first used Sanger sequencing to sequence the genome of a female Sumatran orangutan from a Texas zoo to an average of 5.5 times coverage over more than three billion bases — a feat that cost around $20 million.

For the second stage of the project, they used the Illumina GAIIx platform to resequence 10 more orangutans — including five Sumatran and five Bornean orangutans — for about $20,000 apiece.

"This project, in a way, kind of transitioned the advancement in DNA sequencing technology from the Sanger, $20 million genome to the $20,000 Illumina genome," lead author Devin Locke, an evolutionary genetics researcher at Washington University’s Genome Center, told GenomeWeb Daily News.

Though the genomes of orangutans from both species had unexpectedly high genetic diversity, the team found that the smaller Sumatran population had slightly more diversity than orangutans from Borneo.

"It's not that you have a big [genetic] pool that's shared between both that would indicate that they have a long, storied history of exchanging genetic information," Locke said. "There are island-specific variants on both islands. Island-specific gene pools, if you will, are very deep."

For instance, the team catalogued some 13.2 million potential SNPs in the 10 genomes sequenced with short-read technology.

By incorporating these variants into a demographic model, Locke explained, the researchers found evidence that Sumatran and Bornean orangutans diverged from one another about 400,000 years ago. Past estimates based on selected mitochondrial sequences and/or nuclear markers put the split much further back, around 1 million years.

Down the road, such variants may help in developing an even more refined understanding of orangutan populations, the researchers noted, and may serve as a tool in conservation efforts.

"We're not proposing that this data be used, as is, to make a conservation decision," Locke emphasized. But, he explained, sequence and SNP patterns should prove useful for genetically profiling orangutan populations in zoos or in the wild.

Along with their comparisons of orangutans from Sumatra and Borneo, the team was also able to begin looking at differences between orangutans and other primates.

Among the unique features detected in orangutans, for instance, the researchers found an unusual, repositioned centromere or "neocentromere" on chromosome 12 of both orangutan species. Similar to the newly formed centromeres detected in the horse genome, which was sequenced in late 2009, this orangutan neocentromere provides an opportunity to look at early stages of centromere formation, the team noted.

Moreover, the new study suggests orangutan genomes contain a dearth of rearrangements, segmental duplications, and gene turnover events compared to chimpanzees and humans.

And, they found, whereas human genomes contain an estimated 5,000 human-specific Alu retrotransposons and chimps have 2,300 or so Alu elements of their own, the team tracked down just 250 Alu elements that arose in orangutans since they split from a common primate ancestor.

That, in turn, suggests that the rearrangement ramp-up in human and chimp genomes coincides with a boost in the number of these species-specific Alu elements in the other great apes.

While it's unclear whether the accumulation of species-specific Alu elements preceded the rise in structural rearrangements or vice versa, the team speculated that "the orangutan lineage experienced fewer new insertions and a putative decrease in the number of regions susceptible to post-insertion Alu-mediated recombination events genome-wide, limiting the overall mobile element threat to the genome."

By comparing sequences from human, chimp, orangutan, rhesus macaque, and dog genomes, the researchers were also able to track down new signals of positive selection in primates, including signals affecting genes involved in visual perception, color vision, and lipid metabolism.

"The more you learn about closely related species to humans, the more you can apply that to our understanding of the human genome," Locke said, "for annotating the human genome, detecting sequences that are functional, for finding genes that are rapidly evolving and understanding of evolutionary forces that are acting on our genomes."

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