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Biology of Genomes Presentation Highlights Ancient DNA Potential for Population Analysis

COLD SPRING HARBOR, NY (GenomeWeb News) – Using a new ancient DNA enrichment scheme, a Stanford University-led team has started unraveling relationships for human samples stretching back a few hundred to several thousand years.

At the Biology of Genomes meeting here this week, Meredith Carpenter, a post-doctoral researcher in Carlos Bustamante's Stanford University lab, presented preliminary findings from an analysis of 12 ancient human samples from Peru, Denmark, and Bulgaria — work carried out by investigators at Stanford University, the Natural History Museum of Denmark's Centre for GeoGenetics, and the National Institute of Archaeology at the Bulgarian Academy of Sciences.

Carpenter also provided an overview of the whole-genome capture approach that the group is using to boost representation of ancient DNA in their sequencing libraries, making it possible to get a more refined view of the ancient individuals' relationships to modern-day populations.

The genomes of several ancient humans and hominins have now been sequenced — from the Neandertal to Ötzi the Iceman. But while many of the successfully sequenced specimens were exceptionally well preserved, Carpenter noted, many archeological samples obtained in the field are not.

Between DNA degradation and the infiltration of DNA from other sources — such as microbes in the surrounding soil — libraries made from ancient samples often contain less than 1 percent DNA stemming from the specimen of interest.

Consequently, researchers interested in sequencing such samples are faced with the prospect of shelling out a significant amount of money to generate enough sequence reads that actually represent the ancient samples source rather than environmental contaminants.

To get around this problem, Carpenter and her colleagues came up with a method for using modern human DNA to capture sequences from across the genome in ancient samples — a whole-genome in-solution capture, or WISC, scheme that can significantly bump up ancient DNA representation in a sequencing library.

Using biotinylated RNA probes produced by transcribing modern human DNA, the researchers grab ancient human DNA from Illumina sequencing libraries containing both ancient DNA and environmental contaminants. The captured ancient DNA can then be sequenced, while non-captured genetic material gets tossed out.

The Stanford team has already applied this strategy to 12 ancient samples: four Iron and Bronze Age samples from individuals living in Bulgaria between 500 and 1500 BCE, a Danish hair sample dated at around 1350 BCE, and samples from seven Peruvian mummies estimated to have lived some 500 to 1,000 years ago.

When they sequenced pre- and post-capture libraries with Illumina's MiSeq or HiSeq 2000 instruments, the researchers saw a dramatic jump in the proportion of reads that could be mapped to the human genome, along with a 10-fold rise in the number of unique SNPs found in the samples, on average.

The ability to detect such variants across the genome provides an avenue for getting more refined information about historical human migrations and relationships, Carpenter explained.

In a principal component analysis done using nearly 10,000 SNPs found in post-capture reads from a Bulgarian tooth sample going back some 3,500 years, for instance, the researchers found that the individual clustered most closely with present-day populations in southern Europe.

From their pre-capture data, on the other hand, they found just 900 or so SNPs — enough genetic variation to place the individual in the general vicinity of European populations, but not enough to provide information about more specific population relatedness.

Similarly, sequences generated from post-capture libraries on Peruvian mummy samples contained almost 21,600 SNPs, Carpenter said — a jump from the 1,500 or so SNPs found in sequences from the pre-capture library.

Beyond its ability to enrich for ancient sequences important to the study of human population history, WISC enrichment may also find favor amongst those interested in analyzing museum or forensic samples.

It is also expected to prove useful for sequencing ancient samples from non-human animals — including those without available reference genomes — though Carpenter and her colleagues have not yet tested that notion.