Researcher Chart Progress in Ancient DNA Technology

Over the past 10 years, researchers led by FU Qiaomei of the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP) of the Chinese Academy of Sciences (CAS) have used ancient DNA (aDNA) technology to explore the history of ancient human populations, especially those in East Asia. .

As part of their effort, the researchers reconstructed the entire genomes of two extinct groups of ancient humans—Neanderthals and Denisovans; map the history of migration and global population interactions; uncover the genetic structure of the oldest East Asian people; reveal adaptive genetic changes in East Asian Ice Age populations; and traces the formation of population patterns in northern and southern China and the origins of Austronesian populations in southern China.

Recently, the FU team reviewed the development history of aDNA technology, discussed current technical barriers and solutions, and assessed the future of the technology.

The study was published in Cell on July 21.

The main technological development discussed in this study is high-throughput sequencing, which is a technique to rapidly sequence large amounts of DNA. It can theoretically sequence all DNA molecules in the sample.

Before high-throughput sequencing became commonplace, the aDNA field relied on polymerase chain reaction (PCR) techniques to sequence multiple specific DNA fragments. The researchers were only able to extract a very limited amount of DNA information with this technology and had difficulty distinguishing native aDNA from contaminant DNA.

To complement advances in sequencing, aDNA researchers have also developed improved methods of constructing DNA libraries to better reflect the characteristics of aDNA. Among these methods, uracil-DNA glycosylase (UDG) partial treatment and single-stranded DNA library construction are the two most important. Partial UDG treatment not only retains a portion of the DNA damage signal at the end of the DNA fragment but also removes most of the aDNA damage throughout the molecule. This method improves the accuracy of aDNA sequencing results while maintaining the aDNA features required for validation. Single-stranded DNA library construction allows direct sequencing of damaged and denatured DNA fragments that may be missing in typical modern DNA library construction techniques.

Advances in library construction have had limited efficacy, however, because aDNA samples often contain large amounts of environmental DNA. As a result, useful endogenous aDNA sequences often account for less than 1% of the resulting sequence. To solve this problem, researchers have applied DNA capture technology to the aDNA field by fabricating DNA and RNA probes with sequences similar to their targets. After adding the probe to the sample extract, the target aDNA binds to the probe and is then “taken” from a large amount of environmental DNA. This technology is widely used in early human genome research. Today, more than two-thirds of the early human genome data comes from data captured using the “1240k” probe set.

DNA capture technology not only greatly improves aDNA sequencing efficiency; it also allows recovery of usable data from samples that would otherwise be too degraded for analysis.

Recently, aDNA researchers have pushed the envelope even further by extracting aDNA directly from “soil” (i.e., sediments). This technology has been applied to samples from the Denisova and Baishiya caves, making it possible to recover DNA from ancient humans who lived tens of thousands of years ago.

Despite the useful results, however, the study of aDNA has always been very challenging. aDNA itself is highly susceptible to contamination, and experiments involving aDNA are very complicated. In the past, aDNA extraction and library construction depended almost entirely on manual operations. Recently, several laboratories around the world have begun to integrate several aDNA methods with fully automated robotic pipetting platforms. However, at this time, sample pre-processing still requires manual steps. How to integrate this time-consuming and labor-intensive work into automated systems is the next challenge for experimental aDNA technology.

The application of aDNA technology goes far beyond the early human genome, of course. Paleomolecular research also covers important topics such as tracing ancient epidemics and the evolution of symbiotic microbes through ancient microbial information; use ancient epigenetic information to explore interactions between ancient animals and the environment; and using ancient proteins to explore long-term human evolution, including how aDNA affects modern human physiology and fitness.

aDNA is the genetic information that records human evolution and adaptation over tens of thousands of years. We now know from aDNA research that several important functional genetic haplotypes originated in ancient human populations. These genes are involved in innate immunity, lipid metabolism, high altitude survival, and skin color. However, the function of most of the genetic variants identified by aDNA studies has not been determined.

In the future, scientists may use the latest gene-editing technology to build animal models of aDNA that reveal the function of many unknown aDNA variants. This will help us better understand how modern human physiology and health have been influenced by the genetic inheritance of our ancient ancestors.

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