Researchers review the major milestones of ancient DNA techniques

Ancient DNA (aDNA) technology has been used for the past ten years by researchers working under the direction of Qiaomei Fu at the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP) of the Chinese Academy of Sciences (CAS) to learn more about the past of ancient human populations, particularly those in East Asia.

Researchers review the major milestones of ancient DNA techniques
Advances in aDNA technology since 2010. Image Credit: Institute of Vertebrate Paleontology and Paleoanthropology.

The investigators’ work included reconstructing the entire genomes of the Neanderthals and Denisovans, two extinct groups of archaic humans, mapping the history of global population migrations and interactions, determining the genetic makeup of the earliest East Asians, identifying adaptive genetic changes in East Asian Ice Age populations.

They also traced the formation of population patterns in northern and southern China and determined the ancestry of the Austronesian population.

Lately, Fu’s team reviewed the history of aDNA technological advancement, discussed present-day technical problems and their fixes, and predicted the technology’s future.

The research was published in the journal Cell on July 21st, 2022.

High-throughput sequencing is a key technological advancement that is covered in the study. It is a method for quickly sequencing large amounts of DNA. Theoretically, it is capable of sequencing every DNA molecule in a sample.

The aDNA field depended on polymerase chain reaction (PCR) methods to sequence a few particular DNA fragments before high-throughput sequencing became widespread. With this technology, scientists were only able to extract a very small amount of DNA data and had difficulty telling real aDNA from contaminant DNA.

In addition to improvements in sequencing, aDNA researchers have also created better techniques for building DNA libraries to accurately represent the properties of aDNA. Two of the most crucial of these techniques are the creation of single-stranded DNA libraries and partial uracil-DNA glycosylase (UDG) treatments.

In addition to preserving some of the DNA damage signals at DNA fragment tips, partial UDG treatment also largely eliminates aDNA damage throughout the rest of the molecule. This technique preserves the necessary aDNA features for validation while increasing the accuracy of aDNA sequencing results.

The direct sequencing of damaged and denatured DNA fragments that might be lost in conventional modern DNA library construction techniques is made possible by the use of single-stranded DNA libraries.

However, because aDNA samples frequently contain a significant amount of environmental DNA, developments in library construction have only had limited effectiveness. Because of this, useful endogenous aDNA sequences frequently make up less than 1% of the final sequences.

By developing DNA and RNA probes with target-specific sequences, researchers have applied DNA capture technology to the aDNA field to address this issue. The target aDNA binds to the probes after being added to sample extracts and is then “fished out” from the enormous amount of environmental DNA.

The study of the ancient human genome makes extensive use of this technology. Currently, data obtained using the “1240k” probe set makes up more than two thirds of the ancient human genome data.

In addition to significantly increasing the efficiency of aDNA sequencing, DNA capture technology also makes it possible to recover useful data from samples that would otherwise be too degraded for analysis.

By taking aDNA directly from “soil,” (i.e., sediment) aDNA researchers have recently pushed the boundaries even further. This technology has been used to recover DNA from prehistoric humans who inhabited tens of thousands of years ago using samples from the Denisova and Baishiya caves.

However, despite its useful outcomes, aDNA research has always been very difficult. Because aDNA is highly prone to contamination, aDNA experiments require extreme care. aDNA extraction and library creation previously relied almost completely on manual processes.

Some aDNA methods have recently started to be integrated by a few labs all over the world into fully automated pipetting robot platforms. Pre-processing of samples still needs to be done manually at the moment. The next hurdle for experimental aDNA technology is figuring out how to incorporate this labor- and time-intensive work into an automated system.

The use of aDNA technology extends far beyond the historical human genome. The study of human evolution over long time periods, including how aDNA affects modern humans’ physiology and fitness, is another important area covered by paleomolecular research.

These topics include uncovering ancient epidemics and symbiotic microbial evolution through ancient microbial information; utilizing ancient epigenetic information to investigate the interaction between ancient animals and the environment; and using ancient proteins to study human evolution over longer timeframes.

aDNA is genetic data that has been time-stamped and documents the evolution and adaptation of humans over tens of thousands of years. Several significant functional genetic haplotypes have been found to have their origins in ancient human populations, according to aDNA research.

These genes affect skin tone, lipid metabolism, high-altitude survival, and innate immunity. The majority of the genetic variations discovered by aDNA studies, however, still lack their functions.

Future aDNA animal models that disclose the function of numerous unidentified aDNA variants may be built using the most recent gene-editing technology. This will enable comprehending the impact of the ancient ancestors’ genetic inheritance on the physiology and health of modern humans.

Source:
Journal reference:

Liu, Y., et al. (2022) Evolving ancient DNA techniques and the future of human history. Cell. doi.org/10.1016/j.cell.2022.06.009.

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