aDNA

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Cross-linked aDNA from a 4000 year old liver of an Egyptian priest named Nekht-Ankh (enlarged)

aDNA (from English ancient DNA 'old DNA' ) denotes (mostly over 100 years) old DNA . A typical case are residues of genome molecules from dead organisms .

ADNA research is closely related in terms of goals and methods to genetic forensic medicine and forensic anthropology and uses methods of genetic analysis such as the polymerase chain reaction .

history

The history of aDNA is closely interwoven with the development of the polymerase chain reaction (PCR), a special molecular biological technique that makes it possible to reproduce and examine even small amounts of genetic material. In the early days of aDNA, there were a number of reports on aDNA that later turned out to be incorrect and used material that from today's perspective has no prospect of preserving amplifiable DNA. The results of the investigation of aDNA are therefore still met with reservations today.

The methodology is geared towards obtaining the purest possible, many and large oligonucleotide chains. Depending on the tradition, different tissues are available, however, due to their seclusion, hard tissue ( bone , dentin ) is preferable, in which the DNA of, for example, osteoclasts is best preserved from environmental influences.

After the DNA residues have been obtained and purified from the tissue, the sequences to be examined are first amplified from them in a PCR up to the detection limit. The PCR amplificates can then be examined by fragment sizing or sequencing . Before sequencing , the PCR amplicon is often cloned and selected in order to uncover contamination or specific PCR artifacts .

application areas

The knowledge gained from aDNA is important for genetic biology , palaeozoology , paleobotany and anthropology (especially paleoanthropology ) and, with the latter, also for archeology . The latter developed into a separate branch of science, paleogenetics .

Species identification

Each biological species is characterized by a specific genetic trait pattern, which is why the examination of the genetic material enables a single cell to be clearly allocated to a species. aDNA is used to identify species if the preservation conditions no longer allow any other clear identification options or the selectivity of other methods is too imprecise. For example, sheep and goats cannot be distinguished from one another based on skeletal features alone due to the high similarity in bone structure.

phylogenesis

The evolution of the species and their relationship to one another can be represented statistically on the basis of their various genetic characteristic patterns ; The genetic distance serves as a measure here . Phylogenetic research uses aDNA to classify species that are already extinct.

Individual relationship analysis

Two individuals are related in a biological sense if they have at least one common ancestor. The degree of biological relationship between two individuals can also be determined from their genetic makeup. Methods similar to the genetic paternity test are also used in aDNA analysis. However, the very fragmentary preservation of the DNA molecules, which only allows small sections to be examined, has a limiting effect here. Particular attention is paid to the areas of high variability , i.e. H. Places where mutations often occur. In particular, these are STRs ( Short Tandem Repeats ) and increasingly also SNPs ( Single Nucleotide Polymorphisms ).

The evaluation of mitochondrial DNA is particularly promising here , as it has a much larger number of copies than the DNA of the cell nucleus (about 1000 mitochondrial copies, but only 2 nuclear copies per cell) and thus maintenance problems are alleviated. However, mitochondria are only passed on from the mother to the children, not from the father. H. only the matrilineal line of descent - in the biological sense - can be traced.

Gender Diagnostics

The genetic sex of an individual is under favorable conservation conditions, i.e. H. can be determined when chromosomal DNA is transmitted. In species that, like humans, only have one sex-specific chromosome ( Y chromosome ), safe differentiation options are limited. With the detection of aDNA fragments that originate from the Y chromosome (for example from the SRY region), the genetic sex is clearly proven as male, on the other hand, from the lack of Y-specific characteristics, it cannot be concluded with certainty that the sex is female Imponderable conservation conditions could also be the reason for this.

Despite this uncertainty, molecular sex diagnostics are v. a. applied to human skeletal remains. ADNA is particularly helpful for individuals who, due to their young age at death or unspecific skeletal features, can only be classified in an uncertain manner using biological-anthropological methods.

Identification of individuals and objects

The identifications of historically significant persons with remains can be regarded as exceptions, which usually take place with great public participation. To do this, the scientist first extracts aDNA from tissue samples of the individual in question (bones, hair, clothing), primarily in order to determine the mt haplogroup or, in male individuals, also the Y haplotype . He then compares this with “authentic” DNA, which at best comes from suspected relatives who are still alive. In some cases, reconstructing the person's genetic fingerprint also helps to compare it with that of closely related persons from verified burials. Extraction from personal belongings of the individual in question is also possible, but doubts about the authenticity can lead to problems in the evidence. If there is a significant match between questionable and authentic samples, the individual is considered identified.

Paleopathology

Very few diseases can be clearly diagnosed in skeletons, which is why aDNA research has been trying to detect pathogens of infectious diseases in human remains since around the mid-1990s . In addition to the development of methods, the focus is initially on the detection of possibly extinct infectious bacterial strains and the comparison of historically transmitted disease processes and symptoms with current knowledge about the respective disease. As the number of data increases, this branch can also make an important contribution to historical epidemiology in the future .

Criticism and problems

aDNA evidence is received with skepticism, as it has often proven to be irreproducible. There is a fundamental risk that the test results are falsified by contamination with foreign, recent DNA (including that of the examiner). A 2004 review summarized the concerns and reported e.g. B. from an examination of an old bear tooth, from which human DNA could be detected reproducibly. The work did not come from notorious opponents of such investigations, but was intended to call for special precautionary measures in aDNA analyzes.

Biological half-life

DNA can survive for a long time in dry and cool surroundings, but the sensitive macromolecules dissolve into small chain fragments. Heat, moisture, acidic and basic pH values promote this DNA damage and breakdown into smaller and smaller pieces. aDNA fragments can still be usable with a nucleotide chain length of less than 200 base pairs - this is very short compared to the theoretical total length of, for example, the human genome of 3 × 10 9 base pairs. For given environmental parameters, “ half-lives ” can be calculated with which the expected quality of the results can be estimated.

The researcher Morten Allentoft from Murdoch University in Perth (Australia) speaks for an international research team in the journal “Proceedings of the Royal Society B” of 5.5 DNA breaks per million molecules per year. A changing half-life of the DNA was determined “depending on the temperature and environmental factors”: “At minus five degrees, for example, the half-life for small pieces of DNA in bones is 158,000 years, at higher temperatures it is shorter”. The research team said: “Our half-life calculations show, for example, that it is extremely unlikely to be able to isolate intact DNA fragments from 80 to 85 million year old bones”. It is possible, however, that “primeval genetic material could survive for several hundred thousand to even a million years”. Other scientists contradict this view and show that there are definitely ways to preserve very old aDNA. aDNA extractions and their analyzes are also possible on very old fossils.

The kinetics of DNA decay was measured in the laboratory by means of "accelerated aging" depending on the storage temperature and storage humidity. The measured activation energy of the DNA decay of 155 kJ / mol shows the limits of the long-term stability of DNA at low temperatures.

Post-mortem mutations

It was also found that with very old aDNA, for example from the Miocene , post-mortem mutations are to be expected, since the original base cytosine can then be present as uracil , which makes interpretation difficult.

Another problem that has not yet been researched is so-called “ hot spots ”, because these DNA sites can be changed in this way by chemical reactions after the organism dies. This creates pseudo mutations that need to be recognized.

contamination

Since aDNA is usually transmitted in very small quantities, research uses PCR to first duplicate the pieces obtained. Due to the extremely high sensitivity of PCR, incorrect amplifications are very common, i. H. Instead of the original old target DNA, the genetic material of other organisms (often from soil bacteria ) or modern human DNA that got into the sample as a result of insufficient preparation of the material or improper work is reproduced.

Other problems

So-called inhibitors are of lesser importance , which originate from the DNA's lying environment, for example the floor, and which can prevent the PCR by blocking the enzyme . Frequently, bovine serum albumin , a product obtained from bovine blood protein, added to the binding of iron, the common inhibitor to the reaction mixture. However, if there are indications that PCR inhibition is the cause of false negative results, it helps to use the aDNA sample diluted. Unfortunately, the dilution also reduces the DNA concentration in the sample, which again reduces the chances of PCR success.

After all, the visible preservation of an organism says little about the condition of the aDNA it contains. Thus, for example from bog bodies due to the acidic milieu sun rarely usable DNA extract. Even dry mummies with excellent soft tissue preservation often only contain very small traces of aDNA.

Examples (selection)

The selection gives an overview of the range of aDNA research. Since negative results are also of scientific importance, “famous and important failures” are also listed below.

Amber inclusions

The film and novel entitled “ Jurassic Park ” contributed greatly to the public and even scientific euphoria regarding aDNA in the early 1990s. Historically, fossils in amber (from so-called inclusions ) are used to extract old genetic material that is used to breed new species that are already extinct.

Indeed, it was repeatedly published that not only made of amber sequenceable ancient DNA can be isolated, even from chloroplasts - DNA but also proteins and even viable organisms. This evidence was controversial.

Viruses

  • Influenza A virus H1N1 . - The RNA of the pandemic influenza A virus H1N1 was obtained from tissue samples obtained from victims of the Spanish flu who died in the winter of 1918/19 .
  • "Ancient caribou feces associated virus" (aCFV). - A DNA virus was isolated from the caribou droppings that were deposited on the edge of the Arctic around 700 years ago and reactivated in the cells of a tobacco plant ( Nicotiana benthamiana ).

Prokaryotes

  • Mycobacterium leprae . - Leprosy (also called “leprosy”) was a feared infectious disease for centuries. Their pathogen, Mycobacterium leprae , is as virulent today as it was in the High Middle Ages ; The fact that leprosy has become a rare disease can therefore be attributed to improved hygiene.
  • Mycobacterium tuberculosis . - An open question in paleopathology , the dispute about the origin of the syphilis pathogen ( Treponema pallidum ), was attempted, among other things, by means of aDNA analyzes. However, the targeted search for all known pathogens of the genus Treponema in a study comprising 46 human skeletons was unsuccessful. Incontrast, thediscovery of old tuberculosis bacteria in some of these skeletons in 2005 basically confirmed the possibility of detecting pathogens for certain diseases using aDNA.
In 2014, the genome of Mycobacterium tuberculosis was isolated from three thousand-year-old, pre-Columbian skeletons, demonstrating that the tuberculosis pathogen was spread long before the Europeans invaded South America. In 2001, Mycobacterium tuberculosis DNA was extracted from the skeleton of a 17,000-year-old North American bison .
  • Plague bacterium ( Yersinia pestis ). - In 2011 the genome of the Yersinia pestis strain was described, which infected people in England from 1348 to 1350 during the “Black Death”; for the first time it could be proven that the medieval plague was caused by the same pathogen as the plague diseases in the present.

Plants and mushrooms

  • Cotton ( Gossypium ). - Four finds from archaeological excavations in Brazil , Peru and Egypt - the oldest 3820 to 3630 years old ( cal BP ) - contributed to the understanding of changes in the genome of cotton over the past 4000 years.
  • Einkorn ( Triticum monococcum ). - Parts of the genome could be identified from about 3300 year old seeds of Einkorn that had been preserved in Greece .
  • Potato powdery mildew ( Phytophthora infestans ). - Five DNA samples from herbaria helped to trace changes in the genome of the late blight pathogen in the period since 1845; Phytophthora infestans caused the Great Famine in Ireland between 1845 and 1852.
  • Corn ( Zea mays ). - The comparison of up to 4,700 years old maize with more recent maize variants showed that the maize cultivated today comes from different wild populations.

Animals

aDNA has been used in a large number of papers to clarify relationships in animals, among other things.

Birds

Claws of Haastadler and "Little Eagle"
  • Moa nalos . - Based on the analysis of fossil mtDNA it was shown that these extinct, large, flightless birds that once lived in Hawaii were most closely related to a subfamily of duck birds , the Anatinae , but were not closely related to any of the duck species still alive today.
  • Haastadler ( Harpagornis moorei ). - With a weight of 10 to 15 kilograms and a wingspan of 2 to 3 meters, he was one of New Zealand's top predators . Nonetheless, preserved tissue samples of this extinct species were able to demonstrate that among the recent bird species it was most closely related to Hieraaetus morphnoides ("Little Eagle") , which lives in Australia, and is only around a tenth as large .
  • Dodo ( Raphus cucullatus ). - On the basis of the analysis of fossil rDNA it was proven that these extinct, large, flightless birds that once lived in Mauritius were closely related to the also extinct Rodrigues solitaire from the island of Rodrigues . Of the birds still alive today, the collar pigeons are closest to them.

Mammals

  • Quagga ( Equus quagga quagga ). - The first nucleotide sequences of aDNA were obtained in 1984 from the processing of cells from museum specimens , with the aim of analyzing the relationship between quaggas and other zebra species.
  • Cave bear ( Ursus spelaeus ). - In 1999, the DNA from the cells of a fossil cave bear from the Vindija cave was one of the first partially reconstructed DNA fragments from living things that had died out thousands of years ago. In 2005, the closeness of the relationship between Ursus spelaeus and other bear species was analyzed.
  • Polar bear ( Ursus maritimus ). - The analysis of the DNA of an approximately 120,000-year-old specimen helped shed light on the relationship between polar bears and brown bears and their repeated genetic intermingling.
  • Woolly Mammoth ( Mammuthus primigenius ). - The DNA code for the hemoglobin of a 43,000-year-old woolly mammoth has three sequences that differ from the hemoglobin of an Asian elephant . In 2010, these were incorporated into the DNA sequence for the hemoglobin of an Asian elephant in order to gain knowledge about the mammoth's adaptation to cold. Another study on a 28,000-year-old woolly mammoth provided evidence that this species separated from the African elephant ( Loxodonta africana ) 5 to 6 million years ago .
  • Crete dwarf mammoth ( Mammuthus creticus ). - For the aDNA of a dwarf mammoth from the Mediterranean region, an age of 800,000 years was shown.
  • Steppe bison ( Bos priscus , also: Bison priscus ). - Widespread in Europe during the last glacial period, this wild cattle died out around 9000 years ago. Using aDNA, it was possible to understand that - without intensive human influence - the genetic diversity of this species decreased dramatically as early as 37,000 years ago.
  • Domestic cattle ( Bos primigenius taurus ). - With the help of aDNA, indications of the course of domestication of the aurochs could be obtained.
  • Horse ( genus Equus ) from the Middle Pleistocene. - ADNA was obtained from a horse bone that was preserved in the permafrost soil in Canada , which was dated to an age of 780,000 to 560,000 years.
  • Cave goat ( Myotragus balearicus ). - On the basis of the DNA from 6000 year old bones it was possible to understand that the cave goat , once native to Mallorca and Menorca , is more closely related to the domestic sheep than to the domestic goat .
  • Domestic sheep ( Ovis gmelini aries ). - aDNA was obtained from parchment from the 17th and 18th centuries, so that it could be clarified that these parchments were made from the skin of domestic sheep.
  • Pouchwolf (also: Tasmanian Tiger, Thylacinus cynocephalus ). - DNA was obtained from 12 specimens of the pouch-wolf, which has been extinct since 1936, in museums. Their comparison showed that the genetic variability of the 102 to 159 year old DNA was extremely low. The reason for this is probably that Tasmania had been cut off from Australia for around 10,000 years - after the height of the last Ice Age .
  • Sloths (Folivora). - The Xenarthra , including the sloths are, are an extremely diverse superorder of mammals. To analyze their family relationships, ribosomal DNA (rDNA) from cells obtained from extinct giant sloths (Mylodontidae and Megatheriidae) was compared with rDNA from two-toed sloths and three-toed sloths .
  • Giant Deer ( Megaloceros giganteus ). - This European species became extinct after the height of the last glacial period; its relationship to other species of real deer was analyzed in 2006 using retained mtDNA .
  • Corsican red deer , also Tyrrhenian red deer ( Cervus elaphus corsicanu ). - Using mitochondrial aDNA from around 6,300 to 15,600 (cal BP) old bone finds, it was demonstrated that the population native to Sardinia originates from a population from Italy.

People

Neanderthals

  • Parts of the Neanderthal DNA were sequenced for the first time in 1997 in Svante Pääbo's group; In 2008 the complete mitochondrial DNA and in 2010 more than three billion base pairs (= 60 percent) of the DNA were analyzed.

Denisova man

  • Like the Neanderthal DNA before it, the DNA of the Denisova people was largely reconstructed in Svante Pääbo's group .

Anatomically modern man

The oldest largely sequenced human genome to date comes from the thighbone of a man from an extinct West Siberian population and is around 43,000 to 47,000 years old.
In 1985, the evolutionary geneticist Svante Pääbo was the first to publish the discovery of ancient DNA in samples from an Egyptian mummy. However, due to the lack of control options at the time, he later had to add that his aDNA samples could possibly have been contaminated by modern DNA.
Due to the excellent preservation of soft tissue, the Egyptian mummies are now more often the subject of aDNA investigation, because it is hoped that good conditions of transmission will also be found at the molecular level.
Bormann's death (which later turned out to be suicide during skeletal examinations) in the spring of 1945 has been questioned several times. In 1972 two skeletons were discovered at the Lehrter train station in Berlin, one of which, according to a forensic medical report from forensic odontology (dentition characteristics), could be identified as Bormann. Renewed doubts finally led to a DNA analysis at the end of the 1990s - although according to the definition it was not yet an aDNA test (<75 years), only relatively small residues of DNA could be detected. The correspondence of mitochondrial patterns between the sampled skeleton and a living cousin of Bormann makes a relationship in the maternal line and thus the identification of Bormann probable.
The King of Sweden fell in 1632 during the Battle of Lützen . His body was brought to Stockholm embalmed and buried there. However, parts of his clothing remained in Lützen and are now exhibited there in the museum. The examination of blood residues in the fabric revealed sufficient amounts of old DNA to be able to compare it with the genetic make-up of his descendants in today's Swedish ruling house. The authenticity has been confirmed.

literature

For the introduction

Technical article

  • Jermey J. Austin et al .: Problems of reproducibility - does geologically ancient DNA survive in amber-preserved insects? In: Proceedings of the Royal Society London . Volume 264, No. 1381, 1997. pp. 467–474, doi: 10.1098 / rspb.1997.0067 ( full text (PDF))
  • Jacob S. Sherko, Henry T. Greely: What If Extinction Is Not Forever? In: Science. Volume 340, No. 6128, 2013, pp. 32–33, doi: 10.1126 / science.1236965 , full text (PDF)
  • Beth Shapiro and Michael Hofreiter: A Paleogenomic Perspective on Evolution and Gene Function: New Insights from Ancient DNA. In: Science. Volume 343, No. 6165, 2014, doi: 10.1126 / science.1236573
  • Montgomery Slatkin and Fernando Racimo: Ancient DNA and human history. In: PNAS . Volume 113, No. 23, 2016, pp. 6380–6387, doi: 10.1073 / pnas.1524306113 (free full text)

Individual evidence

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