Paleogenetics: From Ancient Genomes to Modern Humans

by | Sep 14, 2023 | Biological Sciences | 0 comments

Turna DemirciT. , Elif DuymazE.

Paleogenetics is a new branch of science which focuses on ancient DNA (aDNA), genetic materials obtained from archaeological remains1,2. The aDNA was first isolated in 1984 by Higuchi and colleagues from a 150-year-old tissue belonging to the extinct zebra-like animal Equus quagga with bacterial cloning3. About a year later, by combining techniques that involved molecular cloning and hybridization, researchers were able to extract the first aDNA from the muscle tissue of an Egyptian mummy in 19854. The limited amounts of ancient DNA was amplified with the development of the polymerase chain reaction (PCR) method in the mid-1980s, so aDNA research had been accelerated5-9. By 1989, Hagelberg and colleagues, showed that aDNA could also be obtained from bone tissue10. The isolation of aDNA from fossil bones by PCR in 1991 provided concrete evidence that genetic information could remain intact and detectable for long periods of time, even in ancient specimens11. Despite all these developments, the breakthrough in aDNA studies has occurred with the emergence of high-throughput (HT) sequencing and next-generation sequencing (NGS) technologies12,13. 

Paleogenomics is a field of science in which ancient genomic information is reconstructed and analyzed in collaboration with sequencing and computational sciences14-16. Geneticist Svante Pääbo had been deemed worthy of the 2022 Nobel Prize in Physiology or Medicine, pioneered the introduction of paleogenetics and paleogenomics to the scientific world, and showed the importance of aDNA research17,18. In addition to being an essential field for the roadmap of human evolution, paleogenetics also contributes to the discipline of paleopathology in illuminating the spatial changes in human diseases19-21. Although both disciplines offer a unique understanding of the evolutionary processes from the past to the present, the fact that the analyzed material has to be damaged and restructured over time and has a limited amount of biological content requires many scientific disciplines to work together and meticulously2,22. Ancient DNA studies provide benefits about the historical development of plant, animal, and microorganism species, especially the evolution of modern humans and genomic features close to today23-31. This review aims to evaluate the genetic and phenotypic changes and the exciting discoveries in the process, from the discovery of archaic hominins to their effects on modern humans.

1. Inheritance Embedded in Fossils: ancient DNA (aDNA)

aDNA allows for the understanding of unknown aspects of human evolution and provides a golden opportunity for evolutionary research through the invention of platforms such as PCR and NGS that enable targeted or genome-wide interrogations (Figure 1)13. Through these platforms, animal and plant genomes, notably be examined, and tangible evidence has reached about ancient times and their effects on the present32,33. The aDNA study was published by Kjær and colleagues. In December 2022 many known and unknown plant, animal, and pollen species inhabited Northern Greenland at the beginning of the Ice Age. Through environmental aDNA obtained from the sediments, insights have been obtained about the regional ecosystem and the adaptations of bios to the climate change that occurred ~2 million years ago34. Despite all these benefits, isolating aDNA from the discovered remains is still considered a problem that needs to develop due to both the damage in the period until the present and the restriction by the chemicals used to recover the genetic material13,35.

Figure 1. Key milestones pertaining to wet-laboratory method improvement (part a) or dry-laboratory advances (part b)13. aDNA, ancient DNA; LIMS, laboratory information management systems; mtDNA, mitochondrial DNA; NGS, next-generation sequencing; PCA, principal component analysis; PSMC, pairwise sequentially Markovian coalescent; ROH, runs of homozygosity.

2. Archaic Hominins: Ancestors of Modern Humans

According to the microbial fossil record life on Earth began ~3.5 billion years ago in the Precambrian period36. In the late Miocene epoch, ~9.3-6.5 million years ago (Ma), it is believed that hominins (early human form) gained the bipedal and diverged from the Pan (chimpanzee) lineage37. On a genome-wide scale, modern humans and chimpanzees are the closest known species; however, an evolutionary study of the FOXP2 (forkhead box P2) gene has shown that the proteins of this gene cause interspecies differences even though they have similar amino acid sequences38. In another study, the detection of the NOTCH2NL (Notch homolog 2 N-terminal-like) gene co-emerged with the human lineage, further deepening the distinction between chimpanzees and modern humans39. The Middle and Late Pleistocene sheds more light on the evolution of modern humans and archaic hominins40. Nowadays, there are two incompatible models regarding the origins of modern humans. The first is called the “Non-African Event Hypothesis or Recent African Origin (RAO)”. This model claims that Homo sapiens have a single origin in African which occurred between ~200,000 to 100,000 years ago (ka), and archaic hominins are the evolutionary ancestors of modern humans. The other model, the multi-regional evolution model, suggests that Homo sapiens emerged whereby the gradual evolution of archaic hominins within the last 2 Ma41. Along with technological advances in fossil remains dating, evidence is now accumulating that indicates that modern humans differed from archaic hominins in Africa at ~350-200 ka42. There is another hypothesis regarding the speciation of Homo sapiens. Since the present paleoarchaeological remains point to different parts of the African continent as the birthplace of the first modern humans, the necessity of evaluating it from a broad evolutionary biology perspective, taking into account genomic and environmental factors, has led to the progression of the origin of modern humans from the RAO to Pan-Africanism, a mosaic speciation model. Pan-Africanism, or the extended single-African origin hypothesis, claims that in the last common ancestor (LCA) axis, archaic hominins and Homo sapiens speciated inside and outside the African continent (Figure 2)43. The introduction of the genus Homo to the literature dates back to a classification system made in 1735. In this classification, the genus Homo is described with the words nosce te ipsum (know thyself) instead of biological features. In 1856, the human species were identified as Homo neanderthalensis after bone remains were unearthed in Germany’s Neander Valley. In 1864, modern humans were denominated as Homo sapiens by taking into consideration of their morphological characteristics44. With the discovery of Homo erectus in 1895, new extinct species have continued to be added to the taxonomy of Homo since  home erectus was considered the oldest ancestor of man45-47. According to taxonomic classification, early archaic hominins have represented by Homo habilis, Homo rudolfensis, and Homo erectus species48. Existing evidence indicates that Homo sapiens coexisted with Homo neanderthalensis and descended from Homo heidelbergensis with the Denisovans49.

C:\Users\Turna\Desktop\paleogenetics\Figure2.png

Figure 2. Gradual evolution of Homo sapiens according to the Pan-Africanism hypothesis43. (1) The cross-people mosaic combination of representative LCA community traits on the African continent (2) Speciation in a discrete population (red sphere), depending on the structure of the skull spheroid (3) Expansion of a people with skull sphericity in and out of Africa. Dashed lines indicate gene flow among populations of the same and/or different species both within Africa (black and red) as well as outside Africa (red).

2.1. In the Footsteps of Mitochondria: Neanderthals

One of the breakthroughs of paleogenetics was achieved in 1997 with the discovery of the mitochondrial DNA (mtDNA) of recent archaic hominins. Partial sequencing of the hypervariable region I (HVRI) of the mtDNA through the cloning of PCR products from the bone remains of Homo neanderthalensis has shifted perspectives on modern human evolution to genomic information50. Completing complete mtDNA sequencing of the species in 2008 showed no mitogenomic transmission of maternally inherited mtDNA between Neanderthal species and modern humans51. By 2010, Pääbo and colleagues. reported the first genome-wide draft sequence completed by NGS in 21 Neanderthal bones from fossil remains in Croatia52. Extant Neanderthal mtDNA studies have enabled the determination of these archaic hominins’ sub-lineages, genetic diversity, and community structures, with paleogenomics approaches that provide the integration of genomic sequences following the discovery of new fossil remains53-56. The data obtained shows that Homo neanderthalensis disappeared ~40,000 years ago, and its existence in the Near East and Eurasia continued until 400ka57-59.

2.2. Towards Modern Man: Denisovans

Denisova Cave in Siberia opened a new window into the ancestry of modern humans in 2008. Pääbo and colleagues sequenced the mtDNA of a new archaic species, which they identified as Denisova hominin, from the bone dust they obtained from the fossil remains in the cave in 2010, which is estimated to belong to ~1 Ma60. It is estimated that this species, whose nuclear DNA sequence obtained from other fossil remains in Denisova Cave, separated from Neanderthals between 440-390 ka61. Although complete Denisovan skeletal remains have not been found so far, the morphological and anatomical analyzes of the limited remains available support the idea that this species may be closer to Homo sapiens than Neanderthals62-65. Detection of Denisova ancestry in East Asian, South Asian, Siberian and Indian communities, especially in Australians, provides information about the geographical distribution of this species66,67.

3. Human Species and Mixtures

The interest in genome research about preserved or altered genetic traits between ancient and modern humans has increased by the discovery of archaic hominins. A comparative study of the Homo sapiens genome with the genomes of the closest archaic hominins based on single nucleotide changes (SNC) has provided scientists with a unique catalog. SNCs in 571 genes that were similar between modern humans and archaic hominins were identified by this study, which examined cell division, neuron-based features, skull and face, and other phenotypic distinctions68. As research into the origins of modern humans has increased, hybridization and replacement or assimilation models have been proposed as subspecies of the multi-regional evolution model. These approaches suggest that genetic variants move between Homo sapiens and archaic hominins, and the recipient species gains an allelic advantage. The theory of gene flow between isolated hominin groups, defined as adaptive introgression, has motivated an in-depth investigation of mixing between hominins69. More data can be obtained from archaic genomes by the development of NGS technologies, making it relatively possible to detect interspecies introgression70. In a study published in 2018, the discovery of a hybrid individual with a Neanderthal mother and a Denisovan father stands out as strong evidence of interspecies gene mixing71. When and at what stages introgression occurred in the evolutionary process of modern humans is still not fully elucidated; however, there is evidence of an interspecies genotype-phenotype relationship. From aDNA data, predictions can be made about the effects of archaic hominin genomes on modern human phenotype through bioinformatics approaches such as machine learning (ML), genome-wide association studies (GWAS), phenome-wide association studies (pheWAS), polygenic risk scores (PRS), and analysis methods such as linkage disequilibrium (LD) in 2-locus models20,72-75. Studies have shown that the Neanderthal introgression detected in Eurasians contributes approximately 1-3% of the genomic; however, Denisovan introgression was variable. For example, Indigenous peoples living in the Southeast Asian Island and Australian regions were found to represent 5% of the Denisovan genomes; however, it has been determined that this representation differs in the Altai region. In the biology of existing allelic mixtures, the evaluation of the contribution of archaic hominin mixtures to the phenotype is limited, as the obtained mixture data cannot be interpreted globally, and Denisovan DNA cannot be represented in large modern populations76-79. A functional set of SNPs that influence phenotypes associated with archaic hominins in modern humans, such as neurological phenotypes, height, blood coagulation and inflammation, chronotype, skin and hair pigmentation, have been identified by extant studies80.

4. Human Diseases and Archaic Interactions

The life cycle, which takes place on the axis of DNA, RNA, and protein, forms a basis for diseases as well as genetic diversity, with its history dating back to the beginning of life81. While adaptive introgression increases the genomic diversity of modern humans82,83, at the same time, their contribution to disease susceptibility has been an important issue for scientists. It has been predicted that modern humans exhibited the dominant allele profile for survival from archaic genomes through positive selection in evolution84; however, mixtures of genes associated with neurological, dermatological, metabolic, and immunological diseases are also noteworthy85-89. The introgression of the Neanderthal genome has been associated with the development of autoimmune disorders, especially Crohn’s disease (CD), diabetes, multiple sclerosis, and celiac disease81,89. Additionally, it has been reported that this gene flow can act at the RNA level and cause decreased cancer susceptibility79. It has been reported that Denisovan introgestion increases the inheritance of coronary disease and that gene mixtures from archaic hominin to modern humans may play a role in pathophysiological mechanisms91. A recent study showed that genetic inheritance from Neanderthals could increase the risk of liver cancer92. Bioinformatics analyses also enabled the identification of new gene regions related to blood diseases (CYCS), neurological diseases (PRKCH, KCNH5, LRNN1), metabolic diseases (SFRP4, SUMF1) affected by ancient DNA93.

Paleogenetics and paleogenomics are disciplines that emerged with the development of new generation technologies and that allow the spatial and temporal investigation of the evolutionary processes of living things. Curiosity about human evolution and the origins of existence has led to aDNA isolation from fossil remains and the discovery of new archaic hominins. Among all known Homo species, studies on Neanderthals and Denisovans, which are closely related to modern humans, reveal that gene flow, called adaptive introgression, took place in the evolution process. While the genomic signatures that modern humans carry from these archaic hominins provide an advantage in adaptation to life through positive selection, it is a risk factor for some diseases. In the future, with the development of technology, more detailed interrogation of archaic genomes holds promise as potential tools for shedding light on unknown aspects of human evolution and perhaps the discovery of new Homo species.

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