Ancient DNA and Neanderthals | The Smithsonian Institution’s Human …

DNA (deoxyribonucleic acid) is arguably one of the most useful tools that scientists can use to understand living organisms. Our genetic code can tell us a lot about who we are, where come from, and even what diseases we may be predisposed to contracting and acquiring. When studying evolution, DNA is especially important in its application to identifying and separating organisms into species. However, DNA is a fragile molecule, and it degrades over time. For most fossil species, there is essentially no hope of ever acquiring DNA from their fossils, so answers to questions about their appearance, physiology, population structure, and more may never be fully answerable. For more recently extinct species scientists have, and continue to, extract ancient DNA (aDNA) which they use to reconstruct the genome of long-gone ancestors and relatives. One such species is Neanderthals, Homo neanderthalensis.

Neanderthals were the first species of fossil hominins discovered and have secured their place in our collective imagination ever since. The first Neanderthal fossils were found in Engis, Belgium in 1829, but not identified as belonging to Neanderthals until almost 100 years later. The first fossils to be called Neanderthals were found in 1856 in Germany, at a site in the Neander Valley (where Neanderthals get their name from). Neanderthals diverged from modern humans around 500,000 years ago, likely evolving outside of Africa. Most ancestors of Homo sapiens remained in Africa until around 100,000 years ago when modern humans began migrating outwards. In that time, Neanderthals evolved many unique adaptations that helped them survive in cold environments of Europe and Asia. Their short limbs and torso help conserved heat, and their wide noses helped warm and humidify air as they breathed it in. Despite these differences, modern humans and Neanderthals are very closely related and looked similar. We even overlapped with each other-living in the same place at roughly the same time in both the Middle East and Europe. If this is the case, why did Neanderthals go extinct while we survived? We can use DNA to help to answer this question and others, including:

Scientists answer these questions by comparing genomes as whole, as well as specific genes, between humans and Neanderthals. Before getting into the specifics of Neanderthal DNA, it is important to appreciate the structure of DNA itself, why it is so important, and why aDNA can be so difficult to work with.

Fast Facts

You may recognize the basic structure of DNA: two strands arranged in a double-helix pattern with individual bases forming rungs, like a twisting ladder. These bases are adenine (A), thymine (T), guanine (G), and cytosine (C). They form complementary pairs on opposite ends of each ladder rung: adenine across from thymine and cytosine across from guanine. For example, if one side of the twisting ladder reads AATG, the opposing side will read TTAC. It is the sequence of these individual base pairs that makes up our genetic code, or our genome. Errors can occur when DNA is unwound to be replicated with one or more bases being deleted, substituted for others, or newly added. Such errors are called mutations and range from being essentially harmless to deadly.

The main function of DNA is to control the production, timing, and quantity of proteins produced by each cell. This process is called protein synthesis and comes in two main stages: transcription and translation. When the cell needs to produce a protein, an enzyme called RNA polymerase unzips the DNA double-helix and aids in pairing RNA (ribonucleic acid, a molecule related to DNA) bases to the complementary DNA sequence. This first step is called transcription, the product of which is a single-sided strand of RNA that exits the cell. This messenger RNA, or mRNA, goes into the cells cytoplasm to locate an organelle called a ribosome where the genetic information in the mRNA can be translated into a protein. The process of translation involves another kind of RNA, transfer RNA or tRNA, binding to the base sequences on the mRNA. tRNA is carrying amino acids, molecules that will make up the final protein, binding in sequence to create an amino acid chain. This amino acid chain will then twist and fold into the final protein.

Base pairs are arranged in groups of three, or codons, on the mRNA and tRNA, Each codon codes for a single amino acid. Each individual amino acid can be coded for by more than one codon. For example, both AAA and AAG code for the same amino acid lysine. Therefore, a mutation changing the last A to a G will be functionally meaningless. This is known as a silent, or synonymous change. If that last A in the codon mutated to a C, however, the codon AAC codes for asparagine, a different amino acid. This new amino acid could lead to the formation of a completely new protein or make the amino acid chain unable to form a protein at all. This is known as a nonsynonymous change. Nonsynonymous changes are the basis for diversity within a gene pool on which evolution acts.

The total DNA sequence is made up of base pairs, but not all sequences of base pairs serve the same function. Not all parts of the DNA sequence directly code for protein. Base pair sequences within DNA can be split into exons, sequences that directly code for proteins, and introns, sequences that do not directly code for a specific protein. The exon portion of our genome is collectively called the exome, and accounts for only about 1% of our total DNA. Exons and introns together form genes, sequences that code for a protein. On average there are 8.8 exons and 7.8 introns in each gene. The noncoding, or intron, parts of DNA used to be called junk DNA, random or repeating sequences that did not seem to code for anything. Recent research has shown that the majority of the genome does serve a function even if not coding for protein synthesis. These intron sequences can help regulate when genes are turned on or off, control how DNA winds itself to form chromosomes, be remnant clues of an organisms evolutionary history, or serve other noncoding functions.

Most of our total genome is made of up nuclear DNA, or the genetic material located in the nucleus of a cell. This DNA forms chromosomes, X-shaped bundles of DNA, that separate during cell division. Homo sapiens have 23 pairs of chromosomes. Nuclear DNA is directly inherited from both parents with 50% each coming from an organisms biological male and female parents. Therefore, both parents lineages are represented by nuclear DNA with one exception. One of those pairs of chromosomes are called sex chromosomes. Everyone gets some combination of X (male female parent) and Y (male parent only) chromosomes that determine an organisms biological sex. These combinations can come in a variety of possible alternatives outside of XX and XY including XXY, X, and others. Because the Y chromosome is only inherited from a biological male parent, the sequence of the Y chromosome can be used to trace patrilineal ancestry.

DNA is also found in the mitochondria, an organelle colloquially referred to as the powerhouse of the cell. This mitochondrial DNA or mtDNA is much smaller than the nuclear genome, only composing about 37 genes. mtDNA is only inherited from an organisms biological female parent and can be used to trace matrilineal ancestry. Because both Y-chromosome DNA and mtDNA are smaller and inherited form only one parent, thus less subject to mutations and changes, they are more useful in tracing lineages through deep time. However, they pale in comparison to the entire nuclear genome in terms of size and available base sequences to analyze.

Fast Facts

Recall that DNA is made up of base pair sequences that are chemically bonded to the sides of the double-helix structure forming a sort of twisting ladder. As an organic molecule, the component parts of that twisting ladder are subject to degradation over time. Without the functioning cells of a living organism to fix these issues and make new DNA, DNA can degrade into meaningless components somewhat rapidly. While DNA is abundant and readily extracted in living organisms (you can even do your own at-home experiment to extract DNA! https://learn.genetics.utah.edu/content/labs/extraction/howto/) finding useable DNA in extinct organisms gets harder and harder the further back in time that organism died.

The record for the oldest DNA extracted used to go to an ancient horse, dating to around 500,000-700,000 years old (Miller and Lambert 2013). However, in 2021 this was blown out of the water with the announcement of mammoth DNA extracted from specimens over 1 million years old found in eastern Siberian permafrost, permanently frozen ground (van der Valk et al., 2021). These cases of extreme DNA preservation are rare and share a few important factors in common: the specimens are found in very cold, very dry environments, typically buried in permafrost or frozen in caves. The oldest hominin DNA recovered comes from a Neanderthal around 400,000 years old (Meyer et al. 2016), near the beginnings of the Neanderthal species. Finding older DNA in other hominins is unlikely as for most of our evolutionary history hominins lived in the warm, sometimes wet, tropics and subtropics of Africa and Asia where DNA does not preserve well.

When scientists are lucky enough to find a specimen that may preserve aDNA, they must take the utmost care to extract it in such a way as to preserve it and prevent contamination. Just because aDNA is preserved does not mean it is preserved perfectly; it still decomposes and degrades over time, just at a slower rate in cool, dry environments. Because of this, there is always going to be much less DNA from the old organism than there is in even the loose hair and skin cells from the scientists excavating it. Because of this, there are stringent guidelines in place for managing aDNA extraction in the field that scientists must follow (Gilbert et al., 2005 for example). In hominins, this is even more important since human and Neanderthal DNA are so similar that most sequences will be indistinguishable from each other.

Challenges in Sequencing aDNA

When aDNA does preserve, is often highly fragmented, degraded, and has undergone substantial changes from how the DNA appeared in a living organism. In order to sequence the DNA, or read the base pair coding, these damages and changes have to be taken into account and fixed wherever possible. aDNA comes in tattered, fragmented strands that are difficult to read and analyze. One way scientists deal with this is to amplify the aDNA that is preserved so that it is more readily accessible via a process known as polymerase chain reaction (PCR). PCR essentially forces the DNA to self-replicate exponentially so that there are many more copies of the same sequence to compare. Due to the exponential duplication, it is especially important for there to be no contamination of modern DNA in the sample. The amplified sequences can then be compared and aligned to create longer sequences, up to and including entire genes and genomes.

The component parts of DNA also degrade over time. One example is deamination, when cytosine bases degrade into a thymine molecule and guanine bases degrade into an adenine. This could potentially lead to misidentification of sequences, but scientists have developed chemical methods to reverse these changes. Comparison between closely related genomes, such as humans and Neanderthals, can also identify where deamination may have occurred in sequences that do not vary between the two species. Deamination can actually be useful because it is an excellent indicator that the sample you are looking at is genuine aDNA and not DNA from a contaminated source.

aDNA extraction and sequencing is inherently destructive and requires destroying at least part of the fossil sample you are attempting to extract DNA from. That is something that paleoanthropologists want to avoid whenever possible! To rationalize destroying a fossil to extract aDNA, it is common practice to first test this technique other non-hominin fossils from the same site to first confirm that DNA is accessible and in reasonable quantities/qualities. Testing aDNA form other sources, such as a cave bear at a Neanderthal site, can also identify any potential sources of contamination more easily since cave bears and humans are more distantly related.

Fast Facts:

DNA preserves best in cold, dry environments

aDNA must be destructively sampled, amplified, and analyzed prior to looking at the sequence

Neanderthal skull La Ferrassie 1 from La Ferrassie, France

The first analysis of any Neanderthal DNA was mitochondrial DNA (mtDNA), published in 1997. The sample was taken from the first Neanderthal fossil discovered, found in Feldhofer Cave in the Neander Valley in Germany. A small sample of bone was ground up to extract mtDNA, which was then replicated and analyzed.

Researchers compared the Neanderthal mtDNA to modern human and chimpanzee mtDNA sequences and found that the Neanderthal mtDNA sequences were substantially different from both (Krings et al. 1997, 1999). Most human sequences differ from each other by an average of 8.0 substitutions, while the human and chimpanzee sequences differ by about 55.0 substitutions. The Neanderthal and modern human sequences differed by approximately 27.2 substitutions. Using this mtDNA information, the last common ancestor of Neanderthals and modern humans dates to approximately 550,000 to 690,000 years ago, which is about four times older than the modern human mtDNA pool. Since this study was completed, many more samples of Neanderthal mtDNA have been replicated and studied.

Sequencing the Complete Neanderthal Mitochondrial Genome

After successfully sequencing large amounts of mtDNA, a team led by Svante Pbo from the Max Planck Institute reported the first complete mitochondrial DNA (mtDNA) sequence for a Neanderthal (Green et al. 2008). The sample was taken from a 38,000 year old Neanderthal from Vindija Cave, Croatia. The complete mtDNA sequence allowed researchers to compare this Neanderthal mtDNA to modern human mtDNA to see if any modern humans carried the mtDNA from a related group to the Neanderthal group.

Later, Svante Pbos lab sequenced the entire mitochondrial genome of five more Neanderthals (Briggs et al. 2009). Sequences came from two individuals from the Neander Valley in Germany and one each from Mezmaiskaya Cave in Russia, El Sidrn Cave in Spain, and Vindija Cave in Croatia. Though the Neanderthal samples came from a wide geographic area, the Neanderthal mtDNA sequences were not particularly genetically diverse. The most divergent Neanderthal sequence came from the Mezmaiskaya Cave Neanderthal from Russia, which the oldest and eastern-most specimen. Further analysis and sampling or more individuals has led researchers to believe that this diversity was more closely related to age than it was to population-wide variance (Briggs et al. 2009).On average, Neanderthal mtDNA genomes differ from each other by 20.4 bases and are only 1/3 as diverse as modern humans (Briggs et al. 2009). The low diversity might signal a small population size.

There is evidence that some other hominin contributed to the Neanderthal mtDNA gene pool around 270,000 years ago (Posth et al., 2017). A femur discovered in Germany had its mtDNA genotyped and it was found that there was introgression from a non-Neanderthal African hominin, either Homo sapiens or closely related to us, around 270,000 years ago. This mitochondrial genome is also highly divergent from the Neanderthal average discussed previously, indicating that Neanderthals may have been much more genetically diverse in their more distant past.

As for Neanderthal introgression into the modern human mtDNA genome, it is possible that the evidence of such admixture is obscured for a variety of reasons (Wang et al 2013). Primary among these reasons is sample size: There are to date only a dozen or so Neanderthal mtDNA sequences that have been sampled. Because the current sample of Neanderthal mtDNA is so small, it is possible that researchers simply have not yet found the mtDNA in Neanderthals that corresponds to that of modern humans.

Map of Neanderthal extent througout Eurasia.

There have been many efforts to sequence Neanderthal nuclear genes, with an eventual goal to sequence as much of the Neanderthal genome as possible. In 2014, the complete genome of a Neanderthal from the Altai Mountains in Siberia was published (Prufer et al., 2014). This female individuals genome showed that her parents were likely half siblings and that her genetic line showed evidence of high rates of incestuous pairings. It is unclear whether this is due to her living in a small and isolated population or if other factors may have influenced the lineages inbreeding. Their analysis also showed that this individual was closely related to both modern humans and the Denisovans, another ancient human population. By their analysis, there was only a very small margin by which Neanderthal and Denisovan DNA differed exclusively from modern humans.

Fast Facts:

Neanderthals are genetically distinct from modern humans, but are more closely related to us than chimpanzees are

The Neanderthal and modern human lineages diverged about 550,000 years ago

So far, we have no evidence of Neanderthal mtDNA lineages in modern humans

Neanderthals were not as genetically diverse as modern humans were at the same period, indicating that Neanderthals had a smaller population size

Neanderthal nuclear DNA shows further evidence of small population sizes, including genetic evidence of incest

As technology improves, researchers are able to detect and analyze older and more fragmentary samples of DNA

Scientists have also found DNA from another extinct hominin population: the Denisovans. The first remains of the species found were a single fragment of a phalanx (finger bone) and two teeth, all of which date back to about 40,000 years ago (Reich et al., 2010). Since then, a Denisovan mandible, or lower jaw, has been found in Tibet (Chen et al., 2019) and a Denisovan molar has been found in Laos (Demeter et al., 2022). Other fossil hominins, such as the Homo longi remains from northern China (Ji et al., 2021) and the Dali cranium from northwestern China may belong to the Denisovans, but without comparable fossils and genetics it is difficult to know for sure.

This species is the first fossil hominin identified as a new species based on its DNA alone. Denisovans are close relatives of both modern humans and Neanderthals, and likely diverged from these lineages around 300,000 to 400,000 years ago; they are more closely related to Neanderthals than to modern humans. You might be wondering: If we have the DNA of Denisovans, why cant we compare them to modern humans like we do Neanderthals? Why isnt this article about them too? The answer is simply that we dont have enough DNA and fossils to make a comparison. The single-digit specimen pool of Denisovans found to date is statistically far too small a data set to derive any meaningful comparisons. Until we find more Denisovan material, we cannot begin to understand their full genome in the way that we can study Neanderthals. The lack of more (and more morphologically diagnostic) Denisovan fossils is the reason why scientists have not yet given them a species name.

Fast Facts:

Homo sapiens and Homo neanderthalensis are different species, yet you are reading this webpage about them potentially interbreeding with each other. So, what does that mean, exactly? Modern humans and Neanderthals lived in separate regions evolving along separate evolutionary lineages for hundreds of thousands of years. Even so, Neanderthals are still our closest currently known relative. Because of that evolutionary proximity, despite being recognized as different species, it is still possible that members of our two species exchanged genetic information. This exchange of DNA is called introgression, or interbreeding.

When looking for evidence of interbreeding, scientists do not search billions and billions of base pairs. Instead, there are specific regions of the genomes that are known to be highly variable in modern humans along with several million single nucleotide polymorphisms (SNPs), where the given base at a single location can vary among people. The difference between the total genome and these specific regions/sites can lead to some confusion. In terms of the total genome, humans and chimpanzees are 98-99% similar. Yet, it is possible for individuals to have up to 4% Neanderthal DNA. That difference is accounted for in that 4% of the highly variable genome is inherited from a Neanderthal source, not 4% of the entire genome. If one was to look at the modern human genome as a whole, at least 98-99% is the same, inherited from our common ancestor with Neanderthals.

Neanderthals are known to contribute up to 1-4% of the genomes of non-African modern humans, depending on what region of the word your ancestors come from, and modern humans who lived about 40,000 years ago have been found to have up to 6-9% Neanderthal DNA (Fu et al., 2015). Because Neanderthals likely evolve outside of Africa (no Neanderthal fossils have been found in Africa to date) it was thought that there would be no trace of Neanderthal DNA in African modern humans. However, a study in 2020 demonstrated that there is Neanderthal DNA in all African Homo sapiens (Chen at el., 2020). This is a good indicator of how human migration out of Africa worked: that Homo sapiens did not leave Africa in one or more major dispersals, but that there was gene flow back and forth over time that brough Neanderthal DNA into Africa.

The evidence we have of Neanderthal-modern human interbreeding sheds light on the expansion of modern humans out of Africa. These new discoveries refute many previous hypotheses in which anatomically modern humans replaced archaic hominins, like Neanderthals, without any interbreeding. However, even with some interbreeding between modern humans and now-extinct hominins, most of our genome still derives from Africa.

For many years, the only evidence of human-Neanderthal hybridization existed within modern human genes. However, in 2016 researchers published a new set of Neanderthal DNA sequences from Altai Cave in Siberia, as well as from Spain and Croatia, that show evidence of human-Neanderthal interbreeding as far back as 100,000 years ago -- farther back than many previous estimates of humans migration out of Africa (Kuhlwilm et al., 2016). Their findings are the first to show human gene flow into the Neanderthal genome as opposed to Neanderthal DNA into the human genome. These data tells us that not only were human-Neanderthal interbreeding events more frequent than previously thought, but also that an early migration of humans did in fact leave Africa before the population that survived and gave rise to all contemporary non-African modern humans.

We previously mentioned the lack of genetic contributions by Neanderthals into the modern human mtDNA gene pool. As we have shown that Neanderthal-human interbreeding did occur, why wouldnt we find their DNA in our mtDNA as well as our nuclear DNA? There are several potential explanations for this. It is possible that there were at one point modern humans who possessed the Neanderthal mtDNA, but that their lineages died out. It is also highly possible that Neanderthals did not contribute to the mtDNA genome by virtue of the nature of human-Neanderthal admixture. While we know that humans and Neanderthals bred, we have no way of knowing what the possible social or cultural contexts for such breeding would have been.

Because mtDNA is passed down exclusively from mother to offspring, if Neanderthal males were the only ones contributing to the human genome, their contributions would not be present in the mtDNA line. It is also possible that while interbreeding between Neanderthal males and human females could have produced fertile offspring, interbreeding between Neanderthal females and modern human males might not have produced fertile offspring, which would mean that the Neanderthal mtDNA could not be passed down. Finally, it is possible that modern humans do carry at least one mtDNA lineage that Neanderthals contributed to our genome, but that we have not yet sequenced that lineage in either modern humans or in Neanderthals. Any of these explanations could underlie the lack of Neanderthal mtDNA in modern human populations.

Given that scientists have DNA evidence of another hominin species, the Denisovans, is there any evidence for interbreeding among all three species? Yes! Comparison of the Denisovan genome to various modern human populations shows up to 4-6% contribution from Denisovans in non-African modern human populations. This concentration is highest in people from Papua New Guinea and Oceania. It makes sense that interbreeding would appear in these Southeast Asian and Pacific Island communities, as their ancestors migrated from mainland Asia where Denisovan fossils have been found. There is also substantial evidence for Denisovan-Neanderthal interbreeding, including one juvenile female that appears to be a fist generation hybrid of a Neanderthal female parent and Denisovan male parent (Slon et al., 2018). Finding more Denisovan fossils will hopefully mean developing a more complete picture of Denisovan genetics so that scientists can explore these interactions in more detail.

Fast Facts:

Homo neanderthalensis, adult male. Reconstruction based on Shanidar 1 (artist, John Gurche)

While much of the genetic diversity discussed above came from inactive, noncoding, or otherwise evolutionarily neutral segments of the genome, there are many sites that show clear evidence of selective pressure on the variations between modern humans and Neanderthals. Researchers found 78 loci at which Neanderthals had an ancestral state and modern humans had a newer, derived state (Green et al 2010). Five of these genes had more than one sequence change that affected the protein structure. These proteins include SPAG17, which is involved in the movement of sperm, PCD16, which may be involved in wound healing, TTF1, which is involved in ribosomal gene transcription, and RPTN, which is found in the skin, hair and sweat glands. Other changes may not alter the sequence of the gene itself, but alter the factors that control that genes replication in the cell, changing its expression secondarily.

This tells us that these traits were selected for in the evolution of modern humans and were possibly selected against in Neanderthals. Though some of the genomic areas that may have been positively selected for in modern humans may have coded for structural or regulatory regions, others may have been associated with energy metabolism, cognitive development, and the morphology of the head and upper body. These are just a few of the areas where we have non-genetic evidence of differentiation between modern humans and Neanderthals.

While the study of DNA reveals aspects of relatedness and lineage, its primary function is, of course, to control the production of proteins that regulate an organisms biology. Each gene may have a variety of genotypes, which are the variances that can occur within the site of a particular gene. Each genotype codes for a respective phenotype, which is the physical expression of that gene. When we study Neanderthal DNA, we can examine the genotypes at loci of known function and can infer what phenotype the Neanderthals mutations may have expressed in life. Below, explore several examples of Neanderthal genes and the possible phenotypes that they would have displayed.

Ancient DNA has been used to reconstruct aspects of Neanderthal appearance. A fragment of the gene for the melanocortin 1 receptor (MRC1) was sequenced using DNA from two Neanderthal specimens from Spain and Italy: El Sidrn 1252 and Monte Lessini (Lalueza-Fox et al. 2007). MC1Ris a receptor gene that controls the production of melanin, the protein responsible for pigmentation of the hair and skin. Neanderthals had a mutation in this receptor gene which changed an amino acid, making the resulting protein less efficient and likely creating a phenotype of red hair and pale skin. (Thereconstruction below of a male Neanderthal by John Gurche features pale skin, but not red hair) .How do we know what this phenotype would have looked like? Modern humans display similar mutations of MC1R, and people who have two copies of this mutation have red hair and pale skin. However, no modern human has the exact mutation that Neanderthals had, which means that both Neanderthals and humans evolved this phenotype independent of each other.

If modern humans and Neanderthals living in Europe at the same time period both evolved this reduction of pigmentation, it is likely that there was an advantage to this trait. One hypothesis to explain this adaptations advantage involves the production of vitamin D. Our bodies primarily synthesize our supply of vitamin D, rather than relying on vitamin D from food sources. Vitamin D is synthesized when the suns UV rays penetrate our skin. Darker skin makes it harder for sunlight to penetrate the outermost layers and stimulate the production of vitamin D, and while people living in areas of high sun exposure will still get plenty of vitamin D, people who live far from the equator are not exposed to as much sunlight and need to optimize their exposure to the sun. Therefore, it would be beneficial for populations in colder climates to have paler skin so that they can create enough vitamin D even with less sun exposure.

The FOXP2 gene is involved in speech and language (Lai et al. 2001). Mutations in the FOXP2 gene sequence in modern humans led to problems with speech, and oral and facial muscle control. The human FOXP2 gene is on a haplotype that was subject to a strong selective sweep. A haplotype is a set of alleles that are inherited together on the same chromosome, and a selective sweep is a reduction or elimination of variation among the nucleotides near a particular DNA mutation. Modern humans and Neanderthals share two changes in FOXP2 compared with the sequence in chimpanzees (Krause et al. 2007). How did this FOXP2 variant come to be found in both Neanderthals and modern humans? One scenario is that it could have been transferred between species via gene flow. Another possibility is that the derived FOXP2 was present in the ancestor of both modern humans and Neanderthals, and that the gene was so heavily favored that it proliferated in both populations. A third scenario, which the authors think is most likely, is that the changes and selective sweep occurred before the divergence between the populations. While it can be tempting to infer that the presence of the same haplotype in Neanderthals and humans means that Neanderthals had similar complex language capabilities, there is not yet enough evidence for such a conclusion. Neanderthals may also have their own unique derived characteristics in the FOXP2 gene that were not tested for in this study. Genes are just one factor of many in the development of language.

The gene that produces the ABO blood system is polymorphic in humans, meaning that there are more than two possible expressions of this gene. The genes for both A and B blood types are dominant, and O type is recessive, meaning that people who are type A or B can have genotypes of either AA or AO (or BB and BO) and still be A (or B) blood type, but to have type O blood one must have a genotype of OO. Various selection factors may favor different alleles, leading to the maintenance of distinct blood groups in modern human populations. Though chimpanzees also have different blood groups, they are not the same as human blood types. While the mutation that causes the human B blood group arose around 3.5 Ma, the O group mutation dates to around 1.15 Ma. When scientists tested whether Neanderthals had the O blood group they found that two Neanderthal specimens from Spain probably had the O blood type, though there is the possibility that they were OA or OB (Lalueza-Fox et al. 2008). Though the O allele was likely to have already appeared before the split between humans and Neanderthals, it could also have arisen in the Neanderthal genome via gene flow from modern humans.

The ability to taste bitter substances is controlled by a gene, TAS2R38. Some individuals are able to taste bitter substances, while others have a different version of the gene that does not allow them to taste bitter foods. Possession of two copies of the positive tasting allele gives the individual greater perception of bitter tastes than the heterozygous state in which individuals have one tasting allele and one non-tasting allele. Two copies of a non-tasting allele leads to inability to taste bitter substances.

When scientists sequenced the DNA of a Neanderthal from El Sidrn, Spain for the TAS23R38 gene, they found that this individual was heterozygous and thus was able to perceive bitter taste - although not as strongly as a homozygous individual with two copies of the tasting allele would be able to (Lalueza-Fox et al. 2009). Both of these haplotypes are still present in modern people, and since the Neanderthal sequenced was heterozygous, the two alleles (tasting and non-tasting) were probably both present in the common ancestor of Neanderthals and modern humans. Though chimpanzees also vary in their ability to taste bitterness, their abilities are controlled by different alleles than those found in humans, indicating that non-tasting alleles evolved separately in the hominin lineage.

The microcephalin gene relates to brain size during development. A mutation in the microcephalin gene, MCPH1, is a common cause of microcephaly. Mutations in microcephalin cause the brain to be 3 to 4 times smaller in size. A variant of MCPH1, haplogroup D, may have been positively selected for in modern humans and may also have come from an interbreeding event with an archaic population (Evans et al. 2006). All of the haplogroup D variants come from a single copy that appeared in modern humans around 37,000 years ago. However, haplogroup D itself came from a lineage that had diverged from the lineage that led to modern humans around 1.1 million years ago. Although there was speculation that the Neanderthals were the source of the microcephalin haplogroup D (Evans et al. 2006), Neanderthal DNA sequenced does not contain the microcephalin haplogroup D (Green et al. 2010).

While changes to the genome can directly affect the phenotypes displayed in an organism, altering the timing mechanism of protein production can cause very similar effects. MicroRNA (miRNA) is one such mechanism: a cell uses miRNA to suppress the expression of a gene until that gene becomes necessary. One miRNA can target multiple genes by binding its seed region to messenger RNA that would otherwise have carried that information to the ribosome to be transcribed into proteins, preventing transcription from taking place. In hominins, one particular miRNA called miR-1304 is exhibited in both an ancestral and derived condition. The derived condition has a mutation at the seed region which allows it to target more mRNA segments but less effectively. This means that in the derived state, some genes will be more strongly expressed due to a lack of suppression. One such trait is the production of enamelin and amelotin proteins, both used in dental formation during development. The suppression of production in Neanderthals, and subsequent lack of suppression in modern humans, could be a contributing factor to some of the morphological differences between Neanderthal and modern human dentition.

Research shows that Neanderthal DNA has contributed to our immune systems today. A study of the human genome found a surprising incursion of Neanderthal DNA into the modern human genome, specifically within the region that codes for our immune response to pathogens (Dannemann et al 2016). These particular Neanderthal genes would have been useful for the modern humans arriving in Europe whose immune systems had never encountered the pathogens within Europe and would be vulnerable to them, unlike the Neanderthals who had built up generations of resistance against these diseases. When humans and Neanderthals interbred, they passed this genetic resistance to diseases on to their offspring, allowing them a better chance at survival than those without this additional resistance to disease. The evidence of this genetic resistance shows that there have been at least three incursions of nonhuman DNA into the genes for immune response, two coming from Neanderthals and one from our poorly understood evolutionary cousins, the Denisovans.

While many of the genes that we retain for generations are either beneficial or neutral, there are some that have become deleterious in our new, modern lives. There are several genes that our Neanderthal relatives have contributed to our genome that were once beneficial in the past but can now cause health-related problems (Simonti et al 2016). One of these genes allows our blood to coagulate (or clot) quickly, a useful adaptation in creatures who were often injured while hunting. However, in modern people who live longer lives, this same trait of quick-clotting blood can cause harmful blood clots to form in the body later in life. Researchers found another gene that can cause depression and other neurological disorders and is triggered by disturbances in circadian rhythms. Since it is unlikely that Neanderthals experienced such disturbances to their natural sleep cycles, they may never have expressed this gene, but in modern humans who can control our climate and for whom our lifestyle often disrupts our circadian rhythms, this gene is expressed more frequently.

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