Neanderthal genetics testing became possible in the 1990s with advances in ancient DNA analysis. In 2008, the Neanderthal genome project published the full sequence Neanderthal mitochondrial DNA (mtDNA), and in 2010 the full Neanderthal genome. Genetic data is useful in testing hypotheses about Neanderthal evolution and their divergence from early modern humans, as well as understanding Neanderthal demography, and interbreeding between archaic and modern humans.
Modern humans and Neanderthals had multiple different interbreeding episodes, but Neanderthal-derived genes in the present-day human genome descend from an episode 250,000 years ago probably in Eurasia, and 47,000 to 65,000 years ago in the Near East. While 20% of the Neanderthal genome survives today, most people only carry about a few percentage points of Neanderthal DNA, and most Neanderthal-derived DNA is non-coding. Neanderthals maintained a low genetic diversity and suffered from inbreeding depression; consequently most Neanderthal genes were probably selected out of the gene pool. Barring hybrid incompatibility or negative selection, most Neanderthal DNA may descend from the children of modern human females and Neanderthal males. Neanderthals also interbred with Denisovans in the Siberian Altai Mountains.
Genome sequencing
Genetic studies on Neanderthal ancient DNA became possible in the late 1990s. In July 2006, the Max Planck Institute for Evolutionary Anthropology and 454 Life Sciences announced that they would sequence the Neanderthal genome over the next two years. It was hoped the comparison would expand understanding of Neanderthals, as well as the evolution of humans and human brains. They published the full sequence Neanderthal mitochondrial DNA (mtDNA) in 2008. Svante Pääbo noted that, "Contamination was indeed an issue," and they eventually realised that 11% of their mtDNA sample was modern human DNA. Since then, more of the preparation work has been done in clean areas and 4-base pair 'tags' have been added to the DNA as soon as it is extracted so the Neanderthal DNA can be identified.
The first Neanderthal genome sequence was published in 2010, and strongly indicated interbreeding between Neanderthals and early modern humans. This was based on three specimens in Vindija Cave, Croatia, which contained almost 4% archaic DNA (allowing for near complete sequencing of the genome). However, there was approximately 1 error for every 200 letters (base pairs) based on the implausibly high mutation rate, probably due to the preservation of the sample. In 2012, British-American geneticist Graham Coop hypothesised that they instead found evidence of a different archaic human species interbreeding with modern humans, which was disproven in 2013 by the sequencing of a high-quality Neanderthal genome preserved in a 50,000 year old toe (phalanx) bone from Denisova Cave, Siberia.
A visualisation map of the reference modern-human containing the genome regions with high degree of similarity or with novelty according to a 50,000 year old Neanderthal from the Siberian Altai Mountains has been built by Pratas et al.
Neanderthal genomes sequenced include those from Denisova Cave including an offspring of a Neanderthal and a Denisovan, from Chagyrskaya Cave, from Vindija Cave, Mezmaiskaya cave, Les Cottés cave, Goyet Caves and Spy Cave, Hohlenstein-Stadel and Scladina caves Galería de las Estatuas, Gibraltar, and Sidrón Cave.
Evolution Genetic data has been used to test various hypotheses about Neanderthal evolution and identify the last common ancestor (LCA) of Neanderthals and modern humans. Numerous dates have been suggested, such as 538–315, 553–321, 565–503, 654–475, 690–550, 765–550, 741–317, and 800–520,000 years ago; and a dental analysis concluded before 800,000 years ago.
The date of around 250,000 years ago cites "H. helmei" as being the LCA, and the split is associated with the Levallois technique of making stone tools. The date of about 400,000 years ago uses H. heidelbergensis as the LCA. Estimates of 600,000 years ago assume that "H. rhodesiensis" was the LCA, which split off into a modern human lineage and a Neanderthal/H. heidelbergensis lineage. 800,000 years ago has H. antecessor as the LCA, but different variations of this model would push the date back to 1 million years ago. A 2020 analysis of H. antecessor enamel proteomes suggests that H. antecessor is related but not a direct ancestor.
Neanderthals and Denisovans are more closely related to each other than they are to modern humans, meaning the Neanderthal/Denisovan split occurred after their split with modern humans. Before splitting, Neanderthal/Denisovans (or "Neandersovans") migrating out of Africa into Europe apparently interbred with an unidentified "superarchaic" human species who were already present there; these superarchaics were the descendants of a very early migration out of Africa around 1.9 mya. Assuming a mutation rate of 1 × 10−9 or 0.5 × 10−9 per base pair (bp) per year, the Neanderthal/Denisovan split occurred around either 236,000–190,000 or 473,000–381,000 years ago, respectively. Using 1.1 × 10−8 per generation with a new generation every 29 years, the time is 744,000 years ago. Using 5 × 10−10 nucleotide sites per year, it is 616,000 years ago. Using the latter dates, the split had likely already occurred by the time Neanderthal ancestors spread out across Europe.
Demographics Like modern humans, Neanderthals probably descended from a very small population with an effective population—the number of individuals who can bear or father children—of 3,000 to 12,000 approximately. Genetic data suggests that Neanderthals maintained this very low population, proliferating weakly harmful genes due to the reduced effectivity of natural selection. Various studies, using mtDNA analysis, yield varying effective populations, such as about 1,000 to 5,000; 5,000 to 9,000 remaining constant; or 3,000 to 25,000 steadily increasing until 52,000 years ago before declining until extinction. Archaeological evidence suggests that the modern human population at the time of the Neanderthal/modern human transition was ten times higher. Neanderthals may have been at a demographic disadvantage due to a lower fertility rate, a higher infant mortality rate, or a combination of the two. Estimates giving a total population in the higher tens of thousands are contested.
Low population caused a low genetic diversity and probably inbreeding, which reduced the population's ability to filter out harmful mutations (inbreeding depression). It is unclear how this affected a single Neanderthal's genetic burden and, thus, if this caused a higher rate of birth defects than in contemporary modern humans (Cro-Magnons). If it did, it could have contributed to the extinction of the species (mutational meltdown).
Genetic analysis indicates there were at least three distinct geographical groups: Western Europe, the Mediterranean coast, and east of the Caucasus, with some migration among these regions. Over long periods of time, there is evidence of large-scale cross-continental migration. Early specimens from Mezmaiskaya Cave in the Caucasus and Denisova Cave in the Siberian Altai Mountains differ genetically from Western European Neanderthals, whereas later specimens from these caves both have genetic profiles more similar to Western European Neanderthals than to the earlier specimens from the same locations. These suggest large-scale population replacement over time.
Interbreeding
Interbreeding with modern humans
The first Neanderthal genome sequence was published in 2010, and strongly indicated interbreeding between Neanderthals and early modern humans. The genomes of all studied modern populations contain Neanderthal DNA. In all, approximately 20% of the Neanderthal genome appears to have survived in the modern human gene pool.
Various estimates exist for the proportion, such as 1–4% or 3.4–7.9% in modern Eurasians, or 1.8–2.4% in modern Europeans and 2.3–2.6% in modern East Asians. Pre-agricultural Europeans appear to have had similar, or slightly higher, percentages to modern East Asians. The percentage may have decreased in Europeans due to dilution with a group of people which had split off before Neanderthal introgression. Typically, studies have reported finding no significant levels of Neanderthal DNA in Sub-Saharan Africans, but a 2020 study detected 0.3-0.5% in the genomes of five African sample populations, likely the result of Eurasians back-migrating and interbreeding with Africans.
A study of 2,762 Indian genomes found that Indians get between 1% and 2% of their DNA from Neanderthals and Denisovans, and by assembling all the Neanderthal fragments the researchers were able to find 1,524 million base pairs of introgressing Neanderthal DNA and 591 million of Denisovan (compare to the human genome size of around 3000 million). With Icelanders, not as much cumulative Neanderthal DNA was found. This raises the possibility of building the full Neanaderthal genome from living humans.
Neanderthal-derived genes While a large portion of surviving introgression appears to be non-coding DNA with few biological functions, some Neanderthal-derived genes seem to have functional implications.
Due to their small population and resulting reduced effectivity of natural selection, Neanderthals accumulated several weakly harmful mutations, which were introduced to and slowly selected out of the much larger modern human population; the initial hybridised population may have experienced up to a 94% reduction in fitness compared to contemporary humans. By this measure, Neanderthals may have substantially increased in fitness. A 2017 study focusing on archaic genes in Turkey found associations with coeliac disease, malaria severity and Costello syndrome.
Nonetheless, some genes may have helped modern humans adapt to the environment. The putatively Neanderthal Val92Met variant of the MC1R gene may be weakly associated with red hair and UV radiation sensitivity. This variant is primarily found in East Asian populations (especially Taiwanese indigenous peoples) rather than Europeans. "We further discovered that all of the putative Neanderthal introgressive haplotypes carry the Val92Met variant, a loss-of-function variant in MC1R that is associated with multiple dermatological traits including skin color and photoaging. Frequency of this Neanderthal introgression is low in Europeans (~5%), moderate in continental East Asians (~30%), and high in Taiwanese aborigines (60–70%)." Different modern human populations seem to have maintained certain Neanderthal-derived genes due to local evolutionary pressures; for instance, Asian populations showed clustering in functional groups related to complement and haematopoietic pathways, while Europeans showed clustering in functional groups related to the lipid catabolic process."Specifically, genes in the LCP [lipid catabolic process] term had the greatest excess of NLS in populations of European descent, with an average NLS frequency of 20.8±2.6% versus 5.9±0.08% genome wide (two-sided t-test, P<0.0001, n=379 Europeans and n=246 Africans). Further, among examined out-of-Africa human populations, the excess of NLS [Neanderthal-like genomic sites] in LCP genes was only observed in individuals of European descent: the average NLS frequency in Asians is 6.7±0.7% in LCP genes versus 6.2±0.06% genome wide." . Some genes related to the immune system appear to have been affected by introgression, which may have aided migration, such as OAS1, STAT2, TLR6, TLR1, TLR10, and several related to immune response. Of the inherited Neanderthal genome, 25% in modern Europeans and 32% in modern East Asians may be related to viral immunity.