Interbreeding between Neanderthals and modern humans

What we know now

Whether or not modern humans interbred with Neanderthals is a question that has long been of interest to both scholars and lay people alike, but it was not until May 2010 that strong evidence emerged that the answer to the question was ‘yes, probably’.

A project to sequence the Neanderthal genome was commenced in 2006 at the Max Planck Institute for Evolutionary Anthropology (Green, et al., 2006; Green, et al., 2008), and in May 2010, researchers published a first draft of the Neanderthal genome (Green, et al., 2010). With the initial announcement came the dramatic news that made headlines around the world. It turned out that between one and four percent of the genome of modern non-Africans was derived from Neanderthals. In other words, the answer to the million dollar question was ‘yes, they did interbreed – but not in Africa’. The researchers compared the Neanderthal genome with those of five present-day individuals: two indigenous Africans (one San from South Africa and one Yoruba from West Africa) and three Eurasians (one from Papua New Guinea, one from China and one from France). The results showed that Neanderthals were more closely related to non-Africans than to Africans. This is not particularly surprising, as Neanderthals are not known to have lived in Africa. Any interbreeding has generally been supposed to have occurred within the known range of the Neanderthals, in Europe and western Asia. What was unexpected was that no difference was found between Papua New Guinean, Chinese and European individuals in terms of their degree of relatedness to Neanderthals.

The implication is that the interbreeding must have occurred before the ancestors of the present-day Asian, Australasian and European populations diverged from one another – presumably in Southwest Asia soon after modern humans first left Africa, and long before they reached Europe. If the population that left Africa was small, only limited interbreeding would be necessary to leave the Neanderthal contribution fixed in the modern non-African genome for all time, as numbers increased during the subsequent peopling of the world.

Interbreeding was not the only way to interpret these initial results, and the authors of the report said that they could not rule out the possibility that their results reflected substructure in the early modern human populations. In fact, a later independent study favoured this possibility, using a mathematical model to represent a connected string of regional populations spanning Africa and Eurasia. After the string split, the Eurasian and African parts of the range subsequently evolved into Neanderthals and modern humans respectively. For the latter, groups geographically closest to the split (i.e. in North Africa) remained more closely related to Neanderthals than those further south. It was assumed that the non-African world was subsequently populated by a dispersal of one of these northerly groups from Africa (Eriksson & Manica, 2012).

Subsequent work by independent researchers ruled out this substructure scenario (Sankararaman, et al., 2012; Yang, et al., 2012), and appeared to back the view that there had been a single episode of interbreeding very early on in the Out of Africa expansion that led to the peopling of the non-African world (Yotova, et al., 2011). The findings that some Africans do after all carry a Neanderthal genetic signature (Sánchez-Quinto, et al., 2012; Wall, et al., 2013) is not a major problem, as this can be accounted for in terms of a pre-Neolithic ‘Back to Africa’ migration of modern humans from Southwest Asia (Olivieri, et al., 2006; González, et al., 2007; Hodgson, et al., 2014).

A complication is that studies have found no trace of a Neanderthal component in mitochondrial DNA (Caramelli, et al., 2003; Serre, et al., 2004; Caramelli, et al., 2008). On the ‘brief encounter’ picture, this could mean crossbred women were sterile, and thus their mitochondrial DNA was never passed to subsequent generations. Another possibility is that interbreeding between Neanderthals and modern humans was very rare, with only one such event every couple of centuries. The reason could be limited biological compatibility, or it could be that the two mostly avoided interspecific mating. Such a low rate of interbreeding would account for the absence of Neanderthal mitochondrial DNA from the present-day gene pool, but it would still be sufficient to account for the observed levels of Neanderthal DNA in the nuclear genome. However, it would require interbreeding to occur across the whole of the Neanderthal range, not just in Southwest Asia (Currat & Excoffier, 2011; Neves & Serva, 2012).

Between 2012 and 2014, further studies showed that the original conclusion that all non-African populations were related equally to Neanderthals was incorrect, and that the proportion of Neanderthal ancestry in East Asians is 20 to 40 percent higher than it is in Europeans. This implies that interbreeding could not all have happened at a single time and place; some of it must have happened after the ancestral East Asian and European populations separated (Meyer, et al., 2012; Wall, et al., 2013; Vernot & Akey, 2014). Given that Neanderthals lived in Europe but are not known from East Asia, this is unexpected. However, their known range extents to the Altai region north of the Himalayas and a subsequent episode of interbreeding might have occurred there. Alternatively, it is possible that the Neanderthal range actually extended further south, as we know to have been the case for the Denisovans.

The latest work suggests that around 20 percent of the Neanderthal genome survives in the present-day population, albeit individuals each only possess a small fraction of this amount (Vernot & Akey, 2014). 

Many useful Neanderthal genes have been incorporated into the modern genome; for example those involved with the production of keratin, a protein that is used in skin, hair and nails. Possibly the Neanderthal versions of these genes were more suited to the harsh conditions of Ice Age Europe (Sankararaman, et al., 2014). In East Asian populations, many genes involved with protection from UV are of Neanderthal origin (Ding, et al., 2014).

Some deleterious genes also have a Neanderthal connection, including those implicated in Type 2 diabetes and Crohn’s disease. Significantly, Neanderthal DNA was largely absent from the X chromosome and genes associated with modern testes. The implication is that Neanderthal DNA in these regions led to reduced male fertility, or sterility (Sankararaman, et al., 2014), consistent with the view that Neanderthals and modern humans were at the limits of biological compatibility.

These results show that natural selection had a significant role, with both positive and negative selection determining Neanderthal gene frequencies. It is entirely possible that selective factors could be at least partially responsible for the higher incidence of Neanderthal DNA in East Asian populations.

It is now clear that the interactions between Neanderthal and modern populations were complex; and that we are still at a very early stage of understanding them.

References:

1. Green, R. et al., Analysis of one million base pairs of Neanderthal DNA. Nature 444, 330-336 (2006).

2. Green, R. et al., A Complete Neandertal Mitochondrial Genome Sequence Determined by High-Throughput Sequencing. Cell 134, 416–426 (2008).

3. Green, R. et al., A Draft Sequence of the Neandertal Genome. Science 328, 710-722 (2010).

4. Eriksson, A. & Manica, A., Effect of ancient population structure on the degree of polymorphism shared between modern human populations and ancient hominins. PNAS 109 (35), 13956–13960 (2012).

5. Sankararaman, S., Patterson, N., Li, H., Pääbo, S. & Reich, D., The Date of Interbreeding between Neandertals and Modern Humans. PLoS Genetics 8 (10) (2012).

6. Yang, M., Malaspinas, A., Durand, E. & Slatkin, M., Ancient Structure in Africa Unlikely to Explain Neanderthal and Non-African Genetic Similarity. Molecular Biology and Evolution 29 (10), 2987–2995 (2012).

7. Yotova, V. et al., An X-Linked Haplotype of Neandertal Origin Is Present Among All Non-African Populations. Molecular Biology and Evolution 28 (7), 1957-1962 (2011).

8. Sánchez-Quinto, F. et al., North African Populations Carry the Signature of Admixture with Neandertals. PLoS One 7 (10) (2012).

9.  Wall, J. et al., Higher levels of Neanderthal ancestry in East Asians than in Europeans. Genetics 194, 199-209 (2013).

10. Olivieri, A. et al., The mtDNA Legacy of the Levantine Early Upper Palaeolithic in Africa. Science 314, 1757-1770 (2006).

11. González, A. et al., Mitochondrial lineage M1 traces an early human backflow to Africa. BMC Genomics 8 (223) (2007).

12. Hodgson, J., Mulligan, C., Al-Meeri, A. & Raaum, R., Early Back-to-Africa Migration into the Horn of Africa. PLoS Genetics 10 (6), e1004393 (2014).

13. Caramelli, D. et al., Evidence for a genetic discontinuity between Neandertals and 24,000-year-old anatomically modern Europeans. PNAS 100 (11), 6593–6597 (2003).

14.  Serre, D. et al., No Evidence of Neandertal mtDNA Contribution to Early Modern Humans. PLoS Biology 2 (3), 0313-0317 (2004).

15.  Caramelli, D. et al., A 28,000 Years Old Cro-Magnon mtDNA Sequence Differs from All Potentially Contaminating Modern Sequences. PLoS One 3 (7) (2008).

16.  Currat, M. & Excoffier, L., Strong reproductive isolation between humans and Neanderthals inferred from observed patterns of introgression. PNAS 108 (37), 15129-15134 (2011).

17.  Neves, A. & Serva, M., Extremely Rare Interbreeding Events Can Explain Neanderthal DNA in Living Humans. PLoS One 7 (10) (2012).

18.  Meyer, M. et al., A High-Coverage Genome Sequence from an Archaic Denisovan Individual. Science 338, 222-226 (2012).

19. Vernot, B. & Akey, J., Resurrecting Surviving Neandertal Lineages from Modern Human Genomes. Science 343, 1017-1021 (2014).

20.  Sankararaman, S. et al., The genomic landscape of Neanderthal ancestry in present-day humans. Nature 507, 354–357 (2014).

21.  Ding, Q., Hu, Y., Xu, S., Wang, J. & Jin, L., Neanderthal Introgression at Chromosome 3p21.31 Was Under Positive Natural Selection in East Asians. Molecular Biology and Evolution 31 (3), 683-695 (2014).