No Neanderthal-derived Y-chromosomes in modern population

Evidence found of genetic incompatibility

An open access study published in The American Journal of Human Genetics has found no evidence of Neanderthal introgression into modern male Y-chromosome despite it being elsewhere in the modern genome. The study is the first in which a Neanderthal Y-chromosome has been sequenced as all the Neanderthal individuals previously sequenced to 0.1x coverage were women. Women do not have a Y-chromosome, so men inherit their Y-chromosomal DNA exclusively from their fathers. The researchers sequenced the Y-chromosome from a male Neanderthal from the El Sidrón cave site in northern Spain, dating to 49,000 years ago.

The researchers found that the Neanderthal and modern human Y-chromosomes diverged from one another around 588,000 years ago, which is consistent with estimates for when the ancestors of Neanderthals and modern humans diverged from one another. This was not unexpected: the surprise was that no Neanderthal-derived Y-chromosome has ever been observed in a modern male. While this could simply be the result of genetic drift, the researchers found evidence of genetic incompatibility between the Y-chromosomal genes of Neanderthals and modern humans.

They identified protein-coding differences between Neanderthal and modern human Y-chromosomes, including potentially deleterious coding differences in the genes PCDH11Y, TMSB4Y, USP9Y and KDM5D. PCDH11Y and its X-chromosomal counterpart PCDH11X might play a role in brain lateralisation and language development; TMSB4Y might influence sperm production; USP9Y might reduce cell proliferation in malignant tumours; and KDM5D might play a role in suppressing the invasiveness of certain cancers.

Three of these changes are missense mutations, i.e. they alter the amino acid sequence of proteins, which in turn have a biological impact. All three are in genes that produce male-specific minor histocompatibility (H-Y) antigens. Such antigens can trigger an immune response during pregnancy, leading to a miscarriage. These antigens are similar to human leucocyte antigens (HLA) that form part of the body’s immune system, but because the genes are on the Y-chromosome they are specific to men. If only girls were carried to full term, that could explain the absence of any Neanderthal contribution to the present-day Y-chromosome.

Mendez, F., Poznik, D., Castellano, S. & Bustamante, C., The Divergence of Neandertal and Modern Human Y Chromosomes. The American Journal of Human Genetics 98, 728-734 (2016).


Melanesian genomes reveal episodes of interbreeding with Neanderthals and Denisovans

Study demonstrates multiple encounters with archaic humans

In a new attempt to obtain genetic information about Neanderthals and Denisovans, researchers have analysed the genomes of 1,523 genetically-diverse individuals, including 35 Melanesians. Results were compared with known Neanderthal and Denisovan sequences. 1340 Mb of the Neanderthal genome and 304 Mb of the Denisovan genome were obtained.

The Melanesians show between 1.9 and 3.4 percent of Denisovan ancestry. They have an average 104 Mb of archaic sequences: 48.9 Mb of Neanderthal, 42.9 Mb of Denisovan, and 12.2 Mb of ambiguous sequence that could be either. By contrast, only 0.026 Mb (in Esan) to 0.5 Mb (in Luhya) of archaic sequences per individual were found in Africans. An average 65.0 Mb of archaic sequences were found in East Asians; 55.2 Mb in South Asians; and 51.2 Mb in Europeans. Most of these archaic sequences were Neanderthal in origin, although a small fraction (less than 1 percent) in East Asians and South Asians are predicted to be Denisovan. There was evidence for an additional pulse of Neanderthal admixture in Europeans, East Asians, and South Asians compared to Melanesians. The data suggests that there were at least three separate episodes of interbreeding between Neanderthals and modern humans, and one of modern humans interbreeding with Denisovans.

The study also found a statistically-significant overlap between regions depleted of Neanderthal and regions depleted of Denisovan genetic sequences, suggesting that archaic sequences in these regions were deleterious and were purged by the effects of purifying selection. Regions depleted of archaic lineages are contain large numbers of genes associated with specific regions of the brain, particularly in the developing cortex and adult striatum. A large region depleted of archaic sequences spans 11 Mb on chromosome 7 and contains the FOXP2 gene associated with speech and language, as well as genes associated with autism.

It is likely that further studies will reveal an increasingly complex picture of how modern humans have interbred with archaic humans throughout Eurasia. The depletion of archaic sequences from brain-related sequences of the genome might hint at cognitive differences between modern and archaic humans; or these regions might simply be more prone to adverse effects of horizontal gene transfer.

Vernot, B. et al., Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals (10.1126/science.aad9416) (2016).

Modern humans interbred with Neanderthals 100,000 years ago

Ancient DNA from Altai Neanderthal female is first evidence of modern human contribution to Neanderthal genome

Ever since the first draft of the Neanderthal genome was published in 2010, it has been known that Neanderthals interbred with modern humans and it is now believed that around twenty percent of their genome survives in the present-day population. Subsequent work revealed the existence of a new human species in the Russian Altai, the Denisovans, and that parts of their genome also survive in the present-day population. It has also been established that the Altai Denisovans also interbred with Neanderthals in the region and with another as yet unidentified archaic species (probably Homo erectus). What has hitherto been absent up is evidence of gene flow from early modern humans into archaic genomes.

To address this issue, researchers investigated the previously-sequenced genome of a Neanderthal woman who lived in the Altai region 50,000 years ago. They found evidence of gene flow from modern humans into the ancestors of the Altai Neanderthal. The source was unclear, but was thought to be a modern population that either split from the ancestors of all present-day Africans, or was one of the early modern African lineages. It was estimated that the implied interbreeding occurred at least 100,000 years ago – well before the previously-reported gene flow from Neanderthals into modern humans outside Africa 47,000 to 65,000 years ago. However, they did not find evidence for similar gene flow from modern humans into either Denisovans or European Neanderthals.

The traditional view that modern humans did not leave Africa and the Levantine/Arabian region until around 60,000 years ago has been refuted by the discovery of teeth lying within the modern range at Fuyan Cave, China, dating to around 100,000 years ago. If modern humans were in China then it is entirely possible that they were also in the Altai at that time. Other possibilities are the Arabian Peninsula, where there is archaeological (though no fossil) evidence for a modern human presence as long ago as 127,000 years ago and Neanderthals were likely to also have been present; and the Levant where there is fossil evidence for both Neanderthals (Tabun) and modern humans (Skhul and Qafzeh) 120,000 to 110,000 years ago.

Kuhlwilm, M. et al., Ancient gene flow from early modern humans into Eastern Neanderthals. Nature, doi:10.1038/nature16544 (2015).



Adverse effects of interbreeding with Neanderthals

Not all ‘imported’ genes were beneficial
Interbreeding with Neanderthals and Denisovans is believed to have introduced many beneficial genes into the modern genome, helping the immune systems of early modern humans to fight pathogens to which they had not previously been exposed. Other ‘imported’ genes include those involved with the production of keratin, a protein that is used in skin, hair and nails, and in East Asian populations, many genes involved with protection from the sun’s UV rays are of Neanderthal origin. It is likely that the transfer of these genes helped early modern humans to adapt to conditions away from their African homeland.

However, a newly-published study suggests that interbreeding with Neanderthals also had a down side. Researchers analysed the electronic health records (EHR) of 28,000 individuals of European origin and integrated the data with high resolution maps of Neanderthal haplotypes across individual modern human genomes. They carried out a large-scale assessment of the functional effects of DNA inherited from Neanderthals on health-related traits in these individuals. Particular use was made of genotype and phenotype data from the Electronic Medical Records and Genomics Network, which is a consortium that links EHR systems combined with patient genetic data from nine sites across the USA.

Genes of Neanderthal origin were found to be associated with smoking addiction, increased risk of depression, incontinence, bladder pain, urinary tract disorders, protein calorie malnutrition, and actinic keratosis (precancerous skin lesions resulting from exposure to the sun). One gene variant was associated with blood coagulation, increasing the risk of strokes. These results follow on from earlier work which implicated increased risk of Crohn’s disease and type 2 diabetes with Neanderthal genes.

Many of these genes would have been advantageous to Neanderthals: for example, the benefits of enhanced blood coagulation would have greatly outweighed the risk of strokes when injuries leading to significant loss of blood were a part of daily life and few people lived past forty. In other cases, genes were probably once advantageous but adverse effects were triggered by the changes in diet following the coming of agriculture in Neolithic times.

Depression can be triggered by disturbed circadian rhythms. It is possible that Neanderthal brain chemistry and skin responses to sunlight were both linked to the lighting conditions and lifestyles of an era when artificial light consisted of torches and camp fires. In which case, the genes might only have become maladaptive with the advent of widespread artificial lighting.

The methodology used by the researchers is likely to provide further insight into the genetic impact of these ancient encounters between Neanderthals and modern humans.

Simonti, C. et al., The phenotypic legacy of admixture between modern humans and Neandertals. Science 351 (6274), 737-741 (2016).


Did Chinese Homo erectus survive into the Late Pleistocene?

14,000-year-old hominin thigh bone has archaic affinities.

In 2012, human remains differing from the modern condition were reported from two sites 300 km (185 miles) apart in southwest China: Longlin Cave in Guangxi Province, and Maludong (‘Red Deer Cave’) in Yunnan Province. The Longlin remains have been radiocarbon dated to 11,500 years old, and those from Maludong to 14,000 years old. The Longlin remains included a partial skull, a temporal bone fragment probably belonging to the skull, a partial lower jawbone and some fragmentary postcranial bones. The cheek bones of the skull are broad and flared sideways; the browridges conspicuous; the chin less prominent than in Homo sapiens; and the remains are very robust. The Maludong remains include a skullcap, two partial jawbones and a partial thighbone.

Popularly reported as the Red Deer Cave people, the hominins were at first thought to represent a single population, but newly-published work suggests that the Longlin skull has affinities to early modern humans. The bony labyrinth (the bony outer wall of the inner ear) of the temporal bone fragment is modern in appearance and it is possible that the skull’s unusual shape might be the result of interbreeding between archaic and modern humans. It has been suggested that Longlin was located in a ‘hybrid zone’ – a border between relict archaic and modern populations. Similar hybrid zones occur with some non-human primate populations.

The Maludong thighbone is now claimed to show affinities to archaic humans, in particular those from the Early Pleistocene. There is a scarcity of later archaic human remains in East Asia, and the authors of the new report are reluctant to assign the thighbone to a particular archaic human species. However, the likeliest possibility is that the thighbone represents a late survival of Homo erectus in China. Regardless of species, the implications of these new findings is that isolated populations of archaic humans were still in existence in China as late as 11,500 years ago and that some of these populations were interbreeding with modern humans.


1.  Curnoe, D. et al., Human Remains from the Pleistocene-Holocene Transition of Southwest China Suggest a Complex Evolutionary History for East Asians. PLoS One 7(3) (2012).
2.  Curnoe, D., Ji, X., Taçon, P. & Yaozheng, G., Possible Signatures of Hominin Hybridization from the Early Holocene of Southwest China. Scientific Reports 5, 12408 (2015).
3.  Curnoe, D. et al., A Hominin Femur with Archaic Affinities from the Late Pleistocene of Southwest China. PLoS One (2015).





Early modern human from Romania had recent Neanderthal ancestor

Ancient DNA from Peştera cu Oase demonstrates inbreeding no more than four to six generations previously

The cave site of Peştera cu Oase (‘Cave with Bones’) in Romania has yielded some of the earliest fossil remains of modern humans in Europe. The remains of three individuals recovered from the site include a largely-complete lower jawbone (Oase 1), the near-complete skull of a 15-year-old adolescent, and a left temporal bone. The remains are around 40,000 years old and exhibit a mosaic of modern and archaic features. Modern features include the absence of browridges, a narrow nasal aperture, and a prominent chin; but there are also archaic features such as a wide dental arcade and very large molars. There is little doubt that they are modern humans and not Neanderthals, but some aspects of the morphology are consistent with Neanderthal ancestry.

Researchers have now recovered ancient DNA from the Oase 1 jawbone and sequenced the genome. They report that between 6 to 9 percent of the genome is of Neanderthal origin, a higher percentage than for any other modern human genome sequenced to date. Three chromosomal segments of Neanderthal DNA are of considerable length, suggesting that the Neanderthal contribution to the Oase 1 individual occurred so recently in their past that the chromosomal segments of Neanderthal origin had little time to break up due to recombination. The researchers turned their attention to seven segments of the genome that appeared to be of recent Neanderthal origin and from the genetic lengths of these, implied that Oase 1’s Neanderthal ancestor had lived no more than four to six generations earlier, or less than two hundred years.

The existence of such a recent Neanderthal ancestor casts doubts on theories that suggest that interbreeding occurred only very occasionally, or was confined to an early episode soon after modern humans first left Africa. However, the researchers failed to establish a clear relationship between the Oase 1 individual and later modern humans in Europe, suggests that they may have been a member of an early modern human population in Europe that eventually died out without contributing much to later European populations.

Fu, Q. et al., An early modern human from Romania with a recent Neanderthal ancestor. Nature 524, 216-219 (2015).

Evidence of interbreeding between archaic and modern humans – or just highly diverse morphology?

50,000-year-old Tam Pa Ling lower jawbone is a mosaic of archaic and modern features

Tam Pa Ling (‘Cave of the Monkeys’) is a cave site in Huà Pan Province, Laos. A fully-modern partial human skull (TPL1) was recovered in December 2009, followed a year later by a complete human lower jawbone (TPL2). The upper jawbone of TPL1 does not match with TPL2, so the two represent different individuals. The fossils are estimated to be from 46,000 to 63,000 years old, establishing an early presence of modern humans in Southeast Asia.

A newly-published study of the more recent discovery suggests that the TPL2 lower jawbone, though essentially modern, possesses a number of archaic attributes. The most obvious sign of modern affinities is the clear presence of a chin. However, viewed from the side, the jawbone is very robust, particularly at the position of the first and second mandibles. In this respect, TPL2 is closer to the archaic than the modern human condition.

While this mosaic could be evidence of modern humans interbreeding with archaic populations – possibly Denisovans or Homo erectus – the authors of the report take the view that early modern humans in the region simply possessed a large range of morphological variation.

Demeter, F. et al., Early Modern Humans and Morphological Variation in Southeast Asia: Fossil Evidence from Tam Pa Ling, Laos. PLoS One 10 (4), e0121193 (2015).



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.

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).