Home > DNA, Evolution, Neanderthal, Paleoanthropology > The Depletion Of Our Hybrid Neanderthal Heritage – Or Is It?

The Depletion Of Our Hybrid Neanderthal Heritage – Or Is It?

Two competing papers that recently explored the possible genetic effects of Neanderthal-related hybridization, caught my attention. Loss of genetic integrity caused by a hybridization event may lead to rapid genetic changes within a species, what may have been an important agent for the rapid morphological changes associated with the advent of modern humans. However, true hybridization between species, or hybrid speciation, is a punctuated event often characterized by chromosome rearrangements. Both studies intend to describe hybrid-related gene-loss as an ongoing process. Instead, McVicker et al. (2009), referred to in both studies, declared ongoing ‘selection to remove less-fit functional variant from a population’ to the effect of varying sequence differences across the genome between species, not necessarily the result of hybridization.

Vernot & Akey – Resurrecting Surviving Neandertal Lineages from Modern Human Genomes, 2014 (Science)

Anatomically modern humans overlapped and mated with Neandertals such that non-African humans inherit ~1-3% of their genomes from Neandertal ancestors. We identified Neandertal lineages that persist in the DNA of modern humans, in whole-genome sequences from 379 European and 286 East Asian individuals, recovering over 15 Gb of introgressed sequence that spans ~20% of the Neandertal genome (FDR = 5%). Analyses of surviving archaic lineages suggests that there were fitness costs to hybridization, admixture occurred both before and subsequent to divergence of non-African modern humans, and Neandertals were a source of adaptive variation for loci involved in skin phenotypes. Our results provide a new avenue for paleogenomics studies, allowing substantial amounts of population-level DNA sequence information to be obtained from extinct groups even in the absence of fossilized remains.

Sankararaman – The genomic landscape of Neanderthal ancestry in present-day humans, 2014 (Nature)

Genomic studies have shown that Neanderthals interbred with modern humans,and that non-Africans today are the products of this mixture. The antiquity of Neanderthal gene flow into modern humans means that genomic regions that derive from Neanderthals in any one human today are usually less than a hundred kilobases in size. However, Neanderthal haplotypes are also distinctive enough that several studies have been able to detect Neanderthal ancestry at specific loci. We systematically infer Neanderthal haplotypes in the genomes of 1,004 present-day humans. Regions that harbour a high frequency of Neanderthal alleles are enriched for genes affecting keratin filaments, suggesting that Neanderthal alleles may have helped modern humans to adapt to non-African environments. We identify multiple Neanderthal-derived alleles that confer risk for disease, suggesting that Neanderthal alleles continue to shape human biology. An unexpected finding is that regions with reduced Neanderthal ancestry are enriched in genes, implying selection to remove genetic material derived from Neanderthals. Genes that are more highly expressed in testes than in any other tissue are especially reduced in Neanderthal ancestry, and there is an approximately fivefold reduction of Neanderthal ancestry on the X chromosome, which is known from studies of diverse species to be especially dense in male hybrid sterility genes. These results suggest that part of the explanation for genomic regions of reduced Neanderthal ancestry is Neanderthal alleles that caused decreased fertility in males when moved to a modern human genetic background.

In both studies, the identification of introgressed sequences is not exactly done by counting Neandertal-specific mutations. Instead, only a pre-selected set of candidate introgressed sequences, using patterns of variation in contemporary human populations by a method of Plagnol & Wall (2006), is compared to the Neanderthal reference genome. Logically, this involves predominantly ‘adaptive’ sequences, where strong selective forces are at work. Other studies (Hochreiter, Hawks) already attested a completely different picture when departing from Neanderthal-specific mutations eg. to characterize candidate haplotypes, even revealing up to 40% more Neanderthal specific haplotypes in Europe compared to Asia (explained in Rokus Blog: Expanding Hybrids And The Rise Of Our Genetic Common Denominator).
Vernot & Akey’s study compared the fixed differences between modern humans and Neanderthal for introgressed versus non-introgressed sequences, and arrived at 6.1X more fixed differences (FD) for non-introgressed sequences (17.3 vs. 2.8 FD/Mb). This value was claimed as uniform, while larger non-introgressed sequences having more fixed differences were considered significantly depleted of Neanderthal introgression.
Sankararaman (2014): ‘An unexpected finding is that regions with reduced Neanderthal ancestry are enriched in genes, implying selection to remove genetic material derived from Neanderthals.’. Moreover, there is ‘evidence for widespread negative selection against Neanderthal ancestry’ to the result that sequences having a higher density of ‘functionally important elements’ (low B) are ‘significantly correlated to low Neanderthal ancestry’. Since 20% of the genome where B is highest have about 1.54 x higher Neanderthal-like sequences, it could be deduced the portion of Neanderthal sequences on the modern human genome before the onset of this replacement process was ~3% against only ~2% nowadays. However, this does not explain the much higher estimate for Ötzi (5.5%), just a few thousand years ago.

This replacement process hit the X-chromosome harder than elsewhere on the genome, in the current papers dealing with this subject explained as a side-effect of hybridization. However, Vicoso (2006):‘Under some conditions, the X chromosome is expected to accumulate beneficial mutations at a faster rate than the autosomes’. This accumulation process effectively involves the replacement of proven, stable genes by non-deleterious mutated genes by positive selection. Wouldn’t this open the alternative possibility that replacement of conservative (defined ‘Neanderthal’) sequences by ones having a higher count of fixed differences, is just a normal evolutionary process? Instead, negative selection tends to keep the average number of fixed mutations of otherwise stable ‘original’ sequences low – at least until its successful replacement.

The gene content of X chromosomes is generally considered very stable, so large scale replacements should indicate important evolutionary shifts. The X chromosome is thought to preferentially accumulate genes with sex-biased fitness effects, and actually there isn’t any reason not to believe sex-biased fitness was quite important in post-Neanderthal populations. Moreover, nobody would deny the evolutionary shift was high since Neanderthal, and actually only accelerated since the Neolithic revolution.

Wouldn’t it be much more productive to find out where the successful sequences of higher fixed mutation counts are still coming from, and what ongoing genetic process might produce new sequences? The genetic laboratory for evolutionary change is still barely understood. Actually, variable haplotypes are most likely to originate in the copynumbers of duplicate sequences, where mutations are allowed without restriction or deleterious consequence. There is no way to tell apart breakaway mutated duplicates from a modern human genetic heritage whose unity and design we may only presume. Most of all, the Neanderthal genome may have offered a mechanism all of its own to engineer modern genetic replacements:

A comparison to any single present-day human genome reveals that 89% of the detected duplications are shared with Neandertals
We identified only three putative Neandertal-specific duplications with no evidence of duplication among humans or any other primate […] and none contained known genes. (Green et al., 2010)

I suggest the observed process of genetic replacement should first be verified with the Neanderthal duplicated potential before an ongoing removal of Neanderthal derived sequences in modern humans may be taken for granted.


  • Green et al. – A Draft Sequence of the Neandertal Genome, 2010, link
  • Hawks – Which population in the 1000 Genomes Project samples has the most Neandertal similarity?, Blog February 08, 2012, link
  • Hawks – Neandertal ancestry “Iced”, Blog August 15, 2012, link
  • McVicker et al. – Widespread Genomic Signatures of Natural Selection in Hominid Evolution, 2009, link
  • Plagnol & Wall -Possible ancestral structure in human populations, 2006, link
  • Sankararaman – The genomic landscape of Neanderthal ancestry in present-day humans, 2014, link
  • Vernot & Akey – Resurrecting Surviving Neandertal Lineages from Modern Human Genomes, 2014, link
  • Vicoso & Charlesworth – Evolution on the X chromosome: unusual patterns and processes, 2006, link
  1. German Research Project
    February 3, 2014 at 05:53

    Introgression, as opposed to gene flow, does not result in a cline or hybrid zone. This means hybrids return to one or both of the parental populations. F1 hybrids are always at a disadvantage in either parental population. This is because each is adapted to its own environment and a change is usually negative. So, only new alleles which are very, very strongly positive (selectively positive) are retained in the gene pool. Further, when a gene proves itself to be of positive value, genes near it on the chromosome are often dragged along and so appear in higher frequency simply due to the accident of proximity. This happens through recombination and is called genetic linkage. Over many generations this weakens as more and more recombination events take place but this works both for the new Neanderthal alleles and the sapiens alleles. This whole thing results in areas, deserts, devoid of alleles from either the sapiens side or the Neanderthal side. So Otzi had 2000 less years of recombination events and more time for selection under the introgression model.

    This idea all breaks down if either parental populations or the hybrid population is put in a new environment and needs serious new adaption. Then the wider range of genetic variability may be of benefit and perhaps this was what was going on during the Upper Paleolithic.

  2. February 3, 2014 at 15:20

    Yes, indeed. This holds for F1 hybrids. However, Neanderthal hybridization must have happened in an early time window. If geographic distance may be a valid approximation of the heritage of ancient hybridization events, it should be noted that just some incidental benign deviations from Mendelian rules have been observed between extant races. This does not include fertility nor syndromes. Not even the Neanderthal split-off date approximates by far the time depths of known mammal examples where just male-specific infertility has been identified as an issue (eg. Beefalo, polar bears). One investigation on hybridization between European and Japanese mice, separated for ~1 million years and having a much shorter generation time, confirmed the existence of male specific ongoing infertility for F2-Fn hybrids. Oka et al. (2004):
    ‘[…] Japanese wild mouse, Mus musculus molossinus […] and a Western European subspecies, Mus musculus domesticus, diverged from a common ancestor1 million years ago […] The F1 hybrid males of the MSM/Ms and standard inbred strains, the genome of which mostly originated from M. m. domesticus […] are fully fertile. Successive inbreeding of the hybrids, however, gradually reduced fecundity, suggesting that genetic segregation of the two mouse genomes causes hybrid breakdown’
    ‘Hybrid breakdown may be due to disruption of interaction of genes at different loci as the genes segregate after the F1 generation. […] Hybrid breakdown is thus hypothesized to arise when genetic segregation causes alleles of each interacting locus to become homozygous in an improper way.’
    One mechanism to remove deleterious hybrid combinations is during conception: most of the nonviable offspring simply doesn’t reach childhood. This is a fast process. It may be assumed that lethal hybrid incompatibility was resolved early on, within a few generations, as much as fertility problems. Again, this can be confirmed by modern mixed marriages: No ongoing process is known that selectively compromises the currency of genes of any specific origin. Once the genetic repatterning of any hybrid result is accompliced, there should be no major one-sided incompatibility left, only the heterogeneity of competing variability from the pariental lineages of both species. Evolutionary, this is an advantage, not a liability.
    I don’t see how selective processes should specifically target introgressed DNA over tens of millennia, and how this process may subsequently even accelerate afterwards. Hence my conclusion that the assertions of both papers still miss a valid scientific base.

    ‘So, only new alleles which are very, very strongly positive (selectively positive) are retained in the gene pool.’
    But, 20% of the genome where B is highest (i.e. where ‘functionally important elements’ have a higher density) have about 1.54 x higher Neanderthal-like sequences! Negative selection against introgressed genes should be less likely here, though higher (pre-)Neolithic percentages in Europe (Ötzi) and northern Africa (Sanchez-Quinto, 2013) seem to suggest a depletion of functionally neutral Neanderthal sequences as well.

  3. Henry Stevens
    February 4, 2014 at 03:24

    Introgression studies have not involved humans by definition since all humans are considered the same species. But your mixed marriage example is important since certain types of gene flow have taken on aspects of introgression or are introgression-like based on culture. I am thinking of black-white mating in the USA where historically the F1 hybrids were considered black and returned to the black population. Hybrid (clines) almost do not exist outside of one creole population in the South. There would have been a cultural factor with sapiens-Neanderthal hybrids, a pressure for the hybrids to conform to the population norms at least in phenotype.

    Also, in human races there is not real evidence for infertility between those races although in theory and differences should decrease fertility. Humans do not breed at maximum capacity or each female would have 25 or so children. Cultural factors and infant mortality limit numbers in humans and were probably more important in Paleolithic times than any slight decrease in fertility via incompatibility.

    With a change of climate or exploitation of new places to live (besides rock shelters and the plains surrounding the river valleys) the introgression model would break down since neither ancestral population would call the new environments their home. At this point variability would be more important and interbreeding would more resemble gene flow than introgression. We can assume this happened given the large population increase in the Upper Paleolithic. So, over time, the model flipped from introgression to gene flow.

    The time frame for introgression is not so important. It could have been .05 per generation for a number of generations or .20 for one generation. Following the gene flow model the probability of any one allele becoming fixed is its percentage in the population. So it could have been all at once or gradual without being important in the long run.

    One of these articles made the point that actual Neanderthal allelic frequency in the hybrid populations as a whole may be .20 or even higher although within the individual it is still 1 to 3%. This is huge. This is saying we were looking through the telescope from the wrong end.
    Usually, in anthropology or genetics, it is the population which is under discussion, not the individual, so maybe we ought to turn the telescope around.

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