Limits of long-term selection against Neandertal introgression
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Abstract
Several studies have suggested that introgressed Neandertal DNA was subjected to negative selection in modern humans. A striking observation in support of this is an apparent monotonic decline in Neandertal ancestry observed in modern humans in Europe over the past 45,000 years. Here, we show that this decline is an artifact likely caused by gene flow between modern human populations, which is not taken into account by statistics previously used to estimate Neandertal ancestry. When we apply a statistic that avoids assumptions about modern human demography by taking advantage of two high-coverage Neandertal genomes, we find no evidence for a change in Neandertal ancestry in Europe over the past 45,000 years. We use whole-genome simulations of selection and introgression to investigate a wide range of model parameters and find that negative selection is not expected to cause a significant long-term decline in genome-wide Neandertal ancestry. Nevertheless, these models recapitulate previously observed signals of selection against Neandertal alleles, in particular the depletion of Neandertal ancestry in conserved genomic regions. Surprisingly, we find that this depletion is strongest in regulatory and conserved noncoding regions and in the most conserved portion of protein-coding sequences.
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The observations are consistent with NIMs having been primarily under purifying selection for thousands of generations.
“Our observations are consistent with NIMs having been primarily under purifying selection for thousands of generations (Harris and Nielsen, 2016; Petr et al., 2019).”
From The lingering effects of Neanderthal introgression on human complex traits (2023) · cites this paper as Petr et al., 2019
The Results section (page unavailable) reports purifying selection against introgressed deleterious variants and continued, increasingly slow removal of selected variants. But it finds the strongest effect on Neandertal ancestry in the first few hundred generations and no significant long-term genome-wide decline. It therefore does not support describing NIMs broadly as primarily under purifying selection for thousands of generations. (LLM, conf=0.87)
Experimental — accuracy not yet measuredNeanderthal ancestry is depleted in regions of the genome with strong background selection and evolutionary conservation.
“First, Neanderthal ancestry is depleted in regions of the genome with strong background selection and evolutionary conservation18,19,27.”
From Quantifying the contribution of Neanderthal introgression to the heritability of complex traits (2021) · cites this paper as [27]
The Results section, “Neandertal DNA Is Depleted in Regulatory and Conserved Noncoding Sequence” (page unavailable), reports significantly less Neandertal ancestry in conserved phastCons regions than in intronic and intergenic regions. It mentions earlier studies using B values, but our copy does not establish depletion specifically in regions of strong background selection. (LLM, conf=0.83)
Experimental — accuracy not yet measuredNeanderthal ancestry is depleted in regions of the genome with annotated molecular functions, and this depletion is strongest in annotated brain and testis regulatory regions.
“Second, Neanderthal ancestry is depleted in regions of the genome with annotated molecular functions (e.g., genes and gene regulatory elements), and this depletion is strongest in annotated brain and testis regulatory regions27–29.”
From Quantifying the contribution of Neanderthal introgression to the heritability of complex traits (2021) · cites this paper as [27]
The Results section, “Neandertal DNA Is Depleted in Regulatory and Conserved Noncoding Sequence” (page unavailable), reports significant depletion in promoters and conserved regions. It reports no significant depletion in protein-coding sequence relative to intronic and intergenic regions, and does not identify brain or testis regulatory regions as having the strongest depletion. (LLM, conf=0.89)
Experimental — accuracy not yet measuredPrevious studies of regions with Neanderthal ancestry found depletion for evidence of background selection and functional annotations, such as genes and gene regulatory elements active in specific tissues.
“First, previous studies of regions with Neanderthal ancestry found depletion for evidence of background selection and functional annotations, such as genes and gene regulatory elements active in specific tissues18,19,27,29.”
From Quantifying the contribution of Neanderthal introgression to the heritability of complex traits (2021) · cites this paper as [27]
The Results section, “Neandertal DNA Is Depleted in Regulatory and Conserved Noncoding Sequence” (page unavailable), reports previous findings of depletion in conserved and genic regions and this paper’s finding of depletion in promoters and conserved regions. It also says previous studies used B values, a measure of evolutionary conservation. Our copy does not establish depletion specifically in tissue-active regulatory elements or clearly report depletion by evidence of background selection. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIntrogressed archaic DNA has mainly been deleterious and actively removed from coding sequences and conserved non-coding elements.
“beyond general agreement that introgressed archaic DNA has mainly been deleterious and actively removed from coding sequences and conserved non-coding elements [8, 12–14]”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [14]
The Results section, “Neandertal DNA Is Depleted in Regulatory and Conserved Noncoding Sequence” (page not provided), reports strong depletion in promoters and conserved regions, supporting selection against introgression there. But it finds no significant depletion in coding sequence relative to intronic and intergenic regions. The Abstract describes some Neandertal alleles as potentially deleterious, not introgressed archaic DNA as mainly deleterious. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Both Denisovan and Neanderthal aSNPs, especially those within protein coding and conserved non-coding elements, are mostly deleterious and negatively selected in modern humans.
“Evidence indicates that both Denisovan and Neanderthal aSNPs, especially those within protein coding and conserved non-coding elements, are mostly deleterious and negatively selected in modern humans [14, 61].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [14]
The Results section, “Neandertal DNA Is Depleted in Regulatory and Conserved Noncoding Sequence” (page unavailable), supports selection against Neanderthal ancestry in conserved noncoding regions. It reports no significant depletion in protein-coding sequence overall. The paper does not establish that most archaic SNPs are deleterious, and its analysis does not establish the claim for Denisovan SNPs. (LLM, conf=0.90)
Experimental — accuracy not yet measuredaSNPs mostly occur within non-coding sequences.
“First, we confirm previous reports that aSNPs mostly occur within non-coding sequences [9, 14, 64], with a large number falling within highly constitutive and/or functionally inert regions, which might be the result of weaker purifying selection acting on these elements.”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [14]
The Results section, “Neandertal DNA Is Depleted in Regulatory and Conserved Noncoding Sequence” (page unavailable), analyzes Neandertal ancestry at SNPs in intronic and intergenic regions. It does not report that most archaic SNPs occur in noncoding sequence; its ancestry estimates by region do not establish the proportion of SNPs in each region. (LLM, conf=0.73)
Experimental — accuracy not yet measuredIntrogressed variants are depleted in regulatory elements and eQTL generally.
“Given the previously observed depletion for introgressed variants in regulatory elements and eQTL (Petr et al. 2019; Rinker et al. 2020; Telis et al. 2020)”
From Archaic Introgression Shaped Human Circadian Traits (2023) · cites this paper as Petr et al. 2019
The Results section, “Neandertal DNA Is Depleted in Regulatory and Conserved Noncoding Sequence” (page not provided), reports significantly depleted Neandertal ancestry in promoters and conserved regions. It does not report depletion in eQTLs; a search for “eQTL” and “expression quantitative trait loci” found no supporting passage. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe introgressed variants that remain in AMH genomes are the result of complex selective and demographic pressures following admixture.
“The introgressed variants that remain in AMH genomes are the result of complex selective and demographic pressures following admixture9,25,27.”
From Quantifying the contribution of Neanderthal introgression to the heritability of complex traits (2021) · cites this paper as [27]
Introgression of archaic material in modern humans was probably counterselected during an initial stage.
“Although the introgression of archaic material in MHs was probably counterselected during an initial stage (42)”
From Past human expansions shaped the spatial pattern of Neanderthal ancestry (2023) · cites this paper as [42]
The study followed Petr et al. to avoid a bias in the temporal distribution of the F4 statistics.
“We followed Petr et al. (42) to avoid a bias in the temporal distribution of the F4 statistics.”
From Past human expansions shaped the spatial pattern of Neanderthal ancestry (2023) · cites this paper as [42]
After admixture, early events of negative selection removed large parts of archaic DNA, but about 2% of Neandertal ancestry is still found in all present-day non-Africans.
“After admixture, early events of negative selection removed large parts of archaic DNA but ~2% of Neandertal ancestry is still found in all present-day non-Africans [15–17].”
From Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes (2022) · cites this paper as [17]
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“On the other hand, many Neanderthal variants appear to have been deleterious in the modern human genetic background leading to a reduction in Neanderthal ancestry in conserved genomic regions (Sankararaman et al., 2014; Vernot and Akey, 2014; Harris and Nielsen, 2016; Juric et al., 2016; Petr et al., 2019).”
BackgroundResultDenisovan introgression has shaped the immune system of present-day Papuans
Vespasiani, D. M., Jacobs, G. S., Cook, L. E., Brucato, N., Leavesley, M., Kinipi, C., Ricaut, F.-X., Cox, M. P., & Gallego Romero, I. (2022) · PLOS Genetics · doi:10.1371/journal.pgen.1010470 · Cited by 46 · see citing works
“Evidence indicates that both Denisovan and Neanderthal aSNPs, especially those within protein coding and conserved non-coding elements, are mostly deleterious and negatively selected in modern humans [11, 24].”
Neanderthal introgression reintroduced functional ancestral alleles lost in Eurasian populations
Rinker, D. C., Simonti, C. N., McArthur, E., Shaw, D., Hodges, E., & Capra, J. A. (2020) · Nature Ecology & Evolution · doi:10.1038/s41559-020-1261-z · Cited by 44 · see citing works
<i>DLX5/6</i> GABAergic Expression Affects Social Vocalization: Implications for Human Evolution
Levi, G., de Lombares, C., Giuliani, C., Iannuzzi, V., Aouci, R., Garagnani, P., Franceschi, C., Grimaud-Hervé, D., & Narboux-Nême, N. (2021) · Molecular Biology and Evolution · doi:10.1093/molbev/msab181 · Cited by 29 · see citing works
Dannemann, M., Milaneschi, Y., Yermakovich, D., Stiglbauer, V., Kariis, H. M., Krebs, K., Friese, M. A., Otte, C., Estonian Biobank Research Team, Esko, T., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02196-2 · Cited by 23 · see citing works
Self-citationTaskent, O., Lin, Y. L., Patramanis, I., Pavlidis, P., & Gokcumen, O. (2020) · Genetics · doi:10.1534/genetics.120.303167 · Cited by 20 · see citing works
Archaic Introgression Shaped Human Circadian Traits
Velazquez-Arcelay, K., Colbran, L. L., McArthur, E., Brand, C. M., Rinker, D. C., Siemann, J. K., McMahon, D. G., & Capra, J. A. (2023) · Genome Biology and Evolution · doi:10.1093/gbe/evad203 · Cited by 18 · see citing works
“Given the previously observed depletion for introgressed variants in regulatory elements and eQTL (Petr et al. 2019; Rinker et al. 2020; Telis et al. 2020), this enrichment for circadian genes among introgressed eQTL is S3, Supplementary Material online).”
BackgroundPast human expansions shaped the spatial pattern of Neanderthal ancestry
Quilodrán, C. S., Rio, J., Tsoupas, A., & Currat, M. (2023) · Science Advances · doi:10.1126/sciadv.adg9817 · Cited by 12 · see citing works
Effects of introgressed Neanderthal alleles on present-day brain morphology
Zeloni, R., Amaolo, A., Morez Jacobs, A., Zapparoli, E., Akl, Y., Shafie, M., Huerta-Sanchez, E., Pizzagalli, F., Provero, P., Pagani, L., et al. (2026) · bioRxiv · doi:10.64898/2026.04.14.718380
“Indeed, selection against functional introgressed variants has been demonstrated 6,12–14 , and some regions, termed archaic deserts, which make up to 7-40% 5,6,15,16 of the modern human genome, are devoid of recognizable Neanderthal introgression.”
- Authors
- Petr, M., Pääbo, S., Kelso, J., & Vernot, B.
- Affiliations
- Max Planck Institute for Evolutionary Anthropology (DE)
- Corresponding author
- Kelso, Janet
- Vernot, Benjamin
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-01-15
- Volume
- 116
- Issue
- 5
- Pages
- 1639-1644
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6358679
- OpenAlex
- W2952933500
- Cited by
- 211
- References
- 52
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 19 · 2023: 19 · 2022: 61 · 2021: 33 · 2020: 33 · 2019: 18 · 2018: 3
- FWCI
- 167.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
- Funders
- Max-Planck-Gesellschaft
- H2020 European Research Council (694707)
- Topics
- Social Sciences › Anthropology › Pleistocene-Era Hominins and Archaeology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic diversity and population structure
- Keywords
- negative selection, gene flow, conserved genomic regions, regulatory elements, non-coding regions, protein-coding sequences
- MeSH terms
- Alleles, Animals, DNA, Europe, Humans, Selection, Genetic, Conserved Sequence, Evolution, Molecular, RNA, Untranslated, White People, Gene Flow, Neanderthals
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