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Cited by 108Pleistocene-Era Hominins and ArchaeologyForensic and Genetic ResearchGenetic Associations and Epidemiology

A catalog of single nucleotide changes distinguishing modern humans from archaic hominins

Open access
Kuhlwilm, Martin, Boeckx, Cedric·2019·Scientific Reports
DOI 10.1038/s41598-019-44877-xPMC PMC6560109

Published version of a preprint

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Abstract

Throughout the past decade, studying ancient genomes has provided unique insights into human prehistory, and differences between modern humans and other branches like Neanderthals can enrich our understanding of the molecular basis of unique modern human traits. Modern human variation and the interactions between different hominin lineages are now well studied, making it reasonable to go beyond fixed genetic changes and explore changes that are observed at high frequency in present-day humans. Here, we identify 571 genes with non-synonymous changes at high frequency. We suggest that molecular mechanisms in cell division and networks affecting cellular features of neurons were prominently modified by these changes. Complex phenotypes in brain growth trajectory and cognitive traits are likely influenced by these networks and other non-coding changes presented here. We propose that at least some of these changes contributed to uniquely human traits, and should be prioritized for experimental validation.

AI snapshot

Written from the paper’s full text.

TL;DR

This paper catalogs single nucleotide changes that distinguish modern humans from archaic hominins, extending beyond fixed differences to high-frequency variants. It reports 647 protein-altering changes in 571 genes at ≥90% frequency in present-day humans, plus 42 fixed amino acid changes in 36 genes, and highlights cell-division, neuronal, craniofacial, and life-history candidates.

Key findings

  • The authors identify 12,027 fixed human-specific single nucleotide changes, fewer than the previously reported 31,389, but find 29,358 positions with allele frequencies >0.995, indicating similar near-fixation.
  • They report 42 fixed amino acid changes in 36 genes and 647 protein-altering changes in 571 genes at high frequency (≥90%) in present-day humans; Neanderthals carry 159 fixed amino acid changes in the text.
  • Among archaic-lineage high-frequency missense changes, 1,542 genes carry at least one such change, with an overlap of 122 genes between human and archaic high-frequency missense sets, more than expected from random gene sets.
  • Enrichment analyses find 12 GO categories enriched on the human lineage, 17 GWAS traits enriched for genes with human high-frequency missense changes and 11 for archaic ones, and significant protein-protein interaction enrichment among HHMC gene products (P = 0.006).

Methods

  • The study used publicly available high-coverage genotypes from three archaic individuals: one Denisovan, one Altai Neanderthal, and one Vindija Neanderthal, plus exome and chromosome 21 data from Vindija and El Sidrón Neanderthals, mapped to hg19 and covering ~1.8 billion base pairs.
  • Variants were annotated with Ensembl VEP and scored with SIFT, PolyPhen, CADD, GWAVA, and Grantham; allele frequencies came from dbSNP build 147, the 1000 Genomes Project, and ExAC, with ancestral alleles inferred from multiple genome alignments or macaque.
  • Fixed differences required all present-day humans to carry the derived allele and at least two of three archaics to carry the ancestral allele; high-frequency differences required >90% derived in present-day humans and at least the Denisovan and one Neanderthal to carry the ancestral allele.

Limitations

  • The paper states that its data are “not fully exhaustive,” that some loci are variable or less reliable due to low coverage in archaics, and that some previously described protein-altering substitutions were absent because of different genotype-calling and filtering procedures.
  • The authors state that permissive filters may yield incorrect genotypes in some cases, that networks modified by multiple changes cannot be tested with current technologies, and that experimental validation is ultimately needed.
  • Evident from the text: only three archaic individuals are analyzed, archaic variation is not represented equally, the high-frequency cutoff is “somewhat arbitrary,” and enrichment/network results may be biased by gene length or mutation density.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41598-019-44877-x

Cites

211 of 211 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 137 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The study identified 571 genes with non-synonymous changes at high frequency in present-day humans.

    “Here, we identify 571 genes with non-synonymous changes at high frequency.”
    Quote in the paperSubstantial claim
  • Findingown data

    1,542 genes carry at least one HF missense change on the archaic lineage.

    “1,542 genes carry at least one HF missense change on the archaic lineage (archaic-lineage high-frequency missense change, referred to as AHMC, Tables S3, S4).”
    Quote in the paperSubstantial claim
  • Findingown data

    The study finds 12,027 positions in the genome as recently fixed derived in present-day humans while ancestral in archaics.

    “We find a smaller number of only 12,027 positions in the genome, in part due to the inclusion of another archaic individual and different filters, but mainly because of a richer picture of present-day human variation.”
    Quote in the paperSubstantial claim
  • Findingown data

    The study presents a revised list of 36 genes that carry missense substitutions fixed across thousands of human individuals and for which all archaic hominin individuals sequenced so far carry the ancestral state.

    “Here, we present a revised list of 36 genes that carry missense substitutions that are fixed across thousands of human individuals and for which all archaic hominin individuals sequenced so far carry the ancestral state.”
    Quote in the paperSubstantial claim
  • Findingown data

    The study finds no GO enrichment for genes with an excess of changes on the archaic lineage.

    “We find no GO enrichment for genes with an excess of changes on the archaic lineage.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 64
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 39

  • May combine two claims.

    Findingown data

    17,453 (88.9%) of these genes do not carry any fixed human-specific change, and 80.5% do not carry fixed archaic-specific changes.

    “Indeed, 17,453 (88.9%) of these genes do not carry any fixed human-specific change, and 80.5% do not carry fixed archaic-specific changes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The correlation with gene length is weaker for HF human SNCs (R = 0.73), fixed human-specific SNCs (R = 0.25), fixed archaic SNCs (R = 0.37), and HF archaic SNCs (R = 0.82).

    “This correlation is weaker for HF human SNCs (R = 0.73) and fixed human-specific SNCs (R = 0.25), as well as for fixed (R = 0.37) and HF (R = 0.82) SNCs in archaics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Present-day humans carry 42 fixed amino acid changes in 36 genes, while Neanderthals carry 159 such changes.

    “Present-day humans carry 42 fixed amino acid-changes in 36 genes (Table 2, Fig. 2), while Neanderthals carry 159 such changes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study found 78 known or putative transcription factors among the HHMC genes, which is no overrepresentation among genes with HHMCs.

    “We find 78 known or putative transcription factors among the HHMC genes (Table S9) on the modern human lineage57, which is no overrepresentation among genes with HHMCs (with 49.2% of random genes sets containing fewer HHMCs).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Chawla, K., Tripathi, S., Thommesen, L., Lægreid, A. & Kuiper, M. TFcheckpoint: a curated compendium of specific DNA-binding RNA polymerase II transcription factors. Bioinformatics 29, 2519–2520 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The study found 12 genes with deleterious HHMCs according to SIFT, 3 according to PolyPhen, and 16 when using the Grantham score (>180).

    “We assessed the impact of mutations for different deleteriousness scores (Table 2), finding 12 genes with deleterious HHMCs according to SIFT, 3 according to PolyPhen, and 16 when using the Grantham score (>180), measuring the physical properties of amino acid changes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Proteins encoded by genes with synonymous changes on the modern human lineage are enriched for interactions (P = 0.003), as are proteins encoded by genes with AHMCs (P = 1.68 × 10−14).

    “However, proteins encoded by genes with synonymous changes on the modern human lineage seem to be enriched for interactions as well (P = 0.003), as are proteins encoded by genes with AHMCs (P = 1.68 × 10−14), with an enrichment in GO categories related to the extracellular matrix and the cytoskeleton, and proteins with more than 40 interactions (Table S8).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When increasing the frequency cutoff, the number of loci declines sharply, while decreasing it results in a near-linear increase of sites.

    “However, when increasing the frequency cutoff, the number declines sharply, while decreasing it results in a near-linear increase of sites (Fig. S1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Functional enrichment is found for the biological process "cellular component assembly involved in morphogenesis", most strongly for the cellular components cytoskeleton and microtubule, as well as the molecular function "cytoskeletal protein binding".

    “Functional enrichment is found for the biological process “cellular component assembly involved in morphogenesis”, most strongly for the cellular components cytoskeleton and microtubule, as well as the molecular function “cytoskeletal protein binding”.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When testing genes with HHMCs and using the set of genes with AHMCs as background, "gray matter of forebrain" at adolescent age (12-19 years) is enriched, while no enrichment was found for genes with AHMCs.

    “Furthermore, when testing the genes with HHMCs and using the set of genes with AHMCs as background, “gray matter of forebrain” at adolescent age (12–19 years) is enriched, while no enrichment was found for genes with AHMCs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Generally, synonymous changes are found at a similar magnitude as missense changes, but only few SNCs alter start and stop codons, and thousands of changes occur in putative regulatory and untranslated regions.

    “Generally, synonymous changes are found at a similar magnitude as missense changes, but only few SNCs altering start and stop codons, and thousands of changes in putative regulatory and untranslated regions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Gene Ontology categories are neither enriched for HHMCs on the human lineage in a hypergeometric test, nor for genes carrying AHMCs, HF changes in UTRs or transcription factor binding sites.

    “Gene Ontology (GO) categories are neither enriched for HHMCs on the human lineage in a hypergeometric test, nor for genes carrying AHMCs, HF changes in UTRs or transcription factor binding sites.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among genes with multiple HHMCs, TSGA10IP and ABCC12 carry four such changes, and seven more genes (MUC5B, NPAP1, OR10AG1, OR5M9, PIGZ, SLX4, VCAN) carry three HHMCs.

    “Among these, TSGA10IP (Testis Specific 10 Interacting Protein) and ABCC12 (ATP Binding Cassette Subfamily C Member 12) carry four such changes, and seven more genes (MUC5B, NPAP1, OR10AG1, OR5M9, PIGZ, SLX4, VCAN) carry three HHMCs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Modern humans carry 605 amino acid changes at high frequency, amounting to a total of 647 such changes in 571 genes.

    “Additionally, modern humans carry 605 amino acid-changes at high frequency (human-lineage high-frequency missense changes, referred to as HHMCs), amounting to a total of 647 such changes in 571 genes (Table S1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The ratio of HHMCs over synonymous changes is high for chromosome 21 (1.75-fold) and very small for chromosome 13 (0.18-fold).

    “We find a high ratio of HHMCs over synonymous changes for chromosome 21 (1.75-fold), and a very small ratio (0.18-fold) for chromosome 13.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The study finds an enrichment of gene expression in the orbital frontal cortex at infant age (0-2 years) for genes with HHMCs, but no enrichment for genes with AHMCs.

    “We find an enrichment of gene expression in the orbital frontal cortex at infant age (0–2 years) for genes with HHMCs, but no enrichment for genes with AHMCs.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    The study found 17 unique traits enriched for genes with HHMCs, and 11 for genes with AHMCs in the NHGRI-EBI GWAS Catalog.

    “We performed a systematic enrichment screen, finding 17 unique traits enriched for genes with HHMCs, and 11 for genes with AHMCs (Table S7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among genes enriched for changes on the modern human lineage, 18 carry no HF changes on the archaic lineage, and ten of these also fall within the 5% of genes carrying many changes considering their length.

    “Among the genes enriched for changes on the modern human lineage, 18 carry no HF changes on the archaic lineage, and ten of these also fall within the 5% of genes carrying many changes considering their length (ARSJ, CLUAP1, COL20A1, EPPIN, KLHL31, MKNK1, PALMD, RIC3, TDRD7, UBE2H).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Only one gene, SPAG5, carries three fixed protein-coding SNCs, and four genes (ADAM18, CASC5, SSH2 and ZNHIT2) carry two fixed protein-coding changes in all modern humans.

    “Only one gene, SPAG5, carries three such SNCs, and four genes (ADAM18, CASC5, SSH2 and ZNHIT2) carry two fixed protein-coding changes in all modern humans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The study attempted to determine whether an enrichment of genes with HHMCs on the human lineage can be observed in the ventricular zone, but instead finds an enrichment in the intermediate zone, where less than 5% of random gene sets of the same size are expressed.

    “We attempted to determine whether an enrichment of genes with HHMCs on the human lineage can be observed in the ventricular zone59, but instead find an enrichment in the intermediate zone, where less than 5% of random gene sets of the same size are expressed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Miller, J. A. et al. Transcriptional Landscape of the Prenatal Human Brain. Nature 508, 199–206 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    We find a deleterious HHMC in ABHD14A, which is a target of ZIC1.

    “a deleterious HHMC in ABHD14A, which is a target of ZIC188.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Hoshino, J., Aruga, J., Ishiguro, A. & Mikoshiba, K. Dorz1, a novel gene expressed in differentiating cerebellar granule neurons, is down-regulated in Zic1-deficient mouse. Mol. Brain Res. 120, 57–64 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    KIF15, an interactor of KIF18A, might have been under positive selection in modern humans and contains two HHMCs.

    “an interactor of KIF18A, KIF1597, might have been under positive selection in modern humans33, and contains two HHMCs.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [97] Kevenaar, J. T. et al. Kinesin-Binding Protein Controls Microtubule Dynamics and Cargo Trafficking by Regulating Kinesin Motor Activity. Curr. Biol. 26, 849–861 (2017). source

      Not checked in the free run.

    • cites [33] Peyrégne, S., Boyle, M. J., Dannemann, M. & Prüfer, K. Detecting ancient positive selection in humans using extended lineage sorting. Genome Res. 27, 1563–1572 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    The changes in KIF18A, KIF16A and NEK6 can no longer be considered as fixed, but occur at very high frequencies (>99.9%) in present-day humans.

    “The changes in KIF18A, KIF16A and NEK6 can no longer be considered as fixed, but occur at very high frequencies (>99.9%) in present-day humans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Several fixed SNCs on the modern human lineage are observed for CASC5 (two changes) and SPAG5 (three changes), which is also among genes with a relatively high proportion of HF changes.

    “Several fixed SNCs on the modern human lineage are observed for CASC5 (two changes) and SPAG5 (three changes), which is also among genes with a relatively high proportion of HF changes (Table S5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The observation of an enrichment of expression in the ventricular zone is broadly recapitulated when restricting the test to genes with non-synonymous changes at a frequency greater than 99.9% in present-day humans, and this enrichment is not observed for corresponding synonymous and archaic non-synonymous changes.

    “We were able to broadly recapitulate the observation of an enrichment of expression in the ventricular zone if restricting the test to genes with non-synonymous changes at a frequency greater than 99.9% in present-day humans, which is not observed for corresponding synonymous and archaic non-synonymous changes (Table S10).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The gene encoding the transcription factor PRDM10 stands out for carrying HHMCs, being found in selective sweep regions and the second-most interacting protein within the HHMC dataset.

    “The gene encoding the transcription factor PRDM10 stands out for carrying HHMCs, being found in selective sweep regions and the second-most interacting protein within the HHMC dataset.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    SSH2 carries two HHMCs and might be involved in neurite outgrowth.

    “SSH2 (two HHMCs) might be involved in neurite outgrowth99.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Cuberos, H. et al. Roles of LIM kinases in central nervous system function and dysfunction. FEBS Lett. 589, 3795–3806 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    We find one of the most deleterious regulatory SNCs in the Netrin receptor UNC5D, which is critical for axon guidance.

    “we find one of the most deleterious regulatory SNCs in the Netrin receptor UNC5D, which is critical for axon guidance103.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Takemoto, M. et al. Laminar and Areal Expression of Unc5d and Its Role in Cortical Cell Survival. Cereb. Cortex 21, 1925–1934 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    VCAN carries three HHMCs.

    “Versican (VCAN), which promotes neurite outgrowth98, carries three HHMCs”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Wu, Y. et al. Versican V1 Isoform Induces Neuronal Differentiation and Promotes Neurite Outgrowth. Mol. Biol. Cell 15, 2093–2104 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    PIEZO1 carries a non-synonymous change that is almost fixed in modern humans and is another factor in axon guidance.

    “PIEZO1, which carries a non-synonymous change that is almost fixed in modern humans, is another factor in axon guidance100”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Koser, D. E. et al. Mechanosensing is critical for axon growth in the developing brain. Nat. Neurosci. 19, 1592 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    NOVA1 is an interactor of ELAVL4, a gene that codes for a neuronal-specific RNA-binding protein and might have been under positive selection in humans.

    “NOVA1101, which is an interactor of ELAVL4102, a gene that codes for a neuronal-specific RNA-binding protein and might have been under positive selection in humans33,36.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [101] Jensen, K. B. et al. Nova-1 Regulates Neuron-Specific Alternative Splicing and Is Essential for Neuronal Viability. Neuron 25, 359–371 (2000). source

      Not checked in the free run.

    • cites [102] Ratti, A. et al. Post-transcriptional regulation of neuro-oncological ventral antigen 1 by the neuronal RNA-binding proteins ELAV. J. Biol. Chem., https://doi.org/10.1074/jbc.M706082200 (2008). source

      Not checked in the free run.

    • cites [33] Peyrégne, S., Boyle, M. J., Dannemann, M. & Prüfer, K. Detecting ancient positive selection in humans using extended lineage sorting. Genome Res. 27, 1563–1572 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The HHMC in NCOA6 is located nearby and three 5′-UTR variants within a putatively selected region, with an estimated time of selection at around 150 kya.

    “The HHMC is located nearby and three 5′-UTR variants within a putatively selected region36, with an estimated time of selection at around 150 kya (assuming a slow mutation rate).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Zhou, H. et al. A Chronological Atlas of Natural Selection in the Human Genome during the Past Half-million Years. bioRxiv (2015). source

      Not checked in the free run.

    • The authors state this as an assumption: The mutation rate is slow.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    NCOA6 is enriched in HF changes and has been suggested to have been under positive selection on the modern human lineage.

    “This putative transcription factor is enriched in HF changes and has been suggested to have been under positive selection on the modern human lineage33,122.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Peyrégne, S., Boyle, M. J., Dannemann, M. & Prüfer, K. Detecting ancient positive selection in humans using extended lineage sorting. Genome Res. 27, 1563–1572 (2017). source

      Not checked in the free run.

    • cites [122] Racimo, F., Kuhlwilm, M. & Slatkin, M. A test for ancient selective sweeps and an application to candidate sites in modern humans. Mol. Biol. Evol. 31, 3344–3358 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Several proteins in spermatogenesis seem to carry two HHMCs: SSFA2, SPAG17, ADAM18 and WDR52, out of which ADAM18 and SPAG17 also carry AHMCs.

    “we find that several proteins in spermatogenesis seem to carry two HHMCs: Sperm Specific Antigen 2 (SSFA2), Sperm Associated Antigen 17 (SPAG17), ADAM18172 and WDR52173, out of which ADAM18 and SPAG17 also carry AHMCs.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [172] Zhu, G.-Z., Lin, Y., Myles, D. G. & Primakoff, P. Identification of four novel ADAMs with potential roles in spermatogenesis and fertilization. Gene 234, 227–237 (1999). source

      Not checked in the free run.

    • cites [173] Tang, S. et al. Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella. Am. J. Hum. Genet. 100, 854–864 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    A splice site change in IZUMO4 is a possible SNC that might be relevant, since proteins encoded by the IZUMO family form complexes on mammalian sperm.

    “Another possible SNC that might be relevant in this context is a splice site change in IZUMO4, since proteins encoded by the IZUMO family form complexes on mammalian sperm175.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Ellerman, D. A. et al. Izumo is part of a multiprotein family whose members form large complexes on mammalian sperm. Mol. Reprod. Dev. 76, 1188–1199 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    TEX2 is enriched for HF changes in both humans and archaics, with one HHMC and five AHMCs, but its function is not yet known.

    “The gene encoding for the Testis Expressed 2 protein (TEX2) is enriched for HF changes in both humans and archaics, with one HHMC and five AHMCs, but its function is not yet known.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    EPPIN harbors a HHMC and shows no HF changes on the archaic, but 27 such SNCs on the modern human lineage.

    “Another gene harboring a HHMC with similar functions is EPPIN174, which shows no HF changes on the archaic, but 27 such SNCs on the modern human lineage.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Wang, Z., Widgren, E. E., Sivashanmugam, P., O’Rand, M. G. & Richardson, R. T. Association of Eppin with Semenogelin on Human Spermatozoa1. Biol. Reprod. 72, 1064–1070 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Three HHMCs are observed in NPAP1, which might be associated with the Prader-Willi syndrome, involving behavioral problems and a high pain threshold.

    “three HHMCs are observed in NPAP1, which might be associated with the Prader-Willi syndrome, involving behavioral problems and a high pain threshold182.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] Buiting, K. et al. C15orf2 and a novel noncoding transcript from the Prader–Willi/Angelman syndrome region show monoallelic expression in fetal brain. Genomics 89, 588–595 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There were differences between anatomically modern human and Neanderthal brains, and these underlie at least some of the characteristics of our lineage.

    “Thus, it seems reasonable to conclude that there were differences between anatomically modern human and Neanderthal brains, and that these underlie at least some of the characteristics of our lineage42.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Wynn, T. & Coolidge, F. L. The expert Neandertal mind. J. Hum. Evol. 46, 467–487 (2004). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Brain size and encephalization of humans and Neanderthals is similar.

    “while the brain size and encephalization of humans and Neanderthals is similar9,13,14.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Hublin, J.-J., Neubauer, S. & Gunz, P. Brain ontogeny and life history in Pleistocene hominins. Philos. Trans. R. Soc. B Biol. Sci. 370 (2015). source

      Not checked in the free run.

    • cites [13] Trinkaus, E. & Howells, W. W. The Neanderthals. Sci. Am. 241, 118–133 (1979). source

      Not checked in the free run.

    • cites [14] Schoenemann, P. T. Brain Size Scaling and Body Composition in Mammals. Brain. Behav. Evol. 63, 47–60 (2004). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    These networks might be biased due to more mutations and possibly more interactions in longer, multi-domain genes.

    “We caution that these networks might be biased due to more mutations and possibly more interactions in longer, multi-domain genes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Despite no enrichment as a category, single transcription factors on the modern human lineage might have been important, particularly those with an excess of modern human over archaic HF changes (AHR, MACC1, PRDM2, TCF3, ZNF420, ZNF516).

    “Despite no enrichment as a category, single transcription factors on the modern human lineage might have been important, particularly those with an excess of modern human over archaic HF changes (AHR, MACC1, PRDM2, TCF3, ZNF420, ZNF516).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Others, like RB1CC1 or PRDM10 and NCOA6, have been found in selective sweep screens, suggesting contributions of individual transcription factors rather than the whole class of proteins.

    “Others, like RB1CC120 or PRDM10 and NCOA633 have been found in selective sweep screens, suggesting contributions of individual transcription factors, rather than the whole class of proteins.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–9 (2014). source

      Not checked in the free run.

    • cites [33] Peyrégne, S., Boyle, M. J., Dannemann, M. & Prüfer, K. Detecting ancient positive selection in humans using extended lineage sorting. Genome Res. 27, 1563–1572 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Some genes with a large number of human-specific changes might carry these large numbers by chance, while others are depleted.

    “We conclude that some genes with a large number of human-specific changes might carry these large numbers by chance, while others are depleted.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationown data

    Genes like CNTNAP2 and AUTS2 are among the longest genes in the genome, so changes in these genes should be interpreted with caution as they are not unexpected.

    “Of note, genes that have attracted attention in the context of traits related to the “human condition” like CNTNAP2 and AUTS2 are among the longest genes in the genome, hence changes in these genes should be interpreted with caution as they are not unexpected.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    Changes in structural variants or regions not accessible by current sequencing technologies will most likely complement the results.

    “However, changes in structural variants or regions of the genome that are not accessible by current sequencing technologies will most likely complement our results45.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] O’Bleness, M., Searles, V. B., Varki, A., Gagneux, P. & Sikela, J. M. Evolution of genetic and genomic features unique to the human lineage. Nat. Rev. Genet. 13, 853–866 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationown data

    Changes in genes associated to "Cognitive decline (age-related)", "Rheumatoid arthritis" or "Major depressive disorder" might point to pathways that could have been influenced by protein-coding changes on the human lineage.

    “Changes in genes associated to “Cognitive decline (age-related)”, “Rheumatoid arthritis” or “Major depressive disorder” might point to pathways that could have been influenced by protein-coding changes on the human lineage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In archaics, genes are enriched for associations to traits related to body mass index or cholesterol levels, which might reflect differences in their physiology.

    “In archaics, genes are enriched, among others, for associations to traits related to body mass index or cholesterol levels, which might reflect differences in their physiology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The study does not find such extreme ratios for AHMCs and corresponding synonymous changes, suggesting differences in the distribution of amino acid changes between both lineages.

    “We do not find such extreme ratios for AHMCs and corresponding synonymous changes, suggesting differences in the distribution of amino acid changes between both lineages (Fig. S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The number of fixed SNCs decreased substantially, and it is possible that single individuals will be found to carry some of the ancestral alleles for the remaining fixed sites.

    “It is noteworthy that the number of fixed SNCs decreased substantially, and it is possible that single individuals will be found to carry some of the ancestral alleles for the remaining fixed sites.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Not all human-specific changes are beneficial; some may have had deleterious effects or side-effects, possibly increasing risks for neurodevelopmental or neurodegenerative disorders in humans.

    “while most mutations may be rather neutral and have little effect on the phenotype, some may have had deleterious effects or side-effects, possibly increasing the risks for neurodevelopmental or neurodegenerative disorders in humans46–48.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Bufill, E., Blesa, R. & Augusti, J. Alzheimer’s disease: an evolutionary approach. J. Anthropol. Sci.=Riv. di Antropol. JASS 91, 135–157 (2013).

      Not checked in the free run.

    • cites [47] Bufill, E., Agustí, J. & Blesa, R. Human neoteny revisited: The case of synaptic plasticity. Am. J. Hum. Biol. 23, 729–739 (2011). source

      Not checked in the free run.

    • cites [48] Bruner, E. & Jacobs, H. I. L. Alzheimer’s disease: the downside of a highly evolved parietal lobe? J. Alzheimers. Dis. 35, 227–240 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    The 42 protein-altering changes for which the ancestral allele has not been observed in any present-day human constitute the strongest entry points into a molecular understanding of the human condition.

    “The 42 protein-altering changes for which the ancestral allele has not been observed in any present-day human, most of which have been presented before1, constitute without doubt the strongest entry points into a molecular understanding of the human condition, and should be prime candidates for experimental validation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Pääbo, S. The Human Condition—A Molecular Approach. Cell 157, 216–226 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The enrichment of broad categories suggests traits prominently represented by HHMCs, some of which are possibly brain-related.

    “The enrichment of broad categories above suggests traits prominently represented by HHMCs, some of which are possibly brain-related.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Some loci presented are variable across the phylogenetic tree or less reliable due to low coverage in archaics, but the study accepts this to retrieve an inclusive picture of possibly functional recent changes.

    “We admit that some of the loci presented here are variable across the phylogenetic tree, or less reliable due to low coverage in the archaics, but we accept this since our intention is retrieve an inclusive picture of possibly functional recent changes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The "full modernity" of modern humans is constituted from a network of changes, where the presence of single ancestral alleles in some individuals would not lead to "partially modern" phenotype.

    “Hence, we suggest that the “full modernity” of modern humans is constituted from a network of changes, where the presence of single ancestral alleles in some individuals would not lead to “partially modern” phenotype.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Genes with fixed non-synonymous changes in humans are also more often expressed in the ventricular zone of the developing neocortex, compared to fixed synonymous changes.

    “It has been claimed20 that genes with fixed non-synonymous changes in humans are also more often expressed in the ventricular zone of the developing neocortex, compared to fixed synonymous changes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–9 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Among the 15 fixed protein-coding changes identified here but absent from previous analyses, some might have contributed to complex modifications of pathways in cell division, like AHR or DNHD1, as well as other genes with HHMCs, like CHEK1 or TOP2A.

    “Among the 15 fixed protein-coding changes identified here but absent from previous analyses1,20, some might have also contributed to complex modifications of pathways in cell division, like AHR65 or DNHD166 (Supplementary Information 1), as well as other genes with HHMCs, like CHEK167 or the gene encoding for the protein TOP2A68, which shows the largest number of interactions with other HHMC-carry”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Pääbo, S. The Human Condition—A Molecular Approach. Cell 157, 216–226 (2014). source

      Not checked in the free run.

    • cites [20] Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–9 (2014). source

      Not checked in the free run.

    • cites [65] Puga, A., Xia, Y. & Elferink, C. Role of the aryl hydrocarbon receptor in cell cycle regulation. Chem. Biol. Interact. 141, 117–130 (2002). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Studies on avian vocal learners have shown a convergent differential regulation of axon guidance genes of the SLIT-ROBO families in the pallial motor nucleus of the learning species, allowing for the formation of connections virtually absent in the brains of vocal non-learners.

    “Studies conducted on avian vocal learners89,90 have shown a convergent differential regulation of axon guidance genes of the SLIT-ROBO families in the pallial motor nucleus of the learning species, allowing for the formation of connections virtually absent in the brains of vocal non-learners.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Pfenning, A. R. et al. Convergent transcriptional specializations in the brains of humans and song-learning birds. Science (80-.). 346 (2014). source

      Not checked in the free run.

    • cites [90] Wang, R. et al. Convergent Differential Regulation of SLIT-ROBO Axon Guidance Genes in the Brains of Vocal Learners. J. Comp. Neurol. 523, 892–906 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The disease phenotype of macrocephaly might point to genes relevant in the context of brain growth.

    “suggesting that the disease phenotype of macrocephaly might point to genes relevant in the context of brain growth as well.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Mutations in PTEN alter the brain growth trajectory and allocation of cell types through elevated Beta-Catenin signaling.

    “It has been claimed that mutations in PTEN alter the brain growth trajectory and allocation of cell types through elevated Beta-Catenin signaling77.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Chen, Y., Huang, W.-C., Séjourné, J., Clipperton-Allen, A. E. & Page, D. T. Pten Mutations Alter Brain Growth Trajectory and Allocation of Cell Types through Elevated β-Catenin Signaling. J. Neurosci. 35, 10252 LP–10267 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Centrosome-related proteins are overrepresented in studies on the microcephaly phenotype in humans.

    “centrosome-related proteins are overrepresented in studies on the microcephaly phenotype in humans70.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Megraw, T. L., Sharkey, J. T. & Nowakowski, R. S. Cdk5rap2 exposes the centrosomal root of microcephaly syndromes. Trends Cell Biol. 21, 470–480 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The centrosome-cilium interface is critical for early brain development.

    “The centrosome-cilium interface is known to be critical for early brain development”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Megraw, T. L., Sharkey, J. T. & Nowakowski, R. S. Cdk5rap2 exposes the centrosomal root of microcephaly syndromes. Trends Cell Biol. 21, 470–480 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Three genes (CASC5, SPAG5, and KIF18A) have been singled out as involved in spindle pole assembly during mitosis.

    “Indeed, three genes (CASC5, SPAG5, and KIF18A) have been singled out as involved in spindle pole assembly during mitosis1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Pääbo, S. The Human Condition—A Molecular Approach. Cell 157, 216–226 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The extended catalog of changes appears to provide additional support for some hypotheses formulated in earlier work on modern human-specific changes.

    “Our extended catalog of changes appears to provide additional support for some of these hypotheses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TCF3 is known to repress Wnt-Beta-Catenin signaling and maintain the neural stem cell population during neocortical development.

    “the HHMC-carrying transcription factor TCF3, which is known to repress Wnt-Beta-Catenin signaling and maintain the neural stem cell population during neocortical development79.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Kuwahara, A. et al. Tcf3 Represses Wnt–β-Catenin Signaling and Maintains Neural Stem Cell Population during Neocortical Development. PLoS One 9, e94408 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Protein-coding changes in cell cycle-related genes are highly relevant candidates for human-specific traits, with the brain being specifically sensitive to such changes.

    “It has been proposed previously that protein-coding changes in cell cycle-related genes are highly relevant candidates for human-specific traits1,20, with the brain being specifically sensitive to such changes61.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Pääbo, S. The Human Condition—A Molecular Approach. Cell 157, 216–226 (2014). source

      Not checked in the free run.

    • cites [20] Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–9 (2014). source

      Not checked in the free run.

    • cites [61] Omer Javed, A. et al. Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype. Cell Rep. 25, 368–382.e5 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Synonymous HF changes also show an enrichment in the intermediate zone, as well as genes with AHMCs, suggesting an overrepresentation of genes that carry mutations in the coding regions rather than lineage-specific effects.

    “However, synonymous HF changes also show an enrichment in this layer, as well as genes with AHMCs (Table S10), suggesting an overrepresentation of genes that carry mutations in the coding regions rather than lineage-specific effects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Given their similar brain sizes, humans and Neanderthals might both have needed a long overall maturation time.

    “given their similar brain sizes160, humans and Neanderthals might both have needed a long overall maturation time161,162.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [160] Hofman, M. a. Encephalization in hominids: evidence for the model of punctuationalism. Brain. Behav. Evol., https://doi.org/10.1159/000121511 (1983). source

      Not checked in the free run.

    • cites [161] Ponce de León, M. S., Bienvenu, T., Akazawa, T. & Zollikofer, C. P. E. Brain development is similar in Neanderthals and modern humans. Curr. Biol. 26, R665–R666 (2017). source

      Not checked in the free run.

    • cites [162] Rosas, A. et al. The growth pattern of Neandertals, reconstructed from a juvenile skeleton from El Sidrón (Spain). Science (80-.). 357, 1282 LP–1287 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    PRDM10 may be related to dendrite growth and neural crest related changes that contributed to the formation of our distinct modern face.

    “Although little is known about PRDM10, it may be related to dendrite growth147 and neural crest related changes that contributed to the formation of our distinct modern face148.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [147] Siegel, D. A., Huang, M. K. & Becker, S. F. Ectopic dendrite initiation: CNS pathogenesis as a model of CNS development. Int. J. Dev. Neurosci. 20, 373–389 (2002). source

      Not checked in the free run.

    • cites [148] Park, J.-A. & Kim, K. C. Expression patterns of PRDM10 during mouse embryonic development. BMB Rep. 43, 29–33 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The timing of myelination appears to be a good predictor of computational abilities among traits associated with cognitive functions such as language or theory of mind.

    “It is noteworthy that among traits associated with cognitive functions such as language or theory of mind, the timing of myelination appears to be a good predictor of computational abilities109,110.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [109] Skeide, M. A. & Friederici, A. D. The ontogeny of the cortical language network. Nat. Rev. Neurosci. 17, 323 (2016). source

      Not checked in the free run.

    • cites [110] Grosse Wiesmann, C., Schreiber, J., Singer, T., Steinbeis, N. & Friederici, A. D. White matter maturation is associated with the emergence of Theory of Mind in early childhood. Nat. Commun. 8, 14692 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutations in the HHMC-carrying gene encoding for the transcription factor ATRX cause facial dysmorphism.

    “mutations in the HHMC-carrying gene encoding for the transcription factor ATRX cause facial dysmorphism138.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Moncini, S. et al. ATRX mutation in two adult brothers with non-specific moderate intellectual disability identified by exome sequencing. Meta Gene 1, 102–108 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Computational processing might have been facilitated by some of the changes presented here, at least in some of the circuits that have expanded in our lineage.

    “Computational processing might have been facilitated by some of the changes presented here, at least in some of the circuits that have expanded in our lineage111,112, since subtle maturational differences early in development113 may have had a considerable impact on the phenotype.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [111] Mars, R. B., Eichert, N., Jbabdi, S., Verhagen, L. & Rushworth, M. F. S. Connectivity and the search for specializations in the language-capable brain. Curr. Opin. Behav. Sci. 21, 19–26 (2018). source

      Not checked in the free run.

    • cites [112] Ardesch, D. J. et al. Evolutionary expansion of connectivity between multimodal association areas in the human brain compared with chimpanzees. Proc. Natl. Acad. Sci. 116, 7101 LP–7106 (2019). source

      Not checked in the free run.

    • cites [113] Dubois, J. et al. Exploring the Early Organization and Maturation of Linguistic Pathways in the Human Infant Brain. Cereb. Cortex 26, 2283–2298 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Archaic hominins likely had certain language-like abilities.

    “We know that archaic hominins likely had certain language-like abilities123,124”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [123] Dediu, D. & Levinson, S. C. On the antiquity of language: The reinterpretation of neandertal linguistic capacities and its consequences. Front. Psychol. 4, 1–17 (2013). source

      Not checked in the free run.

    • cites [124] Dediu, D. & Levinson, S. C. Neanderthal language revisited: not only us. Curr. Opin. Behav. Sci. 21, 49–55 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Some facial properties may have been present in the earliest fossils attributed to H. sapiens, like the Jebel Irhoud fossils, deviating from craniofacial features which emerged in earlier forms of Homo, and may have become established before some brain-related changes discussed here.

    “Some of these facial properties may have been present in the earliest fossils attributed to H. sapiens, like the Jebel Irhoud fossils4, deviating from craniofacial features which emerged in earlier forms of Homo145, and may have become established before some brain-related changes discussed here11,146.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Hublin, J.-J. et al. New fossils from Jebel Irhoud, Morocco and the pan-African origin of Homo sapiens. Nature 546, 289 (2017). source

      Not checked in the free run.

    • cites [145] Lacruz, R. S. et al. Facial Morphogenesis of the Earliest Europeans. PLoS One 8, e65199 (2013). source

      Not checked in the free run.

    • cites [11] Neubauer, S., Hublin, J.-J. & Gunz, P. The evolution of modern human brain shape. Sci. Adv. 4 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These genes appear to be important in determining bone density, mineralization and remodeling, hence they may underlie differences between archaic and modern human facial growth.

    “These genes appear to be important in determining bone density, mineralization and remodeling, hence they may underlie differences between archaic and modern human facial growth144.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Lacruz, R. S. et al. Ontogeny of the maxilla in Neanderthals and their ancestors. Nat. Commun. 6, 8996 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hybrids of modern and archaic humans must have survived in their communities.

    “hybrids of modern and archaic humans must have survived in their communities125”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Fu, Q. et al. An early modern human from Romania with a recent Neanderthal ancestor. Nature 524, 216–219 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationcitation

    We suggest that modifications of a complex network in cognition or learning took place in modern human evolution, possibly related to other brain-related, vocal tract or neural changes.

    “We suggest that modifications of a complex network in cognition or learning took place in modern human evolution128, possibly related to other brain-related9,16,129,130, vocal tract131 or neural changes132.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [128] Boeckx, C. & Benítez-Burraco, A. Globularity and language-readiness: generating new predictions by expanding the set of genes of interest. Frontiers in Psychology 5, 1324 (2014).

      Not checked in the free run.

    • cites [9] Hublin, J.-J., Neubauer, S. & Gunz, P. Brain ontogeny and life history in Pleistocene hominins. Philos. Trans. R. Soc. B Biol. Sci. 370 (2015). source

      Not checked in the free run.

    • cites [16] Boeckx, C. The language-ready head: Evolutionary considerations. Psychon. Bull. Rev. 24, 194–199 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ADSL has been pointed out before as under positive selection.

    “which has been pointed out before as under positive selection31,33,34,122.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [31] Castellano, S. et al. Patterns of coding variation in the complete exomes of three Neandertals. Proc. Natl. Acad. Sci. USA 111, 6666–71 (2014). source

      Not checked in the free run.

    • cites [33] Peyrégne, S., Boyle, M. J., Dannemann, M. & Prüfer, K. Detecting ancient positive selection in humans using extended lineage sorting. Genome Res. 27, 1563–1572 (2017). source

      Not checked in the free run.

    • cites [34] Racimo, F. Testing for Ancient Selection Using Cross-population Allele Frequency Differentiation. Genetics 202, 733 LP–750 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An introgressed indel from Neanderthals causes an earlier onset of menarche in present-day humans, supporting at least the existence of alleles for earlier maturation in the Neanderthal population.

    “an introgressed indel from Neanderthals causes an earlier onset of menarche in present-day humans30, supporting at least the existence of alleles for earlier maturation in the Neanderthal population.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Chintalapati, M., Dannemann, M. & Prüfer, K. Using the Neandertal genome to study the evolution of small insertions and deletions in modern humans. BMC Evol. Biol. 17, 179 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neanderthal alleles contribute to addiction and, possibly, pain sensitivity in modern humans.

    “It has been found that Neanderthal alleles contribute to addiction and, possibly, pain sensitivity in modern humans176,177.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [176] Simonti, C. N. et al. The phenotypic legacy of admixture between modern humans and Neandertals. Science (80-.). 351, 737 LP–741 (2016). source

      Not checked in the free run.

    • cites [177] Dannemann, M., Prüfer, K. & Kelso, J. Functional implications of Neandertal introgression in modern humans. Genome Biol. 18, 61 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    Differences in childhood adolescence time existed between humans and Neanderthals, after a general developmental delay in the hominin lineage.

    “It has been suggested that differences in childhood adolescence time existed between humans and Neanderthals, after a general developmental delay in the hominin lineage166,167.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [166] Smith, B. H. & Tompkins, R. L. Toward A Life History of the Hominidae. Annu. Rev. Anthropol. 24, 257–279 (1995). source

      Not checked in the free run.

    • cites [167] Bock, J. & Sellen, D. W. Childhood and the evolution of the human life course. Hum. Nat. 13, 153–159 (2002). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Additional human-specific modifications during adolescence might have taken place, possibly linked to changes in myelination.

    “hence additional human-specific modifications during this period might have taken place, possibly linked to changes in myelination described above.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    In some cases genotypes might be incorrect.

    “we caution that in some cases genotypes might be incorrect.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    A delay in reproductive age may influence overall longevity.

    “A delay in reproductive age may influence overall longevity”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dental evidence suggests an earlier maturation in Neanderthals than modern humans.

    “Dental evidence suggests an earlier maturation in Neanderthals than modern humans168”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Smith, T. M. et al. Dental evidence for ontogenetic differences between modern humans and Neanderthals. Proc Natl Acad Sci USA 107, 20923–20928 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Lineage-specific differences in genes related to sperm function or spermatogenesis might have been relevant for the genetic compatibility between humans and Neanderthals.

    “Lineage-specific differences in genes related to sperm function or spermatogenesis might have been relevant for the genetic compatibility between humans and Neanderthals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The permissive filters used increase power compared to previous studies.

    “Although these permissive filters increase power compared to previous studies”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Among genes carrying fixed HHMCs, NCOA6 has been linked to age at menarche and onset of puberty, as well as placental function.

    “Among the genes carrying fixed HHMCs, NCOA6 has also been linked to age at menarche and onset of puberty170, as well as placental function171.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [170] Day, F. R. et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat. Genet. 49, 834–841 (2017). source

      Not checked in the free run.

    • cites [171] Antonson, P. et al. Inactivation of the Nuclear Receptor Coactivator RAP250 in Mice Results in Placental Vascular Dysfunction. Mol. Cell. Biol. 23, 1260–1268 (2003). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Neanderthals might have reached adulthood earlier.

    “it has been claimed that Neanderthals might have reached adulthood earlier169.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Ramirez Rozzi, F. V. & de Castro, J. M. surprisingly rapid growth in Neanderthals. Nature 428 (2004). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Such changes may point to differences in levels of resilience to pain between Neanderthals and modern humans.

    “Such changes may point to differences in levels of resilience to pain between Neanderthals and modern humans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The adjacent exon is not present in all transcripts of IZUMO4, suggesting a functional role of this splice site SNC.

    “The adjacent exon is not present in all transcripts of this gene, suggesting a functional role of this splice site SNC.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Other mutations in OPRM1 are associated to heroin addiction, pain perception, but also sociality traits.

    “Other mutations in this gene are associated to heroin addiction178, and pain perception179, but also sociality traits180.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [178] Shi, J. et al. Sequence variations in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Hum. Mutat. 19, 459–460 (2002). source

      Not checked in the free run.

    • cites [179] Tan, E. et al. Ethnicity and OPRM variant independently predict pain perception and patient-controlled analgesia usage for post-operative pain. Mol. Pain 5, 32 (2009). source

      Not checked in the free run.

    • cites [180] Pearce, E., Wlodarski, R., Machin, A. & Dunbar, R. I. M. Variation in the β-endorphin, oxytocin, and dopamine receptor genes is associated with different dimensions of human sociality. Proc. Natl. Acad. Sci. 114, 5300 LP–5305 (2017). source

      Not checked in the free run.

91 of 91

  • The authors state this as an assumption.

    The mutation rate is slow.

    “assuming a slow mutation rate”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The age distribution of fixed or nearly fixed human-specific derived mutations within archaic hominin deserts that either were annotated as nonsynonymous substitutions or fell within annotated regulatory element binding sites is centered around 600 ka ago.

    “We compiled the ages of all fixed or nearly fixed human-specific derived mutations within archaic hominin deserts that either were annotated as nonsynonymous substitutions (34) or fell within annotated regulatory element binding sites. The age distribution of these mutations is centered around 600 ka ago (Fig. 5A).”

    From An ancestral recombination graph of human, Neanderthal, and Denisovan genomes (2021) · cites this paper as [34]

  • The most detailed study systematically exploring high-frequency (>90%) changes in modern humans for which archaic humans carry the ancestral state found BAZ1B enriched for mutations in modern humans, most of which fall in regulatory regions of the gene.

    “(v) the thus far most detailed study systematically exploring high-frequency (HF) (>90%) changes in modern humans for which archaic humans carry the ancestral state, which found BAZ1B enriched for mutations in modern humans (most of which fall in the regulatory regions of the gene) (15).”

    From Dosage analysis of the 7q11.23 Williams region identifies <i>BAZ1B</i> as a major human gene patterning the modern human face and underlying self-domestication (2019) · cites this paper as [15]

  • The list of genes harboring (nearly) fixed mutations in moderns versus archaics contains three classes: genes harboring high-frequency changes, genes harboring high-frequency missense mutations, and genes enriched for high-frequency mutations in regulatory regions.

    “the list of genes harboring (nearly) fixed mutations in moderns versus archaics contains three classes: (i) genes harboring high-frequency changes (15), (ii) genes harboring high-frequency missense mutations (red barplot), and (iii) genes enriched for high-frequency mutations in regulatory regions (green barplot) [data based on (15)]”

    From Dosage analysis of the 7q11.23 Williams region identifies <i>BAZ1B</i> as a major human gene patterning the modern human face and underlying self-domestication (2019) · cites this paper as [15]

  • Despite the spuriously inflated number of apparently fixed mutations in archaics, the overall extent of overlap between genes affected by BAZ1B dosage and modern and archaic sets does not reveal significantly more hits for archaics.

    “Third, despite the spuriously inflated number of apparently fixed mutations in archaics (15), the overall extent of overlap between genes affected by BAZ1B dosage and our modern and archaic sets does not reveal significantly more hits for archaics.”

    From Dosage analysis of the 7q11.23 Williams region identifies <i>BAZ1B</i> as a major human gene patterning the modern human face and underlying self-domestication (2019) · cites this paper as [15]

  • A large proportion of selective sweeps or high-frequency changes on glutamate receptor genes in AMH relative to archaic Homo are found in regulatory regions that control gene expression.

    “Similarly, a large proportion of selective sweeps or highfrequency changes on glutamate receptor genes in AMH relative to archaic Homo are found in regulatory regions that control gene expression (Peyrégne et al., 2017;Kuhlwilm and Boeckx, 2019).”

    From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Kuhlwilm and Boeckx, 2019

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reported gene-level HHMC counts require at least 650 changes, not 647

    Minor

    The stated 68 genes with multiple HHMCs include two with four and seven with three. Even if each of the other 59 genes has only two, those 68 genes account for 147 changes; adding one for each of the remaining 503 genes gives a minimum of 650, contradicting the reported total of 647.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Gokhman, D. et al. Extensive Regulatory Changes in Genes Affecting Vocal and Facial Anatomy Separate Modern from Archaic Humans. bioRxiv (2017).

Cited by

Sorted by citations

Related

Authors
Kuhlwilm, M., & Boeckx, C.
Affiliations
  • Universitat Pompeu Fabra (ES)
  • Institució Catalana de Recerca i Estudis Avançats (ES)
Corresponding author
Boeckx, Cedric
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-06-11
Volume
9
Issue
1
Pages
8463-8463
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-019-44877-x
PMC
PMC6560109
OpenAlex
W2952005553
Cited by
108
References
211
Citations by year
2026: 6 · 2025: 16 · 2024: 25 · 2023: 17 · 2022: 13 · 2021: 14 · 2020: 8 · 2019: 8 · 2018: 1
FWCI
49.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
Funders
  • European Commission (PIRG-GA-2009-256,413, 256413)
  • Deutsche Forschungsgemeinschaft (KU 3467/1-1)
  • Ministry of Education, Culture, Sports, Science and Technology (JP17H06379)
  • Generalitat de Catalunya (2017- SGR-341, 2017-SGR)
  • Ministerio de Economía y Competitividad (2017-SGR-341, FFI2016-78034-C2-1-P)
  • Fundació Bosch i Gimpera (JP17H06379)
  • Japan Society for the Promotion of Science (JP17H06379)
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 Associations and Epidemiology
Keywords
single nucleotide polymorphisms, modern human evolution, archaic humans, Neanderthals, non-synonymous variants, brain growth trajectories, cognitive characteristics, ancient genomes
MeSH terms
Animals, Humans, Neurons, Nucleotides, Phenotype, Phylogeny, Selection, Genetic, Hominidae, Genome, Human

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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