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

In the paper

“given their similar brain sizes160, humans and Neanderthals might both have needed a long overall maturation time161,162.”

What the sources say

• Not checked yetcites [160] Hofman, M. a. Encephalization in hominids: evidence for the model of punctuationalism. Brain. Behav. Evol., https://doi.org/10.1159/000121511 (1983). source
• Partly supported

  The Abstract (page unavailable) says adult Neanderthal and modern human braincases were similarly capacious and concludes that their postnatal brain development was largely similar. It does not say that either species needed a long overall maturation time, or establish that similar brain size required one. (LLM, conf=0.84)

  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). sourceExperimental — accuracy not yet measured
• Supported

  The Abstract says the juvenile Neandertal’s development followed a broadly human pattern of slow growth between weaning and puberty, which may offset the cost of growing a large brain. It also finds no fundamental difference from modern humans in the overall pace of growth. This supports the citing sentence’s hedged suggestion; the separate brain-size comparison is attached to citation 160, not this source. (LLM, conf=0.86)

  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

In the paper

“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.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  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
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [145] Lacruz, R. S. et al. Facial Morphogenesis of the Earliest Europeans. PLoS One 8, e65199 (2013). sourceExperimental — accuracy not yet measured
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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

In the paper

“which has been pointed out before as under positive selection31,33,34,122.”

What the sources say

• Partly supported

  The Significance section reports an overrepresentation of amino acid-changing substitutions in behavioral-trait genes on the modern human lineage and identifies ADSL as one of those genes. It does not conclude that ADSL itself was under positive selection; enrichment of substitutions is not the same claim. (LLM, conf=0.84)

  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). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results section discusses candidate regions of positive selection, and the Discussion names examples such as SLIT2 and ROBO2, but neither passage identifies ADSL. Searches of our copy for “ADSL” and “adenylosuccinate lyase” found no passage linking that gene to positive selection. (LLM, conf=0.74)

  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). sourceExperimental — accuracy not yet measured
• Supported

  Section 4.3 states that ADSL was previously identified in a region with strong support for positive selection in modern humans. The paper also identifies ADSL as a candidate for selection, which supports the claim that it had been pointed out before. (LLM, conf=0.92)

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Supported

  The Results (page not available) report that neuronal ELAV proteins, including HuD, bind Nova1 mRNA. The paper also describes HuD as a neuron-selective RNA-binding protein. The positive-selection suggestion has separate citations in the citing sentence and is not attributed to this source; the interaction shown here is with Nova1 mRNA, not NOVA1 protein. (LLM, conf=0.88)

  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
• ?Could not verify

  The Discussion identifies other brain-related candidates for ancient selection, including SLIT2, ROBO2, and DCX. Searches for ELAVL4 and its description as a neuronal RNA-binding protein found no passage addressing whether ELAVL4 was under positive selection. The source also does not address the stated NOVA1–ELAVL4 interaction. (LLM, conf=0.72)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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).”

In the paper

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

In the paper

“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”.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [59] Miller, J. A. et al. Transcriptional Landscape of the Prenatal Human Brain. Nature 508, 199–206 (2014). source

In the paper

“a deleterious HHMC in ABHD14A, which is a target of ZIC188.”

What the sources say

• Not checked yetcites [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

In the paper

“an interactor of KIF18A, KIF1597, might have been under positive selection in modern humans33, and contains two HHMCs.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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).”

In the paper

“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).”

In the paper

“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.”

In the paper

“SSH2 (two HHMCs) might be involved in neurite outgrowth99.”

What the sources say

• Not checked yetcites [99] Cuberos, H. et al. Roles of LIM kinases in central nervous system function and dysfunction. FEBS Lett. 589, 3795–3806 (2015). source

In the paper

“we find one of the most deleterious regulatory SNCs in the Netrin receptor UNC5D, which is critical for axon guidance103.”

What the sources say

• Not checked yetcites [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

In the paper

“Versican (VCAN), which promotes neurite outgrowth98, carries three HHMCs”

What the sources say

• Not checked yetcites [98] Wu, Y. et al. Versican V1 Isoform Induces Neuronal Differentiation and Promotes Neurite Outgrowth. Mol. Biol. Cell 15, 2093–2104 (2004). source

In the paper

“PIEZO1, which carries a non-synonymous change that is almost fixed in modern humans, is another factor in axon guidance100”

What the sources say

• Not checked yetcites [100] Koser, D. E. et al. Mechanosensing is critical for axon growth in the developing brain. Nat. Neurosci. 19, 1592 (2016). source

In the paper

“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).”

What the sources say

• Not checked yetcites [36] Zhou, H. et al. A Chronological Atlas of Natural Selection in the Human Genome during the Past Half-million Years. bioRxiv (2015). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“three HHMCs are observed in NPAP1, which might be associated with the Prader-Willi syndrome, involving behavioral problems and a high pain threshold182.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [42] Wynn, T. & Coolidge, F. L. The expert Neandertal mind. J. Hum. Evol. 46, 467–487 (2004). source

In the paper

“while the brain size and encephalization of humans and Neanderthals is similar9,13,14.”

What the sources say

• Not checked yetcites [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 yetcites [13] Trinkaus, E. & Howells, W. W. The Neanderthals. Sci. Am. 241, 118–133 (1979). source
• Not checked yetcites [14] Schoenemann, P. T. Brain Size Scaling and Body Composition in Mammals. Brain. Behav. Evol. 63, 47–60 (2004). source

In the paper

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

In the paper

“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).”

In the paper

“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.”

What the sources say

• Not checked yetcites [20] Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–9 (2014). source
• Not checked yetcites [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

In the paper

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

In the paper

“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.”

In the paper

“However, changes in structural variants or regions of the genome that are not accessible by current sequencing technologies will most likely complement our results45.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [1] Pääbo, S. The Human Condition—A Molecular Approach. Cell 157, 216–226 (2014). source

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [20] Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–9 (2014). source

In the paper

“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”

What the sources say

• Not checked yetcites [1] Pääbo, S. The Human Condition—A Molecular Approach. Cell 157, 216–226 (2014). source
• Not checked yetcites [20] Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–9 (2014). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

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

In the paper

“It has been claimed that mutations in PTEN alter the brain growth trajectory and allocation of cell types through elevated Beta-Catenin signaling77.”

What the sources say

• Not checked yetcites [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

In the paper

“centrosome-related proteins are overrepresented in studies on the microcephaly phenotype in humans70.”

What the sources say

• Not checked yetcites [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

In the paper

“The centrosome-cilium interface is known to be critical for early brain development”

What the sources say

• Not checked yetcites [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

In the paper

“Indeed, three genes (CASC5, SPAG5, and KIF18A) have been singled out as involved in spindle pole assembly during mitosis1.”

What the sources say

• Not checked yetcites [1] Pääbo, S. The Human Condition—A Molecular Approach. Cell 157, 216–226 (2014). source

In the paper

“Our extended catalog of changes appears to provide additional support for some of these hypotheses.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [1] Pääbo, S. The Human Condition—A Molecular Approach. Cell 157, 216–226 (2014). source
• Not checked yetcites [20] Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–9 (2014). source
• Not checked yetcites [61] Omer Javed, A. et al. Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype. Cell Rep. 25, 368–382.e5 (2018). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [148] Park, J.-A. & Kim, K. C. Expression patterns of PRDM10 during mouse embryonic development. BMB Rep. 43, 29–33 (2010). source

In the paper

“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.”

What the sources say

• Not checked yetcites [109] Skeide, M. A. & Friederici, A. D. The ontogeny of the cortical language network. Nat. Rev. Neurosci. 17, 323 (2016). source
• Not checked yetcites [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

In the paper

“mutations in the HHMC-carrying gene encoding for the transcription factor ATRX cause facial dysmorphism138.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“We know that archaic hominins likely had certain language-like abilities123,124”

What the sources say

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

In the paper

“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.”

What the sources say

• Not checked yetcites [144] Lacruz, R. S. et al. Ontogeny of the maxilla in Neanderthals and their ancestors. Nat. Commun. 6, 8996 (2015). source

In the paper

“hybrids of modern and archaic humans must have survived in their communities125”

What the sources say

• Not checked yetcites [125] Fu, Q. et al. An early modern human from Romania with a recent Neanderthal ancestor. Nature 524, 216–219 (2015). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [16] Boeckx, C. The language-ready head: Evolutionary considerations. Psychon. Bull. Rev. 24, 194–199 (2017). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“It has been found that Neanderthal alleles contribute to addiction and, possibly, pain sensitivity in modern humans176,177.”

What the sources say

• Not checked yetcites [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 yetcites [177] Dannemann, M., Prüfer, K. & Kelso, J. Functional implications of Neandertal introgression in modern humans. Genome Biol. 18, 61 (2017). source

In the paper

“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.”

What the sources say

• Not checked yetcites [166] Smith, B. H. & Tompkins, R. L. Toward A Life History of the Hominidae. Annu. Rev. Anthropol. 24, 257–279 (1995). source
• Not checked yetcites [167] Bock, J. & Sellen, D. W. Childhood and the evolution of the human life course. Hum. Nat. 13, 153–159 (2002). source

In the paper

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

In the paper

“we caution that in some cases genotypes might be incorrect.”

In the paper

“A delay in reproductive age may influence overall longevity”

In the paper

“Dental evidence suggests an earlier maturation in Neanderthals than modern humans168”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“Although these permissive filters increase power compared to previous studies”

In the paper

“Among the genes carrying fixed HHMCs, NCOA6 has also been linked to age at menarche and onset of puberty170, as well as placental function171.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“it has been claimed that Neanderthals might have reached adulthood earlier169.”

What the sources say

• Not checked yetcites [169] Ramirez Rozzi, F. V. & de Castro, J. M. surprisingly rapid growth in Neanderthals. Nature 428 (2004). source

In the paper

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

In the paper

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

In the paper

“Other mutations in this gene are associated to heroin addiction178, and pain perception179, but also sociality traits180.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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