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  1. Author Response:

    Reviewer #1:

    In comparison to closely related archaic genomes (i.e., Neanderthal and Denisovan), modern human lineage has an elevated rate of nonsynonymous substitutions in some spindle protein genes (first reported in Prüfer et al. 2014). Following up on this interesting observation, Peyrégne et al performed a detailed study on the human lineage substitutions using both present-day and archaic genomes. In particular, they reported the back introgression of the kinetochore scaffold 1 (KNL1) gene. Using the genetic divergence and segment length, the authors inferred that KNL1 first introgressed from an ancestral modern human lineage to late European Neanderthals, then introgressed back to out-of-Africa modern humans. Surprisingly, they find no evidence for adaptive introgression of KNL1 in Neanderthals, despite the substitutions likely being adaptive in humans, and the Neanderthal copy of KNL1 having been purged from modern humans. Their nonadaptive conclusion is drawn upon the high frequency of other human variants in late European Neanderthals.

    We believe that there is a misunderstanding here. The variants the reviewer refers to are not modern human variants but Neandertal variants that rose in frequency to a similar extent as the KNL1 haplotype.

    However, reconcilation with the estimated 3% human to Neanderthal introgression by Hubisz et al. 2020 might be needed.

    The 3% estimate from Hubisz et al., 2020 is an estimate of the overall, genome-wide gene flow into Neandertals from early modern humans. We reconstruct the history of a single locus (KNL1). We therefore do not see a contradiction to Hubisz et al., 2020.

    The missense substitutions in KNL1, and the differences with the archaic copies, are worth following up in functional studies. Overall, the study nicely uses various population genetic approaches to understand the evolution of these spindle genes. My main concerns are about the robustness of the statistics because of the small sample size of Neanderthals and the low coverage. In particular, it is important to know whether these spindle protein genes are truly outliers in the genome-wide scan, and whether these results are robust to different variant calling protocols for the archaic genomes.

    The observation that the KNL1 region in the Chagyrskaya Neandertal is a genome-wide outlier in its high divergence to other Neandertals and its low divergence to present-day modern human genomes is not affected by the small number of Neandertal genome sequences available.

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  2. Evaluation Summary:

    Peyregne et al. studied the genes encoding proteins of the spindle apparatus. These genes have an elevated number of nonsynonymous substitutions in modern humans, and by comparison of modern and archaic alleles the authors identify that some Neanderthals had already the modern human haplotype at the KNL1 gene, raising the possibility that Neanderthals acquired it from modern humans. This study will be of interest to evolutionary biologists and anthropologists, because it supports the hypothesis that modern humans and Neanderthals interacted more than once in the past.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

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  3. Reviewer #1 (Public Review):

    In comparison to closely related archaic genomes (i.e., Neanderthal and Denisovan), modern human lineage has an elevated rate of nonsynonymous substitutions in some spindle protein genes (first reported in Prüfer et al. 2014). Following up on this interesting observation, Peyrégne et al performed a detailed study on the human lineage substitutions using both present-day and archaic genomes. In particular, they reported the back introgression of the kinetochore scaffold 1 (KNL1) gene. Using the genetic divergence and segment length, the authors inferred that KNL1 first introgressed from an ancestral modern human lineage to late European Neanderthals, then introgressed back to out-of-Africa modern humans. Surprisingly, they find no evidence for adaptive introgression of KNL1 in Neanderthals, despite the substitutions likely being adaptive in humans, and the Neanderthal copy of KNL1 having been purged from modern humans. Their nonadaptive conclusion is drawn upon the high frequency of other human variants in late European Neanderthals. However, reconcilation with the estimated 3% human to Neanderthal introgression by Hubisz et al. 2020 might be needed. The missense substitutions in KNL1, and the differences with the archaic copies, are worth following up in functional studies. Overall, the study nicely uses various population genetic approaches to understand the evolution of these spindle genes. My main concerns are about the robustness of the statistics because of the small sample size of Neanderthals and the low coverage. In particular, it is important to know whether these spindle protein genes are truly outliers in the genome-wide scan, and whether these results are robust to different variant calling protocols for the archaic genomes.

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  4. Reviewer #2 (Public Review):

    The authors set out to study spindle protein genes with missense changes that are fixed in modern humans relative to Neandertals and to reconstruct their evolutionary history. The authors show evidence for positive selection, particularly in the gene SPAG5, and they demonstrate that modern human fixed derived haplotypes at the gene KNL1 were transferred by gene flow from modern humans to early Neandertals and then again back from late Neandertals to modern humans.

    The main argument for the gene-flow hypothesis at KNL1 rests on the timing of mutations and gene flow events by investigating haplotype lengths and divergence within modern humans and between modern humans and Neandertal genomes. This part of the analysis seems technically sound and indeed suggests that a simple model of an ancient separation between Neandertals and modern humans and recent (~50kya) contact does not fit the data, i.e. a second gene flow event at KNL1 around 200kya has to be invoked. The analysis relies strongly on knowing the true mutation rate and the recombination rate in this genomic region. However, by using different datasets to estimate these parameters locally in the genome the authors show that their analysis is at least robust and consistent with the current best estimates of these two parameters in this region. I thus think their conclusion is well justified.

    The analysis reveals two other interesting observations: 1) The two missense changes in KNL1 predate the divergence of Neandertals and modern humans. However, for some reason Neandertals did not inherit these mutations from the ancestral population, only modern humans did. 2) Only derived KNL1 haplotypes that were back-introduced into modern humans from Neandertals persisted until the present day. The ancestral haplotypes were either not transferred or were selected against. I think both observations are only consistent with purifying selection acting at certain points in time in certain populations. However, the current analysis does not focus on this aspect.

    Further, the missense mutation in SPAG5, which seems to have been under positive selection in modern humans and which is not found in Neandertals, is dated to be older than the split between Neandertals and modern humans (Fig. 2C). This suggests that the mutation was not immediately under selection and that it was potentially under purifying selection in Neandertals.

    In general, the study provides very careful analysis and excellent usage of methods for estimating the timing of mutations and introgression events. It suggests that there had been contact between modern humans and Neandertals around 200kya, which is very relevant for understanding human evolutionary history. Further, it suggests strong selection of nonsynonymous mutations at spindle genes. This result will hopefully stimulate further research and functional characterization of these mutations in the future and lead to a better understanding of when and why these mutations had been selected.

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