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. 2022 Jul 11:11:e75464.
doi: 10.7554/eLife.75464.

The evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals

Stéphane Peyrégne  1 , Janet Kelso  1 , Benjamin M Peter  1 , Svante Pääbo  1
Affiliations

The evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals

Stéphane Peyrégne et al. Elife. .

Abstract

Proteins associated with the spindle apparatus, a cytoskeletal structure that ensures the proper segregation of chromosomes during cell division, experienced an unusual number of amino acid substitutions in modern humans after the split from the ancestors of Neandertals and Denisovans. Here, we analyze the history of these substitutions and show that some of the genes in which they occur may have been targets of positive selection. We also find that the two changes in the kinetochore scaffold 1 (KNL1) protein, previously believed to be specific to modern humans, were present in some Neandertals. We show that the KNL1 gene of these Neandertals shared a common ancestor with present-day Africans about 200,000 years ago due to gene flow from the ancestors (or relatives) of modern humans into Neandertals. Subsequently, some non-Africans inherited this modern human-like gene variant from Neandertals, but none inherited the ancestral gene variants. These results add to the growing evidence of early contacts between modern humans and archaic groups in Eurasia and illustrate the intricate relationships among these groups.

Keywords: evolutionary biology; gene flow; genetics; genomics; human; human evolution; neandertals; positive selection; spindle.

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Conflict of interest statement

SP, JK, BP, SP No competing interests declared

Figures

Figure 1.
Figure 1.. Genomic regions around spindle genes where archaic humans fall outside the modern human variation.
Each panel corresponds to the region around the missense change(s) (red stars) in a spindle gene. The grey boxes correspond to exons. The curves give the posterior probability (computed as in Peyrégne et al., 2017) that an archaic genome (Altai Neandertal in red, Denisova 3 in orange) is an outgroup to present-day African genomes at a particular position (dots on the curves correspond to informative positions, that is polymorphic positions or fixed derived substitutions in Africans from the 1,000 Genomes Project phase III, compared to four ape genomes). Chromosomal locations are given on top.
Figure 1—figure supplement 1.
Figure 1—figure supplement 1.. Genomic regions where archaic humans fall outside the modern human variation, identified using the most recent deCODE recombination map (Halldorsson et al., 2019).
Figure 2.
Figure 2.. Evidence for selection in the spindle genes with age estimates of these substitutions.
(A) The genetic length of segments around the missense substitutions where the Altai Neandertal and Denisova 3 fall outside the human variation (Figure 1) using the African-American map, AAmap, or the deCODE map, deCODE19. The grey histogram corresponds to the length distribution of such segments in neutral simulations (Peyrégne et al., 2017). Candidate genes for selection (red) are those with segments longer than 0.025cM (Peyrégne et al., 2017) (vertical red dashed line). (B) Cumulative distributions of pairwise times to the most recent common ancestors (TMRCA) among present-day African chromosomes with the most distant relationships (red; see Methods), or between the chromosomes of present-day Africans and either present-day individuals with the ancestral versions of the missense substitutions (‘Modern (anc)’, in black) or archaic humans (other colors). The pink areas correspond to estimated time intervals for the origin of the missense substitutions and their bounds correspond to the average TMRCAs over the red curve and the next one (back in time), respectively. (C) Summary of ages of substitutions as described in panel B. Genes with evidence of positive selection are highlighted in red.
Figure 3.
Figure 3.. A modern human-like haplotype in some Neandertals.
Genotypes from 13 archaic individuals (y-axis) are shown in a region around the two missense changes (dots) in KNL1. We only show positions (x-axis) that are derived in all Luhya and Yoruba individuals from the 1,000 Genomes Project compared to four great apes (Peyrégne et al., 2017) and at least one high-coverage archaic genome (Chagyrskaya 8, Denisova 3, Vindija 33.19 and Altai Neandertal, i.e., Denisova 5). The colors of the squares and dots represent the genotype, with ancestral and derived alleles. For the low coverage archaic genomes, we randomly sampled a sequence at each position. Red lines indicate the modern human-like haplotype.
Figure 4.
Figure 4.. The modern human-like KNL1 haplotype in Neandertals.
(A) Pairwise differences between two high coverage Neandertal genomes (Chagyrskaya 8 and Altai Neandertal (Denisova 5)) in non-overlapping sliding windows of 276 kb (histogram) and in the KNL1 region (vertical cyan line; chr15:40,818,035–41,094,166, hg19). Windows with less than 10,000 genotype calls for both Neandertals were discarded. (B) The expected length distributions under a model of incomplete lineage sorting based on local recombination rate estimates from the African-American (AA) and deCODE recombination maps and the length of the modern human-like KNL1 haplotype in Neandertals (vertical cyan line). (C) Left panel: Time to the most recent common ancestor (TMRCA) between the Chagyrskaya 8 Neandertal (who carries the modern human-like haplotype) and KNL1 haplotypes in present-day humans with their 95% confidence intervals (bars) for chr15:40,885,107–40,963,160 (hg19). The size of the points corresponds to the number of chromosomes carrying this haplotype in the HGDP dataset. The black rectangles highlight subsets of haplotypes with TMRCAs more recent than the modern-archaic population split time (Prüfer et al., 2017) (shaded pink area). Right panel: Distribution of pairwise TMRCAs between the Neandertal and present-day humans from the HGDP dataset in the region of KNL1 and two other regions with archaic haplotypes in present-day humans (Controls, Zeberg and Pääbo, 2020; Dannemann et al., 2016; COVID risk region: chr3:45,859,651–45,909,024; TLR6, 1 & 10: chr4:38,760,338–38,846,385). We used the Vindija 33.19 genome for the COVID risk haplotype and the Chagyrskaya 8 genome otherwise.
Figure 4—figure supplement 1.
Figure 4—figure supplement 1.. Genotypes of the 12 non-African individuals that inherited one copy of KNL1 from archaic humans.
We show positions within 40kb downstream of the modern-like KNL1 haplotype identified in Chagyrskaya 8 to highlight 7 positions (red marks) where only those 12 individuals (out of 929 individuals across worldwide populations Bergström et al., 2020) carry a derived allele seen in at least one Neandertal genome. We only show positions where at least one of the 12 individuals is heterozygous. The upper panel (‘Archaics’) shows the alleles carried by high-coverage archaic human genomes without the modern-like KNL1 haplotype. The middle panel (‘Chagyrskaya 8-like’) shows the alleles carried by four Neandertal genomes with the modern-human like KNL1 haplotype and the 12 present-day non-African genomes that inherited one copy of KNL1 from archaic humans. The lower panel (‘Other haplotypes’) shows the alleles carried by the other chromosomes (that did not inherit a copy ok KNL1 from archaic humans) of these 12 individuals. For the archaic human genomes, one allele was sampled randomly at heterozygous positions.
Figure 5.
Figure 5.. Schematic illustration of the history of KNL1.
The tree delineated in black corresponds to the average relationship between the modern and archaic human populations. The inner colored trees correspond to the relationship of different KNL1 lineages, with arrows highlighting the direction of gene flow between populations. The corresponding haplotypes are illustrated on the sides of the tree and show the recombination history in the region (e.g. the recombinant Neandertal haplotype with variants of putative archaic origin in non-Africans). Dots correspond to informative positions, and the stars illustrate the missense substitutions. The age of relevant ancestors are marked by horizontal dotted lines. MH: Modern human.
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