The evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals
- Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Germany
Figures
Figure 1 with 1 supplement
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 Peyrégn…
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
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 …
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 …
Figure 4 with 1 supplement
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 …
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 …
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 …
Tables
Appendix 1—table 1
Location and predicted effects of the studied amino acid changes in spindle proteins, as reported in dbNSFP version 4.2 (48).
The predictions are for the ancestral variants. We put “damaging” in between quotation marks as the ancestral versions of ATRX and KATNA1 are unlikely to be damaging (as the ancestral amino acid …
| protein | position | amino acid change | protein domain (Uniprot) | effect prediction for the ancestral variant (MutPred) | potentially “damaging” ancestral variant according to: |
|---|---|---|---|---|---|
| ATRX | 475 | D ->H | - | - | FATHMM; M-CAP |
| KATNA1 | 343 | A ->T | - | - | FATHMM; PrimateAI |
| KIF18A | 67 | R ->K | kinesin motor (11-355) | Loss of methylation (P=0.0087) | - |
| KNL1 | 159 | H ->R | interaction domain with BUB1 and BUB1B (1-728) | - | - |
| 1,086 | G ->S | 2 × 104 AA approximate repeats (855–1201) | Loss of phosphorylation (P=0.0382) | - | |
| NEK6 | 291 | D ->H | protein kinase domain (45-310) | - | - |
| RSPH1 | 213 | K ->Q | - | - | - |
| SPAG5 | 43 | P ->S | - | Loss of phosphorylation (P=0.0244) Gain of catalytic residue (P=0.0179) | - |
| 162 | E ->G | - | - | - | |
| 410 | D ->H | - | - | - | |
| STARD9 | 3,925 | A ->T | - | - | - |
Appendix 1—table 2
Deleteriousness and conservation scores at the studied positions with missense changes in spindle genes, as reported in dbNSFP version 4.2 (48).
A high CADD score indicates that the ancestral variant is likely to be deleterious (Kircher et al., 2014; Rentzsch et al., 2019; Pollard et al., 2010) and a high conservation score means that the …
| gene | position (hg19) rs ID | corresponding amino acid change | Deleteriousness | Conservation | ||
|---|---|---|---|---|---|---|
| CADD score (hg19) | GERP ++RS score | phyloP 100way vertebrate score | phastCons 100way vertebrate score | |||
| KATNA1 | 6–149,918,766 rs73781249 | A343T | 2.051033 | 5.48 | 4.834 | 1.000 |
| SPAG5 | 17–26,925,570 NA | P43S | –0.425670 | –3.57 | –1.404 | 0.000 |
| 17–26,919,777 NA | E162G | 0.296317 | 3.66 | 0.280 | 0.001 | |
| 17–26,919,034 NA | D410H | 1.062743 | 5.4 | 2.032 | 1.000 | |
| KNL1 | 15–40,912,860 rs755472529 | H159R | 0.475454 | 3.7 | –0.016 | 0.001 |
| 15–40,915,640 NA | G1086S | 0.801787 | 4.12 | 1.026 | 0.054 | |
| KIF18A | 11–28,119,295 rs775297730 | R67K | 1.134589 | 2.62 | 0.525 | 0.845 |
| NEK6 | 9–127,113,155 rs146443565 | D291H | –0.293112 | –1.56 | 3.284 | 1.000 |
| ATRX | X-76,939,325 rs146863015 | D475H | –0.141606 | 3.64 | 0.791 | 0.840 |
| RSPH1 | 21–43,897,491 rs146298259 | K213Q | –0.061053 | 1.81 | 0.672 | 0.079 |
| STARD9 | 15–42,985,549 rs573215252 | A3925T | –0.351117 | –2.51 | 0.047 | 0.000 |
Appendix 2—table 1
Age estimates of the missense substitutions in spindle genes.
The ages were estimated in the regions where the Altai Neandertal and Denisova 3 genomes fall outside the human variation (intersection of the regions identified with the African-American and deCODE …
| Gene | chromosome | Region (hg19) | Lower age (kya) | Upper age (kya) |
|---|---|---|---|---|
| ATRX | X | 76,703,773–77,246,471 | NA | NA |
| KATNA1 | 6 | 149,840,973–149,930,425 | 863 | 1,329 |
| KIF18A | 11 | 28,018,167–28,304,293 | 843 | 1,006 |
| KNL1 | 15 | 40,898,141–40,948,306 | 1,027 | 1,690 |
| NEK6 | 9 | 127,109,510–127,113,614 | NA | NA |
| RSPH1 | 21 | 43,897,417–43,897,549 | NA | NA |
| SPAG5 | 17 | 26,875,942–27,045,524 | 677 | 796 |
| STARD9 | 15 | 42,941,540–42,989,160 | 947 | 1,401 |
Appendix 3—table 1
Coverage depth in archaic human genomes at positions with modern human-specific missense substitutions in spindle genes.
The numbers of DNA fragments carrying a particular base are reported in parentheses after the corresponding base. Bases in uppercase were sequenced in the forward orientation, whereas those in …
| Gene | ATRX | KATNA1 | KIF18A | KNL1 | NEK6 | RSPH1 | SPAG5 | STARD9 | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Chr-Position | X-76,939,325 | 6–149,918,766 | 11–28,119,295 | 15–40,912,860 | 15–40,915,640 | 9–127,113,155 | 21–43,897,491 | 17–26,919,034 | 17–26,919,777 | 17–26,925,578 | 15–42,985,549 |
| Ancestral | C | C | C | A | G | G | T | C | T | G | G |
| Derived | G | T | T | G | A | C | G | G | C | A | A |
| Altai Neandertal | C (21) c (31) | C (22) c (15) T* (2) | C (19) c (41) T* (1) | A (24) a (28) | G (33) g (16) | G (23) g (23) | T (18) t (26) | C (17) c (17) | T (18) t (20) a (1) | G (28) g (17) | G (13) g (16) A* (1) |
| Chagyrskaya 8 | C (10) c (9) T (1) t (1) | C (13) c (5) | C (15) c (19) T* (3) | A (1) G* (14) g* (11) | A* (19) a* (8) | G (5) g (7) a (1) | T (17) t (13) | C (11) c (7) T (1) | T (16) t (11) | G (7) g (6) a* (1) | G (8) g (13) |
| Denisova 3 | C (19) c (17) | C (15) c (13) T* (2) | C (17) c (24) | A (20) a (30) | G (25) g (17) a* (1) | G (15) g (14) | T (19) t (27) | C (20) c (14) | T (16) t (11) | G (12) g (6) | G (17) g (12) |
| Denisova 11 | C (1) c (2) | NA | C (1) | a (2) | g (1) | G (1) g (1) | T (4) t (2) | c (2) t (1) | NA | NA | G (1) |
| Goyet Q56-1 | C (1) | NA | C (1) c (5) | G* (1) | A* (1) a* (2) | G (1) g (2) | NA | C (1) | T (1) | G (4) g (2) | G (2) |
| Hohlenstein-Stadel | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Les Cottés Z4-1514 | C (1) c (1) | c (2) T* (1) | C (5) c (4) | A (2) a (4) | G (3) g (2) | NA | T (2) t (1) | NA | T (1) | G (1) | G (1) |
| Mezmaiskaya 1 | c (3) | NA | C (1) c (1) | NA | G (2) | NA | t (2) | C (2) c (1) g* (2) | NA | NA | NA |
| Mezmaiskaya 2 | C (1) | C (1) c (1) T* (1) | C (1) | g* (1) | A* (1) | G (2) g (1) | NA | C (1) | T (1) | G (2) | g (3) |
| Scladina I-4A | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Spy 94 A | NA | c (1) | C (1) | g* (1) | A* (1) a* (3) | NA | T (1) | C (1) | T (1) | g (1) | NA |
| Vindija 33.19 | C (16) c (18) T (1) | C (8) c (11) | C (17) c (20) T* (1) | A (13) a (19) | G (20) g (16) a* (2) | G (8) g (8) | T (22) t (15) | C (12) c (14) | T (15) t (7) | G (15) g (13) a* (1) | G (14) g (14) |
Appendix 3—table 2
Coverage depth of the Mezmaiskaya 1 genome at positions with modern human-specific substitutions in SPAG5.
Only positions covered by at least one DNA sequence are reported. Bases in uppercase were sequenced in the forward orientation, whereas those in lowercase were sequenced in the reverse orientation. …
| Neandertal | Chr-position (rs ID) | Ancestral | Derived | Allele counts |
|---|---|---|---|---|
| Mezmaiskaya 1 | 17–26,864,608 (rs188710272) | A | G | A (1) |
| 17–26,891,162 (NA) | T | G | T (1) | |
| 17–26,892,376 (NA) | A | T | A (2) | |
| 17–26,913,024 (NA) | A | G | a (a) | |
| 17–26,919,034 (NA) | C | G | C (2) c (1) g (2) | |
| 17–26,948,236 (NA) | G | A | g (1) | |
| 17–26,967,723 (rs558276956) | A | G | A (3) | |
| 17–27,005,275 (NA) | G | A | G (1) | |
| 17–27,010,483 (NA) | G | A | g (1) |
Appendix 4—table 1
Positions defining the closely related haplotype between some modern humans and Neandertals.
At these positions, the Chagyrskaya 8 genome differs from other high-quality archaic genomes without the modern human-like haplotype but some African genomes from the HGDP dataset carry the same …
| Chromosome | Position (hg19) rs ID | Reference | Alternative (Chagyrskaya 8-like) | Chagyrskaya 8-like allele frequency in genomes from the HGDP dataset | |
|---|---|---|---|---|---|
| Africans | Non-Africans | ||||
| 15 | 40,885,107 rs16970851 | A | G | 0.32 | 0.41 |
| 40,886,017 rs8034043 | C | T | 0.32 | 0.41 | |
| 40,886,020 rs8034048 | C | G | 0.32 | 0.40 | |
| 40,892,601 rs11855923 | G | A | 0.35 | 0.40 | |
| 40,893,573 rs12905162 | C | A | 0.38 | 0.40 | |
| 40,905,450 rs11856438 | C | T | 0.37 | 0.41 | |
| 40,908,904 rs11852670 | A | G | 0.39 | 0.41 | |
| 40,910,707 rs12914743 | T | C | 0.38 | 0.41 | |
| 40,915,045 rs8041534 | T | G | 0.38 | 0.41 | |
| 40,915,894 rs11070285 | T | C | 0.39 | 0.41 | |
| 40,925,214 rs11856802 | T | A | 0.39 | 0.41 | |
| 40,926,654 rs11854986 | C | G | 0.35 | 0.40 | |
| 40,929,814 rs11070286 | T | C | 0.37 | 0.41 | |
| 40,937,647 rs3092979 | A | G | 0.38 | 0.41 | |
| 40,959,413 rs73396515 | G | A | 0.36 | 0.10 | |
| 40,959,624 rs35047458 | G | A | 0.36 | 0.40 | |
| 40,960,432 rs12902568 | G | A | 0.36 | 0.40 | |
| 40,963,160 rs7182530 | A | G | 0.37 | 0.41 | |
| 40,987,528 rs1801320 | G | C | 0.38 | 0.11 | |
Appendix 5—table 1
Origin of the modern human genomes from the HGDP dataset (Bergström et al., 2020) with a KNL1 copy inherited from Neandertals.
| sample | population | region |
|---|---|---|
| HGDP00125 | Hazara | Central South Asia |
| HGDP00547 | Papuan Sepik | Oceania |
| HGDP00639 | Bedouin | Middle East |
| HGDP00696 | Palestinian | Middle East |
| HGDP00714 | Cambodian | East Asia |
| HGDP00774 | Han | East Asia |
| HGDP00822 | Han | East Asia |
| HGDP00954 | Yakut | East Asia |
| HGDP00960 | Yakut | East Asia |
| HGDP00966 | Yakut | East Asia |
| HGDP01023 | Han | East Asia |
| HGDP01181 | Yi | East Asia |
Appendix 6—table 1
Allele counts at positions with nearly fixed missense variants in the spindle genes of modern humans from the gnomAD database (v2.1.1), (Karczewski et al., 2020).
Columns 7–8 and 9–10 correspond to the allele counts among the 125,748 whole-exome sequences (WES) and the 15,708 whole-genome sequences (WGS), respectively. Anc = Ancestral
| Gene | Chr-Position (rd ID) | Anc | (nearly) fixed | Alleles | VEP Annot. | # Anc (WES) | Total (WES) | # Anc (WGS) | Total (WGS) |
|---|---|---|---|---|---|---|---|---|---|
| ATRX | X-76,939,325 (rs146863015) | C | G | G-C | missense | 66 | 182,745 | 11 | 22,042 |
| KATNA1 | 6–149,918,766 (rs73781249) | C | T | T-C | missense | 259 | 251,190 | 131 | 31,400 |
| KIF18A | 11–28,119,295 (rs775297730) | C | T | T-C | missense | 26 | 249,508 | 1 | 31,396 |
| KNL1 | 15–40,912,860 (rs755472529) | A | G | G-A | missense | NA | NA | 1 | 31,368 |
| G-T | missense | 1 | 227,420 | NA | NA | ||||
| 15–40,915,640 (NA) | G | A | A-G | missense | NA | NA | NA | NA | |
| NEK6 | 9–127,113,155 (rs146443565) | G | C | C-G | missense | 164 | 250,140 | 26 | 31,404 |
| RSPH1 | 21–43,897,491 (rs146298259) | T | G | G-T | missense | 236 | 251,414 | 30 | 31,386 |
| G-A | stop gained | 10 | 251,414 | 1 | 31,386 | ||||
| SPAG5 | 17–26,919,034 (NA) | C | G | G-C | missense | NA | NA | NA | NA |
| 17–26,919,777 (NA) | T | C | C-A | missense | 3 | 251,430 | NA | NA | |
| 17–26,925,578 (NA) | G | A | A-G | missense | NA | NA | NA | NA | |
| A-T | missense | 1 | 251,066 | NA | NA | ||||
| STARD9 | 15–42,985,549 (rs573215252) | G | A | A-G | missense | 5 | 139,342 | 3 | 31,284 |
| A-C | missense | 5 | 139,342 | NA | NA |
