Chromosomal inversions in human populations: A review from an evolutionary perspective
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May 25, 2026
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Abstract
Inversion polymorphisms provided critical case studies in the early development of population genetics. Recently, interest in their evolution has been re-invigorated by the discovery of inversion polymorphism in many animal and plant species using genomic approaches and by new theoretical developments. In parallel, genomic approaches are providing new insights into the origin, prevalence and consequences of inversions in human populations. In this article, I consider how observations on human inversions fit into the prevailing view of inversion polymorphism in the evolutionary biology community. Surveys in humans have revealed many small inversions that are missed in animal and plant studies. These surveys show a mix of origins via non-allelic homologous recombination and non-homologous end-joining processes. Importantly, homologous recombination can lead to recurrent origins with significant evolutionary consequences. Direct selection operates against inversion heterozygotes via both breakpoint and recombination effects. Both fields infer the maintenance of common polymorphisms by balancing selection, arising due to linkage disequilibrium between inversions and the loci they contain, but it remains difficult to identify the underlying causes. Research on non-human species tends to concentrate on large inversions and those maintained at high frequency. As a result, the evolutionary field has much to learn from work on humans about inversion origins and the pathological effects of rare variants. Medical research on inversions may benefit from considering the evolutionary processes underlying their behaviour in human populations.
Keywords:
chromosomal inversions, inversion polymorphism, human genomics, balancing selection, linkage disequilibrium, recombination mechanisms
Article Details
How to Cite
BUTLIN, Roger K..
Chromosomal inversions in human populations: A review from an evolutionary perspective.
Medical Research Archives, [S.l.], v. 14, n. 5, may 2026.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7389>. Date accessed: 23 june 2026.
doi: https://doi.org/10.18103/mra.v14i5.7389.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Dobzhansky T. Evolutionary oscillations in Drosophila pseudoobscura. In: Ecological Genetics and Evolution, ed. Creed R. pp.109-133. Blackwell Publisher, Oxford; 1971.
4. Wellenreuther M, Bernatchez L. Eco-evolutionary genomics of chromosomal inversions. Review. Trends Ecol Evol. Jun 2018;33(6):427-440. doi:10.1016/j.tree.2018.04.002
5. Berdan EL, Barton NH, Butlin R, et al. How chromosomal inversions reorient the evolutionary process. J Evol Biol. 2023 Dec 2023;36(12):1761-1782. doi:10.1111/jeb.14242
6. Stuart KC, Oomen RA, Tigano A, et al. A beginner's guide to structural variants in eco-evolutionary population genomics. Review. Mol Ecol. Jan 2026;35(2)e70216. doi:10.1111/mec.70216
7. Hoff SNK, Maurstad MF, Tørresen OK, et al. Rapid genome modifications including chromosomal fusions and large-scale inversions are key features in Arctic codfish species. Genome Biology. 2026/0 2/16 2026;27(1):100. doi:10.1186/s13059-026-03975-6
8. Kapun M, Flatt T. The adaptive significance of chromosomal inversion polymorphisms in Drosophila melanogaster. Article. Mol Ecol. Mar 2019;28(6): 1263-1282. doi:10.1111/mec.14871
9. Zhang L, Chaturvedi S, Nice CC, Lucas LK, Gompert Z. Population genomic evidence of selection on structural variants in a natural hybrid zone. Article; Early Access. Mol Ecol. 2022; doi:10. 1111/mec.16469
10. Gozashti L, Harringmeyer OS, Hoekstra HE. How repeats rearrange chromosomes: The molecular basis of chromosomal inversions in deer mice. Article. Cell Reports. May 27 2025;44(5)115644. doi:10.1016/j.celrep.2025.115644
11. Harringmeyer OS, Hoekstra HE. Chromosomal inversion polymorphisms shape the genomic landscape of deer mice. Article. Nature Ecology & Evolution. Dec 2022;6(12):1965-+. doi:10.1038/s4 1559-022-01890-0
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13. Stefansson H, Helgason A, Thorleifsson G, et al. A common inversion under selection in Europeans. Article. Nature Genet. Feb 2005;37(2):129-137. doi:10.1038/ng1508
14. Ebert P, Audano PA, Zhu Q, et al. Haplotype-resolved diverse human genomes and integrated analysis of structural variation. Article. Science. Apr 2 2021;372(6537):48-+. eabf7117. doi:10.1126/ science.abf7117
15. Porubsky D, Höps W, Ashraf H, et al. Haplotype-resolved inversion landscape reveals hotspots of mutational recurrence associated with genomic disorders. bioRxiv. 2021:2021.12.20.4723 54. doi:10.1101/2021.12.20.472354
16. Giner-Delgado C, Villatoro S, Lerga-Jaso J, et al. Evolutionary and functional impact of common polymorphic inversions in the human genome. Article. Nat Commun. Sep 17 2019;104222. doi:10. 1038/s41467-019-12173-x
17. Noor MAF, Grams KL, Bertucci LA, Reiland J. Chromosomal inversions and the reproductive isolation of species. Proc Natl Acad Sci U S A. Oct 9 2001;98(21):12084-12088.
18. Yoo D, Rhie A, Hebbar P, et al. Complete sequencing of ape genomes. Article. Nature. May 8 2025;641(8062)doi:10.1038/s41586-025-08816-3
19. Butlin RK. Recombination and speciation. Mol Ecol. Aug 2005;14(9):2621-2635.
20. Faria R, Johannesson K, Butlin RK, Westram AM. Evolving inversions. Trends Ecol Evol. Mar 2019;34(3):239-248. doi:10.1016/j.tree.2018.12.005
21. Jackson BC. Recombination-suppression: how many mechanisms for chromosomal speciation? Genetica. 2011/03/01 2011;139(3):393-402. doi: 10.1007/s10709-011-9558-0
22. Coyne J, Orr H. Speciation. Speciation. Sinauer Associates, Sunderland, M.A.; 2004.
23. Escaramis G, Docampo E, Rabionet R. A decade of structural variants: description, history and methods to detect structural variation. Article. Briefings in Functional Genomics. Sep 2015;14(5): 305-314. doi:10.1093/bfgp/elv014
24. Merayo M, Delgado KM, Salguero D, Orengo DJ. Chromosomal Inversions in Chromosome U of Drosophila subobscura: A Story from Population Studies to Molecular Level. Article. Insects. Jun 1 2025;16(6):1-17.
25. Corbett-Detig RB. Selection on Inversion Breakpoints Favors Proximity to Pairing Sensitive Sites in Drosophila melanogaster. Article. Genetics. Sep 2016;204(1):259-+. doi:10.1534/genetics.116.190389
26. Steinberg KM, Antonacci F, Sudmant PH, et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism. Article. Nature Genet. Aug 2012;44(8):872-+. doi:10.1038/ng.2335
27. Salm MPA, Horswell SD, Hutchison CE, et al. The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism. Article. Genome Res. Jun 2012;22(6):1144-1153. doi:10.1101/gr.126037.111
28. Guerrero RF, Rousset F, Kirkpatrick M. Coalescent patterns for chromosomal inversions in divergent populations. Article. Philosophical Transactions of the Royal Society B-Biological Sciences. Feb 5 2012;367(1587):430-438. doi:10. 1098/rstb.2011.0246
29. Le Moan A, Stankowski S, Rafajlovic M, et al. Coupling of twelve putative chromosomal inversions maintains a strong barrier to gene flow between snail ecotypes. Article. Evolution Letters. Apr 23 2024;8(4):575-586. doi:10.1093/evlett/qrae014
30. Flores M, Morales L, Gonzaga-Jauregui C, et al. Recurrent DNA inversion rearrangements in the human genome. Article. Proc Natl Acad Sci U S A. Apr 10 2007;104(15):6099-6106. doi:10.1073/ pnas.0701631104
31. Connallon T, Olito C. Natural selection and the distribution of chromosomal inversion lengths. Article. Mol Ecol. Jul 2022;31(13):3627-3641. doi: 10.1111/mec.16091
32. Stephenson-Gussinye A, Furlan-Magaril M. Chromosome conformation capture technologies as tools to detect structural variations and their repercussion in chromatin 3D configuration. Review. Frontiers in Cell and Developmental Biology. Jun 29 2023;111219968. doi:10.3389/ fcell.2023.1219968
33. Wright D, Schaeffer SWW. The relevance of chromatin architecture to genome rearrangements in Drosophila. Article. Philosophical Transactions of the Royal Society B-Biological Sciences. Aug 1 2022;377(1856)20210206. doi:10.1098/rstb.2021.0206
34. Wesley CS, Eanes WF. Isoaltion and analysis of the breakpoint sequences of chromosome inversion In(3L)Payne in Drosophila melanogaster. Article. Proc Natl Acad Sci U S A. Apr 12 1994;91(8) :3132-3136. doi:10.1073/pnas.91.8.3132
35. Villoutreix R, de Carvalho CF, Soria-Carrasco V, et al. Large-scale mutation in the evolution of a gene complex for cryptic coloration. Article. Science. Jul 24 2020;369(6502):460-+. doi:10.1126/science.aaz4351
36. Jones ML, Murden SL, Brooks C, et al. Disruption of AP3B1 by a chromosome 5 inversion: a new disease mechanism in Hermansky-Pudlak syndrome type 2. Article. Bmc Medical Genetics. Apr 4 2013;1442. doi:10.1186/1471-2350-14-42
37. Utami KH, Hillmer AM, Aksoy I, et al. Detection of chromosomal breakpoints in patients with developmental delay and speech disorders. Article. Plos One. Mar 6 2014;9(3)e90852. doi:10. 1371/journal.pone.0090852
38. Pang AWC, Migita O, MacDonald JR, Feuk L, Scherer SW. Mechanisms of formation of structural variation in a fully sequenced human genome. Article. Human Mutation. Feb 2013;34(2):345-354. doi:10.1002/humu.22240
39. Anger GJ, Crocker S, McKenzie K, et al. X-Linked Deafness-2 (DFNX2) Phenotype Associated With a Paracentric Inversion Upstream of POU3F4. Article. American Journal of Audiology. Mar 2014; 23(1):1-6. doi:10.1044/1059-0889(2013/13-0018)
40. Brown KK, Reiss JA, Crow K, et al. Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21 .3q35). Article. Human Genetics. Jan 201 0;127(1): 19-31. doi:10.1007/s00439-009-0736-4
41. Lettice LA, Daniels S, Sweeney E, et al. Enhancer-adoption as a mechanism of human developmental disease. Article. Human Mutation. Dec 2011;32(12):1492-1499. doi:10.1002/humu.21615
42. Sturtevant AH, Beadle GW. The relations of inversions in the X chromosome of Drosophila melanogaster to crossing over and disjunction. Article. Genetics. Sep 1936;21(5):554-604.
43. Stathos A, Fishman L. Chromosomal rearrangements directly cause underdominant F-1 pollen sterility in Mimulus lewisii-Mimulus cardinalis hybrids. Evolution. Nov 2014;68(11):3109-3119. doi:10.1111/evo.12503
44. Zhang S, He Y, Lu Y, et al. Meiotic determinants of unbalanced gametogenesis in chromosomal inversion carriers Journal of Human Genetics. 2026/01/01 2026;71(1):41-48. doi:10.10 38/s10038-025-01402-5
45. Chaisson MJP, Sanders AD, Zhao X, et al. Multi-platform discovery of haplotype-resolved structural variation in human genomes. Article. Nat Commun. Apr 16 2019;101784. doi:10.1038/s414 67-018-08148-z
46. Puig M, Casillas S, Villatoro S, Caceres M. Human inversions and their functional consequences. Article. Briefings in Functional Genomics. Sep 2015;14(5):369-379. doi:10.1093/bfgp/elv020
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