A chromosomal inversion is a structural rearrangement in which a segment of a chromosome breaks at two points and reattaches within the same chromosome in the reverse orientation, potentially without loss of genetic material.[1] This reversal alters the order of genes along the chromosome but typically preserves the overall DNA content unless fragments are lost at the breakpoints.[2]Inversions are categorized into two primary types based on their position relative to the centromere: paracentric inversions, which occur entirely on one arm of the chromosome (either the short p arm or the long q arm) and exclude the centromere, and pericentric inversions, which span the centromere and can alter the relative lengths of the chromosome arms.[2] Paracentric inversions are more common in many organisms, while both types are frequently associated with underdominance, reducing heterozygote fitness due to meiotic complications.[3]During meiosis in heterozygous individuals, inversions suppress recombination within the inverted segment, as crossing over can produce gametes with duplications and deletions, leading to inviable offspring and decreased fertility.[3] Evolutionarily, inversions facilitate adaptation by linking beneficial alleles into "supergene" blocks that resist breakdown through recombination, contributing to traits like ecotype differentiation in species such as deer mice and speciation events in plants and animals.[4][3] In humans, while most inversions are benign polymorphisms, those disrupting critical genes can cause developmental disorders or increase susceptibility to conditions like hemophilia or certain cancers, depending on the size, location, and genes affected.[2]
Definition and Classification
Definition
A chromosomal inversion is a structural rearrangement in which a segment of a chromosome breaks at two points, and the intervening portion is reinserted in the reverse orientation relative to the original sequence, effectively rotating it 180 degrees end-to-end.[1][5] This process involves the formation of two double-strand breaks in the DNA, followed by the re-ligation of the fragments in an inverted configuration, preserving the overall chromosome length but altering the linear order of genes within the affected region.[3]Inversions are balanced rearrangements with no net gain or loss of genetic material, meaning the carrier retains a complete set of genes despite the reversal, which can occur somatically or in the germline without immediate phenotypic effects.[5]The size of inversions varies widely, from small-scale events spanning as little as 1 kilobase (kb) of DNA and affecting only a few genes, to large-scale inversions covering up to 100 megabases (Mb) and impacting hundreds of genes across entire chromosome arms.[6] These rearrangements occur across eukaryotes, including in humans where an average genome harbors 117–156 inversions, and in model organisms like Drosophila melanogaster, where they have been extensively studied for their roles in genetic variation.[7][8] Inversions are further distinguished as paracentric, which do not include the centromere, or pericentric, which do.[9]
Types
Chromosomal inversions are primarily classified into two types based on their positional relationship to the centromere: paracentric and pericentric. These classifications arise from the location of the breakpoints that define the inverted segment, influencing the overall structure of the chromosome while maintaining a balanced rearrangement with no net loss or gain of genetic material.[10]Paracentric inversions involve two breakpoints within a single chromosome arm, excluding the centromere entirely. This type thus confines the reversal to either the short (p) arm or the long (q) arm, preserving the centromere's position and the chromosome's overall morphology.[11][12]In contrast, pericentric inversions encompass the centromere, with one breakpoint in the p arm and the other in the q arm. Such inversions can alter chromosome morphology by changing the relative lengths of the arms or the arm ratio, potentially affecting banding patterns visible under cytogenetic analysis.[10][13] While paracentric inversions do not shift the centromere or substantially modify chromosome length, pericentric ones may lead to noticeable changes in these features, distinguishing their structural impacts.[11]Inversions are typically intrachromosomal, occurring within a single chromosome; interchromosomal variants, which would involve segments from different chromosomes, are exceedingly rare and generally classified under other rearrangement types rather than true inversions.[1][14]
Formation and Mechanisms
Molecular Mechanisms
Chromosomal inversions primarily arise from double-strand breaks (DSBs) in DNA that are repaired through error-prone mechanisms, leading to the reversal of a chromosomal segment. One key pathway involves non-homologous end joining (NHEJ), where DSB ends are directly ligated without a homologous template, often resulting in blunt joins or small deletions/insertions at breakpoints. In cases where short microhomologies (1-6 bp) are present at the break sites, microhomology-mediated end joining (MMEJ), a variant of alternative end joining, facilitates repair by annealing complementary sequences, which can invert the intervening segment if breaks occur in an appropriate orientation. Studies of human inversions resolved by whole-genome sequencing have shown that approximately 62% exhibit signatures of NHEJ or MMEJ, such as nucleotide losses or microhomology usage, underscoring their prevalence in cytogenetically visible inversions.[15][16][15]Another prominent mechanism is ectopic recombination, particularly non-allelic homologous recombination (NAHR) between repetitive DNA sequences oriented in inverted directions. This process occurs when homologous but non-allelic repeats, such as transposons or Alu elements, misalign during meiosis or mitosis, prompting crossover that inverts the enclosed genomic region. For instance, in Drosophila buzzatii, the Galileo transposon has been documented to generate natural inversions through ectopic recombination between oppositely oriented copies, leaving chimeric target site duplications at breakpoints. In humans, Alu/Alu recombination accounts for a subset of inversions, though overall, NAHR contributes to only about 33% of resolved cases, often in regions with low-copy repeats. Transposable elements (TEs), including LINEs and SINEs, further promote this by providing substrates for misalignment, as seen in tandem TE insertions mediating inversions across species.[15][17][15]Replication errors also play a role, especially in smaller inversions, through mechanisms like fork stalling and template switching (FoSTeS). During DNA replication, stalling at repetitive or difficult-to-replicate regions can cause the replication fork to switch to a nearby template in an inverted orientation, resulting in inversion of the replicated segment. This process, often coupled with microhomology-mediated break-induced replication (MMBIR), generates complex rearrangements including inversions with templated insertions or copy-number variants. Analysis of human inversion breakpoints indicates that 38% involve FoSTeS/MMBIR signatures, particularly for inversions under 10 kb, highlighting its contribution to submicroscopic variants.[18][15][18]The genomic architecture significantly influences inversion hotspots, with breakpoints frequently clustering in regions rich in low-copy repeats (LCRs), segmental duplications, or palindromic sequences that predispose to breakage and misalignment. Segmental duplications, sharing >90% identity over >1 kb, are enriched at inversion boundaries—up to 50% of cases show elevated density compared to the genomic average—facilitating NAHR or DSB formation via replication stress. Palindromic AT-rich regions, prone to secondary structures, further elevate risk by stalling replication forks or inducing DSBs, as observed in both human and rodent genomes. These architectural features create vulnerability points, explaining the non-random distribution of inversions across chromosomes.[16][18][16]
Causes and Frequency
Chromosomal inversions can arise from mutagenic causes that induce double-strand breaks in DNA, leading to erroneous rejoining of chromosome segments. Exposure to ionizing radiation, such as X-rays, has been shown to produce paracentric inversions in mammalian germ cells by causing chromosome breakage and subsequent repair errors.[19] Similarly, certain chemicals, including alkylating agents, generate DNA lesions that increase the rate of chromosomal rearrangements, including inversions, through mechanisms like non-homologous end joining.[20]Endogenous factors contribute significantly to inversion formation by promoting DNA damage or repair inaccuracies during cellular processes. Defects in DNA repair pathways, such as those involving BRCA1 and BRCA2 genes, lead to genomic instability and an elevated incidence of inversions alongside other rearrangements like duplications.[21] Additionally, errors at meiotic recombination hotspots can result in inversions through aberrant crossover events or stalled replication forks that necessitate error-prone repair.[22]The frequency of chromosomal inversions varies across populations and genomes, reflecting both spontaneous and induced origins. In humans, large inversions are detected in approximately 1-2 per 1,000 prenatal cytogenetic analyses, though polymorphic inversions affecting up to 0.6% of the genome occur at rates of 2.7 × 10⁻⁴ per locus per generation in recurrent hotspots.[10][23] Inversions are more prevalent in organisms with highly repetitive genomes, such as plants, where repetitive sequences facilitate misalignment and repair errors, leading to accumulation rates of 4-28 inversions per million generations.[24][25]In terms of organismal variation, inversions occur more frequently and often persist as adaptive polymorphisms in species like Drosophila, where they form clines and seasonal fluctuations in frequency due to selective advantages in heterogeneous environments.[26] In contrast, mammals, including humans, exhibit lower frequencies of fixed inversions, with many being deleterious and associated with reduced fertility or disease rather than adaptation.[27]
Detection
Cytogenetic Methods
Cytogenetic methods rely on microscopic visualization of chromosomes to identify structural rearrangements such as inversions, which appear as reversals in the order of chromosomal bands or segments. These techniques are particularly useful for detecting large-scale inversions that alter chromosomemorphology, such as pericentric inversions that may change arm ratios.Karyotyping, a foundational cytogenetic approach, involves staining and arranging chromosomes from a cell sample to reveal banding patterns. G-banding, achieved by treating chromosomes with Giemsa stain after trypsin exposure, highlights light and dark bands that correspond to euchromatin and heterochromatin regions, allowing detection of inversions through disrupted or reversed band sequences along the chromosome arms. Similarly, C-banding targets constitutive heterochromatin, which is enriched in centromeric and telomeric regions, and can reveal inversions involving these areas by showing altered staining patterns in pericentric regions. These methods typically resolve inversions spanning several megabases, providing a visual map of chromosomal architecture during metaphase.Fluorescence in situ hybridization (FISH) enhances karyotyping by using fluorescently labeled DNA probes that bind to specific chromosomal loci, enabling precise mapping of inversion breakpoints. In inversion detection, probes are designed to flank the suspected rearrangedregion; a normal chromosome shows two distinct signals, while an inverted one displays signals in reversed orientation or proximity, confirming the span and orientation of the inversion. This technique is especially valuable for validating suspected inversions observed in banding patterns, offering higher specificity for heterozygous carriers where subtle changes might be overlooked.Chromosomal painting employs multiplex FISH with chromosome-specific probes to label entire chromosomes or segments in different colors, facilitating comparative analysis across species or individuals. This method detects fixed inversions by revealing differences in probe hybridization patterns, such as reversed colocalization of painted regions, which indicate evolutionary or polymorphic inversions. It is particularly applied in cytogenetic studies of speciation, where interspecies hybrids show asynaptic regions or loops during meiosis due to inversion heterozygosity.Despite their utility, cytogenetic methods have inherent limitations in resolution and sensitivity. They primarily detect large inversions exceeding 5 megabases, as smaller rearrangements may not produce visible banding disruptions or signal changes without additional phenotypic indicators like abnormal morphology. Balanced inversions, which do not alter chromosome length or number, often require complementary techniques for confirmation if no overt cytological anomalies are present.
Genomic and Molecular Techniques
Whole-genome sequencing (WGS) has become a cornerstone for detecting chromosomal inversions at high resolution by leveraging signatures of structural variation in sequencing data. Discordant read pairs, where the mapped distance or orientation between paired reads deviates from expectations, indicate potential inversion breakpoints by spanning the rearranged regions. Split reads, which align partially to one location and partially to another across the breakpoint, provide precise nucleotide-level mapping of inversion junctions. These approaches are particularly effective for identifying inversions larger than the read length, with tools like those implemented in NGS pipelines enabling robust detection across diverse genomes.[28][29][30]Long-read sequencing technologies, such as Pacific Biosciences (PacBio) HiFi and Oxford Nanopore Technologies (ONT), excel at resolving complex inversions within repetitive genomic regions where short-read methods falter. These platforms generate reads spanning kilobases to megabases, allowing direct visualization and breakpoint delineation of inversions embedded in tandem repeats or segmental duplications. For instance, ONT has been used to fine-map inversion breakpoints disrupting genes like MEIS2, confirming structural changes with base-pair precision. PacBio and ONT together enhance structural variant calling in challenging loci, improving sensitivity for clinically relevant inversions.[31][32][33]In population genomics, linkage disequilibrium (LD) patterns serve as indirect signatures to infer inversion polymorphisms, as inversions suppress recombination and create extended haplotype blocks with reduced heterozygosity across the rearranged segment. Genome-wide SNP data reveal these signatures, enabling the genotyping of inversion carriers without direct breakpoint sequencing, particularly for common variants in natural populations. Recent advances have improved detection of small inversions under 1 kb through split-read analysis in short-read sequencing and long-read technologies. These developments, highlighted in comprehensive reviews of inversion genomics, have expanded the catalog of cryptic variants in eukaryotic genomes.[34][35]
Biological Effects
Impacts on Meiosis and Recombination
In individuals heterozygous for a chromosomal inversion, homologous chromosomes must form an inversion loop during synapsis in meiosis I to achieve proper pairing of the inverted segment with its normal counterpart.[36] This loop structure disrupts normal alignment, leading to suppression of recombination within the inverted region to prevent the production of unbalanced gametes that would result from crossing over.[3] Without this suppression, crossovers inside the loop generate structurally abnormal chromosomes, which are typically inviable or lead to gametic lethality.[37]The consequences of recombination differ between paracentric and pericentric inversions. In paracentric inversions, which do not involve the centromere, a single crossover within the inversion loop produces one dicentric chromatid (forming a bridge at anaphase) and one acentric fragment, resulting in gametes with duplications and deletions of genetic material.[36] These abnormal products are excluded from viable gametes, effectively halving the number of functional spores or gametes if a crossover occurs.[38] In pericentric inversions, which encompass the centromere, crossovers within the loop yield gametes with duplications and deletions but without dicentric bridges or acentric fragments; instead, the unbalanced chromosomes segregate unevenly, producing recombinant gametes that carry partial trisomy or monosomy for the inverted segments.[3] Double crossovers can sometimes restore balance, but single or odd-numbered crossovers predominate in causing inviability.[37]Overall, inverted segments act as barriers to recombination in heterozygotes, dramatically reducing crossover rates—often to near zero for large inversions—compared to homozygous regions.[3] This suppression preserves co-adapted gene complexes by preventing the breakup of linked alleles that have evolved together, maintaining their integrity across generations.[3] In terms of gamete viability, heterozygotes for inversions theoretically produce approximately 50% unbalanced gametes if recombination occurs within the inverted region, though actual rates are lower due to the strong selective pressure against such events during meiosis.[38]
Phenotypic and Fertility Consequences
Balanced carriers of chromosomal inversions are typically phenotypically normal, as the rearrangement does not alter the total genetic content.[11] However, these individuals face an elevated risk of producing unbalanced gametes during meiosis, which can result in offspring with aneuploidy, including partial trisomies or monosomies that often lead to miscarriage or congenital anomalies.[39] For instance, in human carriers of pericentric inversions, the risk of chromosomal imbalance in offspring is estimated at 5-10%, with many such pregnancies ending in spontaneous abortion at higher rates than the general population.[40]Unbalanced inversions, arising from recombination in parental carriers, produce recombinant chromosomes that cause partial trisomy or monosomy of chromosomal segments, leading to distinct syndromes characterized by developmental delays, intellectual disability, and physical malformations.[41] These recombinant abnormalities disrupt gene dosage and function, resulting in viable but affected offspring in a subset of cases, though most unbalanced products are inviable and contribute to early pregnancy loss.[11] The severity of the phenotype depends on the size of the duplicated or deleted segment and the genes involved, with larger imbalances more likely to cause profound health issues.Fertility in inversion heterozygotes is often reduced due to the production of inviable gametes from unbalanced recombination within the inverted region, a phenomenon known as semisterility.[42] This effect is particularly pronounced in organisms like Drosophila melanogaster, where pericentric inversion heterozygotes exhibit approximately 50% gamete inviability, and in plants such as maize, where heterozygous inversions lead to partial pollen sterility that varies with inversion size and centromere proximity.[42] In humans, the impact is subtler but manifests as decreased fecundity and higher miscarriage rates, with the degree of fertility impairment scaling with the inversion's length and position relative to recombination hotspots.[39]Clinically, chromosomal inversions warrant prenatal screening in carriers, particularly through invasive diagnostics like amniocentesis or chorionic villus sampling when a familial inversion is identified, to detect unbalanced rearrangements in the fetus.[43] Recent studies from 2024-2025 have linked de novo or inherited inversions that disrupt key neurodevelopmental genes—such as SHANK2 or ARID1B—to disorders including intellectual disability, autism spectrum features, and speech delays, emphasizing the need for genomic evaluation in affected individuals.[44][45] These findings highlight inversions' role in gene disruption as a underrecognized contributor to neurodevelopmental phenotypes, informing targeted counseling and testing protocols.
Evolutionary Implications
Role in Adaptation and Speciation
Chromosomal inversions play a pivotal role in adaptation by suppressing recombination within inverted regions, thereby locking together co-adapted alleles that confer fitness advantages in specific environments. This mechanism allows populations to maintain adaptive gene complexes despite gene flow from neighboring populations, facilitating rapid evolutionary responses to selective pressures such as varying temperatures or dietary resources. For instance, in scenarios where migrants introduce maladapted alleles, inversions can drive the spread of locally beneficial variants to high frequency, enhancing survival and reproduction in heterogeneous habitats.[46]Inversions have been linked to adaptive traits in pest management, such as insecticide resistance in malaria mosquitoes (Anopheles spp.), where at least 49 inversions, including smaller ones, have been associated with traits like polymorphisms such as 2La that enhance tolerance to pyrethroids and other chemicals through linked metabolic genes, complicating vector control efforts.[47] Recent advances from 2023 to 2025 underscore the adaptive significance of inversions in plant evolution, where they bridge microevolutionary adaptation—such as local fitness variation in Mimulus guttatus—to macroevolutionary speciation, as seen in sunflowers (Helianthus spp.) where they drive hybrid speciation and ecological divergence via recombination suppression and sterility barriers.[48]In the context of speciation, inversions contribute to reproductive isolation by generating hybrid dysfunction in heterozygotes, where suppressed recombination leads to reduced fertility or viability, thereby limiting gene flow between diverging populations. This effect is particularly pronounced in inversion heterozygotes, promoting the accumulation of Dobzhansky-Muller incompatibilities and accelerating lineage divergence. Recent studies highlight parallel evolution driven by inversions, such as in seaweed flies (Coelopa frigida), where the Cf-Inv(4.1) inversion exhibits latitudinal clines correlated with thermal variation across continents, maintaining polymorphism and aiding ecotype specialization without direct evidence of speciation but implying reduced gene flow.[46][49]Inversions also form supergenes that stabilize complex traits under conflicting selection. For mimicry, the P locus inversion in Heliconius numata butterflies maintains wing-pattern polymorphism through antagonistic frequency-dependent selection, where natural selection favors common morphs for predator avoidance while sexual selection promotes rare morphs via disassortative mating, preserving diversity. Similarly, inversions accumulate sexually antagonistic alleles, creating supergenes that balance fitness trade-offs between sexes; simulations and Drosophila melanogaster experiments demonstrate how inversions like ln(3R)K link survival benefits in females with reproductive advantages in males, sustaining polymorphism at predictable frequencies.[50][51]
Historical Development and Models
The discovery of chromosomal inversions traces back to 1921, when Alfred H. Sturtevant identified the first example in Drosophila melanogaster through genetic linkage mapping, revealing a rearrangement that altered gene order and suppressed recombination between certain loci.[3] This breakthrough, based on comparing chromosome maps across Drosophila species, established inversions as a mechanism for structural variation in genomes and highlighted their role in generating linkage disequilibrium.[52] Sturtevant's work laid the foundation for understanding how such rearrangements could influence inheritance patterns, particularly in model organisms like Drosophila, which became central to early genetic studies.[53]In the mid-20th century, cytogenetic approaches expanded the study of inversions beyond insects to plants and mammals, with researchers employing chromosome banding and karyotyping to document polymorphic inversions in species such as maize and various rodents.[54] Theodosius Dobzhansky's investigations in the 1930s and 1940s further advanced the field by demonstrating widespread inversion polymorphisms in natural Drosophila populations, linking them to geographic clines and adaptive variation through analysis of polytene chromosomes in salivary glands.[55] These studies emphasized inversions' prevalence and their potential to maintain genetic diversity, influencing population genetics theory during this era.[56]Theoretical modeling of inversions gained momentum with the 2006 work of Mark Kirkpatrick and Nick Barton, who developed a framework showing how inversions could facilitate adaptive fixation by capturing co-adapted gene complexes and reducing recombination in hybridizing populations, thereby promoting local adaptation and potentially speciation.[57] More recent models, from 2023 to 2025, have incorporated the effects of deleterious mutations and sexual antagonism on fixation probabilities; for instance, simulations demonstrate that partially recessive deleterious alleles can increase the likelihood of inversion spread by sheltering them from purging, while balanced sexual antagonism—where alleles benefit one sex but harm the other—can sustain polymorphism or drive fixation in sex-linked contexts.[58][59]
Nomenclature
Standards and Notation
The International System for Human Cytogenomic Nomenclature (ISCN) provides a standardized framework for describing chromosomal inversions in human karyotypes, using the prefix "inv" followed by the chromosome number and breakpoints in parentheses.[60] For example, a pericentric inversion on chromosome 9 with breakpoints at bands p11 and q13 is denoted as 46,XX,inv(9)(p11q13), indicating a female karyotype with the inversion spanning the centromere. This notation specifies the type of inversion—paracentric if both breakpoints are on the same arm (p or q), or pericentric if on opposite arms—based on the band designations.[60]Band-level annotation in ISCN relies on G-banding patterns to identify breakpoints, with chromosomes oriented from the short arm telomere (pter) to the long arm telomere (qter) for consistent description.[61] Breakpoints are denoted using region, band, and sub-band levels (e.g., p21.1 for the first sub-band of region 2 on the p arm), ensuring precise localization relative to centromeric and telomeric ends.[60] This hierarchical system facilitates unambiguous reporting in cytogenetic analyses.In genomic and molecular contexts, inversions are described using nucleotide coordinates from reference assemblies like GRCh38, often following Human Genome Variation Society (HGVS) recommendations, such as NC_000009.12:g.100000_200000inv for an inversion on chromosome 9 between positions 100000 and 200000.[62] This format specifies the inverted segment's start and end positions in the forward (5' to 3') orientation, integrating seamlessly with sequencing data and variant call formats.[63]Species-specific adaptations exist for non-human organisms; in Drosophila melanogaster, inversions are denoted as In(chromosome arm)designator, such as In(2L)t for a paracentric inversion on the left arm of chromosome 2 identified by the "t" marker.[64] This convention, maintained by FlyBase, uses numeric chromosome identifiers, arm letters (L for left, R for right), and unique alphanumeric designators to track polymorphic inversions.[64]
Application in Research
Chromosomal inversion nomenclature plays a crucial role in integrating structural variant annotations within major genomic databases, facilitating the identification and cataloging of polymorphic inversions across populations. In the UCSC Genome Browser, inversions are annotated using tracks such as the HPRC Inversions summary, which visualizes inversion locations and frequencies in human reference genomes like hg38, enabling researchers to query breakpoint coordinates and haplotype associations directly from the interface.[65] Similarly, Ensembl's Variant Effect Predictor (VEP) classifies inversions as a distinct structural variant type, incorporating them into variation databases with standardized allele descriptions and overlap predictions against genes and regulatory elements, supporting automated annotation pipelines for large-scale genomic datasets.[66]The standardized nomenclature enhances research utility by providing consistent reporting frameworks in population genetics and comparative genomics studies. For instance, the "inv" designation from the International System for Cytogenomic Nomenclature (ISCN), including precise nucleotide breakpoints (e.g., inv(16)(p13.11q22.1)(15,709,259_67,088,566)), allows for unambiguous tracking of inversion haplotypes across diverse cohorts, as seen in analyses of brain morphology variations linked to inversion polymorphisms.[63][7] This uniformity aids in comparative studies, where inversion orientations and frequencies are compared between species to infer evolutionary histories, reducing errors in haplotype reconstruction from SNP data.Despite these advances, challenges persist in nomenclature, particularly for small inversions, where ambiguities arise from imprecise breakpoint resolution and overlapping classifications with other variants like translocations.[67] Length-based definitions often lead to inconsistencies, as small inversions (<50 bp) are underrepresented in annotations due to detection limitations in short-read sequencing. Recent proposals from 2024, such as graph-based phasing methods for diploid assemblies, advocate for phased notation in long-read data to explicitly denote haplotype-specific inversion states (e.g., distinguishing inverted alleles on maternal vs. paternal chromosomes), improving accuracy in heterozygous contexts.[68]In evolutionary studies, ISCN-based nomenclature has been adapted for non-human organisms to enable cross-species comparisons. For example, in mice, the Mouse Genome Informatics (MGI) guidelines use symbols like In(1)1Rk to denote inversions on specific chromosomes, incorporating lab codes and endpoint distinctions (proximal/distal) for tracking in population and breeding research.[69] These adaptations facilitate the annotation of inversions in model organisms like Drosophila or plants, where similar breakpoint-inclusive formats support analyses of adaptive polymorphisms without relying on human-centric standards.[63]
Notable Examples
In Animals
In Drosophila melanogaster, the inversion In(3R)Payne, also known as 3RP, plays a key role in seasonal adaptation by influencing clinal variation in allele frequencies that respond to climatic gradients, with its prevalence fluctuating temporally to enhance fitness under varying environmental conditions.[70][71] This inversion, along with other polymorphic inversions such as In(2L)t and In(3R)Mo, maintains balanced polymorphisms that affect multiple fitness components, including viability, fecundity, and resistance to environmental stressors, often through suppressed recombination that preserves adaptive gene complexes.[72][26] These inversions contribute to local adaptation by linking ecologically relevant traits, demonstrating how structural variants can drive population-level responses to selective pressures without direct phenotypic disruption.[73]In humans, the pericentric inversion inv(9)(p11q13) is one of the most common structural variants, occurring in approximately 1-3% of the population and generally classified as a benign heteromorphism with no significant impact on carrier fertility or health.[74][75] In contrast, the pericentric inversion inv(8)(p23.1q22.1) carries reproductive risks, as heterozygous carriers face approximately a 6% chance of producing offspring with recombinant chromosome 8 [rec(8)], leading to recombinant 8 syndrome characterized by intellectual disability, congenital heart defects, and urogenital anomalies due to unbalanced duplication and deletion of chromosomal segments.[76][77] This syndrome arises from crossover events within the inversion loop during meiosis, highlighting the potential for inversions to generate viable but deleterious gametes.[78]In the malaria vector Anopheles gambiae, the paracentric inversion 2La is strongly associated with insecticide resistance, particularly to pyrethroids and organochlorines, by capturing alleles that enhance detoxificationenzyme expression and reduce susceptibility, thereby aiding vector survival in sprayed environments.[47] Studies have shown that 2La is associated with adaptive traits beyond resistance, including thermal tolerance through gene expression modulation and desiccation resistance, supporting ecological diversification across African habitats.[79][80] This inversion's fixation in certain populations underscores its role in suppressing maladaptive recombination, promoting the spread of resistance haplotypes amid intensifying vector control efforts.[81]Additional examples include diet-linked inversions in Drosophila species, where a 2025 study identified a novel inversion on chromosome 2 associated with metabolic adaptation to varying nutritional environments, influencing lipid and carbohydrate processing genes to optimize fitness on high-sugar or protein-restricted diets.[82] In mammals, pericentric inversions on the Y chromosome have driven evolutionary restructuring, such as in primates where an ancient inversion disrupted pseudoautosomal regions, accelerating Y-specific degeneration while preserving spermatogenesis genes through reduced recombination with the X chromosome.[83][84] These events illustrate how inversions facilitate sex chromosomeevolution by stabilizing male-biased gene functions against deleterious mutations.
In Plants and Other Organisms
Chromosomal inversions have been documented in various plant species, often playing key roles in adaptation, speciation, and sex determination. In Arabidopsis thaliana, de novo genome assembly of the Ler-0 strain revealed 47 inversions relative to the Col-0 reference, with one notable 1.17 Mb inversion on chromosome 4 encompassing 186 genes and showing signatures of divergent selection linked to fecundity under drought conditions.[24][85] This inversion, estimated at around 5,000 years old, highlights how structural variants can rapidly influence environmental responses in model plants.[85]In maize (Zea mays), a large 50 Mb pericentric inversion on chromosome 1, known as Inv1n-I and Inv1n-S, spans approximately 700 genes and exhibits clinal variation along altitudinal gradients, associating with adaptive traits like flowering time and stresstolerance.[85] This inversion, dated to about 296,000 years ago, suppresses recombination to maintain co-adapted allele combinations beneficial for highland versus lowland environments.[85] Similarly, in rice (Oryza sativa and wild relatives), widespread inversions contribute to genetic diversity; a prominent 6 Mb inversion on chromosome 6 in Australian wild rice (O. rufipogon) aligns with domestication sweeps and phenotypic divergence.[86] Two large inversions in cultivated rice further suppress recombination, fixing key agronomic traits like semi-dwarfism.[87]Inversions also drive ecological speciation in wild sunflowers (Helianthus petiolaris and H. annuus), where multiple large inversions—ranging from 1.4 Mb to 235 Mb across 10 linkage groups and involving 75 to 1,387 genes—reduce gene flow and capture adaptive loci for traits such as seed size and nutrient tolerance in dune habitats.[24][85] These structures, originating around 1.5 million years ago, facilitate hybrid speciation under divergent selection.[85] In monkeyflower (Mimulus guttatus), a 6 Mb inversion (DIV1) on chromosome 8 affects 362 genes and correlates with flowering time and life-history shifts between annual and perennial ecotypes, promoting reproductive isolation.[85]Papaya (Carica papaya) features two large inversions defining non-recombining regions on X and Y chromosomes, essential for sex determination and chromosome evolution.[24]Beyond plants, inversions occur in algae and fungi, often linked to mating systems. In the green alga Chlamydomonas reinhardtii, the mating-type (MT) locus on the mitochondrial chromosome includes two inversions and four translocations within a 1.1 Mb region, suppressing recombination to maintain mating-type alleles and prevent selfing.[88] This structure underscores inversions' role in algal sexual evolution. In fungi, small inversions are common; for instance, in Saccharomyces sensu stricto yeasts, pervasive micro-inversions (spanning few genes) alter gene order and expression, contributing to species divergence without large fitness costs.[89] Filamentous fungi like Aspergillus exhibit high inversion frequencies, with mesosynteny preserved across distantly related species due to recurrent inversions that reshape chromosomes while conserving gene content.[90] These examples illustrate inversions' conserved function in non-animal eukaryotes for modulating recombination and adaptation.