Investigation of inversion polymorphisms in the human genome using principal components analysis

Despite the significant advances made over the last few years in mapping inversions with the advent of paired-end sequencing approaches, our understanding of the prevalence and spectrum of inversions in the human genome has lagged behind other types of structural variants, mainly due to the lack of a cost-efficient method applicable to large-scale samples. We propose a novel method based on principal components analysis (PCA) to characterize inversion polymorphisms using high-density SNP genotype data. Our method applies to non-recurrent inversions for which recombination between the inverted and non-inverted segments in inversion heterozygotes is suppressed due to the loss of unbalanced gametes. Inside such an inversion region, an effect similar to population substructure is thus created: two distinct "populations" of inversion homozygotes of different orientations and their 1:1 admixture, namely the inversion heterozygotes. This kind of substructure can be readily detected by performing PCA locally in the inversion regions. Using simulations, we demonstrated that the proposed method can be used to detect and genotype inversion polymorphisms using unphased genotype data. We applied our method to the phase III HapMap data and inferred the inversion genotypes of known inversion polymorphisms at 8p23.1 and 17q21.31. These inversion genotypes were validated by comparing with literature results and by checking Mendelian consistency using the family data whenever available. Based on the PCA-approach, we also performed a preliminary genome-wide scan for inversions using the HapMap data, which resulted in 2040 candidate inversions, 169 of which overlapped with previously reported inversions. Our method can be readily applied to the abundant SNP data, and is expected to play an important role in developing human genome maps of inversions and exploring associations between inversions and susceptibility of diseases.     

Molecular,genetic and evolutionary analysis of a paracentric inversion in Arabidopsis thaliana

Chromosomal inversions can provide windows onto the cytogenetic, molecular, evolutionary and demographic histories of a species. Here we investigate a paracentric 1.17‐Mb inversion on chromosome 4 of Arabidopsis thaliana with nucleotide precision of its borders. The inversion is created by Vandal transposon activity, splitting an F‐box and relocating a pericentric heterochromatin segment in juxtaposition with euchromatin without affecting the epigenetic landscape. Examination of the RegMap panel and the 1001 Arabidopsis genomes revealed more than 170 inversion accessions in Europe and North America. The SNP patterns revealed historical recombinations from which we infer diverse haplotype patterns, ancient introgression events and phylogenetic relationships. We find a robust association between the inversion and fecundity under drought. We also find linkage disequilibrium between the inverted region and the early flowering Col‐FRIGIDA allele. Finally, SNP analysis elucidates the origin of the inversion to South‐Eastern Europe approximately 5000 years ago and the FRI‐Col allele to North‐West Europe, and reveals the spreading of a single haplotype to North America during the 17th to 19th century. The ‘American haplotype’ was identified from several European localities, potentially due to return migration.     

Haplotypes of single cancer driver genes and their local ancestry in a highly admixed long-lived population of Northeast Brazil

Admixed populations have not been examined in detail in cancer genetic studies. Here, we inferred the local ancestry of cancer-associated single nucleotide polymorphisms (SNPs) and haplotypes of a highly admixed Brazilian population. SNP array was used to genotype 73 unrelated individuals aged 80-102 years. Local ancestry inference was performed by merging genotyped regions with phase three data from the 1000 Genomes Project Consortium using RFmix. The average ancestry tract length was 9.12-81.71 megabases. Strong linkage disequilibrium was detected in 48 haplotypes containing 35 SNPs in 10 cancer driver genes. All together, 19 risk and eight protective alleles were identified in 23 out of 48 haplotypes. Homozygous individuals were mainly of European ancestry, whereas heterozygotes had at least one Native American and one African ancestry tract. Native-American ancestry for homozygous individuals with risk alleles for HNF1B, CDH1, and BRCA1 was inferred for the first time. Results indicated that analysis of SNP polymorphism in the present admixed population has a high potential to identify new ancestry-associated alleles and haplotypes that modify cancer susceptibility differentially in distinct human populations. Future case-control studies with populations with a complex history of admixture could help elucidate ancestry-associated biological differences in cancer incidence and therapeutic outcomes.     

Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation

The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)-gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome.     

Nucleotide,Cytogenetic and Expression Impact of the Human Chromosome 8p23.1 Inversion Polymorphism

Background

The human chromosome 8p23.1 region contains a 3.8–4.5 Mb segment which can be found in different orientations (defined as genomic inversion) among individuals. The identification of single nucleotide polymorphisms (SNPs) tightly linked to the genomic orientation of a given region should be useful to indirectly evaluate the genotypes of large genomic orientations in the individuals.

Results

We have identified 16 SNPs, which are in linkage disequilibrium (LD) with the 8p23.1 inversion as detected by fluorescent in situ hybridization (FISH). The variability of the 8p23.1 orientation in 150 HapMap samples was predicted using this set of SNPs and was verified by FISH in a subset of samples. Four genes (NEIL2, MSRA, CTSB and BLK) were found differentially expressed (p<0.0005) according to the orientation of the 8p23.1 region. Finally, we have found variable levels of mosaicism for the orientation of the 8p23.1 as determined by FISH.

Conclusion

By means of dense SNP genotyping of the region, haplotype-based computational analyses and FISH experiments we could infer and verify the orientation status of alleles in the 8p23.1 region by detecting two short haplotype stretches at both ends of the inverted region, which are likely the relic of the chromosome in which the original inversion occurred. Moreover, an impact of 8p23.1 inversion on gene expression levels cannot be ruled out, since four genes from this region have statistically significant different expression levels depending on the inversion status. FISH results in lymphoblastoid cell lines suggest the presence of mosaicism regarding the 8p23.1 inversion.     

IL12B and IL23R gene SNPs in Japanese psoriasis

Psoriasis is a common human skin disease whereby abnormal production of inflammatory mediators is believed to play an important role in its pathogenesis. The IL12B gene, which encodes the shared IL-12p40 subunit in two cytokines, IL-12 and IL-23, and the IL23R gene, which encodes a subunit of the receptor for IL-23, were identified as psoriasis-susceptibility genetic factors in recent candidate gene and genome-wide association studies of Chinese and Europeans. Since there are significant differences in the incidence of psoriasis between Europeans and Japanese suggesting a genetic ethnic effect, we examined the association of IL12B and IL23R gene polymorphisms with psoriasis in a cohort of Japanese. In this study, we genotyped two SNPs (rs3212227 and rs6887695) in the IL12B gene and one SNP (rs11209026) in the IL23R gene using 560 Japanese psoriasis cases and 560 controls and compared our results with those previously published for Europeans and Asians. Our study showed significant associations between psoriasis and both IL12B gene SNPs, rs3212227 (odds ratio (OR)?=?1.35, P?=?4.94E-04) and rs6887695 (OR?=?1.32, P?=?2.00E-03), but no significant association between psoriasis and the IL23R SNP, rs11209026. Furthermore, a significant haplotype association was found for the IL12B gene protective haplotype C-C (OR?=?0.71, P?=?1.84E-04) in Japanese, as previously elucidated in the studies of European ancestry.     

Investigation of the origins of human autosomal inversions

A significant proportion of both pericentric and paracentric inversions have recurrent breakpoints and so could either have arisen through multiple independent events or be identical by descent (IBD) with a single common ancestor. Of two common variant inversions previously studied, the inv(2)(p11q13) was genuinely recurrent while the inv(10)(p11.2q21.2) was IBD in all cases tested. Excluding these two variants we have ascertained 257 autosomal inversion probands at the Wessex Regional Genetics Laboratory. There were 104 apparently recurrent inversions, representing 35 different breakpoint combinations and we speculated that at least some of these had arisen on more than one occasion. However, haplotype analysis identified no recurrent cases among eight inversions tested, including the variant inv(5)(p13q13). The cases not IBD were shown to have different breakpoints at the molecular cytogenetic level. No crossing over was detected within any of the inversions and the founder haplotypes extended for variable distances beyond the inversion breakpoints. Defining breakpoint intervals by FISH mapping identified no obvious predisposing elements in the DNA sequence. In summary the vast majority of human inversions arise as unique events. Even apparently recurrent inversions, with the exception of the inv(2)(p12q13), are likely to be either derived from a common ancestor or to have subtly different breakpoints. Presumably the lack of selection against most inversions allows them to accumulate and disperse amongst different populations over time. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The Effect of Genomic Inversions on Estimation of Population Genetic Parameters from SNP Data

In recent years it has emerged that structural variants have a substantial impact on genomic variation. Inversion polymorphisms represent a significant class of structural variant, and despite the challenges in their detection, data on inversions in the human genome are increasing rapidly. Statistical methods for inferring parameters such as the recombination rate and the selection coefficient have generally been developed without accounting for the presence of inversions. Here we exploit new software for simulating inversions in population genetic data, invertFREGENE, to assess the potential impact of inversions on such methods. Using data simulated by invertFREGENE, as well as real data from several sources, we test whether large inversions have a disruptive effect on widely applied population genetics methods for inferring recombination rates, for detecting selection, and for controlling for population structure in genome-wide association studies (GWAS). We find that recombination rates estimated by LDhat are biased downward at inversion loci relative to the true contemporary recombination rates at the loci but that recombination hotspots are not falsely inferred at inversion breakpoints as may have been expected. We find that the integrated haplotype score (iHS) method for detecting selection appears robust to the presence of inversions. Finally, we observe a strong bias in the genome-wide results of principal components analysis (PCA), used to control for population structure in GWAS, in the presence of even a single large inversion, confirming the necessity to thin SNPs by linkage disequilibrium at large physical distances to obtain unbiased results.     

Direct evidence for suppression of recombination within two pericentric inversions in humans: a new sperm-FISH technique.

Crossover within a pericentric inversion produces reciprocal recombinant chromosomes that are duplicated/deficient for all chromatin distal to the breakpoints. In view of this fact, a new technique is presented for estimating the frequency of recombination within pericentric inversions. YAC probes were selected from within the q- and p-arm flanking regions of two human inversions, and two-color FISH analysis was performed on sperm from heterozygous inversion carriers. A total of 6,006 sperm were analyzed for chromosome 1 inversion (p31q12), and 3,168 were analyzed for chromosome 8 inversion (p23q22). Both inversions displayed suppression of crossing-over, although the amount of suppression differed between the two inversions. The recombination frequency of 13.1% recorded for chromosome 8 inversion was similar to the frequency of 11.4% previously estimated by the human/hamster-fusion method. For chromosome 1 inversion, the recombination frequency of 0. 4% reported here was below the limits of detection of the fusion technique. The simplicity of the FISH technique and the ease of scoring facilitate analysis of a sample-population size much larger than previously had been possible.     

The Effect of Inversion at 8p23 on BLK Association with Lupus in Caucasian Population

To explore the potential influence of the polymorphic 8p23.1 inversion on known autoimmune susceptibility risk at or near BLK locus, we validated a new bioinformatics method that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion in a Caucasian population. Methods: Principal components analysis (PCA) was performed using markers inside the inversion territory followed by k-means cluster analyses on 7416 European derived and 267 HapMaP CEU and TSI samples. A logistic regression conditional analysis was performed. Results: Three subgroups have been identified; inversion homozygous, heterozygous and non-inversion homozygous. The status of inversion was further validated using HapMap samples that had previously undergone Fluorescence in situ hybridization (FISH) assays with a concordance rate of above 98%. Conditional analyses based on the status of inversion were performed. We found that overall association signals in the BLK region remain significant after controlling for inversion status. The proportion of lupus cases and controls (cases/controls) in each subgroup was determined to be 0.97 for the inverted homozygous group (1067 cases and 1095 controls), 1.12 for the inverted heterozygous group (1935 cases 1717 controls) and 1.36 for non-inverted subgroups (924 cases and 678 controls). After calculating the linkage disequilibrium between inversion status and lupus risk haplotype we found that the lupus risk haplotype tends to reside on non-inversion background. As a result, a new association effect between non-inversion status and lupus phenotype has been identified ((p = 8.18×10⁻⁷, OR = 1.18, 95%CI = 1.10–1.26). Conclusion: Our results demonstrate that both known lupus risk haplotype and inversion status act additively in the pathogenesis of lupus. Since inversion regulates expression of many genes in its territory, altered expression of other genes might also be involved in the development of lupus.     

Megabase-scale inversion polymorphism in the wild ancestor of maize

Chromosomal inversions are thought to play a special role in local adaptation, through dramatic suppression of recombination, which favors the maintenance of locally adapted alleles. However, relatively few inversions have been characterized in population genomic data. On the basis of single-nucleotide polymorphism (SNP) genotyping across a large panel of Zea mays, we have identified an ～50-Mb region on the short arm of chromosome 1 where patterns of polymorphism are highly consistent with a polymorphic paracentric inversion that captures >700 genes. Comparison to other taxa in Zea and Tripsacum suggests that the derived, inverted state is present only in the wild Z. mays subspecies parviglumis and mexicana and is completely absent in domesticated maize. Patterns of polymorphism suggest that the inversion is ancient and geographically widespread in parviglumis. Cytological screens find little evidence for inversion loops, suggesting that inversion heterozygotes may suffer few crossover-induced fitness consequences. The inversion polymorphism shows evidence of adaptive evolution, including a strong altitudinal cline, a statistical association with environmental variables and phenotypic traits, and a skewed haplotype frequency spectrum for inverted alleles.     

Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies

With a draft genome-sequence assembly for the chimpanzee available, it is now possible to perform genome-wide analyses to identify, at a submicroscopic level, structural rearrangements that have occurred between chimpanzees and humans. The goal of this study was to investigate chromosomal regions that are inverted between the chimpanzee and human genomes. Using the net alignments for the builds of the human and chimpanzee genome assemblies, we identified a total of 1,576 putative regions of inverted orientation, covering more than 154 mega-bases of DNA. The DNA segments are distributed throughout the genome and range from 23 base pairs to 62 mega-bases in length. For the 66 inversions more than 25 kilobases (kb) in length, 75% were flanked on one or both sides by (often unrelated) segmental duplications. Using PCR and fluorescence in situ hybridization we experimentally validated 23 of 27 (85%) semi-randomly chosen regions; the largest novel inversion confirmed was 4.3 mega-bases at human Chromosome 7p14. Gorilla was used as an out-group to assign ancestral status to the variants. All experimentally validated inversion regions were then assayed against a panel of human samples and three of the 23 (13%) regions were found to be polymorphic in the human genome. These polymorphic inversions include 730 kb (at 7p22), 13 kb (at 7q11), and 1 kb (at 16q24) fragments with a 5%, 30%, and 48% minor allele frequency, respectively. Our results suggest that inversions are an important source of variation in primate genome evolution. The finding of at least three novel inversion polymorphisms in humans indicates this type of structural variation may be a more common feature of our genome than previously realized.     

Analysis of segmental duplications reveals a distinct pattern of continuation-of-synteny between human and mouse genomes

About 5% of the human genome consists of large-scale duplicated segments of almost identical sequences. Segmental duplications (SDs) have been proposed to be involved in non-allelic homologous recombination leading to recurrent genomic variation and disease. It has also been suggested that these SDs are associated with syntenic rearrangements that have shaped the human genome. We have analyzed 14 members of a single family of closely related SDs in the human genome, some of which are associated with common inversion polymorphisms at chromosomes 8p23 and 4p16. Comparative analysis with the mouse genome revealed syntenic inversions for these two human polymorphic loci. In addition, 12 of the 14 SDs, while absent in the mouse genome, occur at the breaks of synteny; suggesting a non-random involvement of these sequences in genome evolution. Furthermore, we observed a syntenic familial relationship between 8 and 12 breakpoint-loci, where broken synteny that ends at one family member resumes at another, even across different chromosomes. Subsequent genome-wide assessment revealed that this relationship, which we named continuation-of-synteny, is not limited to the 8p23 family and occurs 46 times in the human genome with high frequency at specific chromosomes. Our analysis supports a non-random breakage model of genomic evolution with an active involvement of segmental duplications for specific regions of the human genome. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Sequence-Level Analysis of the Major European Huntington Disease Haplotype

Huntington disease (HD) reflects the dominant consequences of a CAG-repeat expansion in HTT. Analysis of common SNP-based haplotypes has revealed that most European HD subjects have distinguishable HTT haplotypes on their normal and disease chromosomes and that ∼50% of the latter share the same major HD haplotype. We reasoned that sequence-level investigation of this founder haplotype could provide significant insights into the history of HD and valuable information for gene-targeting approaches. Consequently, we performed whole-genome sequencing of HD and control subjects from four independent families in whom the major European HD haplotype segregates with the disease. Analysis of the full-sequence-based HTT haplotype indicated that these four families share a common ancestor sufficiently distant to have permitted the accumulation of family-specific variants. Confirmation of new CAG-expansion mutations on this haplotype suggests that unlike most founders of human disease, the common ancestor of HD-affected families with the major haplotype most likely did not have HD. Further, availability of the full sequence data validated the use of SNP imputation to predict the optimal variants for capturing heterozygosity in personalized allele-specific gene-silencing approaches. As few as ten SNPs are capable of revealing heterozygosity in more than 97% of European HD subjects. Extension of allele-specific silencing strategies to the few remaining homozygous individuals is likely to be achievable through additional known SNPs and discovery of private variants by complete sequencing of HTT. These data suggest that the current development of gene-based targeting for HD could be extended to personalized allele-specific approaches in essentially all HD individuals of European ancestry.     

Chromosomal Inversions between Human and Chimpanzee Lineages Caused by Retrotransposons

The long interspersed element-1 (LINE-1 or L1) and Alu elements are the most abundant mobile elements comprising 21% and 11% of the human genome, respectively. Since the divergence of human and chimpanzee lineages, these elements have vigorously created chromosomal rearrangements causing genomic difference between humans and chimpanzees by either increasing or decreasing the size of genome. Here, we report an exotic mechanism, retrotransposon recombination-mediated inversion (RRMI), that usually does not alter the amount of genomic material present. Through the comparison of the human and chimpanzee draft genome sequences, we identified 252 inversions whose respective inversion junctions can clearly be characterized. Our results suggest that L1 and Alu elements cause chromosomal inversions by either forming a secondary structure or providing a fragile site for double-strand breaks. The detailed analysis of the inversion breakpoints showed that L1 and Alu elements are responsible for at least 44% of the 252 inversion loci between human and chimpanzee lineages, including 49 RRMI loci. Among them, three RRMI loci inverted exonic regions in known genes, which implicates this mechanism in generating the genomic and phenotypic differences between human and chimpanzee lineages. This study is the first comprehensive analysis of mobile element bases inversion breakpoints between human and chimpanzee lineages, and highlights their role in primate genome evolution.     

A fetus with recombinant of chromosome 8 inherited from her carrier father

Summary A pericentric inversion of chromosome 8, inv(8)(p23q22), in a male carrier resulted in an unbalanced recombinant, rec(8)dup q, inv(8)(p23q22), which was diagnosed prenatally. The features seen in the aborted fetus resembled the features seen in a previously affected child who received the identical recombinant from her carrier mother. In this particular inversion involving chromosome 8, both male and female carriers risk producing an unbalanced progeny. Different familial pericentric inversions are reviewed for the presence or absence of unbalanced recombinants.     

Two new balancer chromosomes on mouse chromosome 4 to facilitate functional annotation of human chromosome 1p

To facilitate genetic screens to identify and maintain recessive mutations that map to the short arm of human chromosome 1, we have utilized chromosome engineering to generate two mouse strains that carry large inversions on the distal region of mouse chromosome 4. The inversion intervals are 16 and 22 cM in size together they cover approximately half of chromosome 4. Since recombination between the wild-type and inversion chromosomes does not occur within these inversion intervals, mutant alleles of genes mapping to this region can be identified and maintained. Therefore, these inversion chromosomes work as balancer chromosomes. These inversions have the additional advantage that they are tagged with genes encoding the visible coat color markers tyrosinase and agouti, and therefore the dosage of the inversion chromosome (+/+, Inv/+, Inv/Inv) can be visually recognized. These inversion strains will be extremely useful for mutagenesis screens that focus on functional annotation of human chromosome 1p.     

Pre-Columbian origins of Native American dog breeds,with only limited replacement by European dogs,confirmed by mtDNA analysis

Dogs were present in pre-Columbian America, presumably brought by early human migrants from Asia. Studies of free-ranging village/street dogs have indicated almost total replacement of these original dogs by European dogs, but the extent to which Arctic, North and South American breeds are descendants of the original population remains to be assessed. Using a comprehensive phylogeographic analysis, we traced the origin of the mitochondrial DNA lineages for Inuit, Eskimo and Greenland dogs, Alaskan Malamute, Chihuahua, xoloitzcuintli and perro sín pelo del Peru, by comparing to extensive samples of East Asian (n = 984) and European dogs (n = 639), and previously published pre-Columbian sequences. Evidence for a pre-Columbian origin was found for all these breeds, except Alaskan Malamute for which results were ambigous. No European influence was indicated for the Arctic breeds Inuit, Eskimo and Greenland dog, and North/South American breeds had at most 30% European female lineages, suggesting marginal replacement by European dogs. Genetic continuity through time was shown by the sharing of a unique haplotype between the Mexican breed Chihuahua and ancient Mexican samples. We also analysed free-ranging dogs, confirming limited pre-Columbian ancestry overall, but also identifying pockets of remaining populations with high proportion of indigenous ancestry, and we provide the first DNA-based evidence that the Carolina dog, a free-ranging population in the USA, may have an ancient Asian origin.     

A comparison of the association between large haplotype blocks under selection and the presence/absence of inversions

Inversions may contribute to ecological adaptation and phenotypic diversity, and with the advent of “second” and “third” generation sequencing technologies, the ability to detect inversion polymorphisms has been enhanced dramatically. A key molecular consequence of an inversion is the suppression of recombination allowing independent accumulation of genetic changes between alleles over time. This may lead to the development of divergent haplotype blocks maintained by balancing selection. Thus, divergent haplotype blocks are often considered as indicating the presence of an inversion. In this paper, we first review the features of a 7.7 Mb inversion causing the Rose‐comb phenotype in chicken, as a model for how inversions evolve and directly affect phenotypes. Second, we compare the genetic basis for alternative mating strategies in ruff and timing of reproduction in Atlantic herring, both associated with divergent haplotype blocks. Alternative male mating strategies in ruff are associated with a 4.5 Mb inversion that occurred about 4 million years ago. In fact, the ruff inversion shares some striking features with the Rose‐comb inversion such as disruption of a gene at one of the inversion breakpoints and generation of a new allele by recombination between the inverted and noninverted alleles. In contrast, inversions do not appear to be a major reason for the fairly large haplotype blocks (range 10–200 kb) associated with ecological adaptation in the herring. Thus, it is important to note that divergent haplotypes may also be maintained by natural selection in the absence of structural variation.     

Population Genomics of Inversion Polymorphisms in Drosophila melanogaster

Chromosomal inversions have been an enduring interest of population geneticists since their discovery in Drosophila melanogaster. Numerous lines of evidence suggest powerful selective pressures govern the distributions of polymorphic inversions, and these observations have spurred the development of many explanatory models. However, due to a paucity of nucleotide data, little progress has been made towards investigating selective hypotheses or towards inferring the genealogical histories of inversions, which can inform models of inversion evolution and suggest selective mechanisms. Here, we utilize population genomic data to address persisting gaps in our knowledge of D. melanogaster''s inversions. We develop a method, termed Reference-Assisted Reassembly, to assemble unbiased, highly accurate sequences near inversion breakpoints, which we use to estimate the age and the geographic origins of polymorphic inversions. We find that inversions are young, and most are African in origin, which is consistent with the demography of the species. The data suggest that inversions interact with polymorphism not only in breakpoint regions but also chromosome-wide. Inversions remain differentiated at low levels from standard haplotypes even in regions that are distant from breakpoints. Although genetic exchange appears fairly extensive, we identify numerous regions that are qualitatively consistent with selective hypotheses. Finally, we show that In(1)Be, which we estimate to be ∼60 years old (95% CI 5.9 to 372.8 years), has likely achieved high frequency via sex-ratio segregation distortion in males. With deeper sampling, it will be possible to build on our inferences of inversion histories to rigorously test selective models—particularly those that postulate that inversions achieve a selective advantage through the maintenance of co-adapted allele complexes.