Megabases In Length Research Articles

The genome sequence of the narrow-waisted bark beetle, Salpingus planirostris (Fabricius, 1787)

We present a genome assembly from a narrow-waisted bark beetle, Salpingus planirostris (Arthropoda; Insecta; Coleoptera; Salpingidae). The genome sequence is 127.50 megabases in length. Most of the assembly is scaffolded into 13 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 15.53 kilobases in length.

The genome sequence of the Large Blue butterfly, Phengaris (Maculinea) arion (Linnaeus, 1758)

We present a genome assembly from a female Phengaris arion (the Large Blue butterfly; Arthropoda; Insecta; Lepidoptera; Lycaenidae). The genome sequence is 544.50 megabases in length. Most of the assembly is scaffolded into 23 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 15.7 kilobases in length.

The genome sequence of the Western Capercaillie Tetrao urogallus Linnaeus, 1758.

We present a genome assembly from an individual male Tetrao urogallus (the Western Capercaillie; Chordata; Aves; Galliformes; Phasianidae). The genome sequence is 1,013.2 megabases in length. Most of the assembly is scaffolded into 39 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 16.68 kilobases in length.

Interspecific cytogenomic comparison reveals a potential chromosomal centromeric marker in Proceratophrys frog species.

Among the repetitive elements, satellite DNA (SatDNA) emerges as extensive arrays of highly similar tandemly repeated units, spanning megabases in length. Given that the satDNA PboSat01-176, previously characterized in P. boiei, prompted our interest for having a high abundance in P. boiei and potential for centromeric satellite, here, we employed various approaches, including low coverage genome sequencing, followed by computational analysis and chromosomal localization techniques in four Proceratophrys species and, investigating the genomic presence and sharing, as well as its potential for chromosomal centromere marker in Proceratophrys frog species. Our findings demonstrate that PboSat01-176 exhibits high abundance across all four Proceratophrys species, displaying distinct characteristics that establish it as the predominant repetitive DNA element in these species. The satellite DNA is prominently clustered in the peri/centromeric region of the chromosomes, particularly in the heterochromatic regions. The widespread presence of PboSat01-176 in closely related Proceratophrys species reinforces the validity of the library hypothesis for repetitive sequences. Thus, this study highlighted the utility of the satDNA family PboSat01-176 as a reliable centromeric marker in Proceratophrys species, with potential to be applied in other species of anuran amphibians. The observed sharing and maintenance of this sequence within the genus suggest possibilities for future research, particularly through expanded sampling to elucidate parameters that underlie the library hypothesis and the evolutionary dynamics of satDNA sequences.

Divergence and gene flow history at two large chromosomal inversions underlying ecotype differentiation in the long-snouted seahorse.

Chromosomal inversions can play an important role in divergence and reproductive isolation by building and maintaining distinct allelic combinations between evolutionary lineages. Alternatively, they can take the form of balanced polymorphisms that segregate within populations until one arrangement becomes fixed. Many questions remain about how inversion polymorphisms arise, how they are maintained over the long term, and ultimately, whether and how they contribute to speciation. The long-snouted seahorse (Hippocampus guttulatus) is genetically subdivided into geographic lineages and marine-lagoon ecotypes, with shared structural variation underlying lineage and ecotype divergence. Here, we aim to characterize structural variants and to reconstruct their history and suspected role in ecotype formation. We generated a near chromosome-level genome assembly and described genome-wide patterns of diversity and divergence through the analysis of 112 whole-genome sequences from Atlantic, Mediterranean, and Black Sea populations. By also analysing linked-read sequencing data, we found evidence for two chromosomal inversions that were several megabases in length and showed contrasting allele frequency patterns between lineages and ecotypes across the species range. We reveal that these inversions represent ancient intraspecific polymorphisms, one likely being maintained by divergent selection and the other by pseudo-overdominance. A possible selective coupling between the two inversions was further supported by the absence of specific haplotype combinations and a putative functional interaction between the two inversions in reproduction. Lastly, we detected gene flux eroding divergence between inverted alleles at varying levels for the two inversions, with a likely impact on their dynamics and contribution to divergence and speciation.

Genomic Characterization of 2 Cutibacterium acnes Isolates from a Surgical Site Infection Reveals Large Genomic Inversion.

Cutibacterium acnes is a common commensal of human skin but may also present as an opportunistic pathogen in prosthetic joint and wound infections. Unfortunately, few complete genomes of C. acnes are publicly available, and even fewer are of isolates associated with infection. Here we report the isolation, characterization, and complete genomes of 2 C. acnes isolates from a surgical site infection of an elbow. We used standard microbiological methods for phenotypic characterization and performed whole genome sequencing on 2 C. acnes isolates using a combination of short-read and long-read sequencing. Antibiotic susceptibility testing showed beta-lactamase negative and low minimal inhibitory concentrations to all antibiotics tested, with the exception of metronidazole. We assembled complete genomes of the 2 isolates, which are approximately 2.5 megabases in length. The isolates belong to the single-locus sequence type (SLST) H1 and the multi-locus sequence type (MLST) IB. Both isolates have similar composition of known virulence genes, and we found no evidence of plasmids but did find phage-associated genes. Notably, the 2 genomes are 99.97% identical but contain a large genomic inversion encompassing approximately half of the genome. This is the first characterization of this large-scale genomic inversion in nearly identical isolates from the same wound. This report adds to the limited numbers of publicly available infection-associated complete genomes of C. acnes.

Genome-wide single-molecule analysis of long-read DNA methylation reveals heterogeneous patterns at heterochromatin that reflect nucleosome organisation.

High-throughput sequencing technology is central to our current understanding of the human methylome. The vast majority of studies use chemical conversion to analyse bulk-level patterns of DNA methylation across the genome from a population of cells. While this technology has been used to probe single-molecule methylation patterns, such analyses are limited to short reads of a few hundred basepairs. DNA methylation can also be directly detected using Nanopore sequencing which can generate reads measuring megabases in length. However, thus far these analyses have largely focused on bulk-level assessment of DNA methylation. Here, we analyse DNA methylation in single Nanopore reads from human lymphoblastoid cells, to show that bulk-level metrics underestimate large-scale heterogeneity in the methylome. We use the correlation in methylation state between neighbouring sites to quantify single-molecule heterogeneity and find that heterogeneity varies significantly across the human genome, with some regions having heterogeneous methylation patterns at the single-molecule level and others possessing more homogeneous methylation patterns. By comparing the genomic distribution of the correlation to epigenomic annotations, we find that the greatest heterogeneity in single-molecule patterns is observed within heterochromatic partially methylated domains (PMDs). In contrast, reads originating from euchromatic regions and gene bodies have more ordered DNA methylation patterns. By analysing the patterns of single molecules in more detail, we show the existence of a nucleosome-scale periodicity in DNA methylation that accounts for some of the heterogeneity we uncover in long single-molecule DNA methylation patterns. We find that this periodic structure is partially masked in bulk data and correlates with DNA accessibility as measured by nanoNOMe-seq, suggesting that it could be generated by nucleosomes. Our findings demonstrate the power of single-molecule analysis of long-read data to understand the structure of the human methylome.

When Size Really Matters: The Eccentricities of Dystrophin Transcription and the Hazards of Quantifying mRNA from Very Long Genes.

At 2.3 megabases in length, the dystrophin gene is enormous: transcription of a single mRNA requires approximately 16 h. Principally expressed in skeletal muscle, the dystrophin protein product protects the muscle sarcolemma against contraction-induced injury, and dystrophin deficiency results in the fatal muscle-wasting disease, Duchenne muscular dystrophy. This gene is thus of key clinical interest, and therapeutic strategies aimed at eliciting dystrophin restoration require quantitative analysis of its expression. Approaches for quantifying dystrophin at the protein level are well-established, however study at the mRNA level warrants closer scrutiny: measured expression values differ in a sequence-dependent fashion, with significant consequences for data interpretation. In this manuscript, we discuss these nuances of expression and present evidence to support a transcriptional model whereby the long transcription time is coupled to a short mature mRNA half-life, with dystrophin transcripts being predominantly nascent as a consequence. We explore the effects of such a model on cellular transcriptional dynamics and then discuss key implications for the study of dystrophin gene expression, focusing on both conventional (qPCR) and next-gen (RNAseq) approaches.

A strategy for complete telomere-to-telomere assembly of ciliate macronuclear genome using ultra-high coverage Nanopore data

Ciliates contain two kinds of nuclei: the germline micronucleus (MIC) and the somatic macronucleus (MAC) in a single cell. The MAC usually have fragmented chromosomes. These fragmented chromosomes, capped with telomeres at both ends, could be gene size to several megabases in length among different ciliate species. So far, no telomere-to-telomere assembly of entire MAC genome in ciliate species has been finished. Development of the third generation sequencing technologies allows to generate sequencing reads up to megabases in length that could possibly span an entire MAC chromosome. Taking advantage of the ultra-long Nanopore reads, we established a simple strategy for the complete assembly of ciliate MAC genomes. Using this strategy, we assembled the complete MAC genomes of two ciliate species Tetrahymena thermophila and Tetrahymena shanghaiensis, composed of 181 and 214 chromosomes telomere-to-telomere respectively. The established strategy as well as the high-quality genome data will provide a useful approach for ciliate genome assembly, and a valuable community resource for further biological, evolutionary and population genomic studies.

Chromothripsis drives the evolution of gene amplification in cancer

Focal chromosomal amplification is an important route to generating cancer through mediating over-expression of oncogenes1–3 or to developing cancer therapy resistance by increasing expression of a gene whose action diminishes efficacy of an anti-cancer drug. Here we used whole-genome sequencing of clonal isolates developing chemotherapeutic resistance to identify chromothripsis as a major driver of extrachromosomal DNA (ecDNA) amplification into circular double minutes (DMs) through PARP- and DNA-PKcs-dependent mechanisms. Longitudinal analyses revealed that DMs undergo continuing structural evolution to promote increased drug tolerance through additional chromothriptic events. In-situ Hi-C sequencing is used to demonstrate that DMs preferentially tether near chromosome ends where they re-integrate when DNA damage is present. Intrachromosomal amplifications formed initially under low-level drug selection undergo continuing breakage-fusion-bridge cycles, generating >100 megabase-long amplicons that we show become trapped within interphase bridges and then shattered, producing micronuclei that mediate DM formation. Similar genome rearrangement profiles linked to localized gene amplification are identified in human cancers with acquired drug resistance or with oncogene amplifications. We propose that chromothripsis is a primary mechanism accelerating genomic DNA amplification and which enables rapid acquisition of tolerance to altered growth conditions.

Minimap2: pairwise alignment for nucleotide sequences.

Recent advances in sequencing technologies promise ultra-long reads of ∼100 kb in average, full-length mRNA or cDNA reads in high throughput and genomic contigs over 100 Mb in length. Existing alignment programs are unable or inefficient to process such data at scale, which presses for the development of new alignment algorithms. Minimap2 is a general-purpose alignment program to map DNA or long mRNA sequences against a large reference database. It works with accurate short reads of ≥100 bp in length, ≥1 kb genomic reads at error rate ∼15%, full-length noisy Direct RNA or cDNA reads and assembly contigs or closely related full chromosomes of hundreds of megabases in length. Minimap2 does split-read alignment, employs concave gap cost for long insertions and deletions and introduces new heuristics to reduce spurious alignments. It is 3-4 times as fast as mainstream short-read mappers at comparable accuracy, and is ≥30 times faster than long-read genomic or cDNA mappers at higher accuracy, surpassing most aligners specialized in one type of alignment. https://github.com/lh3/minimap2. Supplementary data are available at Bioinformatics online.

Redundancy analysis allows improved detection of methylation changes in large genomic regions

BackgroundDNA methylation is an epigenetic process that regulates gene expression. Methylation can be modified by environmental exposures and changes in the methylation patterns have been associated with diseases. Methylation microarrays measure methylation levels at more than 450,000 CpGs in a single experiment, and the most common analysis strategy is to perform a single probe analysis to find methylation probes associated with the outcome of interest. However, methylation changes usually occur at the regional level: for example, genomic structural variants can affect methylation patterns in regions up to several megabases in length. Existing DMR methods provide lists of Differentially Methylated Regions (DMRs) of up to only few kilobases in length, and cannot check if a target region is differentially methylated. Therefore, these methods are not suitable to evaluate methylation changes in large regions. To address these limitations, we developed a new DMR approach based on redundancy analysis (RDA) that assesses whether a target region is differentially methylated.ResultsUsing simulated and real datasets, we compared our approach to three common DMR detection methods (Bumphunter, blockFinder, and DMRcate). We found that Bumphunter underestimated methylation changes and blockFinder showed poor performance. DMRcate showed poor power in the simulated datasets and low specificity in the real data analysis. Our method showed very high performance in all simulation settings, even with small sample sizes and subtle methylation changes, while controlling type I error. Other advantages of our method are: 1) it estimates the degree of association between the DMR and the outcome; 2) it can analyze a targeted or region of interest; and 3) it can evaluate the simultaneous effects of different variables. The proposed methodology is implemented in MEAL, a Bioconductor package designed to facilitate the analysis of methylation data.ConclusionsWe propose a multivariate approach to decipher whether an outcome of interest alters the methylation pattern of a region of interest. The method is designed to analyze large target genomic regions and outperforms the three most popular methods for detecting DMRs. Our method can evaluate factors with more than two levels or the simultaneous effect of more than one continuous variable, which is not possible with the state-of-the-art methods.

TAREAN: a computational tool for identification and characterization of satellite DNA from unassembled short reads.

Satellite DNA is one of the major classes of repetitive DNA, characterized by tandemly arranged repeat copies that form contiguous arrays up to megabases in length. This type of genomic organization makes satellite DNA difficult to assemble, which hampers characterization of satellite sequences by computational analysis of genomic contigs. Here, we present tandem repeat analyzer (TAREAN), a novel computational pipeline that circumvents this problem by detecting satellite repeats directly from unassembled short reads. The pipeline first employs graph-based sequence clustering to identify groups of reads that represent repetitive elements. Putative satellite repeats are subsequently detected by the presence of circular structures in their cluster graphs. Consensus sequences of repeat monomers are then reconstructed from the most frequent k-mers obtained by decomposing read sequences from corresponding clusters. The pipeline performance was successfully validated by analyzing low-pass genome sequencing data from five plant species where satellite DNA was previously experimentally characterized. Moreover, novel satellite repeats were predicted for the genome of Vicia faba and three of these repeats were verified by detecting their sequences on metaphase chromosomes using fluorescence in situ hybridization.

EXHAUSTIVE COMPUTATION OF EXACT DUPLICATIONS VIA SUPER AND NON-NESTED LOCAL MAXIMAL REPEATS

We propose and implement a method to obtain all duplicated sequences (repeats) from a chromosome or whole genome. Unlike existing approaches our method makes it possible to simultaneously identify and classify repeats into super, local, and non-nested local maximal repeats. Computation verification demonstrates that maximal repeats for a genome of several gigabases can be identified in a reasonable time, enabling us to identified these maximal repeats for any sequenced genome. The algorithm used for the identification relies on enhanced suffix array data structure to achieve practical space and time efficiency, to identify and classify the maximal repeats, and to perform further post-processing on the identified duplicated sequences. The simplicity and effectiveness of the implementation makes the method readily extendible to more sophisticated computations. Maxmers can be exhaustively accounted for in few minutes for genome sequences of dozen megabases in length and in less than a day or two for genome sequences of few gigabases in length. One application of duplicated sequence identification is to the study of duplicated sequence length distributions, which our found to exhibit for large lengths a persistent power-law behavior. Variation of estimated exponents of this power law are studied among different species and successive assembly release versions of the same species. This makes the characterization of the power-law regime of sequenced genomes via maximal repeats identification and classification, an important task for the derivation of models that would help us to elucidate sequence duplication and genome evolution.

Discovery of common sequences absent in the human reference genome using pooled samples from next generation sequencing.

BackgroundSequences up to several megabases in length have been found to be present in individual genomes but absent in the human reference genome. These sequences may be common in populations, and their absence in the reference genome may indicate rare variants in the genomes of individuals who served as donors for the human genome project. As the reference genome is used in probe design for microarray technology and mapping short reads in next generation sequencing (NGS), this missing sequence could be a source of bias in functional genomic studies and variant analysis. One End Anchor (OEA) and/or orphan reads from paired-end sequencing have been used to identify novel sequences that are absent in reference genome. However, there is no study to investigate the distribution, evolution and functionality of those sequences in human populations.ResultsTo systematically identify and study the missing common sequences (micSeqs), we extended the previous method by pooling OEA reads from large number of individuals and applying strict filtering methods to remove false sequences. The pipeline was applied to data from phase 1 of the 1000 Genomes Project. We identified 309 micSeqs that are present in at least 1% of the human population, but absent in the reference genome. We confirmed 76% of these 309 micSeqs by comparison to other primate genomes, individual human genomes, and gene expression data. Furthermore, we randomly selected fifteen micSeqs and confirmed their presence using PCR validation in 38 additional individuals. Functional analysis using published RNA-seq and ChIP-seq data showed that eleven micSeqs are highly expressed in human brain and three micSeqs contain transcription factor (TF) binding regions, suggesting they are functional elements. In addition, the identified micSeqs are absent in non-primates and show dynamic acquisition during primate evolution culminating with most micSeqs being present in Africans, suggesting some micSeqs may be important sources of human diversity.Conclusions76% of micSeqs were confirmed by a comparative genomics approach. Fourteen micSeqs are expressed in human brain or contain TF binding regions. Some micSeqs are primate-specific, conserved and may play a role in the evolution of primates.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-685) contains supplementary material, which is available to authorized users.

Transfusion-Dependent Alpha-Spectrin Deficient Hemolytic Anemia Due to Maternal Uniparental Disomy

Abstract 1030▪▪This icon denotes a clinically relevant abstractWe studied a girl with hereditary spherocytosis who required in utero transfusions and remained transfusion-dependent after birth. Initial clinical, laboratory, and biochemical characteristics of this patient have been described (Blood 78:3043, 1991). Severe alpha-spectrin deficiency was observed in membranes prepared from her marrow-derived cultured erythroid cells. Since this report, despite splenectomy at age 2 years, the proband remains transfusion-dependent. Our goal was to determine the molecular basis of the patient’s transfusion-dependent anemia. Typically, alpha-spectrin deficiency is recessively inherited due to homozygous or compound heterozygous inactivating mutations of the alpha-spectrin gene. Genomic DNA from the proband was amplified using primers flanking the 52 coding exons and promoter region of the alpha-spectrin gene. Capillary electrophoresis-based nucleotide sequencing identified a homozygous nonsense mutation in exon 19 of the alpha-spectrin gene. The mother was heterozygous for this mutation; the father did not carry the mutation. To determine if a deletion involving the alpha-spectrin gene locus leading to homozygosity of the nonsense mutation in the proband was present, array comparative genomic hybridization (aCGH) was performed using the 44K CGH microarray (G4426A; Agilent Technologies, Santa Clara, CA). This array includes 44,000 60-mer oligonucleotides covering the entire human genome at a density of ∼14–15 oligonucleotides/MB. No deletions or rearrangements were identified by aCGH. To interrogate the alpha-spectrin locus at higher resolution, SNP typing of proband and parental genomic DNA was performed using the Illumina HumanHap 550 BeadChip. This array contains >550,000 SNPs and includes twenty intragenic SNPs in the alpha-spectrin gene locus. These studies identified a large region of homozygosity at 1q21, approximately 10 megabases in length, extending from rs6657293 (154,995,473, hg18) to rs6670426 (165,730,530) including the PRCC gene (155,003,897) to the CD247 gene (165,888,000) on chromosome 1q in genomic DNA from the proband. This region of homozygosity includes the alpha-spectrin gene locus and 158 other genes. Analyses of the SNP data also confirmed paternity and maternity, with a P-P-C heritability of 0.9997 and no inheritance violations in the alpha-spectrin gene region. Finally, to exclude the possibility of an intragenic microdeletion in the alpha-spectrin gene locus, copy number profiling using quantitative, real-time PCR was performed. Amplicons included exon 19, the location of the nonsense mutation, as well as exons 2, 17, 40, 52 and the 3’UTR. The proband and both parents had 2 copies of the corresponding alpha-spectrin region at all sites examined. No deletions were identified, excluding the possibility that a small deletion of the SPTA1 gene is the cause of homozygosity of exon 19 in the proband. Together, these data indicate there is partial maternal uniparental disomy of chromosome 1 in the proband and that reduction to homozygosity of the 1q region containing the maternal SPTA nonsense mutation is responsible for the alpha-spectrin deficient hemolytic anemia phenotype. This is the first case of uniparental disomy leading to an erythrocyte membrane-associated hemolytic anemia. The homozygosity associated with uniparental disomy consists of duplicated copies of alleles from a single chromosome, leading to increased risk of homozygosity for deleterious recessive mutations. Uniparental disomy should be considered when unexpected results are obtained during carrier testing in a recessive disorder. Disclosures:No relevant conflicts of interest to declare.

A Novel Role for Minimal Introns: Routing mRNAs to the Cytosol

BackgroundIntrons and their splicing are tightly coupled with the subsequent mRNA maturation steps, especially nucleocytoplasmic export. A remarkable fraction of vertebrate introns have a minimal size of about 100 bp, while majority of introns expand to several kilobases even megabases in length.Principal FindingsWe carried out analyses on the evolution and function of minimal introns (50–150 bp) in human and mouse genomes. We found that minimal introns are conserved in terms of both length and sequence. They are preferentially located toward 3′ end of mRNA and non-randomly distributed among chromosomes. Both the evolutionary conservation and non-random distribution are indicative of biological relevance. We showed that genes with minimal introns have higher abundance, larger size, and tend to be universally expressed as compared to genes with only large introns and intron-less genes. Genes with minimal introns replicate earlier and preferentially reside in the vicinities of open chromatin, suggesting their unique nuclear position and potential relevance to the regulation of gene expression and transcript export.ConclusionsBased on these observations, we proposed a nuclear-export routing model, where minimal introns play a regulatory role in selectively exporting the highly abundant and large housekeeping genes that reside at the surface of chromatin territories, and thus preventing entanglement with other genes located at the interior locations.

Investigating DNA migration in pulsed fields using a miniaturized FIGE system

PFGE is a well-established technique for fractionation of DNA fragments ranging from kilobases to megabases in length. But many of these separations require an undesirable combination of long experiment times (often approaching tens of hours) and application of high voltages (often approaching tens of kV). Here, we present a simple miniaturized FIGE apparatus capable of separating DNA fragments up to 32.5 kb in length within 3 h using a modest applied potential of 20 V. The device is small enough to be imaged under a fluorescence microscope, permitting the migrating DNA bands to be observed during the course of the separation run. We use this capability to investigate how separation performance is affected by parameters including the ratio of forward and backward voltage, pulse time, and temperature. We also characterize the dependence of DNA mobility on fragment size N, and observe a scaling in the vicinity of N(-0.5) over the size range investigated. The high speed, low power consumption, and simple design of this system may help enable future studies of DNA migration in PFGE to be performed quickly and inexpensively.

Splicing Factor SPF30 Bridges an Interaction between the Prespliceosome Protein U2AF35 and Tri-small Nuclear Ribonucleoprotein Protein hPrp3

Spliceosome assembly is a dynamic process involving the sequential recruitment and rearrangement of small nuclear ribonucleoproteins (snRNPs) on a pre-mRNA substrate. Here we identify several spliceosome protein interactions with different domains of human splicing factor SPF30 that have the potential to mediate the addition of the tri-snRNP to the prespliceosome. In particular, we show that the C-terminal tails of SmD1, SmD3, and the protein Lsm4 interact with the central Tudor domain of SPF30. We identify a novel interaction between the N-terminal domain of SPF30 and U2AF35, a prespliceosome protein that has a role in recognizing the 3' splice site and recruiting U2 snRNP. We also show that the C terminus of SPF30 interacts with a middle domain of hPrp3, a component of U4/U6 di-snRNP and the tri-snRNP. Importantly, we show that the U2AF35 and hPrp3 interactions with SPF30 can occur simultaneously, thereby potentially linking 3' splice site recognition with tri-snRNP addition. Finally, we note that SPF30 and its partner-interacting domains are not conserved in yeast, suggesting this interaction network may play an important role in the complex splicing observed in higher eukaryotes.

Evidence for large inversion polymorphisms in the human genome from HapMap data

Knowledge about structural variation in the human genome has grown tremendously in the past few years. However, inversions represent a class of structural variation that remains difficult to detect. We present a statistical method to identify large inversion polymorphisms using unusual Linkage Disequilibrium (LD) patterns from high-density SNP data. The method is designed to detect chromosomal segments that are inverted (in a majority of the chromosomes) in a population with respect to the reference human genome sequence. We demonstrate the power of this method to detect such inversion polymorphisms through simulations done using the HapMap data. Application of this method to the data from the first phase of the International HapMap project resulted in 176 candidate inversions ranging from 200 kb to several megabases in length. Our predicted inversions include an 800-kb polymorphic inversion at 7p22, a 1.1-Mb inversion at 16p12, and a novel 1.2-Mb inversion on chromosome 10 that is supported by the presence of two discordant fosmids. Analysis of the genomic sequence around inversion breakpoints showed that 11 predicted inversions are flanked by pairs of highly homologous repeats in the inverted orientation. In addition, for three candidate inversions, the inverted orientation is represented in the Celera genome assembly. Although the power of our method to detect inversions is restricted because of inherently noisy LD patterns in population data, inversions predicted by our method represent strong candidates for experimental validation and analysis.