Discovery of Human Inversion Polymorphisms by Comparative Analysis of Human and Chimpanzee DNA Sequence Assemblies

Feuk, Lars; MacDonald, Jeffrey R.; Tang, Terence; Carson, Andrew R.; Li, Martin; Rao, G. P.; Khaja, Razi; Scherer, Stephen W.

doi:10.1371/journal.pgen.0010056

Cited by 152 publications

(150 citation statements)

References 33 publications

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“…At the same time we uncovered 167 human-chimpanzee microinversions missed in ref. 3. These findings reveal some limitations of chaining and netting (2) as a microinversion detection tool in ref.…”

mentioning

confidence: 75%

Microinversions in mammalian evolution

Chaisson¹,

Raphael

Pevzner

2006

Proc. Natl. Acad. Sci. U.S.A.

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We propose an approach for identifying microinversions across different species and show that microinversions provide a source of low-homoplasy evolutionary characters. These characters may be used as ''certificates'' to verify different branches in a phylogenetic tree, turning the challenging problem of phylogeny reconstruction into a relatively simple algorithmic problem. We estimate that there exist hundreds of thousands of microinversions in genomes of mammals from comparative sequencing projects, an untapped source of new phylogenetic characters.genome rearrangements ͉ phylogenetics C hromosomal inversions have been used as phylogenetic characters since Dobzhansky and Sturtevant in 1938. Recent comparisons of whole mammalian genomes have revealed a surprisingly large number of microinversions (1, 2). While the microinversions were first met with skepticism and were attributed to assembly errors and alignment artifacts, recent comparative study of human and chimpanzee genomes convincingly proved that microinversions are indeed widespread (3). We therefore decided to perform a fine-grained search for inversions across many mammals in the greater cystic fibrosis transmembrane conductance regulator (CFTR) region. This is a 1.8-megabase region on chromosome 7 in the human genome that encompasses the CFTR gene, and its many neighboring genes, that was sequenced for the ENCyclopedia Of DNA Elements (ENCODE) project (4, 5). We found that microinversions are frequent across all species and occur at roughly one microinversion per megabase per 66 million years of evolution. We show that microinversions have low homoplasy and thus provide ample characters for phylogenetic studies.Our work follows in the steps of the pioneering work by Okada's group (6) and Lake's group (7) that demonstrated the power of repeat-based and deletion-based characters to resolve difficult phylogeny problems that the traditional point mutation analysis failed to resolve. The repeat-based and deletion-based approaches, although very successful, have some drawbacks as reviewed in ref. 8. However, Bashir et al. (9) and Kriegs et al. (10) recently demonstrated that many repeat-based characters may be extracted from genomic sequences to alleviate these drawbacks and to resolve some existing controversies. Our work reveals a source of low-homoplasy phylogenetic characters that complement these previous studies in two respects. First, microinversion homoplasy (if any) may be detected, and such characters can be simply deleted from further consideration without affecting the tree reconstruction algorithm. Second, microinversions may be identified as long as there is a detectable sequence similarity thus not necessarily limiting the comparison to close species as in the case of repeats and deletions. Indeed, Bourque et al. (11) documented many microinversions between human and chicken genomes, whereas Fischer et al. (12) found many microinversions between yeast genomes, which are molecularly as diverse as the genomes of the entire phylum of chord...

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confidence: 75%

Microinversions in mammalian evolution

Chaisson¹,

Raphael

Pevzner

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…We speculate that the overall ''rate of rearrangement'' is largely constant among all ape genomes but that fewer SDs drive fewer homology-mediated events and, consequently, nonhomology-based mechanisms contribute more significantly to large-scale chromosomal rearrangements in gibbons. Many SD-mediated events have occurred among great apes, but because of the predominance of interspersed duplication blocks within close proximity along a chromosome, a large number of these African-ape events are below the level of cytogenetic resolution and instead are observed as an abundance of smaller structural variant events (Feuk et al 2005;Newman et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Sequencing human–gibbon breakpoints of synteny reveals mosaic new insertions at rearrangement sites

Girirajan¹,

Chen²,

Graves³

et al. 2008

Genome Res.

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The gibbon genome exhibits extensive karyotypic diversity with an increased rate of chromosomal rearrangements during evolution. In an effort to understand the mechanistic origin and implications of these rearrangement events, we sequenced 24 synteny breakpoint regions in the white-cheeked gibbon (Nomascus leucogenys, NLE) in the form of highquality BAC insert sequences (4.2 Mbp). While there is a significant deficit of breakpoints in genes, we identified seven human gene structures involved in signaling pathways (DEPDC4, GNG10), phospholipid metabolism (ENPP5, PLSCR2), boxidation (ECH1), cellular structure and transport (HEATR4), and transcription (ZNF461), that have been disrupted in the NLE gibbon lineage. Notably, only three of these genes show the expected evolutionary signatures of pseudogenization. Sequence analysis of the breakpoints suggested both nonclassical nonhomologous end-joining (NHEJ) and replicationbased mechanisms of rearrangement. A substantial number (11/24) of human-NLE gibbon breakpoints showed new insertions of gibbon-specific repeats and mosaic structures formed from disparate sequences including segmental duplications, LINE, SINE, and LTR elements. Analysis of these sites provides a model for a replication-dependent repair mechanism for double-strand breaks (DSBs) at rearrangement sites and insights into the structure and formation of primate segmental duplications at sites of genomic rearrangements during evolution.

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“…Inversion polymorphisms have been discovered mostly from comparative sequence analysis of humans and chimpanzees (Feuk et al 2005) and from paired-end mapping, where orientations of sequences from either end of a piece of DNA are inverted with respect to the reference sequence (Tuzun et al 2005;Korbel et al 2007). Current inversion genotyping methods rely on identification of the breakpoint and the assumption that all inverted alleles share the same breakpoint.…”

Section: Structural Variation and Its Importancementioning

confidence: 99%

Defensins and the dynamic genome: What we can learn from structural variation at human chromosome band 8p23.1

Hollox

Barber²,

Brookes³

et al. 2008

Genome Res.

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Over the past four years, genome-wide studies have uncovered numerous examples of structural variation in the human genome. This includes structural variation that changes copy number, such as deletion and duplication, and structural variation that does not change copy number, such as orientation and positional polymorphism. One region that contains all these types of variation spans the chromosome band 8p23.1. This region has been studied in some depth, and the focus of this review is to examine our current understanding of the variation of this region. We also consider whether this region is a good model for other structurally variable regions in the genome and what the implications of this variation are for clinical studies. Finally, we discuss the bioinformatics challenges raised, discuss the evolution of the region, and suggest some future priorities for structural variation research.

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Discovery of Human Inversion Polymorphisms by Comparative Analysis of Human and Chimpanzee DNA Sequence Assemblies

Cited by 152 publications

References 33 publications

Microinversions in mammalian evolution

Microinversions in mammalian evolution

Sequencing human–gibbon breakpoints of synteny reveals mosaic new insertions at rearrangement sites

Defensins and the dynamic genome: What we can learn from structural variation at human chromosome band 8p23.1

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