A recurrent inversion on the eutherian X chromosome

Abstract

Chromosomal inversions have an important role in evolution, and an increasing number of inversion polymorphisms are being identified in the human population. The evolutionary history of these inversions and the mechanisms by which they arise are therefore of significant interest. Previously, a polymorphic inversion on human chromosome Xq28 that includes the FLNA and EMD loci was discovered and hypothesized to have been the result of nonallelic homologous recombination (NAHR) between near-identical inverted duplications flanking this region. Here, we carried out an in-depth study of the orthologous region in 27 additional eutherians and report that this inversion is not specific to humans, but has occurred independently and repeatedly at least 10 times in multiple eutherian lineages. Moreover, inverted duplications flank the FLNA-EMD region in all 16 species for which high-quality sequence assemblies are available. Based on detailed sequence analyses, we propose a model in which the observed inverted duplications originated from a common duplication event that predates the eutherian radiation. Subsequent gene conversion homogenized the duplications, thereby providing a continuous substrate for NAHR that led to the recurrent inversion of this segment of the genome. These results provide an extreme example in support of the evolutionary breakpoint reusage hypothesis and point out that some near-identical human segmental duplications may, in fact, have originated >100 million years ago.duplication ͉ gene conversion ͉ inversion polymorphism C hromosomal rearrangements were among the first types of genetic variation to be studied and have been proposed to play an important role in genome evolution and the phenotypic differences within and between species (1, 2). The recent availability of genomic data from multiple species has led to the unexpected discovery that structural variation, including inversions, is relatively common in the human population (3, 4), as well as between closely related species, such as human and chimpanzee (5-7). Comparisons of the positions of evolutionary breakpoints in different mammalian lineages suggest that a small fraction of the mammalian genome is particularly prone to rearrangement and constitute breakpoint ''hotspots'' that have been reused over the course of mammalian evolution (e.g., refs. 8 and 9). Therefore, a conserved property of mammalian genomes appears to be the presence of a limited number of fragile regions that commonly mediate chromosomal rearrangements. This observation contrasts with the long-held view that evolutionary breakpoints are distributed randomly across the genome (10), and there has been considerable debate pitting the random breakage model versus the fragile breakage/breakpoint reusage hypothesis (11).One mechanism known to mediate chromosomal rearrangements is nonallelic recombination between homologous sequences (NAHR). In humans, 5% of the genome is comprised of segmental duplications, which are typically defined as duplications Ͼ1 kb in length and Ͼ90% ...

Validation and Genotyping of Multiple Human Polymorphic Inversions Mediated by Inverted Repeats Reveals a High Degree of Recurrence

“…For polymorphic inversions found in natural populations, the recurrence of inversions mediated by NAHR between SDs had already been postulated by comparison of different lineages in mammals [59] or primates [21], [67], and there was some evidence that it could occur in humans as well [12], [68]. In addition, experimentally it was suggested that some inversions could appear repeatedly in human cells [69], [70], although these results should be confirmed with independent techniques.…”

The origins and impact of primate segmental duplications

“…Given the high dynamism of these regions, it is common to find recurrent events at nearly identical locations within the genome. A 150 Kb human polymorphic inversion on chromosome Xq28, for example, has been shown to be recurrently inverted in eutherian evolution at least a dozen times [84] owing, in part, to the presence of a diverse array of duplicated sequences located at the inversion breakpoint in almost every mammalian species. Similarly, a 970 Kb inversion polymorphism on human chromosome 17q21.31 is predicted to have inverted at least three times independently in the orangutan, human and chimpanzee lineages [36,85].…”

Testing chromosomal phylogenies and inversion breakpoint reuse in Drosophila. The martensis cluster revisited

“…Another putative case of inversion recurrence, that of the pericentric inversions PTR XVI in chimpanzee and GGO XVI in gorilla has been disproven as the breakpoints are located at non-identical positions and thus must have occurred independently in the two lineages (Goidts et al 2004). So far, the only convincing case of a recurrent inversion is that of the relatively small (~40 kb) FLNA-EMD inversion in eutherians (Cáceres et al 2007). This inversion is the result of non-allelic homologous recombination between a conserved pair of inverted duplications on the X chromosome.…”