1 and Table 6, which is published as supporting information on the PNAS web site) without a full-length (20 kb) LCR16a element. After excluding ancestral segments, we find only one exception where a block exists (LCR16uw, Fig. Of the 11 other LCR16 elements considered in this analysis ( Table 1), all map within 109 kb of an LCR16a duplication. The duplication blocks range in size from 604,376 bp (16p12.1/11.2) to solo copies of the LCR16a element (≈19,794 bp in length) (Table 5, which is published as supporting information on the PNAS web site, and Fig. Three blocks map to 16q22, whereas the remainder are distributed along the short arm of chromosome 16, where they occupy an estimated 11% of the euchromatin. In humans, there are 17 complex blocks of LCR16 duplication (4.2 Mb of sequence) that contain 23 distinct copies of LCR16a with fewer copies of other flanking LCR16 segmental duplications (Table 4, which is published as supporting information on the PNAS web site, and Fig. We investigated the detailed organization of these regions among nonhuman primate species by sequencing large-insert clones from a diverse panel of primates to address questions regarding the mechanism of origin, the extent of structural variation among primates, and the relationship of these complex structures to the rapidly evolving LCR16a segment. The finished chromosome 16 sequence ( 18) provided the basis for a detailed analysis of these regions. We subsequently identified a gene family, morpheus, within LCR16a that showed significant signatures of positive selection. The majority of these were duplicated in an interspersed configuration throughout the chromosome. ( 17) identified at least 20 distinct gene-rich LCR16 elements, ranging in size from a few kilobases to >50 kb in length, termed LCR16a–t. During the initial sequence analysis of this chromosome, Loftus et al. More than 10% of the euchromatic portion of human chromosome 16p consists of segmental duplications known as LCR16 (low-copy repeat sequences on chromosome 16) ( 16, 17). Human chromosome 16 represents one of the most extreme examples of such recent segmental-duplication activity ( 15). The mechanism by which hundreds of kilobases of genomic sequence becomes duplicatively transposed to a new location on a chromosome is unknown. Detailed studies of a few of the underlying regions ( 9, 11, 14) suggest that duplications have occurred in a stepwise fashion, involving subsequent larger segments of duplication as secondary events. This property has created regions of the genome that are complex mosaics of different genomic segments ( 7) where novel genes, fusion genes, and gene families have emerged ( 2, 8 – 13). In humans and other great-ape genomes, ≈450 duplication hubs have been identified that have been the target of duplications from many different ancestral loci. Although recent duplications are common among other animal genomes, they are typically organized as clusters of tandemly arrayed segments ( 6). Our data support a model of duplication where the probability that a segment of DNA becomes duplicated is determined by its proximity to core duplicons, such as LCR16a.īased on the current sequenced animal genomes, human genomic architecture is unique in the abundance of large segmental duplications that are interspersed at discrete locations in the genome ( 1 – 5). Breakpoint analysis of lineage-specific insertions suggests coordinated deletion of repeat-rich DNA at the target site, in some cases deleting genes in that species. This process has mobilized duplication blocks (15–200 kb in size) to new genomic locations in each species. Euchromatic sequence that flanks sites of LCR16a integration are frequently lineage-specific duplications. We provide evidence that this particular segment has been active independently in each great ape and human lineage at different points during evolution. Based on a comparative analysis of primate genomes, we show that a particular segmental duplication (LCR16a) has been the source locus for the formation of the majority of intrachromosomal duplications blocks on human chromosome 16.
The underlying mechanism by which the interspersed pattern of human segmental duplications has evolved is unknown.
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