Complex human chromosomal and genomic rearrangements

Abstract

Copy number variation (CNV) is a major source of genetic variation among humans. In addition to existing as benign polymorphisms, CNVs can also convey clinical phenotypes, including genomic disorders, sporadic diseases and complex human traits. CNV results from genomic rearrangements that can represent simple deletion or duplication of a genomic segment, or be more complex. Complex chromosomal rearrangements (CCRs) have been known for some time but their mechanisms have remained elusive. Recent technology advances and high-resolution human genome analyses have revealed that complex genomic rearrangements can account for a large fraction of non-recurrent rearrangements at a given locus. Various mechanisms, most of which are DNA-replication-based, for example fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR), have been proposed for generating such complex genomic rearrangements and are probably responsible for CCR.

Figure 1

Frequency of specific chromosomes involved in CCR. The x-axis lists specific human chromosomes and the y-axis shows the percentage of times a particular chromosome is involved in a complex rearrangement. Data complied on the basis of 226 CCRs.

Figure 2

Resolutions of genomic complexities. Resolving complex genomic rearrangements can require different genome analysis tools. (a) Complex rearrangements of the short arm of human chromosome 17 revealed by FISH analysis (adapted, with permission, from Ref. [47]). (b) Complex rearrangement at 1q revealed by BAC aCGH. A BAC array is shown on the left with the chromosome numbers depicted above. The y-axis shows log ratios of patient versus control BAC aCGH with green dots showing gain and red dots showing loss. To the right is a depiction of the complex rearrangement. (c) The additional small duplication of a potential complex rearrangement (duplication–normal–duplication) at 17p11.2 was confirmed by oligonucleotide aCGH. Copy number gains were shown in red. See Ref. [67] for an alternative explanation of these data. (d) FoSTeS-mediated complex PLP1 duplication was revealed by breakpoint sequencing in the apparent ‘simple’ rearrangement cases without detectable complexity by oligonucleotide aCGH (adapted, with permission, from Ref. [59]). Abbreviations: del, deletion; DistRef, distal reference sequence; dup, duplication; nml, normal; ProxRef, proximal reference sequence; 1264F, forward sequence of Subject 1264.

Figure 3

Breakpoint grouping of the genomic rearrangements at the PLP1 and MECP2 loci. (a) Proposed FoSTeS-associated breakpoints of PLP1 rearrangements are grouped near LCRs (A–E). Adapted, with permission, from Ref. [59]. (b) Proposed FoSTeS-associated breakpoints of MECP2 rearrangements are grouped near LCRs (L, J and K). Top: alignment of the join points of patients carrying complex rearrangements, including those with triplication, to the genomic location based on the data reported in Ref. [62]. Note that the distal breakpoint of the patients carrying triplication is mapped within the same region in all six patients. This region is the LCR K (it can be either K1 or K2 because there is a high frequency of polymorphic inversion involving both within the population) that spans 11.3 kb at Xq28. Bottom: alignments of the join points obtained by DNA sequencing for the patients carrying MECP2 duplications. Adapted, with permission, from Ref. [62].