Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis

Abstract

Unbalanced translocations are a relatively common type of copy number variation and a major contributor to neurodevelopmental disorders. We analyzed the breakpoints of 57 unique unbalanced translocations to investigate the mechanisms of how they form. Fifty-one are simple unbalanced translocations between two different chromosome ends, and six rearrangements have more than three breakpoints involving two to five chromosomes. Sequencing 37 breakpoint junctions revealed that simple translocations have between 0 and 4 base pairs (bp) of microhomology (n = 26), short inserted sequences (n = 8), or paralogous repeats (n = 3) at the junctions, indicating that translocations do not arise primarily from nonallelic homologous recombination but instead form most often via nonhomologous end joining or microhomology-mediated break-induced replication. Three simple translocations fuse genes that are predicted to produce in-frame transcripts of SIRPG-WWOX, SMOC2-PROX1, and PIEZO2-MTA1, which may lead to gain of function. Three complex translocations have inversions, insertions, and multiple breakpoint junctions between only two chromosomes. Whole-genome sequencing and fluorescence in situ hybridization analysis of two de novo translocations revealed at least 18 and 33 breakpoints involving five different chromosomes. Breakpoint sequencing of one maternally inherited translocation involving four chromosomes uncovered multiple breakpoints with inversions and insertions. All of these breakpoint junctions had 0-4 bp of microhomology consistent with chromothripsis, and both de novo events occurred on paternal alleles. Together with other studies, these data suggest that germline chromothripsis arises in the paternal genome and may be transmitted maternally. Breakpoint sequencing of our large collection of chromosome rearrangements provides a comprehensive analysis of the molecular mechanisms behind translocation formation.

Human Structural Variation: Mechanisms of Chromosome Rearrangements

“…Deletions and duplications mediated by HERV–HERV recombination at three intrachromosomal loci were sequenced in a recent study [43]. Similarly to other HERV-mediated chromosome rearrangements [44–46], all the CNVs are flanked by HERV-H elements that are at least 3 kb in length and 93–96% identical. The longer length and significant sequence identity of intact HERV-H elements may make them particularly recombinogenic.…”

“…Two recent studies of unbalanced translocations reported different types of DNA repair at junctions [45,46]. Sequencing the junctions of 37 unbalanced translocations revealed that 34 lacked extensive sequence homology [46].…”

“…Two recent studies of unbalanced translocations reported different types of DNA repair at junctions [45,46]. Sequencing the junctions of 37 unbalanced translocations revealed that 34 lacked extensive sequence homology [46]. Three unbalanced translocations had breakpoints consistent with NAHR between pairs of LINEs, HERVs, or short SDs; however, most breakpoint junctions had blunt ends, microhomology, inserted sequence, or inversions, indicating that most unbalanced translocations arise by NHEJ or MMBIR.…”

“…Although in this group NAHR between paralogous repeats appeared to be the 'driver' of unbalanced translocations, this is unlikely to be the major mechanism of translocation formation. In both unbalanced translocation studies, LINE and HERV elements were capable of NAHR, whereas no Alu – Alu events were detected [45,46]. Indeed, Alu – Alu recombination has been reported in only three translocations [53–55].…”

Mining for Structural Variations in Next-Generation Sequencing Data

“…Unless breakpoints disrupt important developmental genes, balanced translocations do not affect phenotype [15]. However, during gamete formation such chromosomes may segregate in unbalanced manner or unbalanced translocations may occur de novo and lead to monosomy and trisomy of different chromosome segments [16], which account for approximately 1% of developmental delay and intellectual disability cases in human [17][18][19]. Robertsonian translocations are a type of SVs resulting from chromosome end breaks near centromeric regions of two acrocentric chromosomes and their reciprocal exchange, which results in one large metacentric chromosome and one very small chromosome that is usually lost without phenotype effect.…”