Sequence analysis of chromosome translocations in neurodevelopmental disorders 公开

Weckselblatt, Brooke (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/pz50gx10c?locale=zh
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Abstract

Translocation is one of the most common structural chromosome abnormalities observed in humans. Constitutional unbalanced translocations result in partial monosomy and partial trisomy of many genes, which may lead to neurodevelopmental disorders. We analyzed the breakpoints of 57 unique unbalanced translocations to investigate the mechanisms of how they form. 51 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 zero and four basepairs (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 non-allelic homologous recombination, but instead form most often via non-homologous end joining or microhomology-mediated break-induced replication. 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 zero to four bp of microhomology consistent with chromothripsis, and both de novo events occurred on paternal alleles. Together with other studies, these data suggest that constitutional chromothripsis arises in the paternal genome, and may be transmitted maternally. In addition, we analyzed genes at the breakpoints of these interchromosomal translocations and at the breakpoints of intrachromosomal duplication CNVs. Three simple translocations fuse genes that are predicted to produce in-frame transcripts, and we predicted six in-frame fusion genes at sequenced duplication breakpoints; four gene fusions were formed by tandem duplications, one by two interconnected duplications, and one by duplication inserted at another locus. These unique fusion genes could be related to clinical phenotypes and warrant further study.Breakpoint sequencing of our large collection of chromosome rearrangements provides a comprehensive analysis of the molecular mechanisms behind translocation formation.

Table of Contents

Chapter 1: Introduction............................................................................ 1
References................................................................................................. 20
Chapter 2: Unbalanced translocations arise from diverse mutational
mechanisms............................................................................................ 35
References................................................................................................ 47
Chapter 3: Next generation sequencing of unbalanced translocations reveals
complex chromosome rearrangements including chromothripsis............. 59
References................................................................................................. 72
Chapter 4: Fusion genes are a product of unbalanced translocations and
duplication CNVs .................................................................................... 83
References................................................................................................ 93
Chapter 5: Conclusions and future studies.............................................. 100
References................................................................................................ 113

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