Molecular Mechanisms of Complex Genome Rearrangements in the Human Germline

Dear Colleagues,

Since routine karyotyping became available, first, numerical and, later, structural changes in the human chromosome complement have been detected. Since our ability to detect the latter class is limited by the resolution of chromosome banding, a continuing endeavor to develop methods with increased resolution arose. After the first draft of the nucleotide sequence of the human genome was completed in 2001 two developments have revolutionized our capabilities to detect structural genome changes. First, arrays of probes representing unique positions within the human genome, and, second, methods for massive parallel sequencing became available. Arrays with growing numbers of probes allowed us to detect ever-smaller losses and gains of chromosomal segments, down to a single exon. With massive parallel sequencing of paired-end and mate-pair libraries, even more rearrangements were detected, and their breakpoints resolved. The genomes of patients and healthy individuals have been proven to harbor numerous losses, gains, insertions, and inversions. The unexpectedly large number of those within the genome of a single individual challenged our notions of simple and complex genome rearrangements. The structure of the rearrangements and their breakpoint sequences prompted investigators to propose numerous potential mechanisms of origin, including non-allelic homologous recombination, replication-based mechanisms, canonical and alternative non-homologous end joining, retrotransposition, chromoanasynthesis, chromothripsis, and breakage fusion bridge cycles. The outcome of complex genome rearrangements comprises losses, gains, insertions, gene truncation and gene fusion, and disruptions of topologically associated domains.

Now is a good time to gather the evidence and analyze these models in depth. We invite you to summarize your thoughts in a review of one or several mechanisms of origin of complex genome rearrangements in the human germline and their phenotypic effects.

Dr. Martin Poot
Dr. Ron Hochstenbach
Guest Editors

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• non-allelic homologous recombination
• chromoanasynthesis
• chromothripsis
• breakage fusion bridge cycles
• non-homologous end joining
• insertion-translocation
• inversions
• deletions
• tandem duplications