The human genome is not a static library of information but a dynamic structure subject to alterations. These changes, known as chromosomal rearrangements, involve large segments of DNA being moved, deleted, or copied. These events do not happen randomly, instead concentrating in specific locations called cis-regulatory modules (CRMs). CRMs are switches that control when and where genes are turned on or off. The observation that major structural changes to chromosomes occur in these control regions provides a new perspective on gene regulation, pointing to a relationship between DNA structure and its function.
Understanding the Genomic Players
Cis-regulatory modules (CRMs) are sequences of non-coding DNA that manage gene expression. They do not code for proteins but act as instructions that dictate a gene’s activity level. These modules include enhancers that boost gene expression, silencers that repress it, and promoters where the machinery to read a gene assembles.
Chromosomal rearrangements are substantial structural changes to the chromosome. Unlike small mutations that might alter a single letter of the genetic code, these are large-scale events. The primary types of rearrangements are:
- Deletions, which involve the loss of a chromosome segment.
- Duplications, where a segment is copied one or more times.
- Inversions, where a segment breaks off, flips, and reattaches.
- Translocations, where a piece of one chromosome breaks off and attaches to another.
Why Rearrangements Cluster in Regulatory Regions
The clustering of chromosomal rearrangements within CRMs is a consequence of the genome’s physical and functional nature. The genome is folded into complex three-dimensional structures, bringing distant CRMs into close physical contact with the genes they regulate. This organization occurs within self-interacting regions known as Topologically Associating Domains (TADs), where DNA sequences contact each other more frequently than with sequences outside the domain. The boundaries of these TADs are hotspots for chromosomal breaks. The proteins that maintain these boundaries, such as CTCF and cohesin, create an architectural environment that may contribute to this fragility.
The constant folding and unfolding of chromatin within these active domains can also place physical strain on the DNA backbone. CRMs are also hubs of intense biochemical activity, densely packed with binding sites for regulatory proteins. This constant assembly and disassembly of protein complexes on the DNA can induce mechanical stress, making the DNA more prone to double-strand breaks. When the cell’s repair machinery attempts to fix these breaks, errors can lead to the characteristic deletions, duplications, or inversions.
Consequences of Regulatory Rearrangements
When a chromosomal rearrangement occurs within or near a cis-regulatory module, it can have major effects on gene expression. One well-documented consequence is “enhancer hijacking,” which happens when a rearrangement moves a powerful enhancer close to a gene it does not normally regulate. If this newly positioned gene is a proto-oncogene (a gene with the potential to cause cancer), its inappropriate activation can lead to uncontrolled cell growth and tumor formation.
For example, a translocation might place a strong enhancer from a highly active gene next to a proto-oncogene that is usually inactive. The result is that the proto-oncogene is now switched on at high levels, driving the cell towards a cancerous state. Beyond enhancer hijacking, rearrangements can disrupt gene regulation in other ways. A deletion might remove a necessary enhancer, silencing a gene that needs to be active. An inversion could separate a gene from its promoter, making it impossible to transcribe. A rearrangement can also disrupt a TAD boundary, breaking down the insulation between regulatory neighborhoods and exposing a gene to new regulatory influences.
Implications for Disease and Evolution
The consequences of rearrangements in regulatory regions extend to both disease and evolution. In medicine, this mechanism is a recognized cause of various conditions. Specific cancers are driven by the enhancer hijacking of oncogenes like MYC, where a rearrangement places MYC under the control of a potent enhancer, leading to its overexpression. Developmental disorders can also arise from these events, such as when rearrangements affect the regulation of genes like SHH, which is involved in limb and brain development.
From an evolutionary perspective, this same mechanism can be a powerful engine for generating new traits. A change in when or where a gene is expressed can have a greater impact on an organism’s form than a change in the protein the gene produces. By rearranging the regulatory landscape, evolution can experiment with new patterns of gene expression without altering the protein building blocks. This process can lead to the development of novel features and adaptations, contributing to the diversity of life.