Our genetic blueprint is organized into chromosomes, tightly packaged bundles of DNA that house our genes. Each human cell contains 23 pairs of these structures. Sometimes, large-scale changes alter the physical arrangement of DNA within a chromosome, an event known as a chromosomal rearrangement. These mutations can involve shifts in the location of genetic material or changes in its overall amount. This type of genetic variation is present in about 0.5% of all newborns and can influence health, contribute to disease, and drive evolutionary changes.
Classifying Chromosomal Rearrangements
Rearrangements are classified as either balanced or unbalanced. In balanced rearrangements, no genetic material is lost or gained. In unbalanced rearrangements, there is a net loss or gain of genetic information, which is more likely to result in clinical effects because the dosage of genes is altered.
A deletion occurs when a segment of a chromosome, and the genes it contains, is lost. This can range from a single-gene deletion to the loss of a substantial portion of a chromosome. In contrast, a duplication happens when a part of a chromosome is repeated, resulting in extra copies of genes. This can lead to an overproduction of the proteins they encode, disrupting normal cellular processes.
An inversion occurs when a chromosome segment breaks off, flips 180 degrees, and reattaches. If the inverted segment includes the centromere, it is a pericentric inversion. If the break occurs in a single arm and does not involve the centromere, it is a paracentric inversion.
Translocations occur when a piece of one chromosome attaches to another. In a reciprocal translocation, two different chromosomes exchange segments. A Robertsonian translocation involves the fusion of the long arms of two acrocentric chromosomes, while their short arms are often lost. A less common event is a ring chromosome, where a chromosome’s broken ends fuse together, potentially losing genetic material from the tips.
Origins of Chromosomal Alterations
Many rearrangements originate from mistakes during DNA replication or repair. For instance, double-strand breaks in DNA are a common precursor. While repair systems are designed to fix these breaks, they can sometimes rejoin the wrong ends, leading to a rearrangement.
Errors during cell division, particularly meiosis, are another source. In meiosis, the process that creates sperm and egg cells, mistakes during the exchange of genetic material (crossing over) can lead to deletions, duplications, or inversions. A similar process, non-allelic homologous recombination (NAHR), can also generate rearrangements when it occurs between similar but not identical DNA sequences.
Certain chromosomal regions, known as fragile sites, are more susceptible to breaking. The genome’s architecture, including repetitive DNA sequences, can also facilitate misalignments during cell division. While many changes arise spontaneously, they can be induced by external factors called mutagens, such as ionizing radiation, certain chemicals, and some viral infections.
Identifying Chromosomal Rearrangements
Diagnosing chromosomal rearrangements requires laboratory techniques that visualize chromosomes or analyze DNA at high resolution.
Karyotyping
Karyotyping is the classic method of staining and examining a person’s complete set of chromosomes under a microscope. It allows cytogeneticists to identify large-scale changes, like major translocations and deletions, by observing alterations in the size, shape, and banding pattern of the chromosomes.
Fluorescence In Situ Hybridization (FISH)
Fluorescence In Situ Hybridization (FISH) detects more subtle changes using fluorescently labeled DNA probes that bind to specific chromosome sequences. FISH can pinpoint a deletion, duplication, or translocation with much higher resolution than standard karyotyping.
Chromosomal Microarray Analysis (CMA)
Chromosomal Microarray Analysis (CMA) scans the genome for small deletions and duplications known as copy number variations (CNVs). This method detects imbalances too small to be seen with a karyotype and is useful for identifying the genetic cause of developmental delays and congenital anomalies.
Next-Generation Sequencing (NGS)
Next-Generation Sequencing (NGS), including Whole Genome Sequencing (WGS), provides the highest resolution view of the genome. It can identify all types of rearrangements and pinpoint the exact DNA breakpoints. NGS is applied in prenatal screening, cancer diagnostics, and for unexplained genetic conditions.
Consequences of Structural Chromosomal Changes
The effects of a chromosomal rearrangement can vary widely, from having no noticeable impact to causing severe genetic disorders.
Balanced rearrangements, such as inversions and reciprocal translocations, are often asymptomatic in the carrier because no genetic material is lost. However, they can pose problems for reproduction. Carriers may produce gametes (sperm or egg) with an unbalanced set of chromosomes, which can lead to infertility, recurrent miscarriages, or the birth of a child with health problems.
Unbalanced rearrangements involve the loss or gain of genetic material and are more likely to have direct health consequences. For example, Cri-du-chat syndrome results from a deletion on chromosome 5 and is characterized by a distinctive cry in infants and developmental delays. Similarly, some cases of Down syndrome are caused by a Robertsonian translocation involving chromosome 21, which results in an extra copy of its genetic material.
Structural changes also play a role in cancer. A well-known example is the Philadelphia chromosome, a translocation between chromosomes 9 and 22. This event creates a fusion gene (BCR-ABL) that drives Chronic Myeloid Leukemia (CML) and is a target for specific therapies.
From an evolutionary perspective, chromosomal rearrangements contribute to the divergence of species. Over time, the accumulation of different rearrangements between populations can create reproductive barriers. If members from these groups reproduce, their chromosomes may not pair correctly during meiosis, leading to inviable offspring and reinforcing their separation into distinct species.