We inherit two copies of almost every gene, one from each biological parent. These inherited gene versions, known as alleles, account for the natural variations we observe among individuals.
Understanding Genetic Basics
Each gene has multiple possible versions, called alleles, and an individual inherits two alleles for each gene. When these two inherited alleles for a specific gene are identical, the individual is considered “homozygous” for that gene. If the two alleles are different, the individual is “heterozygous” for that gene.
Alleles can interact in different ways, often described as dominant or recessive. A dominant allele expresses its trait even if only one copy is present, effectively masking the presence of a recessive allele. A recessive allele, conversely, only expresses its trait if an individual inherits two copies of it. In a heterozygous state, where one allele is functional and dominant, it can often compensate for a non-functional or altered recessive allele, maintaining normal biological processes.
What Loss of Heterozygosity Means
Loss of Heterozygosity (LOH) describes a specific genetic event where a cell, which initially possessed two different alleles for a particular gene, loses one of them. This typically involves the loss of the normal, functional allele, leaving behind only the altered or non-functional version. As a result, the cell effectively becomes homozygous for the previously altered allele at that specific location on the chromosome. This loss of the protective, functional genetic copy can have significant consequences for cell behavior.
How Loss of Heterozygosity Occurs
LOH can arise through several cellular mechanisms, all leading to the elimination of one allele. One common way is through a deletion, where a segment of a chromosome containing the normal allele is physically removed. Another mechanism is mitotic recombination, which involves the exchange of genetic material between homologous chromosomes during cell division, potentially resulting in a cell inheriting two copies of the altered allele. Non-disjunction, an error during cell division where chromosomes fail to separate properly, can also lead to LOH by causing a cell to receive only the chromosome carrying the altered allele. Additionally, gene conversion, a process where genetic information from one allele is copied over and replaces the normal allele, contributes to this loss.
Why Loss of Heterozygosity Matters
LOH holds considerable significance in biological processes, particularly in disease development. It plays a role in the “two-hit hypothesis,” which explains how certain diseases, especially many cancers, arise. For individuals who inherit one non-functional copy of a tumor suppressor gene, they typically remain healthy because the other functional copy still performs its role in regulating cell growth. Tumor suppressor genes act like brakes on cell division, preventing uncontrolled proliferation.
LOH represents the “second hit” in this hypothesis, as it eliminates the remaining functional copy of the tumor suppressor gene. With the loss of this normal allele, only the non-functional version remains, removing the cell’s natural brake on growth. This can lead to uncontrolled cell division and tumor formation. LOH is a frequent finding in numerous cancers, including breast, colon, lung, and ovarian cancers. For example, LOH affecting the BRCA1 and BRCA2 genes is associated with increased breast and ovarian cancer risk, while LOH at the TP53 gene is commonly seen in many cancer types, including lung and colon.