1.5.15 Allelic Imbalance Definition

Allelic Imbalance Definition is the description of a state in which the two alleles of a given genetic locus within a diploid cell are not present, expressed, or represented in equal proportion, such that one allele contributes a disproportionately greater or lesser share of the DNA copy number, the transcribed RNA, or the resulting protein product relative to the other allele at that same locus. Allelic imbalance is a broad descriptive concept that can arise from several distinct underlying mechanisms, including unequal loss or gain of chromosomal material, differential transcriptional regulation of the two alleles, or skewed inheritance patterns, and it is widely used in cancer cell biology as a measurable indicator of underlying genomic instability and clonal genetic alteration.

Conceptual Basis of Allelic Imbalance

The Normal Diploid Expectation

In a normal diploid somatic cell, each autosomal genetic locus is present in two copies, one inherited from each parent, and under typical circumstances these two copies are each present at a single copy number and are each expressed at broadly comparable levels, subject to normal biological variability. Allelic imbalance describes any deviation from this expected condition of parity between the two allelic copies of a locus.

Distinguishing Allelic Imbalance from Simple Mutation

Allelic imbalance is conceptually distinct from a point mutation or small insertion or deletion affecting a single allele's sequence. Whereas a point mutation changes the sequence content of one allele without necessarily altering its relative copy number or expression proportion, allelic imbalance specifically concerns the quantitative relationship between the two alleles, regardless of whether either allele's underlying sequence has been altered.

Mechanisms Producing Allelic Imbalance

Copy Number-Based Allelic Imbalance

The most common mechanism producing allelic imbalance in cancer cells is a change in the copy number of one allele relative to the other. This can occur through loss of one allele, such as through a chromosomal deletion or loss of an entire chromosome, or through selective amplification of one allele, such as through localized gene amplification or duplication of the chromosome segment carrying that allele. In either circumstance, the ratio of one allele's copy number to the other's departs from the normal one-to-one relationship.

Loss of Heterozygosity as a Specific Form of Allelic Imbalance

A specific and biologically significant form of allelic imbalance occurs when one allele at a locus is completely lost, leaving only the second allele present, a condition referred to as loss of heterozygosity. This form of allelic imbalance is of particular importance in cancer cell biology when the retained allele carries an inactivating alteration, since the loss of the other, previously functional, allele removes the last remaining functional copy of the gene.

Expression-Based Allelic Imbalance

Allelic imbalance can also occur without any change in the copy number of either allele, through unequal transcriptional activity between the two alleles. Differential promoter activity, differential chromatin accessibility, or epigenetic silencing of one allele, such as through promoter methylation, can cause one allele to be transcribed at a substantially higher or lower level than the other, producing an imbalance detectable at the level of messenger RNA even when both alleles remain present in equal genomic copy number.

Imprinting-Related Allelic Imbalance

At certain genetic loci, allelic imbalance is a normal and expected condition arising from genomic imprinting, in which one parental allele is programmed to be transcriptionally silent while the other parental allele is actively expressed. In cancer cell biology, disruption of normal imprinting patterns, including loss of imprinting or loss of the active allele, can convert this normally regulated allelic imbalance into an abnormal contributor to disease.

Detection of Allelic Imbalance

Use of Heterozygous Marker Sites

Detection of allelic imbalance requires the presence of a genetic position at which an individual is heterozygous, meaning that the two inherited alleles differ from one another in sequence, so that the relative contribution of each allele can be distinguished and measured. Common marker types used for this purpose include single nucleotide polymorphisms and short repeat sequences that vary in length between alleles.

Quantitative Comparison Approaches

Once a heterozygous marker site is identified, allelic imbalance is assessed by quantitatively comparing the signal, sequence read count, or expression level attributable to each allele. A significant departure from the expected equal contribution, beyond what would be expected from ordinary measurement variability, is interpreted as evidence of allelic imbalance at that locus.

Significance of Allelic Imbalance Within Cancer Cell Biology

Allelic Imbalance as a Marker of Genomic Instability

Widespread allelic imbalance across many loci within a tumor genome is regarded as a marker of underlying genomic instability, reflecting the accumulation of chromosomal rearrangements, segmental deletions, and segmental amplifications that characterize many cancer cell genomes as they progress.

Relevance to Tumor Suppressor Gene Inactivation

Allelic imbalance is of particular relevance when it results in loss of heterozygosity at a locus containing a tumor suppressor gene, since this event can complete the inactivation of that gene when combined with a prior alteration affecting the remaining allele, contributing directly to the loss of a growth-restraining function within the cell.