Absence of Heterozygosity and Its Role in Genetics and Oncology

Genetic variations influence both normal biological processes and disease development. One such variation, the absence of heterozygosity (AOH), occurs when both copies of a chromosomal region are identical, which can have significant implications for inherited conditions and cancer.

Understanding AOH helps reveal genetic risks and contributes to disease progression. Researchers and clinicians analyze these patterns to improve diagnostics and treatment strategies.

Genetic Mechanisms

AOH arises from genetic processes that create regions of identical alleles. This can result from uniparental disomy (UPD), identity by descent (IBD), or copy-neutral loss of heterozygosity (cnLOH). Each mechanism contributes to homozygous regions, influencing biological outcomes depending on the affected genes.

Uniparental disomy occurs when an individual inherits both copies of a chromosome or segment from one parent instead of one from each. This can result from meiotic errors, such as trisomy rescue, where a trisomic embryo loses one chromosome to restore a diploid state. If the lost chromosome is from the other parent, the remaining homologous pair is identical, leading to AOH. Depending on whether the affected region contains imprinted genes—where expression is parent-of-origin specific—this can result in developmental disorders or altered gene regulation.

Identity by descent arises when both parents share a common ancestor, increasing the likelihood that their offspring inherit identical chromosomal segments. This is particularly relevant in consanguineous populations, where long stretches of homozygosity are more frequent. Studies show that such regions can unmask recessive mutations, increasing the risk of autosomal recessive disorders. Genome-wide analyses of consanguineous populations reveal AOH spanning several megabases, underscoring its role in genetic disease susceptibility.

Copy-neutral loss of heterozygosity, a somatic event, occurs through mitotic recombination or gene conversion, where a DNA segment is replaced by an identical copy from the homologous chromosome without altering overall copy number. This mechanism is significant in tissues with high cellular turnover, as it can lead to homozygous expression of previously heterozygous mutations. In cases where a tumor suppressor gene is affected, cnLOH can promote disease by eliminating the functional allele while retaining a pathogenic variant.

Detection Methods

Identifying AOH requires genomic technologies capable of detecting long stretches of homozygosity. Microarray-based genotyping and next-generation sequencing (NGS) are the primary methods used to analyze AOH, each offering distinct advantages based on resolution and scope.

Single nucleotide polymorphism (SNP) arrays assess allele frequencies at hundreds of thousands to millions of loci, identifying regions where heterozygous SNPs are absent. While effective for large-scale screening, SNP arrays have limitations in detecting smaller AOH regions or distinguishing between UPD and cnLOH.

For higher resolution, next-generation sequencing (NGS) provides a more precise approach by analyzing individual nucleotide sequences. Whole-genome sequencing (WGS) offers comprehensive coverage, identifying AOH at a single-base level, while whole-exome sequencing (WES) focuses on coding regions, making it useful for pinpointing disease-related mutations.

Computational tools interpret AOH from genomic data. Bioinformatics pipelines analyze SNP array or sequencing results to map homozygous regions, differentiate between inherited and somatic events, and estimate AOH extent. Programs like BAFSegmentation and PennCNV analyze B-allele frequency (BAF) and log R ratio (LRR) to detect deviations from expected heterozygosity patterns, while GATK’s HaplotypeCaller integrates sequencing depth and variant allele frequencies to refine detection.

In clinical practice, AOH interpretation depends on patient ancestry, family history, and disease presentation. Long homozygous stretches in consanguineous individuals suggest inherited AOH, whereas isolated regions in tumors point to somatic events like cnLOH. Genetic counselors and clinicians use these findings to assess disease risks, guide targeted testing, and inform treatment decisions. Identifying AOH in specific chromosomal regions can prompt further analysis for recessive mutations or imprinting disorders, leading to earlier diagnosis and intervention.

Role In Inherited Conditions

AOH can indicate an increased likelihood of recessive genetic disorders, particularly when large homozygous regions encompass disease-associated genes. When an individual inherits two identical copies of a chromosomal segment, any pathogenic recessive mutations within that region become fully expressed, as no functional allele compensates. This is evident in autosomal recessive disorders such as cystic fibrosis, sickle cell anemia, and Tay-Sachs disease.

Certain populations, such as the Amish, Ashkenazi Jewish, and some Middle Eastern communities, exhibit a higher prevalence of AOH due to historical patterns of endogamy and founder effects. These groups have elevated frequencies of specific recessive disorders, including Bloom syndrome, Gaucher disease, and congenital adrenal hyperplasia. Genome-wide studies show that individuals from consanguineous unions can have homozygous regions spanning several megabases, increasing the probability of recessive disease expression. Clinicians use this information for genetic counseling, offering carrier screening and preimplantation genetic diagnosis (PGD) to at-risk families.

Beyond recessive diseases, AOH plays a role in imprinting disorders, where gene expression depends on parental origin rather than sequence variation. Conditions such as Prader-Willi syndrome and Angelman syndrome arise from disruptions in imprinted regions, often due to UPD. In cases of maternal or paternal UPD, an individual inherits two copies of a chromosome from one parent and none from the other, leading to improper gene expression. This mechanism is also implicated in Beckwith-Wiedemann syndrome and Silver-Russell syndrome, where AOH affects growth regulation. Understanding these inheritance patterns allows for earlier diagnosis and targeted management strategies.

Role In Oncology

AOH significantly influences cancer development, particularly by inactivating tumor suppressor genes. Unlike traditional loss-of-function mutations involving deletions or point mutations, AOH can eliminate the normal allele while retaining a pathogenic variant. This is frequently observed in malignancies such as acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and various solid tumors, where cnLOH enables unchecked proliferation of compromised cells. Unlike deletions, AOH does not trigger a compensatory DNA damage response, allowing cancerous cells to evade detection.

In hematologic malignancies, AOH is particularly relevant due to the high turnover of blood progenitor cells and susceptibility to mitotic recombination. Studies identify recurrent cnLOH in genes such as TP53, JAK2, and RUNX1—each crucial for cell cycle regulation, apoptosis, or differentiation. For example, cnLOH affecting JAK2 in myeloproliferative neoplasms leads to homozygous expression of the JAK2 V617F mutation, driving uncontrolled JAK-STAT signaling and accelerating disease progression.

Solid tumors also exhibit AOH in cancer-associated chromosomal regions. Gliomas frequently show cnLOH on chromosome 10q, impacting the PTEN tumor suppressor gene, while colorectal cancers often harbor AOH in regions affecting APC and SMAD4. These alterations contribute to tumor evolution by disrupting DNA repair, cell adhesion, and growth regulation. Identifying AOH in these cancers is crucial for molecular diagnostics, guiding targeted therapies and prognostic assessments.

Common Chromosomal Regions

Certain chromosomal regions are more frequently affected by AOH due to their association with inherited disorders or cancer-related genes. These regions tend to be larger in consanguineous individuals and in tumors where cnLOH contributes to disease progression. Chromosomes with imprinted regions or tumor suppressor genes are particularly susceptible, making them critical areas of genetic and oncological research.

In inherited conditions, chromosome 15q11-q13 is notably affected by AOH, particularly in cases of UPD. This region is linked to Prader-Willi and Angelman syndromes, where AOH disrupts imprinting. Similarly, chromosome 11p15 is frequently involved in Beckwith-Wiedemann syndrome, where AOH alters growth-regulating genes. Large homozygous stretches on chromosome 6p in consanguineous populations can unmask recessive mutations responsible for conditions like congenital adrenal hyperplasia. These findings shape diagnostic and screening strategies.

In oncology, recurrent AOH is observed in chromosomal regions linked to tumorigenesis. Chromosome 17p, which contains the TP53 tumor suppressor gene, frequently exhibits cnLOH in glioblastomas and hematologic malignancies, resulting in homozygous loss of functional TP53. Similarly, chromosome 9p21, home to the CDKN2A and CDKN2B genes, is commonly affected by cnLOH in melanoma and lung cancer, leading to unchecked cell cycle progression. In hematologic cancers, AOH on chromosome 7q is associated with myelodysplastic syndromes, worsening disease severity. The repeated identification of these regions in different malignancies underscores AOH’s role in cancer progression and its value in guiding molecular diagnostics and targeted therapies.