Our genetic makeup, largely composed of DNA, provides instructions for building and operating our bodies. While we share many similarities, subtle differences exist, making each person unique. These natural variations contribute to the diverse range of traits observed across the human population, influencing everything from eye color to how our bodies respond to environmental factors.
The Basics of Genetic Variation
A gene is a specific segment of DNA that carries instructions for building a protein or performing a specific function. Each gene exists in different versions, known as alleles. For most genes, individuals inherit two alleles, one from each parent, located on paired chromosomes called homologous chromosomes. When an individual inherits two identical alleles for a particular gene, they are described as homozygous for that gene. Conversely, if they inherit two different alleles for a specific gene, they are considered heterozygous. This interplay of homozygous and heterozygous states across countless genes contributes to the vast diversity seen in human traits.
Defining Absence of Heterozygosity
Absence of heterozygosity, often referred to as AOH, describes genomic regions where an individual has inherited identical alleles from both parents. This means that instead of having different versions of a gene or DNA segment on their two homologous chromosomes, they have two copies that are exactly the same. While these regions are inherently homozygous, the term “absence of heterozygosity” emphasizes that these segments could potentially have shown variation but do not. AOH can span a wide range of sizes, from small segments encompassing a few genes to large regions covering an entire chromosome. The presence of AOH indicates a lack of genetic diversity within that specific genomic area.
How Absence of Heterozygosity Arises
AOH can arise through several biological mechanisms. A common cause is consanguinity, which occurs when parents are related by blood and share common ancestors. This increases the likelihood that their offspring will inherit identical chromosomal segments and alleles from both parents, resulting in large AOH regions across the genome.
Another mechanism involves chromosomal deletions, where a segment of a chromosome is lost. If an individual has a deletion on one chromosome and the corresponding region on the homologous chromosome is identical, it can lead to AOH. Uniparental disomy (UPD) is where an individual inherits both copies of a chromosome, or part of a chromosome, from only one parent instead of receiving one copy from each. This results in two identical copies from the same parent, leading to AOH for that region.
Mitotic recombination, or loss of heterozygosity (LOH), is a process that typically occurs in somatic cells rather than being inherited. During cell division, genetic material can be rearranged, leading to the loss of one allele and the duplication of the other. This results in a region that was once heterozygous becoming homozygous.
Health Consequences of Absence of Heterozygosity
AOH can have health implications, primarily by unmasking recessive alleles. Many genetic disorders are recessive, meaning a person must inherit two copies of a disease-causing allele to develop the condition. When AOH occurs in a region containing a recessive disease allele, the individual inherits two identical copies, leading to the disorder. For instance, if an AOH region contains a gene for cystic fibrosis and a disease-causing allele is present, the individual will develop the condition because there is no functional allele to compensate.
Uniparental disomy can also lead to disorders involving imprinted genes. These genes are expressed only from the copy inherited from a specific parent, either the mother or the father. If AOH due to UPD results in both copies of an imprinted gene coming from the wrong parent, it can disrupt normal gene function. This mechanism underlies conditions such as Prader-Willi syndrome and Angelman syndrome, which arise from issues with imprinted genes on chromosome 15.
Loss of heterozygosity (LOH) is relevant in the development and progression of cancer. Many tumor suppressor genes, which regulate cell growth and prevent tumor formation, require both copies to be functional. If an individual inherits one non-functional copy of a tumor suppressor gene, and then experiences LOH in a somatic cell that removes the functional copy, the cell loses its ability to control growth. This “second hit” can initiate or accelerate tumor development, making LOH a common finding in various cancers.
Identifying Absence of Heterozygosity
Identifying AOH typically involves advanced genetic technologies that analyze an individual’s entire genome. One widely used method is the SNP array, or single nucleotide polymorphism array. These arrays contain millions of probes that detect single nucleotide variations across the genome, identifying large regions with identical alleles and no variation. The pattern of these identical stretches helps pinpoint AOH regions.
Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are also powerful tools for detecting AOH. WGS involves reading the entire DNA sequence of an individual, while WES focuses on the protein-coding regions of genes. Both methods identify AOH by revealing extended stretches of DNA where the two inherited copies are identical. These advanced sequencing techniques provide information about the genome’s composition.
AOH detection is employed for various clinical and research purposes. It is used in diagnostic settings to investigate the genetic basis of developmental delays or unexplained medical conditions. AOH detection also plays a role in carrier screening for recessive disorders and in cancer research to understand tumor genetics.