Heterozygous Genotype: Traits and Diseases

Heterozygous is a term used in genetics to describe when two variations of a gene, known as alleles, are paired at the same location (locus) on a chromosome. By contrast, homozygous is when there are two copies of the same allele at the same locus.

The term heterozygous is derived from "hetero," meaning different, and "zygous," meaning related to a fertilized egg, or zygote.

Determining Traits

Humans are called diploid organisms because they have two alleles at each locus, with one allele inherited from each parent. The specific pairing of alleles translates to variations in an individual’s genetic traits.

An allele can either be dominant or recessive. Dominant alleles are those that express a trait even if there is only one copy. Recessive alleles can only express themselves if there are two copies.

One such example is the genetic inheritance of brown eyes, which is dominant, and blue eyes, which is recessive. If the alleles are heterozygous, the dominant allele would express itself over the recessive allele, resulting in brown eyes.

At the same time, the person would be considered a "carrier" of the recessive allele, meaning that the blue-eye allele could be passed to offspring even if that person has brown eyes.

Alleles can also be incompletely dominant, an intermediate form of inheritance where neither allele is expressed completely over the other.

An example of this might include an allele corresponding to dark skin, in which a person has more melanin, when paired with an allele corresponding to light skin, in which there is less melanin. This might create a skin tone somewhere in between.

Disease Development

Beyond the physical characteristics of an individual, the pairing of heterozygous alleles can sometimes translate into a higher risk of certain conditions such as birth defects or autosomal disorders (diseases inherited through genetics).

If an allele is mutated, a disease can be passed to offspring even if the parent experiences no signs of the disorder. With respect to heterozygosity, this could take one of several forms:

• If the alleles are heterozygous recessive, the faulty mutated allele would be recessive and not express itself. Instead, the person would be a carrier.
• If the alleles are heterozygous dominant, the faulty allele would be dominant. In such a case, the person may or may not be affected (compared to homozygous dominance where the person would be affected).

Other heterozygous pairings would simply predispose a person to a health condition such as celiac disease and certain types of cancer. This doesn’t mean that a person will get the disease; it simply suggests that the individual is at higher risk.

Other factors, such as lifestyle and environment, would also play a part.

Single Gene Disorders

Single gene disorders are those that are caused by a single mutated allele rather than two. If the mutated allele is recessive, the person will usually not be affected.

However, if the mutated allele is dominant, the mutated copy can override the recessive copy and cause either a less severe form of a disease or a fully symptomatic disease.

Single gene disorders are relatively rare. Among some of the more common heterozygous dominant disorders are:

• Huntington’s disease, an inherited disorder that results in the death of brain cells. The disease is caused by a dominant mutation in either one or both alleles of a gene called Huntingtin.
• Neurofibromatosis type-1 is an inherited disorder in which nerve tissue tumors develop on the skin, spine, skeleton, eyes, and brain. Only one dominant mutation is needed to trigger this effect.
• Familial hypercholesterolemia (FH) is an inherited disorder characterized by high cholesterol levels, specifically "bad" low-density lipoproteins (LDLs). It is by far the most common of these disorders, affecting around one of every 500 people.

A person with a single gene disorder has a 50/50 chance of passing the mutated allele to a child who will become a carrier.

If both parents have a heterozygous recessive mutation, their children will have a one-in-four chance of developing the disorder. The risk will be the same for every birth.

If both parents have a heterozygous dominant mutation, their children have a 50% chance of getting the dominant allele (partial or complete symptoms), a 25% chance of getting both dominant alleles (symptoms), and a 25% of getting both recessive alleles (no symptoms).

Compound Heterozygosity

Compound heterozygosity is the state where there are two different recessive alleles at the same locus that, together, can cause disease. These are typically rare disorders that are often linked to race or ethnicity.

Among these conditions are:

Tay-Sachs disease

Tay-Sachs disease is a rare, inherited disorder that causes the destruction of nerve cells in the brain and spinal cord. It is a highly variable disorder that can cause disease during infancy, adolescence or later adulthood.

While Tay-Sachs is caused by genetic mutations of the HEXA gene, it is the specific pairing of the alleles that ultimately determines which form the disease takes. Some combinations translate to childhood disease, while others translate to later onset disease.

Phenylketonuria

Phenylketonuria (PKU) is a genetic disorder primarily affecting children in which a substance known as phenylalanine accumulates in the brain. This causes seizures, brain disorders, and intellectual disability. There is a vast diversity of genetic mutations associated with PKU, the pairings of which can lead to milder or more severe forms of the disease.

Other diseases in which compound heterozygotes can play a part are cystic fibrosis, sickle cell anemia, and hemochromatosis (excessive iron in the blood).

Heterozygote Advantage

While a single copy of a disease allele usually doesn’t result in illness, there are cases where it can provide protection against other diseases. This is a phenomenon referred to as heterozygote advantage.

In some cases, a single allele can alter the physiological function of an individual in such a way as to make that person resistant to certain infections. Among the examples:

Sickle cell anemia

Sickle cell anemia is a genetic disorder caused by two recessive alleles. Having both alleles causes the malformation and rapid self-destruction of red blood cells. Having only one allele can cause a less severe condition called sickle cell trait in which only some cells are malformed.

These milder changes are enough to provide a natural defense against malaria by killing off the infected blood cells faster than the parasite can reproduce.

Cystic fibrosis

Cystic fibrosis (CF) is a recessive genetic disorder that can cause a severe impairment of the lungs and digestive tract. In persons with homozygous alleles, CF causes a thick, sticky buildup of mucus in the lungs and gastrointestinal tract.

In persons with heterozygous alleles, the same effect, albeit reduced, can lower a person’s vulnerability to cholera and typhoid fever. By increasing mucus production, a person is less susceptible to the damaging effect of infectious diarrhea.