Understanding the Mechanisms of Inheritance

In this section, we will explore how traits are passed from parents to their children, building on the foundational work of Gregor Johann Mendel. Most traits that make up an individual are inherited through what are known as Mendelian inheritance patterns, such as autosomal dominant and autosomal recessive inheritance. However, with advances in genetic research, we now know that not all traits follow these classic patterns. Some involve more complex, non-Mendelian inheritance mechanisms, and many are also influenced by environmental factors that affect how genes are expressed.

We will explore these concepts, with a specific focus on Huntington’s disease and its autosomal dominant pattern of inheritance. Remember, each person inherits genetic information from both biological parents, which means every gene comes in pairs, making its function complete.

Autosomal Recessive Inheritance

Autosomal recessive inheritance occurs when an individual inherits two copies (a “double dose”) of an altered gene. Individuals those who carry only one copy of the mutated gene are considered carriers. Carriers do not show symptoms of the disease but can pass the altered gene to their children. When two carrier parents have a biological child together, there is a chance that the child inherits both altered gene. In individuals who inherit two altered copies of the gene, the body cannot produce required amounts of normal protein, or it may produce high levels of altered protein. Examples of autosomal recessive diseases include cystic fibrosis, sickle cell anemia, and Tay-Sachs disease.

Figure 1. Autosomal Recessive inheritance pattern

When two carriers have a child, there is a:

25% chance the child inherits two normal gene copies, not developing the disease or being a carrier.
50% chance the child becomes a carrier like the parents.
25% chance the child inherits two affected gene copies, potentially showing symptoms of the condition.

This means that typically, both parents need to be carriers for their child to inherit the condition, highlighting the recessive nature of the gene.

Autosomal Dominant Inheritance

Autosomal dominant inheritance occurs when an individual inherits just one altered copy of a gene. One copy of the altered gene is enough to interfere with the protein production, which can either decreased levels of normal protein, or may produce high levels of altered protein. Therefore, when one of the parent carries a copy of the altered gene, each of their biological children has a chance of inheriting that copy of the gene and therefore a risk of developing the condition. Huntington’s disease is an example of a condition that follows autosomal dominant inheritance pattern.

Figure 2. Autosomal Dominant inheritance pattern

For someone affected by an autosomal dominant condition, each child they have has a:

50% chance of inheriting the altered gene, and therefore potentially developing the condition
50% chance of inheriting the working gene copy, meaning they will not develop the condition or pass it on

This pattern means that a parent only needs one altered gene copy for the condition to be passed on. While Huntington’s disease follows a clear autosomal dominant inheritance pattern, other factors such as gene expansion size, age of onset, and individual biological differences can influence how and when symptoms develop.

Non-Mendelian Factors of Inheritance in Huntington’s Disease

Navigating the scientific aspects of Huntington’s disease can be a bit overwhelming, with research sometimes feeling like a maze. Rest assured, we are here to simplify it for you. Our goal is to provide information in a way that not only keeps you informed but also helps you grasp the complexities of Huntington’s disease. Below, we dive into the fascinating non-mendelian factors of inheritance. If you have not had the chance yet, we recommend reading the “Mechanisms of HD” content to build a solid foundation. Huntington’s disease, characterised by the abnormal expansion of CAG repeats in the HTT gene, was initially associated with mendelian genetics.

However, our understanding has evolved to uncover additional layers of complexity. In this section, we discuss three crucial aspects: Reduced Penetrance, Anticipation, and Non-CAG Modifiers. These factors challenge traditional views by demonstrating that predicting the course of Huntington’s disease involves more than just counting CAG repeats.

Reduced penetrance

The term “penetrance” measures the proportion of people who develop the symptoms of any condition as opposed to the individuals who live their entire life without developing any symptoms associated to the gene mutation. Surprisingly, some individuals carrying the mutated form of the HTT gene (with 36-39 CAG repeats) never show symptoms of Huntington’s disease. Reduced penetrance is likely influenced by genetics, environment, and lifestyle, making it challenging to predict a person’s risk of passing on the condition.

Figure 1: Reduced penetrance (Only for individuals with 36-39 CAG repeats)

In Figure 1, the lighter shade represents an individual with a CAG repeat between 36-41, who does not exhibit any symptoms of Huntington’s Disease throughout their lifetime, despite having a sibling with the same number of CAG repeats who does exhibit symptoms similar to their parent. However, the non-symptomatic sibling will still produce abnormal protein and is at a 50% risk of having children who can develop Huntington’s Disease.

Anticipation

In families with Huntington’s disease, it’s observed that the disease’s onset occurs earlier in successive generations. This phenomenon, called anticipation, may be linked to increased instability in the CAG repeats during reproduction, leading to earlier symptom appearance.

Figure 2: Anticipation (Only for individuals with 36-39 CAG repeats)

In figure 2, the increasing intensity of the colour with each passing generation signifies increase in CAG repeats, a phenomenon that occurs during reproduction. This increase in the CAG repeats is assumed to result in early onset and severe symptoms in each passing generation.

Non-CAG modifiers

Recent studies suggest that factors such as age, lifestyle, and other genes beyond the CAG repeats can impact symptom development in Huntington’s Disease. For instance, individuals with 38 CAG repeats may begin experiencing symptoms in their early 50s, while others with the same number of CAG repeats may not show any symptoms until their late 60s. This variation is believed to be influenced by factors such as lifestyle choices, mental health, and gut health. Additionally, genes involved in DNA repair mechanisms and other adjacent genetic factors also play a role in determining the age of symptom onset.

While it is essential to understand, Mendelian and Non-Mendelian factors influencing complexity of Huntington’s disease. Click the button below to learn more about the HTT gene and how changes in this gene affect the body.

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