GENETICS
Huntington’s disease
In scientific terms, heritability is a statistical concept that describes how much of the variation in each trait can be attributed to genetic variation. Heritability estimates range from zero to one. Heritability close to zero indicates that almost all the variability in a trait among people is due to environmental factors, with very little influence from genetic differences. Characteristics such as religion or language spoken have a heritability of zero because they are not under genetic control. Heritability close to one indicates that almost all the variability in a trait comes from genetic differences, with very little contribution from environmental factors. Most complex traits in people, such as intelligence and multifactorial diseases, have a heritability somewhere in the middle, suggesting that their variability is due to a combination of genetic and environmental factors.
When we refer to a disease as a heritable disease, we are strongly referring to the action of genes and the traits we get from either or both of our parents. These diseases are commonly explained to “run in the family”. If one person in your family is affected by the disease, then there is a chance that another person is also affected.
To refer to a disease as heritable, it needs to meet a major criterion, and that is, it needs to be caused by a genetic mutation that can be passed on from one or both parents. A parent having a mutation in their genes does not necessarily mean that they will pass it down to their offspring. The place of the mutated gene affects whether it is passed on or not. A mutation can happen in two types of cells and that determines if it can be inherited or not. These mutations are germline mutations and somatic mutations. Mutations in germline cells are heritable, but not the ones in somatic cells.
Just because a mutation is inherited does not necessarily mean that the disease will occur. Some mutations are purely recessive, meaning if only one of the parents passes it on, the offspring will not have the disease. However, some mutations are purely dominant, meaning it does not matter whether one or both parents have it. If one of them passes their mutation to their offspring, they will be affected. An example of this is Huntington’s disease.
Although genetic mutations play an important role in the presence of a disease, other factors also play a role. When discussing a disease, we should always keep in mind the concept of nature versus nurture. Nature, genetics, is what we refer to as the genetic factor. It is something we were born with and not affected by our surroundings. Nurture is what we consider an environmental factor, it includes physical activity, diet, living style, and so on.
Huntington’s disease is an autosomal dominant disorder that leads to the progressive degeneration of nerve cells in the brain that affects movement, cognitive functions, and emotions. This disease is rare, however, the fact that it does not have any cure and that it is a heritable disease makes it harder to deal with. It is a genetic disorder mainly caused by a mutation in the HTT gene. HTT gene is the gene that provides the instruction to make proteins called Huntington. This mutation results in excessive production of cytosine, adenine, and guanine (CAG). The repeats of the number of CAGs determine if the disease could be a complete inheritance or incomplete inheritance. Let’s assume two siblings have one parent with Huntington’s disease and they both inherit the genes. If sibling A has 41 or more CAG repeats, then the disease will have a complete penetrance, meaning sibling A will have the disease along with the gene. Sibling B, on the other hand, has 36-40 CAG repeats. In this case, sibling B will have an incomplete penetrance, meaning they will not have the disease, but the gene would still be present.
Huntington’s disease like other diseases has two factors that play an important role, they are nature and nurture. If Huntington’s disease is heritable, what does nurture have to do with it? First, let’s start with what nature means regarding Huntington’s disease. Nature plays a very big role in the development of this disease because the primary cause is a genetic mutation. A heritability score of 0.6-0.8, further proves the effects of nature, genetics, on its development. Genetic inheritance plays a crucial role in deciding whether a person will develop this disease or not. Nurture, however, will not determine whether you will have this disease or not, but influences the age of onset and the progression of the symptoms. By the environment, we are referring to certain lifestyles which may include diet or even stress. There are studies on how stress affects the course of Huntington’s.
Heritability has historically been estimated from twin studies. Identical twins have almost no differences in their DNA, while fraternal twins share, on average, 50% of their DNA. By studying the prevalence of the disease in twin and fraternal twins, researchers can determine which factor plays more role in its presence. If a trait appears to be more similar in identical twins than in fraternal twins (when they were raised together in the same environment), genetic factors likely play an important role in determining that trait. Researchers can also calculate an estimate of the heritability of a disease by comparing a trait in identical twins versus fraternal twins.
Considering the similarity in their DNA we would assume that Huntington’s disease would have a similar expressivity in twins. However, there are twin studies that reported both twins having Huntington’s but with different onset and course. Reports show a pair of 55-year-old monozygotic twin sisters with HD due to a 45-CAG repeat who showed phenotypic discordance for the disease. At age 43, twin 1 showed anxiety, irritability, and mildly aggressive behavior. At age 46, she had prominent hyperkinesis, behavioral disturbances, and mild cognitive deterioration. By age 54, she had an independence scale of 30%. Twin 2 had an onset at age 51 of depressive symptoms and mild hyperkinesis. By age 54, she had an independence scale of 50%. The age of onset differed by 8 years regarding behavioral changes, or by 6 years regarding chorea movements. The first twin showed prominent chorea hyperkinesis and aggressivity, while the second had severe depression with marked withdrawal and mild chorea hyperkinesis. If the study was not regarding twins, we could have considered environmental and genetic factors as the cause of the variable expressivity. However, the twin study led to the conclusion that the variable expressivity could be due to epimutations in critical DNA regions.
In conclusion, we have discussed in this paper the definition of heritability and how we can use the heritability number to determine whether the variability in a trait is due to environmental factors or genetic factors. Environmental factors are factors that we refer to as nurture, they are factors that are dependent on the surroundings of the person. Genetic factors are the factors that depend on your genes, which we refer to as nature. The genetic factor is where our family history is taken into more consideration. Unfortunately, there are no treatments that can change the course of Huntington’s disease, but there are many clinical trials underway that could possibly slow down or stop the progression. With these trials and research, the future of Huntington’s disease treatments is promising.