Back To CourseBiology 102: Basic Genetics
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Human genetics can be complicated, especially when you think about all of the different types of inheritance that are possible. At least there are some genetic conditions that are simple, like autosomal dominant conditions, right? Well, not so fast! We are talking about biology here, and one of the most important lessons I've learned over the years is that there is almost always an exception to the rule when it comes to biological systems. This applies to dominant human conditions as well.
You see, when a person inherits a dominant allele, we expect them to exhibit a particular trait or set of traits that constitute a condition or syndrome. However, what we find in reality is that a dominant allele will affect different people in different ways, and even people with the same specific genotype can show phenotypic variability, or a range of different phenotypes. There are two technical terms that geneticists use to describe phenotypic variability: expressivity and penetrance.
Expressivity is the extent to which a trait or condition is expressed. In other words, expressivity refers to how mild or severe the phenotype is and which of the hallmarks of the condition are present in the phenotype. Many genetic conditions have been identified as a set of characteristics that occur together. These conditions are called syndromes and are groupings of recognizable characteristics that occur together and have a common cause. Genetic syndromes are often quite variable in their expressivity.
Let's take, for example, the rare autosomal dominant syndrome Peutz-Jeghers Syndrome, which we will call PJS for short. PJS is a syndrome where affected individuals have the following characteristics. The first characteristic is dark spots reminiscent of freckles in and around the mouth and lips and sometimes on the fingers and toes. This is a drawing of twin sisters who both have PJS. The spots around their mouths are examples of what the spots often look like in PJS patients.
The second characteristic is high numbers of gastrointestinal polyps, which are basically outgrowths of the intestinal wall. In this simplified diagram, you can see a polyp growing out from the intestinal wall and an instrument that a doctor can use to remove polyps from the gastrointestinal tract.
The third characteristic of PJS is an increased risk of various types of cancer. All of these characteristics are hallmarks of PJS, but there is a lot of variability among individuals for each of these characteristics, and not every PJS patient exhibits all three. Some people may have the dark spots around their mouth and lots of gastrointestinal polyps but never develop cancer, while others may have few polyps, no dark spots, and develop several cancerous tumors in their lifetime.
Expressivity doesn't just refer to the number of characteristics a patient has; it can also refer to the severity of any single characteristic or the severity of the entire condition as a whole. For example, in PJS, the number of gastrointestinal polyps varies significantly from patient to patient. Some have only a few, while others may have hundreds over the course of their lifetime.
In addition, a general susceptibility to multiple types of cancers introduces an inherent variability into this condition. It's difficult to determine whether the severity of something like cancer risk changes from patient to patient. However, it is clear that some patients develop more severe and aggressive forms of cancer than others, so in this sense, the severity of the resulting cancers is variable.
So what is the cause of this variation in expressivity? Nobody can really say with certainty that they know the exact cause of variability or that there even is a single cause. But two of the most popular explanations are: 1. A person's genetic background may influence the expressivity of dominant traits, and 2. Different specific mutations within the causative gene may cause differences in expressivity between patients.
For example, a PJS mutation in one family may create a completely ineffective protein to be produced, while a PJS mutation in a second family may create a protein that is only partially defective. The reasoning here is that the family with the more severe mutation would have more severe symptoms as well.
However, this theory has many critics, based on data collected from several PJS families where family members had variable expressivity even though they all shared the same mutation. In one family, a father with PJS only had polyps, his son only had dark spots, and his daughter had both polyps and dark spots. In truth, expressivity appears to be influenced by many factors, which may include unknown environmental factors or even random chance.
While expressivity is a very qualitative measure of variability, penetrance is a more quantitative measure. Penetrance is the percentage of individuals with a dominant allele who also exhibit the dominant phenotype. Now I know that some of you are scratching your heads here because we assume that if a person has a dominant gene, they will also have the dominant phenotype. This is true for some conditions, like PJS, which is thought to have penetrance of 100% or very close to it. However, many conditions don't follow the Mendelian genetics so faithfully. These conditions are said to have incomplete penetrance, and an estimate of the percentage of penetrance can be made from pedigrees, and family history data, and now DNA sequencing can also be used.
To help demonstrate the difference between penetrance and expressivity, let's take a look at another autosomal dominant condition called retinitis pigmentosa 11, which we will abbreviate to RP11. RP11 follows the same invariant pattern in all affected individuals. First, the person experiences visual field loss and night blindness in their teen years, and then the disease progresses to the point that most individuals are considered legally blind by the time they reach their thirties, although complete vision loss is uncommon.
In RP11, the symptoms, severity, and age of onset are all very consistent among affected individuals, even from different families. However, the penetrance of RP11 is estimated to be somewhere in the range of 60-70%. This means that approximately one out of every three people who carry the mutation is completely unaffected, but he or she is still able to pass the gene and the condition along to their children.
Now we've looked at two different autosomal dominant conditions - one that shows complete penetrance and highly variable expressivity and another that shows incomplete penetrance and very little variation in expressivity. However, penetrance and expressivity aren't mutually exclusive; there are many other genetic conditions which exhibit both incomplete penetrance and variable expressivity.
The causes of incomplete penetrance have proven to be just as elusive as the causes of variable expressivity. For now, there does not seem to be any single universal cause of incomplete penetrance across all genetic conditions. Instead, it appears as though condition-specific theories may be necessary to explain the causes of incomplete penetrance.
In summary, although autosomal dominant conditions may seem simple and straightforward, in reality, most of these conditions are actually a little more complicated. Dominant alleles sometimes affect different people in different ways, and even people with the same specific genotype can show phenotypic variability, or a range of different phenotypes. There are two technical terms that geneticists use to describe phenotypic variability: expressivity and penetrance.
Expressivity is the extent to which a trait or condition is expressed. In other words, expressivity refers to how mild or severe the phenotype is and which of the hallmarks of the condition are present. Penetrance is the percentage of individuals with a dominant allele that also exhibit the dominant phenotype. For a genetic condition like retinitis pigmentosa 11, which has only about 60-70% penetrance, it means that about two-thirds of the people who have the causative allele will also suffer from the condition. Meanwhile, the other thirty-something percent will not show any signs of the condition at all. As a result, even autosomal dominant conditions will sometimes skip generations if the condition shows incomplete penetrance.
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Back To CourseBiology 102: Basic Genetics
8 chapters | 113 lessons