In this video, we’ll learn about inherited disorders, how they differ from other causes of disease, how they’re transmitted, and how to predict the chances of an individual inheriting a disorder based on their genetic heritage. And we’ll work through some example problems as well.
Let’s start by taking a general look at what an inherited disorder is and what it’s not. A disorder is an abnormal condition which disrupts normal function, and disorders can be caused by underlying disease or environmental and social conditions. Here are a few more specific causes of disorders. Pathogens such as some bacteria, viruses, and more that can cause infectious disease often lead to disorders of certain organ systems, such as a virus that disrupts the functioning of our respiratory system. Our immune systems can react against harmless substances from outside our body, triggering allergies such as hay fever, or the structures in our own body, leading to an autoimmune response such as lupus.
Parasites such as ticks may carry infectious agents like Rocky Mountain spotted fever, and they can also weaken or damage their host. Harmful chemicals and radiation in the environment can also cause disorders, as well as a lack of resources or stressful conditions. Disorders can also be caused by changes to an individual’s genome, such as a DNA mutation that leads to sickle cell anemia or an abnormal chromosome structure that leads to Down syndrome. And there’s a great deal of interaction between these causal factors, such as our genetic information in our genes and alleles that can predispose us to the effects of any or all of these other factors.
Environmental stresses can similarly predispose individuals to other causative factors and may even cause mutations that lead to abnormal function, including cancer or heritable disease. We already noted that some parasites can carry infectious agents, and viral pathogens can also cause genetic changes, leading to increased susceptibility to effects of other factors. There are additional causes of disorders and more interactions between them, and the causes of disorders aren’t necessarily clear cut. But in this video, we’ll limit our scope to how certain alleles in our DNA can lead to heritable disorders.
First, let’s review genetic inheritance, which is all about transferring DNA molecules from one generation to the next. To do this, DNA molecules coil up into structures called chromosomes, of which humans have 23 pairs. Genes are sections of DNA molecules that generally code for proteins that affect our traits. And each is located at the same place on a certain chromosome for individuals of the same species. But the same gene doesn’t have to have completely identical genetic code between individuals. And this is why individuals of a species have the same general characteristics, such as having two eyes on the front of the head for humans, while they can still have different traits, such as different colored eyes. These different versions of the same gene are called alleles, and they’re typically represented by capital or lowercase letters.
In this example, the capital G represents a dominant allele that codes for green eyes, and the lowercase g represents a recessive allele that codes for blue eyes. Next, the DNA molecules make identical copies of themselves, producing replicated chromosomes that generally have an X shape and have the same information on each side. And the parents to be use a specialized cell division process called meiosis to make the gametes of eggs and sperm into which half of their chromosomes will be sorted. Let’s see how this occurs. We have the chromosomes inside cells from each of the parents to be here now. But instead of putting in the normal 23 pairs of chromosomes in our simplified cell diagrams here, we’ll only put one pair. Our chromosomes come in pairs since we get one chromosome of each pair from each parent, which means we still need to add another replicated chromosome to each of these cells.
Now, each of the cell diagrams for the parents to be here contain one pair of chromosomes, one from each of their mothers and one from each of their fathers, that have the same genes in the same locations although the alleles have some differences. The father to be here has inherited recessive lowercase g alleles from both of his parents, while the mother to be here has inherited a dominant capital G allele from one of her parents and a recessive lowercase g allele from her other parent. Now we can list the letters representing the alleles inherited by each parent to be as their genotypes for the eye color gene. So the mother to be will have one capital G and one lowercase g, while the father’s genotype needs to have two lowercase g’s. And we can also list their phenotype or physical trait that’s expressed by this combination of alleles.
Now these cells divide, and we can see that the chromosomes sort into similar but not identical halves. Each chromosome of a pair is separated from the other, and for humans that happens for 23 pairs. These cells divide again, along with the replicated chromosome in each, producing four cells that will mature into gametes. If these sperm and egg cells unite in the process of fertilization, the baby’s first cell will be produced, and its genotype will be capital G lowercase g. Capital letters, like this capital G here, represent dominant alleles, and alleles are dominant if one copy is sufficient to express that trait. And lowercase letters, like this lowercase g here, represent recessive alleles. For the trait of a recessive allele to be expressed, two copies of that allele are required.
So what will the baby’s phenotype or physical trait be given that it has a capital G lowercase g genotype? Well, the baby has one copy of the dominant capital G allele that codes for green eyes, so the baby’s eyes should be green. The baby also has one copy of the recessive lowercase g allele that codes for blue eyes. But the baby doesn’t have blue eyes because two copies of that allele are required to express the trait. But that’s why the father who does have two lowercase g alleles has blue eyes. So the phenotype for the capital G lowercase g genotype is green eyes. But what about if the genotype was capital G capital G? Then what would be the phenotype? Since one copy of a dominant allele is enough to have that trait show up or be expressed, two copies are more than enough, and the phenotype will still be green eyes.
Now, we’re ready to model the transmission of alleles that can lead to disorders and predict the likelihood of an individual inheriting a disease based on the genotypes of their parents. Let’s first take a look at the inheritance of recessive alleles that can lead to disease, and we’ll use the example of cystic fibrosis or CF, which causes the air sacs in the lungs to become progressively clogged and can lead to death at a young age. The gene that can cause CF is located on chromosome pair number seven. We’ll use the symbol capital F to represent the dominant normal allele of this gene and lowercase f to represent the recessive allele that codes for a dysfunctional protein that directly causes the buildup of mucus and other fluids in the affected organs.
Our goal will be to calculate the probability of inheriting each possible genotype and phenotype for any possible offspring born to parents that have the genotypes capital F lowercase f. Possible genotypes include capital F capital F, capital F lowercase f, and lowercase f lowercase f. But let’s learn some vocabulary terms for these genotypes, so we don’t have to say capital F and lowercase f so often. We can use the term homozygous dominant for capital F capital F. The prefix homo- means same and dominant refers to the capital letters. And we have two with the same capital letters, so that makes sense. The prefix hetero- in the term heterozygous means different, so that works out for genotypes that have both a capital and a lowercase letter. And the term homozygous recessive means two of the same recessive alleles.
We’ll use a diagram called the Punnett square to help solve this problem, and we’ll write the steps of how to fill out the Punnett square up here. The first step is to write the genotypes of the gametes on the outside of the Punnett square. Now, we have the gametes on the outside of the Punnett square, and we have the genotypes of each of the parents on the outside of the Punnett square as well. So both parents can make gametes with the normal dominant capital F allele, as well as gametes with the disease-causing recessive lowercase f allele. In step two, we start to produce the possible offspring genotypes by dropping the top gamete genotypes into the smaller squares below. And in step three, we complete the offspring genotypes by pulling across the genotypes from the gametes on the left into the squares to the right.
The convention is to write dominant alleles first in genotypes. Another couple of things, you can do steps two and three in whichever order you want; that doesn’t matter. And the type of gamete on the top or side of the Punnett square doesn’t matter as well. So we’ve completed the Punnett square. It’s time to move on to calculating probabilities of inheriting these different genotypes.
One of the four squares in the Punnett square contains the homozygous dominant genotype. We can write that as a fraction by writing one homozygous dominant square as the part over four total Punnett square cells as the whole. Two of the four squares contain the heterozygous genotype, so we can write that fraction as two over four. And we can simplify that fraction by dividing both the numerator and the denominator by two, giving us one-half. And one of the four squares is occupied by the homozygous recessive genotype, so we can also write the fraction one-quarter. Probabilities are also commonly given as percents, so we should calculate those as well. To do this, you should first divide each numerator by its denominator and then multiply by 100 percent.
So we can say that any child born to this couple will have a one-quarter or 25 percent chance of inheriting the homozygous dominant genotype, a one-half or 50 percent chance of inheriting the heterozygous genotype, and a one-quarter or 25 percent chance of inheriting the homozygous recessive genotype.
Now we need to determine the phenotypes for each of these genotypes. The normal allele here is dominant, so having either one or two of these alleles will lead to an unaffected phenotype, which means that an individual will not have cystic fibrosis. Using the same logic for the heterozygous genotype, one dominant allele is enough to be unaffected, which again means no CF. But these individuals will be carriers, which means they can pass this disease-causing allele onto their offspring. The disease-causing allele in cystic fibrosis is recessive.
To express a recessive trait, you need two copies of the recessive allele, which is what homozygous recessive individuals have. So their phenotype is affected, and they do have CF. So any child born to this couple will have a 25 percent chance of being unaffected and not being a carrier, a 50 percent chance of being unaffected by CF but still being a carrier, and they’ll have a 25 percent chance of being affected by CF.
Now, let’s take a look at the inheritance of disorders that are caused by a dominant allele or alleles. And we’ll use the example of Huntington’s disease or HD. In Huntington’s disease, the normal allele is recessive; we’ll represent it with lowercase h. The disease-causing allele is dominant and we’ll use capital H to represent it. We still wanna calculate the probability of inheriting each possible genotype and phenotype of any possible offspring from parents with the genotypes heterozygous and homozygous recessive.
The first step of the Punnett square is to list the gamete genotypes on the outside, and we get those from the parent genotypes. The mother can produce eggs with either a dominant disease-causing allele or a recessive normal allele, while the father produces sperm with only the normal recessive allele. In step two, we copy the genotypes of the gametes on top of the Punnett square into the smaller squares below. And in step three, we copy the gamete genotypes from the gametes on the left into the squares to the right.
We finished our Punnett square, so let’s go ahead and calculate the probability of inheriting each possible genotype. It’s not possible for this couple to produce any homozygous dominant offspring, so the probability there is simply gonna be zero. Two of the four squares contain the heterozygous genotype, while the other two squares contain homozygous recessive genotypes. So for those, we can write the fractions as two over four. The fraction two over four can be simplified by dividing the numerator and the denominator by two, giving us one-half for each. To calculate the percents, divide the numerator by the denominator, which gives us 0.5, and multiply by 100 percent. So the chance of any child born to this couple inheriting the homozygous dominant genotype is zero, while the chance of inheriting the heterozygous genotype is one-half or 50 percent. And that’s the same for the homozygous recessive genotype.
The allele that causes Huntington’s disease is dominant, so you only need one of those alleles to be affected by the disease. And therefore, anyone with a homozygous dominant or heterozygous genotype would be affected. The only unaffected genotype in a dominant disorder is the homozygous recessive genotype. So any child born to this couple has a 50 percent chance of being affected by Huntington’s disease and a 50 percent chance that they won’t. Since both the homozygous dominant and heterozygous genotypes lead to affected phenotypes, when you calculate the probability of the affected phenotype, these should be added together.
Next, let’s review some key points from this video. Here are some instructions on how to complete a Punnett square and how to analyze them in terms of genetic disorders.