Pedigree Analysis

Pedigrees are some of the most fun and exciting tools we have in inheritance studies. Learning how to analyze them requires pattern recognition and deductive reasoning, but these learning processes are not complicated since they are visual. By using common sense and some fundamental principles, we can analyze pedigrees for just about any trait - from black hair color to osteogenesis imperfecta to dimples.

Definition of Pedigree Analysis in Biology

Pedigree analysis is an examination, or demonstration of the inheritance pattern of particular trait(s) in human beings. It can be represented by a pedigree chart, which is a visual representation of a family tree linking family members and their genetic trail.

In the context of genetics, medicine, and biology, these traits are typically diseases and disorders. Think of pedigrees as a family tree, but instead of perhaps going into detail about ethnic backgrounds or country of origin, pedigrees describe who has, who doesn't have, and who carries a genetic disorder (or multiple disorders!).

Pedigree analysis is visualized with a chart or diagram that maps out all relevant members of a family and exactly how they are related to one another. Most pedigrees have a basic level of detail - they demonstrate who's married to who, who is deceased, and the number of progeny and their sex.

Some pedigrees are more detailed, perhaps demonstrating the cause of death for those deceased, or adopted vs biological children.

Regardless of their level of detail, pedigrees highlight who is affected by the disorder in question and who is not. Those affected are typically marked in black, while those unaffected (considered the normal phenotype) have no coloring (or white). The typical denotations in the pedigree analysis are seen below (Fig. 1).

Figure 1: Typical pedigree symbols.

Pedigrees easily demonstrate the phenotypes of the individuals being studied. We can then use them to determine the genotypes of existing family members. We can even use them to predict the genotype and phenotype of future offspring, like in a married couple who wants to know the odds of one of their children having a particular disease.

Pedigree Analysis Examples

We know the basic structures of pedigrees, the meaning of their symbols, and that they are used in genetics to study inheritance patterns. But what are the possible inheritance patterns we can see using pedigrees? And which traits have which kind of particular inheritance pattern? We will determine the answers to these questions with examples of each pedigree, of which there are six in Mendelian genetics.

1. Autosomal Recessive Trait - a Pedigree Analysis of Galactosemia

The first and most common inheritance pattern that can be analyzed by pedigree is that of the autosomal recessive trait. What kind of genes have an autosomal recessive pattern? Thankfully, most genetic diseases! Why thankfully? Well, because an autosomal recessive trait must have two alleles in order for it to appear in the phenotype of an individual, thus the chances of suffering from a recessive trait are lower than those of suffering from a dominant trait. This creates three classes of individuals when it comes to an autosomal recessive pattern of inheritance: those who have the disease (homozygous recessive), those who are carriers (heterozygous), and those who are neither (homozygous dominant).

Let's use the disease galactosemia to study this.

This build-up of galactose can be toxic to certain tissues of the body. Galactose is present in lactose, which is present in milk, so the first symptoms of galactosemia usually appear in the first couple days of life, after the new baby drinks formula or breast milk. These symptoms include vomiting, diarrhea, being really weak, and even cataracts due to excess galactose in the eyes.

Galactosemia is an autosomal recessive disorder. Both mom and dad need at least one copy of this disorder for one of their children to have it. Let's look at a pedigree with such a scenario (Fig. 2).

Figure 2: Galactosemia pedigree.

This is a simple pedigree, but we can see that this heterozygous couple (genotypes Gg) had one child with galactosemia, and three children with the normal phenotype. Because this is an autosomal recessive trait, carriers will not have the disease or any symptoms.

What if we were look at a pedigree analysis of galactosemia (or any other autosomal recessive trait), but it was not labelled as such? What tricks would we use to classify the trait being studied in the pedigree as autosomal recessive? Let's look at an unlabeled example to assess this (Fig. 3).

Figure 3: Autosomal recessive pedigree.

Looking at the youngest generation (generations are often labelled, with the oldest generation being I, their descendants being II, and the youngest being III), we can see there is a male child who is affected by galactosemia. We can see that neither his sisters nor his parents have galactosemia. Thus, we can rule out:

• autosomal dominant (at least one parent would have to have the disorder to pass it down),
• Y-linked (the father must pass this down, so he would have the disorder)
• mitochondrial (a mother passes this down to all her children), and
• X-linked dominant (the mother would have to have this disorder to pass it down to her son). However, we cannot rule out X-linked recessive.

Let us look further up this pedigree, at the first generation. We see there is another person affected with this trait in this family, in Generation-I. This affected woman gave birth to two sons, and two daughters. None of those children are affected (draw this pedigree yourself to get some practice!).

Let us consider the scenario in which the trait this woman has is X-linked recessive. She would have to have two copies of this allele to have the disease, because women have two X-chromosomes. So she would only have the disordered allele to give to her children, and while her daughters would get a normal X-chromosome from their father, all her sons would get an affected X-chromosome from her and a normal Y-chromosome from their father, and thus would have to be affected as well. That is not the inheritance pattern we see here, and this rules out the possibility that this trait, in this case galactosemia, is inherited in an X-linked recessive pattern.

Now, if this affected woman in Generation-I has an autosomal recessive trait, then her genotype must include two copies of the affected allele (gg) and she would once again be able to distribute only this to her offspring, However, if their father has a homozygous healthy genotype, GG (which is typically assumed), then all their progeny would have the Gg heterozygous genotype. All four of their children in Generation-II would be carriers. This explains how the woman in Generation-II, who married a random man who perhaps was a carrier as well, gave rise to an affected offspring.

2. Autosomal Dominant - How We Can Use Pedigree Analysis to Find Genetic Disorders With This Inheritance Pattern

Generally, autosomal dominant disorders are present in every generation. This is in contrast to autosomal recessive disorders that are said to "skip generations". Autosomal dominant traits are one of the easiest to recognize on pedigrees because every person exhibiting the trait has at least one parent exhibiting the trait. (Fig. 4)

Figure 4: Autosomal Dominant pedigree.

Let's say this is a pedigree of a family with Huntington's, a disease that causes problems with movement, neurological and psychiatric problems, often resulting in premature death. How can we know that this disease is inherited in an autosomal dominant fashion? We see in Generation-I an affected man passes it on to three of his children- two daughters and one son. Each affected person in Generation-II passes the disorder on to at least one of their children, and the Generation-II son who did not inherit the disorder, and did get married, did not pass it on to any of his four children. Thus, that son is homozygous for the normal allele, and the affected individuals are all heterozygous for this trait.

3. X-linked Recessive

X-linked recessive disorders are passed from a woman (who is typically a heterozygote carrier) to both her sons and daughters. However, all her sons will have the trait of the disorder, and her daughters (assuming her husband has the normal genotype) will either be carriers or homozygous for the normal allele (Fig. 5). If a man happens to have an X-linked recessive disorder, he cannot pass it down to his sons, whom he must pass his Y chromosome down to. Therefore all his sons will be unaffected, but his daughters may be carriers.

Figure 5: X-linked recessive pedigree.

The above pedigree may seem very complex, but we can break it down to understand some basic principles. Firstly, all affected individuals are males and they are inheriting this disorder from parents, both of which are not affected. If this disorder had an autosomal recessive inheritance, it would be seen in both male and female descendants. Because it is exclusively seen in males, we can safely presume the disorder is X-linked recessive.

4. X-linked Dominant

Most X-linked disorders are recessive, but a few are dominant. This means that the parent who has the trait also has the disorder, and when they pass this trait down the children who receive it will be affected as well (Fig. 6).

Figure 6: X-linked dominant pedigree.

A woman with an X-linked dominant disorder passes it down to her sons and daughters equally. One of the biggest hints suggesting X-linked dominant disorders is that a man who has an X-linked dominant disorder must pass it down to all his daughters, as that is the only chromosome he can give them.

5. Y-linked Disorders

Very few disorders or traits have been discovered to be Y-linked. In fact, the preponderance of disorders that primarily affect men is typically due to the presence of a single X-chromosome, such that whatever disordered trait is on that chromosome cannot be masked by the normal trait that would be on a paired X-chromosome in females.

Figure 7: Y-linked pedigree.

Ultimately, we can know Y-linked traits because they never occur in females, only in males (Fig. 7). And an affected male must pass the trait down to all his sons. Some forms of deafness are Y-linked.

6. Mitochondrial Inheritance

Mitochondrial inheritance is maternal, meaning we get our mitochondria from our mothers. Thus, an affected woman passes down a trait to all her children, and only her daughters can pass it on to their children (Fig. 8).

Figure 8: Mitochondrial inheritance pedigree.

Human Pedigree Analysis: Problem Sheet

Now that we know the six major groupings of pedigree analysis, we can develop a problem sheet - in the form of a table- to help us consolidate the principles of each pedigree (Table 1).

Table 1: Hints for pedigree analysis problem sheets. Chisom, StudySmarter.