3.3: Pedigrees

To study the inheritance patterns of genes in humans and other species for which controlled matings are not possible, geneticists use the analysis of pedigrees and populations.

Figure \(\PageIndex{1}\): Polydactyly (six fingers in this case) is an example of a human trait that can be studied by pedigree analysis. (Wikipedia-en:User:DRGNU23-GFDL)

Pedigree charts are diagrams that show the phenotypes and/or genotypes for a particular organism and its ancestors. While commonly used in human families to track genetic diseases, they can be used for any species and any inherited trait. Geneticists use a standardized set of symbols to represent an individual’s sex, family relationships and phenotype. These diagrams are used to determine the mode of inheritance of a particular disease or trait, and to predict the probability of its appearance among offspring. Pedigree analysis is therefore an important tool in both basic research and genetic counseling.

Each pedigree chart represents all of the available information about the inheritance of a single trait (most often a disease) within a family. The pedigree chart is therefore drawn using factual information, but there is always some possibility of errors in this information, especially when relying on family members’ recollections or even clinical diagnoses. In real pedigrees, further complications can arise due to incomplete penetrance (including age of onset) and variable expressivity of disease alleles, but for the examples presented in this book, we will presume complete accuracy of the pedigrees. A pedigree may be drawn when trying to determine the nature of a newly discovered disease, or when an individual with a family history of a disease wants to know the probability of passing the disease on to their children. In either case, a tree is drawn, as shown in Figure \(\PageIndex{2}\), with circles to represent females, and squares to represent males. Matings are drawn as a line joining a male and female, while a consanguineous mating (closely related is two lines.

Figure \(\PageIndex{2}\): Symbols used in drawing a pedigree. (Original-Deyholos-CC:AN)

The affected individual that brings the family to the attention of a geneticist is called the proband (or propositus). If an individual is known to have symptoms of the disease (affected), the symbol is filled in. Sometimes a half-filled in symbol is used to indicate a known carrier of a disease; this is someone who does not have any symptoms of the disease, but who passed the disease on to subsequent generations because they are a heterozygote. Note that when a pedigree is constructed, it is often unknown whether a particular individual is a carrier or not, so not all carriers are always explicitly indicated in a pedigree. For simplicity, in this chapter we will assume that the pedigrees presented are accurate, and represent fully penetrant traits.

Given a pedigree of an uncharacterized disease or trait, one of the first tasks is to determine which modes of inheritance are possible and then which mode of inheritance is most likely. This information is essential in calculating the probability that the trait will be inherited in any future offspring. We will mostly consider five major types of inheritance: autosomal dominant (AD), autosomal recessive (AR), X-linked dominant (XD), X-linked recessive (XR), and Y-linked (Y).

Autosomal Dominant (AD)

When a disease is caused by a dominant allele of a gene, every person with that allele will show symptoms of the disease (assuming complete penetrance), and only one disease allele needs to be inherited for an individual to be affected. Thus, every affected individual must have an affected parent. A pedigree with affected individuals in every generation is typical of AD diseases. However, beware that other modes of inheritance can also show the disease in every generation, as described below. It is also possible for an affected individual with an AD disease to have a family without any affected children, if the affected parent is a heterozygote. This is particularly true in small families, where the probability of every child inheriting the normal, rather than disease allele is not extremely small. Note that AD diseases are usually rare in populations, therefore affected individuals with AD diseases tend to be heterozygotes (otherwise, both parents would have had to been affected with the same rare disease). Achondroplastic dwarfism, and polydactyly are both examples of human conditions that may follow an AD mode of inheritance.

Figure \(\PageIndex{3}\): A pedigree consistent with AD inheritance. (Original-Deyholos-CC:AN)

X-linked dominant (XD)

In X-linked dominant inheritance, the gene responsible for the disease is located on the X-chromosome, and the allele that causes the disease is dominant to the normal allele in females. Because females have twice as many X-chromosomes as males, females tend to be more frequently affected than males in the population. However, not all pedigrees provide sufficient information to distinguish XD and AD. One definitive indication that a trait is inherited as AD, and not XD, is that an affected father passes the disease to a son; this type of transmission is not possible with XD, since males inherit their X chromosome from their mothers.

Figure \(\PageIndex{5}\): Some types of rickets may follow an XD mode of inheritance. (Wikipedia-Mrish-CC:AS) (middle and left) Two pedigrees consistent with XD inheritance. (Original-Deyholos_CC:AN)

Autosomal recessive (AR)

Diseases that are inherited in an autosomal recessive pattern require that both parents of an affected individual carry at least one copy of the disease allele. With AR traits, many individuals in a pedigree can be carriers, probably without knowing it. Compared to pedigrees of dominant traits, AR pedigrees tend to show fewer affected individuals and are more likely than AD or XD to “skip a generation”. Thus, the major feature that distinguishes AR from AD or XD is that unaffected individuals can have affected offspring.

Figure \(\PageIndex{6}\): (left) Many inborn errors of metabolism, such as phenylketonuria (PKU) are inherited as AR. Newborns are often tested for a few of the most common metabolic diseases. (Wikipedia-U.S. Air Force photo/Staff Sgt. Eric T. Sheler-PD) (right) A pedigree consistent with AR inheritance. (Original-Deyholos_CC:AN)

X-linked recessive (XR)

Because males have only one X-chromosome, any male that inherits an X-linked recessive disease allele will be affected by it (assuming complete penetrance). Therefore, in XR modes of inheritance, males tend to be affected more frequently than females in a population. This is in contrast to AR and AD, where both sexes tend to be affected equally, and XD, in which females are affected more frequently. Note, however, in the small sample sizes typical of human families, it is usually not possible to accurately determine whether one sex is affected more frequently than others. On the other hand, one feature of a pedigree that can be used to definitively establish that an inheritance pattern is not XR is the presence of an affected daughter from unaffected parents; because she would have had to inherit one X-chromosome from her father, he would also have been affected in XR.

Figure \(\PageIndex{8}\): Some forms of colour blindness are inherited as XR-traits. Colour blindness is diagnosed using tests such as this. Ishihara Test. (Wikipedia-unknown-PD) (right) A pedigree consistent with XR inheritance. (Original-Deyholos-CC:AN)

Y-linked and Mitochondrial Inheritance.

Two additional modes are Y-linked and Mitochondrial inheritance.

Only males are affected in human Y-linked inheritance (and other species with the X/Y sex determining system). There is only father to son transmission. This is the easiest mode of inheritance to identify, but it is one of the rarest because there are so few genes located on the Y-chromosome. An example of Y-linked inheritance is the hairy-ear-rim phenotype seen in some Indian families. As expected this trait is passed on from father to all sons and no daughters. Y-chromosome DNA polymorphisms can be used to follow the male lineage in large families or through ancient ancestral lineages. For example, the Y-chromosome of Mongolian ruler Genghis Khan (1162-1227 CE), and his male relatives, accounts for ~8% of the Y-chromosome lineage of men in Asia (0.5% world wide).

Mutations in Mitochondrial DNA are inherited through the maternal line (from your mother). There are some human diseases associated with mutations in mitochondria genes. These mutations can affect both males and females, but males cannot pass them on as the mitochondria are inherited via the egg, not the sperm. Mitochondrial DNA polymorphisms are also used to investigate evolutionary lineages, both ancient and recent. Because of the relative similarity of sequence mtDNA is also used in species identification in ecology studies.