Medelian Genetics 2: Advanced Mendelian Genetics

Pedigrees

Many human diseases are genetically inherited. A healthy person in a family in which some members suffer from a recessive genetic disorder may want to know if they have the disease-causing gene and what risk exists of passing the disorder on to their offspring. Of course, doing a test cross in humans is unethical and impractical. Instead, geneticists use pedigree analysis  to study the inheritance pattern of human genetic diseases (Figure 6.2).

Pedigree charts show the phenotypes and/or genotypes of a particular organism and its ancestors. While commonly used in human families to track genetic diseases, they can be used for any species and inherited trait. Geneticists use standardised 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. Therefore, Pedigree analysis is an important tool in basic research and genetic counselling.

Each pedigree chart represents all 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. Still, 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 the age of onset) and variable expressivity of disease alleles. Despite these real-world complications, for the examples presented in this book, we will assume complete accuracy of the pedigrees. A pedigree may be drawn when determining 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 6.2, with circles representing females and squares representing males. Matings are drawn as a line joining a male and female, while consanguineous mating (mating between closely related individuals) is two lines.

The affected individual that brings the family to the attention of a geneticist is called the proband. 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. 

Autosomal Dominant

When a dominant allele of a gene causes a disease, 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. Complete penetrance is when the gene or genes for a trait are expressed in all the population who have the genes. As opposed to incomplete penetrance where the genetic trait is expressed in only part of the population and can change depending on variables such as age, environmental and lifestyle factors.

A pedigree with affected individuals in every generation is typical of autosomal dominant 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 autosomal dominant 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 autosomal dominant diseases are usually rare in populations; therefore, affected individuals with autosomal dominant diseases tend to be heterozygotes (otherwise, both parents would have had to be affected with the same rare disease). Achondroplastic dwarfism and polydactyly are examples of human conditions that may follow an autosomal dominant mode of inheritance.

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 2 X-chromosomes whereas males have only 1, females tend to be more frequently affected than males in the population. However, not all pedigrees provide sufficient information to distinguish x-linked dominant and autosomal dominant. One definitive indication that a trait is inherited as autosomal dominant and not X-linked dominant, is when an affected father passes the disease to a son. This type of transmission is not possible with X-linked dominant inheritance since males inherit their X chromosome from their mothers.

Autosomal Recessive

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

Many inborn errors of metabolism, such as phenylketonuria (PKU), are inherited as autosomal recessive. Newborns are often tested for a few of the most common metabolic diseases. A pedigree consistent with autosomal recessive inheritance is displayed in Figure 6.5.

 

X-linked Recessive

Because males have only one X-chromosome, any male that inherits an X-linked recessive disease allele will be affected by it. Therefore, in X-linked recessive mode of inheritance, males tend to be affected more frequently than females in a population. This is in contrast to autosomal traits, where both sexes tend to be affected equally, and X-linked dominant, where 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 X-linked recessive 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 X-linked recessive.

Some forms of colour blindness are inherited as X-linked recessive traits. A pedigree consistent with X-linked recessive inheritance is displayed in Figure 6.6 below.

 

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. 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, and his male relatives, account for ~8% of the Y-chromosome lineage of men in Asia (0.5% worldwide).

Mutations in Mitochondrial DNA (mtDNA) are inherited through the maternal line. There are some human diseases associated with mutations in mitochondrial 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.

Polygenic Inheritance

Most of the phenotypic traits commonly used in introductory genetics are qualitative. This means the phenotype exists in only two (or possibly a few more) discrete, alternative forms, such as purple or white flowers, or red or white eyes. These qualitative traits are therefore said to exhibit discrete variation. On the other hand, many interesting and important traits exhibit continuous variation, meaning they exhibit a continuous range of phenotypes that are usually measured quantitatively, such as intelligence, body mass, blood pressure in animals (including humans), and yield, water use, or vitamin content in crops. Traits with continuous variation are often complex, and do not show the simple Mendelian segregation ratios (e.g., 3:1) observed with some qualitative traits. Many complex traits are heavily influenced by the environment; nevertheless, complex traits can often have a component that is heritable, and which must therefore involve one or more genes.

How can genes, which are inherited (in the case of a diploid) as, at most, two variants each, explain the wide range of continuous variation observed for many traits? The lack of an immediately obvious explanation to this question was one of the early objections to Mendel’s explanation of the mechanisms of heredity. However, upon further consideration, it becomes clear that the more loci that contribute to the trait, the more phenotypic classes may be observed for that trait (Figure 6.7).

If the number of phenotypic classes is sufficiently large (as with three or more loci), individual classes may become indistinguishable (particularly when environmental effects are included), and the phenotype appears as a continuous variation (Figure xx). Thus, quantitative traits are sometimes called polygenic traits, because it is assumed that their phenotypes are controlled by the combined activity of many genes. Note that this does not imply that each of the individual genes has an equal influence on a polygenic trait — some may have a major effect, while others only minor. Furthermore, any single gene may influence more than one trait, whether these traits are quantitative or qualitative traits. 

 

Multifactorial Inheritance

Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell disease and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders.

 

Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. Researchers continue to look for major contributing genes for many common complex disorders.

Genetic Predispositions

A genetic predisposition (sometimes also called genetic susceptibility) is an increased likelihood of developing a particular disease based on a person’s genetic makeup. A genetic predisposition results from specific genetic variations that are often inherited from a parent. These genetic changes contribute to the development of a disease but do not directly cause it. Some people with a predisposing genetic variation will never get the disease while others will, even within the same family.

Genetic variations can have large or small effects on the likelihood of developing a particular disease. For example, certain mutations in the BRCA1 or BRCA2 genes greatly increase a person’s risk of developing breast cancer and ovarian cancer. Variations in other genes, such as BARD1 and BRIP1, also increase breast cancer risk, but the contribution of these genetic changes to a person’s overall risk appears to be much smaller.

Current research is focused on identifying genetic changes that have a small effect on disease risk but are common in the general population. Although each of these variations only slightly increases a person’s risk, having changes in several different genes may combine to increase disease risk significantly. Changes in many genes, each with a small effect, may underlie susceptibility to many common diseases, including cancer, obesity, diabetes, heart disease, and mental illness.

In people with a genetic predisposition, the risk of disease can depend on multiple factors in addition to an identified genetic change. These include other genetic factors (sometimes called modifiers) as well as lifestyle and environmental factors. Although a person’s genetic makeup cannot be altered, some lifestyle and environmental modifications (such as having more frequent disease screenings and maintaining a healthy weight) may be able to reduce disease risk in people with a genetic predisposition.

Co-Dominance

A variation on incomplete dominance, where one of the alleles appears in the phenotype in the heterozygote but not to the exclusion of the other, is codominance. Codominance is where both alleles for the same characteristic are simultaneously expressed in the heterozygote. An example of codominance occurs in the ABO blood groups of humans. The A and B alleles are expressed in the form of A or B molecules present on the surface of red blood cells. Homozygotes (IAIA and IBIB) express either the A or the B phenotype, and heterozygotes (IAIB) express both phenotypes equally. The IAIB individual has blood type AB. In a self-cross between heterozygotes expressing a codominant trait, the three possible offspring genotypes are phenotypically distinct. However, the 1:2:1 genotypic ratio characteristic of a Mendelian monohybrid cross still applies (Figure 6.10).

 

Multiple Alleles

Mendel implied that only two alleles, one dominant and one recessive, could exist for a given gene. We now know that this is an oversimplification. Although individual humans (and all diploid organisms) can only have two alleles for a given gene, multiple alleles may exist at the population level, such that many combinations of two alleles are observed. Note that when many alleles exist for the same gene, the convention is to denote the most common phenotype or genotype in the natural population as the wild type (often abbreviated “+”). All other phenotypes or genotypes are considered variants (mutants) of this typical form, meaning they deviate from the wild type. The variant may be recessive or dominant to the wild-type allele.

An example of multiple alleles is the ABO blood-type system in humans. In this case, there are three alleles circulating in the population which determine the blood-type protein on the surface of red blood cells. The IA allele codes for A molecules on the red blood cells, the IB allele codes for B molecules on the surface of red blood cells, and the i allele codes for no molecules on the red blood cells. In this case, the IA and IB alleles are codominant with each other and are both dominant over the i allele. Although there are three alleles present in a population, each individual only gets two of the alleles from their parents. This produces the genotypes and phenotypes shown in Figure xx. Notice that instead of three genotypes, there are six different genotypes when there are three alleles. The number of possible phenotypes depends on the dominance relationships between the three alleles.

 

Complex Blood Genetics

The major human A, B, AB, O, and Rh blood groups that result from the presence or absence of glycoprotein antigens embedded in red blood cell membranes and the presence or absence in the blood of antibodies against the antigens. Typically, an exposure to antigens (e.g., foreign substances like bacteria, viruses, and toxins) generates immunoglobulins, the antibody molecules of our immune system.

The immunoglobulins are glycoproteins. Since blood-group antibodies already in the blood of a healthy person are not a response to foreign antigen invasion, they are something of a paradox.

You probably know that blood groups must be compatible for a successful blood transfusion. A mismatch between donor and recipient can be devastating. An interaction of the red-cell antigens of one blood group with antibodies in another blood group will cause the red cells to clump, restricting blood flow, and ultimately killing the transfusion recipient. Figure 6.12 summarises why transfusions with mismatched A, B, AB, and O blood groups must be avoided.

 

When red blood cells carrying one or both antigens are exposed to the corresponding antibodies, they agglutinate; that is, clump together. People usually have antibodies against those red cell antigens that they lack. The antigens in the ABO system are O-linked glycoproteins with their sugar residues exposed at the cell surface. The terminal sugar determines whether the antigen is A or B.

The critical principle to be followed is that transfused blood must not contain red cells that the recipient’s antibodies can clump. Although theoretically it is possible to transfuse group O blood into any recipient, the antibodies in the donated plasma can damage the recipient’s red cells. Thus, when possible, transfusions should be done with exactly-matched blood.

Now, thanks to enzymes produced by members of the gut microbiome, the absolute requirement that blood groups must be matched for safe transfusions may someday be a thing of the past! One of these enzymes is a glycosidase that can digest the sugars on A and B antigens on the surfaces of A, B, and AB blood cells. This effectively converts them to type O red blood cells! Check the Red Cross website (About A, B, AB, & O Blood Types-Red Cross) or Wikipedia (Other Blood Types) for more details about blood groups. See Conversion of A, B & AB to O for a summary of recent research on enzymatically converting all blood types to type O.

The Rh System

Rh antigens are transmembrane proteins with loops exposed at the surface of red blood cells. They appear to be used for the transport of carbon dioxide and/or ammonia across the plasma membrane. They are named for the rhesus monkey in which they were first discovered.

There are a number of Rh antigens. Red cells that are “Rh-positive” express the one designated D. About 15% of the population have no RhD antigen and thus are “Rh-negative”. The major importance of the Rh system for human health is to avoid the danger of RhD incompatibility between mother and foetus.

During birth, there is often a leakage of the baby’s red blood cells into the mother’s circulation. If the baby is Rh-positive (having inherited the trait from its father) and the mother Rh-negative, these red cells will cause her to develop antibodies against the RhD antigen. The antibodies, usually of the IgG class, do not cause any problems for that child, but can cross the placenta and attack the red cells of a subsequent Rh+ foetus. This destroys the red cells producing anaemia and jaundice. The disease, called erythroblastosis fetalis or hemolytic disease of the newborn, may be so severe as to kill the foetus or even the newborn infant. It is an example of an antibody-mediated cytotoxicity disorder.

Although certain other red cell antigens (in addition to Rh) sometimes cause problems for a foetus, an ABO incompatibility does not. Why is an Rh incompatibility so dangerous when ABO incompatibility is not?

It turns out that most anti-A or anti-B antibodies are of the IgM class and these do not cross the placenta. In fact, an Rh−/type O mother carrying an Rh+/type A, B, or AB foetus is resistant to sensitisation to the Rh antigen. Presumably her anti-A and anti-B antibodies destroy any foetal cells that enter her blood before they can elicit anti-Rh antibodies in her. This phenomenon has led to an extremely effective preventive measure to avoid Rh sensitisation. Shortly after each birth of an Rh+ baby, the mother is given an injection of anti-Rh antibodies. The preparation is called Rh immune globulin (RhIG) or Rhogam. These passively acquired antibodies destroy any foetal cells that got into her circulation before they can elicit an active immune response in her.

Rh immune globulin came into common use in the United States in 1968, and within a decade the incidence of Rh haemolytic disease became very low.

Sex-Linked Genes

In humans, as well as in many other animals and some plants, the sex of the individual is determined by sex chromosomes. The sex chromosomes are one pair of non-homologous chromosomes. Until now, we have only considered inheritance patterns among non-sex chromosomes, or autosomes. In addition to 22 homologous pairs of autosomes, human females have a homologous pair of X chromosomes, whereas human males have an XY chromosome pair. Although the Y chromosome contains a small region of similarity to the X chromosome so that they can pair during meiosis, the Y chromosome is much shorter and contains many fewer genes. In fact, when Nettie Stevens discovered that the X and Y chromosomes were the determinants of sex, she differentiated them only by size. (Note that in this case and in the description below, the terms X and Y chromosome were not used at the time.) When a gene being examined is present on the X chromosome, but not on the Y chromosome, it is said to be X-linked.

Eye colour in Drosophila was one of the first X-linked traits to be identified. Thomas Hunt Morgan mapped this trait to what became known as the X chromosome in 1910. Like humans, Drosophila males have an XY chromosome pair, and females are XX. In flies, the wild-type eye colour is red (XW) and it is dominant to white eye colour (Xw) (Figure 6.14). Because of the location of the eye-colour gene, reciprocal crosses do not produce the same offspring ratios. Males are said to be hemizygous, because they have only one allele for any X-linked characteristic. Hemizygosity makes the descriptions of dominance and recessiveness irrelevant for XY males. Drosophila males lack a second allele copy on the Y chromosome; that is, their genotype can only be XWY or XwY. In contrast, females have two allele copies of this gene and can be XWXW, XWXw, or XwXw.

 

In an X-linked cross, the genotypes of F₁ and F₂ offspring depend on whether the recessive trait was expressed by the male or the female in the P₁ generation. With regard to Drosophila eye colour, when the P₁ male expresses the white-eye phenotype and the female is homozygous red-eyed, all members of the F₁ generation exhibit red eyes (Figure 6.14). The F₁ females are heterozygous (XWXw), and the males are all XWY, having received their X chromosome from the homozygous dominant P₁ female and their Y chromosome from the P₁ male.

A subsequent cross between the XWXw female and the XWY male would produce only red-eyed females (with XWXW or XWXw genotypes) and both red- and white-eyed males (with XWY or XwY genotypes). Now, consider a cross between a homozygous white-eyed female and a male with red eyes. The F₁  generation would exhibit only heterozygous red-eyed females (XWXw) and only white-eyed males (XwY). Half of the F₂ females would be red-eyed (XWXw) and half would be white-eyed (XwXw). Similarly, half of the F₂ males would be red-eyed (XWY) and half would be white-eyed (XwY). 

 

Discoveries in fruit fly genetics can be applied to human genetics. When a female parent is homozygous for a recessive X-linked trait, she will pass the trait on to 100 percent of her offspring. Her male offspring are, therefore, destined to express the trait, as they will inherit their father’s Y chromosome. In humans, the alleles for certain conditions (some forms of colour blindness, haemophilia, and muscular dystrophy) are X-linked. Females who are heterozygous for these diseases are said to be carriers and may not exhibit any phenotypic effects. These females will pass the disease to half of their sons and will pass carrier status to half of their daughters; therefore, recessive X-linked traits appear more frequently in males than females.

In some groups of organisms with sex chromosomes, the sex with the non-homologous sex chromosomes is the female rather than the male. This is the case for all birds. In this case, sex-linked traits will be more likely to appear in the female, in which they are hemizygous.

Sex-linked Disorders 

Sex-linkage studies in Morgan’s laboratory provided the fundamentals for understanding X-linked recessive disorders in humans, which include red-green colour blindness, and Types A and B haemophilia. Because human males need to inherit only one recessive mutant X allele to be affected, X-linked disorders are disproportionately observed in males. Females must inherit recessive X-linked alleles from both of their parents in order to express the trait. When they inherit one recessive X-linked mutant allele and one dominant X-linked wild-type allele, they are carriers of the trait and are typically unaffected. Carrier females can manifest mild forms of the trait due to the inactivation of the dominant allele located on one of the X chromosomes.

However, female carriers can contribute the trait to their male children, resulting in the male exhibiting the trait, or they can contribute the recessive allele to their female children, resulting in the children being carriers of the trait (Figure 6.15). Although some Y-linked recessive disorders exist, typically they are associated with infertility in males and are therefore not transmitted to subsequent generations.

 

Applications in real world

Carrier screening for autosomal recessive disorders is an established public health strategy that has significantly reduced the incidence and burden of several genetic conditions, particularly among populations with elevated genetic risk or a known family history of disease. When implemented alongside appropriate pre-test and post-test genetic counselling, carrier screening programs have achieved substantial reductions in disease prevalence. For example, rates of β-thalassaemia have declined by approximately 80-90% in Greece and Italy, while the incidence of Tay-Sachs disease has decreased by around 90% among Ashkenazi Jewish populations in the United States and Israel (Xiao & Lauschke, 2021).

Continued advances in carrier screening technologies are expected to improve understanding of the genetic architecture of diseases within specific geographic and population groups. This is particularly relevant for isolated populations, where founder mutations can result in a markedly increased prevalence of certain genetic conditions. Such patterns have been observed in Inuit communities, Druze populations in Israel, and Dutch and Finnish populations (Xiao & Lauschke, 2021). Because founder mutations are often absent from conventional screening panels, individuals from these populations may not receive the full benefits of standard pan-ethnic carrier screening approaches, highlighting the need for more population-specific testing strategies (Xiao & Lauschke, 2021).

References

Xiao, Q., & Lauschke, V. M. (2021). The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders. NPJ genomic medicine, 6(1), 41. https://doi.org/10.1038/s41525-021-00203-x