Human matings, like those of experimental organisms, provide many examples of single-gene inheritance. However, controlled experimental crosses cannot be made with humans, and so geneticists must resort to scrutinizing medical records in the hope that informative matings have been made (such as monohybrid crosses) that could be used to infer single-gene inheritance. Such a scrutiny of records of matings is called pedigree analysis. A member of a family who first comes to the attention of a geneticist is called the propositus. Usually, the phenotype of the propositus is exceptional in some way; for example, the propositus might have some type of medical disorder. The investigator then traces the history of the phenotype through the history of the family and draws a family tree, or pedigree, by using the standard symbols given in Figure 2-18.

To see single-gene inheritance, the patterns in the pedigree have to be interpreted according to Mendel’s law of equal segregation, but humans usually have few children and so, because of this small progeny sample size, the expected 3:1 and 1:1 ratios are usually not seen unless many similar pedigrees are combined. The approach to pedigree analysis also depends on whether one of the contrasting phenotypes is a rare disorder or both phenotypes of a pair are common (in which case they are said to be “morphs” of a polymorphism). Most pedigrees are drawn for medical reasons and therefore concern medical disorders that are almost by definition rare. In this case, we have two phenotypes: the presence and the absence of the disorder. Four patterns of single-gene inheritance are revealed in pedigrees. Let’s look, first, at recessive disorders caused by recessive alleles of single autosomal genes.

The affected phenotype of an autosomal recessive disorder is inherited as a recessive allele; hence, the corresponding unaffected phenotype must be inherited as the corresponding dominant allele. For example, the human disease phenylketonuria (PKU), discussed earlier, is inherited in a simple Mendelian manner as a recessive phenotype, with PKU determined by the allele p and the normal condition determined by P. Therefore, people with this disease are of genotype p/p, and people who do not have the disease are either P/P or P/p. Recall that the term wild type and its allele symbols are not used in human genetics because wild type is impossible to define.

What patterns in a pedigree would reveal autosomal recessive inheritance? The two key points are that (1) generally the disorder appears in the progeny of unaffected parents and (2) the affected progeny include both males and females. When we know that both male and female progeny are affected, we can infer that we are most likely dealing with simple Mendelian inheritance of a gene on an autosome, rather than a gene on a sex chromosome. The following typical pedigree illustrates the key point that affected children are born to unaffected parents:

From this pattern, we can deduce a simple monohybrid cross, with the recessive allele responsible for the exceptional phenotype (indicated in black). Both parents must be heterozygotes—say, A/a; both must have an a allele because each contributed an a allele to each affected child, and both must have an A allele because they are phenotypically normal. We can identify the genotypes of the children (shown left to right) as A/–, a/a, a/a, and A/–. Hence, the pedigree can be rewritten as follows:

This pedigree does not support the hypothesis of X-linked recessive inheritance, because, under that hypothesis, an affected daughter must have a heterozygous mother (possible) and a hemizygous father, which is clearly impossible because the father would have expressed the phenotype of the disorder.

Notice that, even though Mendelian rules are at work, Mendelian ratios are not necessarily observed in single families because of small sample size, as predicted earlier. In the preceding example, we observe a 1:1 phenotypic ratio in the progeny of a monohybrid cross. If the couple were to have, say, 20 children, the ratio would be something like 15 unaffected children and 5 with PKU (a 3:1 ratio), but, in a small sample of 4 children, any ratio is possible, and all ratios are commonly found.

The family pedigrees of autosomal recessive disorders tend to look rather bare, with few black symbols. A recessive condition shows up in groups of affected siblings, and the people in earlier and later generations tend not to be affected. To understand why this is so, it is important to have some understanding of the genetic structure of populations underlying such rare conditions. By definition, if the condition is rare, most people do not carry the abnormal allele. Furthermore, most of those people who do carry the abnormal allele are heterozygous for it rather than homozygous. The basic reason that heterozygotes are much more common than recessive homozygotes is that, to be a recessive homozygote, both parents must have the a allele, but, to be a heterozygote, only one parent must have it.

The birth of an affected person usually depends on the rare chance union of unrelated heterozygous parents. However, inbreeding (mating between relatives, sometimes referred to as consanguinity in humans) increases the chance that two heterozygotes will mate. An example of a marriage between cousins is shown in Figure 2-19. Individuals III-5 and III-6 are first cousins and produce two homozygotes for the rare allele. You can see from Figure 2-19 that an ancestor who is a heterozygote may produce many descendants who also are heterozygotes. Hence, two cousins can carry the same rare recessive allele inherited from a common ancestor. For two unrelated persons to be heterozygous, they would have to inherit the rare allele from both their families. Thus, matings between relatives generally run a higher risk of producing recessive disorders than do matings between nonrelatives. For this reason, first-cousin marriages contribute a large proportion of people with recessive diseases in the population.

Some other examples of human recessive disorders are shown in Figure 2-20. Cystic fibrosis is a disease inherited on chromosome 7 according to Mendelian rules as an autosomal recessive phenotype. Its most important symptom is the secretion of large amounts of mucus into the lungs, resulting in death from a combination of effects but usually precipitated by infection of the respiratory tract. The mucus can be dislodged by mechanical chest thumpers, and pulmonary infection can be prevented by antibiotics; thus, with treatment, cystic fibrosis patients can live to adulthood. The cystic fibrosis gene (and its mutant allele) was one of the first human disease genes to be isolated at the DNA level, in 1989. This line of research eventually revealed that the disorder is caused by a defective protein that normally transports chloride ions across the cell membrane. The resultant alteration of the salt balance changes the constitution of the lung mucus. This new understanding of gene function in affected and unaffected persons has given hope for more effective treatment.

Human albinism also is inherited in the standard autosomal recessive manner. The mutant allele is of a gene that normally synthesizes the brown or black pigment melanin, normally found in skin, hair, and the retina of the eye (Figure 2-21).

What pedigree patterns are expected from autosomal dominant disorders? Here, the normal allele is recessive, and the defective allele is dominant. It may seem paradoxical that a rare disorder can be dominant, but remember that dominance and recessiveness are simply properties of how alleles act in heterozygotes and are not defined in reference to how common they are in the population. A good example of a rare dominant phenotype that shows single-gene inheritance is pseudoachondroplasia, a type of dwarfism (Figure 2-22). In regard to this gene, people with normal stature are genotypically d/d, and the dwarf phenotype could be in principle D/d or D/D. However, the two “doses” of the D allele in the D/D genotype are believed to produce such a severe effect that this genotype is lethal. If this belief is generally true, all dwarf individuals are heterozygotes.

In pedigree analysis, the main clues for identifying an autosomal dominant disorder with Mendelian inheritance are that the phenotype tends to appear in every generation of the pedigree and that affected fathers or mothers transmit the phenotype to both sons and daughters. Again, the equal representation of both sexes among the affected offspring rules out inheritance through the sex chromosomes. The phenotype appears in every generation because, generally, the abnormal allele carried by a person must have come from a parent in the preceding generation. (Abnormal alleles can also arise de novo by mutation. This possibility must be kept in mind for disorders that interfere with reproduction because, here, the condition is unlikely to have been inherited from an affected parent.) A typical pedigree for a dominant disorder is shown in Figure 2-23. Once again, notice that Mendelian ratios are not necessarily observed in families. As with recessive disorders, persons bearing one copy of the rare A allele (A/a) are much more common than those bearing two copies (A/A); so most affected people are heterozygotes, and virtually all matings that produce progeny with dominant disorders are A/a × a/a. Therefore, if the progeny of such matings are totaled, a 1:1 ratio is expected of unaffected (a/a) to affected (A/a) persons.

Huntington disease is an example of a disease inherited as a dominant phenotype determined by an allele of a single gene. The phenotype is one of neural degeneration, leading to convulsions and premature death. Folk singer Woody Guthrie suffered from Huntington disease. The disease is rather unusual in that it shows late onset, the symptoms generally not appearing until after the person has reached reproductive age (Figure 2-24). When the disease has been diagnosed in a parent, each child already born knows that he or she has a 50 percent chance of inheriting the allele and the associated disease. This tragic pattern has inspired a great effort to find ways of identifying people who carry the abnormal allele before they experience the onset of the disease. Now there are molecular diagnostics for identifying people who carry the Huntington allele.

Some other rare dominant conditions are polydactyly (extra digits), shown in Figure 2-25, and piebald spotting, shown in Figure 2-26.

The alternative phenotypes of a polymorphism (the morphs) are often inherited as alleles of a single autosomal gene in the standard Mendelian manner. Among the many human examples are the following dimorphisms (with two morphs, the simplest polymorphisms): brown versus blue eyes, pigmented versus blond hair, ability to smell Freesias (a fragrant type of flower) versus inability, widow’s peak versus none, sticky versus dry earwax, and attached versus free earlobes. In each example, the morph determined by the dominant allele is written first.

The interpretation of pedigrees for polymorphisms is somewhat different from that of rare disorders because, by definition, the morphs are common. Let’s look at a pedigree for an interesting human case. Most human populations are dimorphic for the ability to taste the chemical phenylthiocarbamide (PTC); that is, people can either detect it as a foul, bitter taste or—to the great surprise and disbelief of tasters—cannot taste it at all. From the pedigree in Figure 2-27, we can see that two tasters sometimes produce nontaster children, which makes it clear that the allele that confers the ability to taste is dominant and that the allele for nontasting is recessive. Notice in Figure 2-27 that almost all people who marry into this family carry the recessive allele either in heterozygous or in homozygous condition. Such a pedigree thus differs from those of rare recessive disorders, for which the conventional assumption is that all who marry into a family are homozygous normal. Because both PTC alleles are common, it is not surprising that all but one of the family members in this pedigree married persons with at least one copy of the recessive allele.

Polymorphism is an interesting genetic phenomenon. Population geneticists have been surprised at discovering how much polymorphism there is in natural populations of plants and animals generally. Furthermore, even though the genetics of polymorphisms is straightforward, there are very few polymorphisms for which there are satisfactory explanations for the coexistence of the morphs. But polymorphism is rampant at every level of genetic analysis, even at the DNA level; indeed, polymorphisms observed at the DNA level have been invaluable as landmarks to help geneticists find their way around the chromosomes of complex organisms, as will be described in Chapter 4. The population and evolutionary genetics of polymorphisms is considered in Chapters 17 and 19.

Let’s look at the pedigrees of disorders caused by rare recessive alleles of genes located on the X chromosome. Such pedigrees typically show the following features:

In the pedigree analysis of rare X-linked recessives, a normal female of unknown genotype is assumed to be homozygous unless there is evidence to the contrary.

Perhaps the most familiar example of X-linked recessive inheritance is red–green color blindness. People with this condition are unable to distinguish red from green. The genes for color vision have been characterized at the molecular level. Color vision is based on three different kinds of cone cells in the retina, each sensitive to red, green, or blue wavelengths. The genetic determinants for the red and green cone cells are on the X chromosome. Red–green color-blind people have a mutation in one of these two genes. As with any X-linked recessive disorder, there are many more males with the phenotype than females.

Another familiar example is hemophilia, the failure of blood to clot. Many proteins act in sequence to make blood clot. The most common type of hemophilia is caused by the absence or malfunction of one of these clotting proteins, called factor VIII. A well-known pedigree of hemophilia is of the interrelated royal families in Europe (Figure 2-29).

The original hemophilia allele in the pedigree possibly arose spontaneously as a mutation in the reproductive cells of either Queen Victoria’s parents or Queen Victoria herself. However, some have proposed that the origin of the allele was a secret lover of Victoria’s mother. Alexis, the son of the last czar of Russia, inherited the hemophilia allele ultimately from Queen Victoria, who was the grandmother of his mother, Alexandra. Nowadays, hemophilia can be treated medically, but it was formerly a potentially fatal condition. It is interesting to note that the Jewish Talmud contains rules about exemptions to male circumcision clearly showing that the mode of transmission of the disease through unaffected carrier females was well understood in ancient times. For example, one exemption was for the sons of women whose sisters’ sons had bled profusely when they were circumcised. Hence, abnormal bleeding was known to be transmitted through the females of the family but expressed only in their male children.

Duchenne muscular dystrophy is a fatal X-linked recessive disease. The phenotype is a wasting and atrophy of muscles. Generally, the onset is before the age of 6, with confinement to a wheelchair by age 12 and death by age 20. The gene for Duchenne muscular dystrophy encodes the muscle protein dystrophin. This knowledge holds out hope for a better understanding of the physiology of this condition and, ultimately, a therapy.

A rare X-linked recessive phenotype that is interesting from the point of view of sexual differentiation is a condition called testicular feminization syndrome, which has a frequency of about 1 in 65,000 male births. People with this syndrome are chromosomally males, having 44 autosomes plus an X and a Y chromosome, but they develop as females (Figure 2-30). They have female external genitalia, a blind vagina, and no uterus. Testes may be present either in the labia or in the abdomen. Although many such persons marry, they are sterile. The condition is not reversed by treatment with the male hormone androgen, and so it is sometimes called androgen insensitivity syndrome. The reason for the insensitivity is that a mutation in the androgen-receptor gene causes the receptor to malfunction, and so the male hormone can have no effect on the target organs that contribute to maleness. In humans, femaleness results when the male-determining system is not functional.

The inheritance patterns of X-linked dominant disorders have the following characteristics in pedigrees (Figure 2-31):

This mode of inheritance is not common. One example is hypophosphatemia, a type of vitamin D–resistant rickets. Some forms of hypertrichosis (excess body and facial hair) show X-linked dominant inheritance.

Only males inherit genes in the differential region of the human Y chromosome, with fathers transmitting the genes to their sons. The gene that plays a primary role in maleness is the SRY gene, sometimes called the testis-determining factor. Genomic analysis has confirmed that, indeed, the SRY gene is in the differential region of the Y chromosome. Hence, maleness itself is Y linked and shows the expected pattern of exclusively male-to-male transmission. Some cases of male sterility have been shown to be caused by deletions of Y-chromosome regions containing sperm-promoting genes. Male sterility is not heritable, but, interestingly, the fathers of these men have normal Y chromosomes, showing that the deletions are new.

There have been no convincing cases of nonsexual phenotypic variants associated with the Y chromosome. Hairy ear rims (Figure 2-32) have been proposed as a possibility, although disputed. The phenotype is extremely rare among the populations of most countries but more common among the populations of India. In some families, hairy ear rims have been shown to be transmitted exclusively from fathers to sons.

When a disorder with well-documented single-gene inheritance is known to be present in a family, knowledge of transmission patterns can be used to calculate the probability of prospective parents’ having a child with the disorder. For example, consider a case in which a newly married husband and wife find out that each had an uncle with Tay-Sachs disease, a severe autosomal recessive disease caused by malfunction of the enzyme hexosaminidase A. The defect leads to the buildup of fatty deposits in nerve cells, causing paralysis followed by an early death. The pedigree is as follows:

The probability of the couple’s first child having Tay-Sachs can be calculated in the following way. Because neither of the couple has the disease, each can only be an unaffected homozygote or heterozygote. If both are heterozygotes, then they each stand a chance of passing the recessive allele on to a child, who would then have Tay-Sachs disease. Hence, we must calculate the probability of their both being heterozygotes, and then, if so, the probability of passing the deleterious allele on to a child.

In some Jewish communities, the Tay-Sachs allele is not as rare as it is in the general population. In such cases, unaffected people who marry into families with a history of Tay-Sachs cannot be assumed to be T/T. If the frequency of T/t heterozygotes in the community is known, this frequency can be factored into the product-rule calculation. Nowadays, molecular diagnostic tests for Tay-Sachs alleles are available, and the judicious use of these tests has drastically reduced the frequency of the disease in some communities.