Human Pedigree Analysis

In humans, controlled crosses cannot be made, so geneticists must resort to scrutinizing family
records in the hope that informative matings have been made that can be used to deduce dominance
and distinguish autosomal from X-linked inheritance. The investigator traces the history of
some variant phenotype back through the history of the family and draws up a family tree,
or pedigree, using the standard symbols given in Figure 4-17. The clues in the pedigree have to be
interpreted differently depending on whether one of the contrasting phenotypes is a rare disorder or
whether both phenotypes of a pair are common morphs of a polymorphism. The genetic disorders
of human beings can be dominant or recessive phenotypes and can be either autosomal or X-linked.
The four categories are discussed in the following sections.

Figure 4-17
Symbols used in human pedigree analysis.(After W. F. Bodmer and L. L. Cavalli-Sforza,Genetics,
Evolution, and Man.Copyright © 1976 by W. H. Freeman and Company.)

Autosomal Recessive Disorders

The unusual phenotype of a recessive disorder is determined by homozygosity for a recessive
allele, and the unaffected phenotype is determined by the corresponding dominant allele. In
Chapter 3 we saw that phenylketonuria (PKU) is a recessive phenotype. PKU is determined by an
allele that we can call p, and the normal condition by P. Therefore, sufferers of this disease are
of genotype p/p, and unaffected people are either P/P or P/p. What patterns in a pedigree would
reveal such an inheritance? Two key points are that generally the disease appears in the progeny of
unaffected parents and that the affected progeny include both males and females equally. When we
know that both male and female phenotypic proportions are equal, we can assume that we are
dealing with autosomal inheritance, not X-linked inheritance. The following typical pedigree
illustrates the key point that affected children are born to unaffected parents:

From this pattern we can immediately deduce autosomal inheritance, with the recessive
allele responsible for the exceptional phenotype (indicated by shading). Furthermore, we can
deduce that the parents must both be heterozygotes, P/p. (Both must have a p allele because each
contributed one to each affected child, and both must have a P allele because the people are
phenotypically normal.) We can identify the genotypes of the children (in the order shown) as P/–
, p/p, p/p, and P/–. Hence, the pedigree can be rewritten

Notice another interesting feature of pedigree analysis: even though Mendelian rules are at work,
Mendelian ratios are rarely observed in single families because the sample sizes are too small. In
the above example, we see a 1:1 phenotypic ratio in the progeny of what is clearly a monohybrid
cross, in which we might expect a 3:1 ratio. If the couple were to have, say, 20 children, the ratio
would undoubtedly be something like 15 unaffected children and 5 with PKU (the expected
monohybrid 3:1 ratio), but in a sample of four any ratio is possible and all ratios are commonly
found.
In the case of a rare recessive allele, in the population most of these alleles will be found in
heterozygotes, not in homozygotes. The reason is a matter of probability: to conceive a
recessive homozygote, both parents must have had the p allele, but to conceive a heterozygote all
that is necessary is one parent with the allele. The formation of an affected individual usually
depends on the chance union of unrelated heterozygotes, and for this reason the pedigrees of
autosomal recessives look rather bare, generally with only siblings of one cross affected.
Inbreeding (mating between relatives) increases the chance that a mating will be between two
heterozygotes. An example of a cousin marriage is shown in Figure 4-18. Individuals III-5 and III-6
are first cousins and produce two children. You can see from the figure that an ancestor who is
a heterozygote may produce many descendants who are also heterozygotes. Matings between
relatives thus run a higher risk of producing abnormal homozygous recessives than do matings
between nonrelatives. It is for this reason that first cousin marriages are responsible for a large
portion of recessive diseases in human populations.
Figure 4-18
Pedigree of a rare recessive phenotype determined by a recessive allelea. Gene symbols normally
are not included in pedigree charts, but genotypes are inserted here for reference. Note that
individuals II-1 andII-5 marry into the family; they are assumed (more...)
Albinism is another rare condition that is inherited in a Mendelian manner as an
autosomal recessive phenotype in many animals, including humans. The striking ―white‖
phenotype is caused by a defect in an enzyme that synthesizes melanin, the pigment responsible for
most black and brown coloration of animals. In humans, such coloration is most evident in hair,
skin, and retina, and its absence in albinos (who have the homozygous recessive genotype a/a)
leads to white hair, white skin, and eye pupils that are pink because of the unmasking of the red
hemoglobin pigment in blood vessels in the retina. The inheritance and molecular genetics of
albinism are integrated in Figure 4-20.
Figure 4-20
Genetics and the molecular biology of albinism. In the pedigree, parents heterozygous for the
recessive albinism allele produce three A/– progeny, who have melanin in their cells, and
one a/a male, who is albino. The three panels at the bottom of the figure show why this is so.
The gene for the A allele codes for a polypeptide necessary to convert tyrosine to melanin.
A mutation in the gene for the a allele causes the replacement of a threonine with a lysine. The
resulting polypeptide is unable to catalyze melanin production. The single A allele in
heterozygotes encodes sufficient functional polypeptide to create melanin. The a/a individual
produces no functional polypeptide and, hence, no melanin.

MESSAGE
In pedigrees, an autosomal recessive disorder is revealed by the appearance of
the phenotype in the male and female progeny of unaffected individuals.
In autosomal dominant disorders, the normal allele is recessive and the abnormal allele is dominant.
It might seem paradoxical that a rare disorder can be dominant, but remember that dominance and
recessiveness are simply reflections of how alleles act and are not defined in terms
of predominance in the population. An example of a rare autosomal dominant
phenotype is achondroplasia, a type of dwarfism. In this case, people with normal stature are
genotypically d/d, and the dwarf phenotype in principle could be D/d or D/D. However, it is
believed that in D/D individuals the two ―doses‖ of the D allele produce such a severe effect that
this genotype is lethal. If true, all achondroplastics are heterozygotes.
In pedigree analysis, the main clues for identifying an autosomal dominant disorder are that
the phenotype tends to appear in every generation of the pedigree and that affected fathers and
mothers transmit the phenotype to both sons and daughters. Again, the representation of both sexes
among the affected offspring argues against X-linked inheritance. The phenotype appears in every
generation because generally the abnormal allele carried by an individual must have come from a
parent in the previous generation. (Abnormal alleles can arise de novo by mutation. This is
relatively rare, but must be kept in mind as a possibility.) A typical pedigree for a dominant
disorder is shown in Figure 4-22. Once again, notice that Mendelian ratios are not necessarily
observed in families. As with recessive disorders, individuals bearing one copy of the rare allele
(A/a) are much more common than those bearing two copies (A/A), so most affected people are
heterozygotes, and virtually all matings involving dominant disorders are A/a × a/a. Therefore,
when the progeny of such matings are totaled, a 1:1 ratio is expected of unaffected (a/a) to affected
individuals (A/a).

Figure 4-22
Pedigree of a dominant phenotype determined by a dominant allele A. In this pedigree, all the
genotypes have been deduced.
Huntington’s disease is an example of an autosomal dominant disorder. The phenotype is one of
neural degeneration, leading to convulsions and premature death. However, it is a late-onset
disease, the symptoms generally not appearing until after the person has begun to have children.
Each child of a carrier of the abnormal allele stands a 50 percent chance of inheriting the allele and
the associated disease. This tragic pattern has led to a drive to find ways of identifying people who
carry the abnormal allele before they experience the onset of the disease. The discovery of the
molecular nature of the mutant allele, and of neutral DNA mutations that act as ―markers‖ close to
the affected allele on the chromosome, has revolutionized this sort of diagnosis.

MESSAGE
Pedigrees of autosomal dominant disorders show affected males and females in each
generation and also show affected men and women transmitting the condition to equal
proportions of their sons and daughters.
In human populations there are many examples of polymorphisms (generally dimorphisms) in
which the alternative phenotypes of the character are determined by alleles of a single gene, for
example, the dimorphisms for chin dimple versus none, attached earlobes versus unattached,
widow’s peak versus none, and so on. The interpretation of pedigrees for dimorphisms is somewhat
different from those for rare disorders, because by definition the morphs in a dimorphism are
common. Let’s look at a pedigree for an interesting human dimorphism. Most human populations
are dimorphic for the ability to taste the chemical phenylthiocarbamide (PTC): 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 4-23, we can see that two tasters sometimes produce nontaster
children. This makes it clear that the allele for ability to taste is dominant and that the allele for
nontasting is recessive. Notice, however, 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 it is conventional to assume that all who marry
into a family are homozygous normal. As both PTC alleles are common, it is not surprising that all
but one of the family members in this pedigree married individuals with at least one copy of the
recessive allele.

Figure 4-23
Pedigree for the ability to taste the chemical PTC.
MESSAGE
In a polymorphism the contrasting morphs are often determined by alleles of a single
autosomal gene.

X-Linked Recessive Disorders

Few phenotypes determined by alleles on the differential region of the X chromosome are related
to sex determination. Phenotypes with X-linked recessive inheritance typically show the following
patterns in pedigrees:
1.
Many more males than females show the phenotype under study. This is because a female
showing the phenotype can result only from a mating in which both the mother and the
A a a
father bear the allele (for example, X /X × X /Y), whereas a male with the phenotype
can be produced when only the mother carries the allele. If the recessive allele is very rare,
almost all individuals showing the phenotype are males.
2.
None of the offspring of an affected male are affected, but all his daughters must be
heterozygous ―carriers‖ because females must receive one of their X chromosomes from
their fathers. Half the sons born to these carrier daughters are affected (Figure 4-24).
Perhaps the best-known example is hemophilia, a malady in which a person’s blood fails to
clot. Many proteins must interact in sequence to make blood clot. The most common type of
hemophilia is caused by the absence or malfunction of one of these proteins, called factor
VIII. The most famous cases of hemophilia are found in the pedigree of the interrelated royal
families of Europe (Figure 4-25). The original hemophilia allele in the pedigree arose
spontaneously (as a mutation) in the reproductive cells of Queen Victoria’s parents or of
Queen Victoria herself. Alexis, the son of the last czar of Russia, inherited the allele
ultimately from Queen Victoria, who was the grandmother of his mother Alexandra.
Nowadays, hemophilia can be treated, but it was formerly a potentially fatal condition. It is
interesting to note that in the Jewish Talmud there are rules about exemptions to male
circumcision which show clearly 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.
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 12 and death by 20. The gene for Duchenne muscular dystrophy has now
been isolated and shown to encode a muscle protein, dystrophin. Such insight 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 afflicted with this syndrome are
chromosomally males, 44A + XY, but they develop as females (Figure 4-26). 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 people are happily married, they are, of
course, sterile. The condition is not reversed by treatment with male hormone (androgen), so
it is sometimes called androgen insensitivity syndrome. The reason for the insensitivity is
that the causative allele codes for a malfunctioning androgen receptor protein, so male
hormone can have no effect on the target organs that are involved in maleness. In humans,
femaleness results when the male-determining system is not functional.

Figure 4-24
Pedigree showing that X-linked recessive alleles expressed in males are then carried unexpressed
by their daughters in the next generation, to be expressed again in their sons. Note that III-3 and III-
4 cannot be distinguished phenotypically.
Figure 4-25
The inheritance of the X-linked recessive condition hemophilia in the royal families of Europe. A
recessive allele causing hemophilia (failure of blood clotting) arose in the reproductive cells of
Queen Victoria, or one of her parents, through mutation. This hemophilia allele spread into other
royal families by intermarriage. (a) This partial pedigree shows affected males and carrier females
(heterozygotes). Most spouses marrying into the families have been omitted from the pedigree for
simplicity. Can you deduce the likelihood of the present British royal family’s harboring the
recessive allele? (b) A painting showing Queen Victoria surrounded by her numer-ous descendants.
[(a) Modified from C. Stern, Principles of Human Genetics, 3d ed. Copyright © 1973 by W. H.
Freeman and Company. (b) Royal Collection, St. James’s Palace. Copyright © Her Majesty Queen
Elizabeth II.

X-Linked Dominant Disorders

Pedigrees of rare X-linked dominant phenotypes show the following characteristics:
1.
Affected males pass the condition on to all their daughters but to none of their sons (Figure
4-27).
2.
Females married to unaffected males pass the condition on to half their sons and daughters.

Figure 4-27
Pedigree of an X-linked dominant disorder.
There are few examples of X-linked dominant phenotypes in humans. One is hypophosphatemia, a
type of vitamin D–resistant rickets.
The mechanisms of X-linked dominance and recessiveness in humans are somewhat complicated
by the phenomenon of X chromosome inactivation found in mammals.
Calculating Risks in Pedigree Analysis
When a disease allele is known to be present in a family, knowledge of simple gene transmission
patterns can be used to calculate the probability of prospective parents’ having a child with the
disorder. For example, a married couple finds out that each had an uncle with Tay-Sachs disease (a
severe autosomal recessive disease). The pedigree is as follows:

The probability of their having a child with Tay-Sachs can be calculated in the following way. The
question is whether or not the man and woman are heterozygotes (it is clear that they do not have
the disease) because if they are both heterozygotes then they stand a chance of having an affected
child.
1.
The man’s grandparents must have both been heterozygotes T/t because they produced
a t/t child (the uncle). Therefore, they effectively constituted a monohybrid cross. The man’s
father could be T/T or T/t, but we know that the relative probabilities of these genotypes
must be 1/4 and 1/2, respectively (the expected progeny ratio in a monohybrid cross is
1/4 T/T, 1/2 T/t, and 1/4 t/t). Therefore, there is a 2/3 probability that the father is
a heterozygote [calculated as 1/2 divided by ( + 1/4+1/2)].
2.
The man’s mother must be assumed to be T/T, since she married into the family and disease
alleles generally are rare. Thus if the father is T/t, then the mating to the mother was
a cross T/t × T/T and the expected progeny proportions are 1/2 T/T and 1/2 T/t.
3.
The overall probability of the man’s being a heterozygote must be calculated using a
statistical rule called the product rule, which states that the probability of two independent
events both occurring is the product of their individual probabilities. Hence the probability
of the man’s being a heterozygote is the probability of his father’s being a
heterozygote times the probability of the father having a heterozygous son, which is 2/3 ×
1/2 = 1/3.
4.
Likewise the probability of the man’s wife being heterozygous is also 1/3.
5.
If they are both heterozygous (T/t), then the probability of their having a t/t child is 1/4, so
overall the probability of the couple having an affected child is 1/3 × 1/3 × 1/4 = 1/36; in
other words, a 1 in 36 chance.
HUMAN GENETICS

Problems:
1. An albino woman has two normal daughters, who each marry normal men and have normal children. What is the probability that a first
cousin marriage will produce an albino child?

I AA

AA Aa Aa AA
II

III ½ ½
Aa Aa

IV ?

2. PKU and albinism are two unlinked autosomal, recessive disorders in humans. If a man and a woman who are each heterozygous for both
traits marry, what is the chance that their first child will either be albino or has PKU?
3. The ability to curl the tongue is a dominant trait in humans. If 2 heterozygous have 5 children, what is the chance that 3 of them will be
curlers?
4. If 2 individuals are heterozygous for albinism has 5 children, what is the probability that they will have 2 normal sons, 2 normal
daughters, and one albino son?