Unit 9 Human Pedigree Analysis

UNIT 9
HUMAN PEDIGREE
ANALYSIS

Structure
9.1 Introduction Significance of Pedigree Analysis

Expected Learning Outcomes 9.4 Techniques to Separate the Effect

of Genes and Environment
9.2 Pedigree Analysis
Twins Studies
Autosomal Dominant Traits
Adoption Studies
Autosomal Recessive Traits
9.5 Summary
X-Linked Dominant Traits
9.6 Terminal Questions
X-Linked Recessive Traits
9.7 Answers
Y-Linked Traits
9.8 Further Readings
9.3 Limitations of Pedigree
Analysis

9.1 INTRODUCTION
In the preceding unit you have learnt about organelle heredity and epigenetics.
Geneticists routinely carry out specific crosses in model organisms such as
Drosophila and bacteria to test their hypotheses. In these organisms one can
perform controlled matings; their generation time is short, in addition to other
useful characteristics (refer Unit 1). The same approach is not feasible with
humans.

In this unit you shall learn about pedigree analysis and how to predict the most
likely mode of inheritance and its applications. In addition the techniques used
to disentangle the relative contribution of genes and environment will be
discussed. 159
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Expected Learning Outcomes

After studying this unit, you should be able to:

 construct pedigrees from the given information using standard

symbols;

 predict the most likely pattern of inheritance of a trait from the

available information;
 calculate the risk of transmitting a deleterious trait;

 assign genotypes to as many members as possible;

 indicate the salient characteristics of different modes of inheritance;

 highlight the importance and limitations of pedigree analysis; and

 explain how twin and adoption studies are useful in genetic studies.

9.2 PEDIGREE ANALYSIS

The study of human heredity has been one of the major focuses of geneticists
A pedigree is a
pictorial who seek to understand the pattern of transmission of traits and their
representation prevalence in different ethnic groups. Inspite of the restrictions on the kinds of
of a family tree. experiments that can be performed with humans, the inherent desire to know
our race is so strong that we have progressed tremendously over the years.

One such non invasive technique is pedigree analysis, which is a pictorial

representation of a family tree outlining the inheritance of one or more
characteristics. The person from whom the pedigree is initiated is called the
proband and is usually designated by an arrow. The symbols commonly used
in depicting pedigrees are summarized in Fig. 9.1.

160 Fig. 9.1: Standard symbols used in Pedigrees.

Unit 9 Human Pedigree Analysis

Pedigree analysis is very handy in predicting the likely mode of inheritance of

a trait. For example, autosomal dominant traits should not skip generations
and appear with equal frequency in both sexes provided that the trait is fully
penetrant and not sex influenced. The other alternative is to try and exclude
other patterns of inheritance wherever possible. This definitely brings us closer
to the actual pattern with much greater level of confidence. For example, a
son inherits an X chromosome from his mother. If a trait is passed from father
to son, the possibility of X-linked inheritance is ruled out. Similarly for an X-
linked dominant trait, an affected father is unlikely to have unaffected
daughters. In the following subsections the traits described are rare and
unless otherwise mentioned fully penetrant.

All single gene controlled traits are now called Mendelian, irrespective of
whether they are present on autosomes or sex chromosomes (non-
Mendelian). It is possible to obtain information about them from the freely
accessible OMIM (Online Mendelian Inheritance in Man) database. We shall
now describe salient characteristics of five basic Mendelian pedigree patterns.
Note all enlisted features of a given pattern may not be evident in a given
pedigree largely due to small family size and incomplete records. Therefore it
is sometimes possible only to suggest the most likely mode of inheritance.

SAQ 1
Who is a proband in a pedigree?

9.2.1 Autosomal Dominant Traits

You know that a character is dominant (and not genes) if it manifests in the
heterozygote and recessive if its effect is masked by the dominant allele. Most
human dominant syndromes are known only in heterozygotes due to rarity of
recessive allele and poor survival/ lethality of homozygotes. The
characteristics of autosomal dominant traits include:

 An affected progeny usually has one affected parent unless it arises due
to a new mutation during gametogenesis.

 It is transmitted through either sex.

 Both males and females are equally likely to be affected.

 Does not skip generations except in case of incomplete penetrance.

 A mating between an affected (heterozygous) and unaffected parent has

50% chance of producing affected offsprings.

 In case the trait is fully penetrant unaffected parents do not transmit the
trait.

Examples of human autosomal dominant traits are neurofibromatosis (tumour

like growths on the body), familial hypercholesterolemia, phenylthiocarbamide
(PTC) tasting, Marfan syndrome and brachydactyly (short fingers). A typical
pedigree of an autosomal dominant trait with no complications is depicted in
Fig. 9.2.
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Fig. 9.2: Pedigree of an autosomal dominant trait.

9.2.2 Autosomal Recessive Traits

Autosomal recessive traits appear only when an individual carries both copies
of a recessive allele. They share some characteristics with autosomal
dominant traits since both are encoded by autosomal genes; they occur with
equal frequency in both sexes and are transmitted by both males and females.
Their distinguishing characteristics are:

 They tend to skip generations.

 The affected individuals are generally born to unaffected parents

(heterozygous carriers that are usually asymptomatic).

 The incidence of the trait increases in consanguineous marriages

(matings between close relatives), due to shared alleles.

 In a mating between heterozygous carriers, there is 25% chance of

having affected offsprings which may not always be evident in small
families.

Fig. 9.3: Pedigree of an autosomal recessive trait. (Source: Essential Genetics

by Hartl and Jones).
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Autosomal recessive traits include Phenylketonuria (PKU), cystic fibrosis,

alkaptonuria, Glycogen storage diseases, Tay Sachs disease (lipid storage
disease) and sickle cell anemia. Some of these you have come across in
metabolic disorders.

9.2.3 X-Linked Dominant Traits

The characteristics of an X-linked dominant trait are:

 X-linked dominant traits appear in both females and males but they are
more common in females than males.

 They do not skip generations like autosomal dominant traits.

 A male inherits an X-linked dominant trait from his mother only and
he passes it on to all his daughters.

 A female on the other hand receives an X-chromosome from both

parents and therefore either parent can transmit the trait.

 The offsprings of an affected mother has 50% chance of being affected

irrespective of their sex.

 Each child has an affected parent.

 Females are often more mild but variably affected than males (due to
random X inactivation). Some diseases affect only females presumably
due to in-utero lethality in males.

Fig. 9.4: A pedigree of an X-linked dominant trait. (Source: Genetics:

A conceptual approach by Benjamin A. Pierce).
X-linked dominant disorders are relatively uncommon as compared to other
Mendelian diseases. Hypophosphatemia (familial vitamin D-resistant rickets) is
an example of X-linked dominant trait in humans. Patients with this disease 163
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have bone deformities, curved legs, stiff spines & joints and mild growth
deficiencies like rickets which is not cured by vitamin D supplements. The
disorder is due to faulty transport of phosphate, particularly in kidney cells
which results in excretion of large amounts of phosphate in urine. Males with
hypophosphatemia are often more severely affected as compared to females.
Other examples are Rett syndrome, renal phosphate transport disorder and
incontinentia pigment type I (affects only females).

9.2.4 X-Linked Recessive Traits

The inheritance pattern of an X-linked recessive trait is exemplified by the
pedigree in Fig.9.5. A highlighting feature of these traits is that it affects
predominantly males which generally inherit from asymptomatic carrier
mothers. You know that males are hemizygous for most X-linked genes. The
other guiding characteristics are:

 The trait tends to skip generations and is passed from unaffected mother
to son to granddaughter (criss-cross pattern).

 An unaffected mother may have affected male relatives.

 Roughly 50% sons of a carrier mother are affected and 50% are
unaffected carrier daughters (may not appear in this ratio because of
small family size).

 X-linked recessive trait is never passed from father to son as he inherits

Y-chromosome from his father, not his X.

 All daughters of an affected man will be carriers if the mother is

homozygous dominant.

Fig. 9.5: A pedigree of X-linked recessive trait. (Source: Assessment test bank
for Introduction to Genetic analysis by Griffith et al.).

Examples of X linked recessive traits include classic haemophilia, red green

color blindness, Lesch Nyhan syndrome, Duchenne Muscular Dystrophy
(DMD), and Menkes disease.
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SAQ 2
How will you differentiate between X-linked recessive and autosomal
recessive mode of inheritance?

9.2.5 Y-Linked Traits

Y-linked traits (holandric traits) are passed from father to all sons if the gene is
located on the non homologous region (non-recombining) of the Y
chromosome (Fig.9.6). In such cases only males are affected. These traits
never skip generations. Mutations in Y-linked genes are known to affect male
fertility.

Fig. 9.6: Inheritance of a Y-linked Trait. (Source: Human Molecular Genetics by

T. Strachan A. P. Reed).

SAQ 3
Choose the correct option:
i) Autosomal recessive traits often appear in pedigrees with one
or more consanguineous matings because:
a) they tend to skip generations.
b) a mutant allele is more likely to be shared between
carrier relatives than among unrelated people.
c) they are usually born to unaffected parents.
d) they are more common in females than males.

ii) A male affected with an X-linked dominant trait will have what
proportion of affected offspring’s?
a) all offsprings

b) all sons and no daughters

c) all daughters and no sons
d) unpredictable due to reduced penetrance.

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Apart from these five basic pedigree pattern of inheritance you have learnt in
the preceding chapter about organelle heredity. It is by two semiautonomous
organelles namely, mitochondria and chloroplast. Both organelles have
circular DNA which code for rRNA, tRNA and variable number of proteins,
depending on the source. The transmission of these organelles is uniparental
and generally maternal.

9.3 LIMITATIONS OF PEDIGREE ANALYSIS

Pedigree analysis although informative is not always the best choice. There
are multiple issues which limit its usefulness when applied to humans. Some
of these limitations are:

 A small family size is unlikely to have progenies in the expected

proportion. It is rarely possible to predict with confidence the possible
mode of inheritance by analysing a single pedigree.

 The family records are generally incomplete.

 Controlled matings are not possible; they are dictated by multiple factors
(family expectations, ethnic group, and romance) rather than based on
the requirements of a geneticist.
 Long generation time in humans; they reach reproductive maturity
around 12-14 years of age and most reproduce when they are 18 years
or older.
 Incomplete penetrance of a dominant condition is a frequent
complication. In other words the trait occasionally skips generations. It is
a major bottleneck in genetic counselling. Reduced penetrance is
observed particularly in late onset diseases.
 Some conditions are manifested only when inherited from one of the
parents. This occurs in case of imprinted genes.
 Male lethality of certain X-linked dominant conditions may further
complicate pedigree analysis. In that case an affected female (XA Xa)
passes it on to half her daughters and none to her sons.
 Some diseases are caused by mutations in two or more genes. This
happens in multi step pathways such as blood clotting. The genes
encoding enzymes catalysing different steps may follow a different
pattern of inheritance (locus heterogeneity). In such a situation pedigree
analysis yields ambiguous assessment especially for poorly understood
rare diseases.
Due to these constraints, genetic studies of humans are more complex and
difficult.
9.3.1 Significance of Pedigree Analysis
You have leant how pedigree analysis allows us to predict the most likely
pattern of inheritance of a trait. This in turn helps a genetic counsellor in
166 educating prospective parents about the risks of transmitting a trait; the need
Unit 9 Human Pedigree Analysis

for prenatal (before birth) and / postnatal (after birth) testing and management
of children born with genetic abnormalities for which specific treatment is
lacking. The advice of a counsellor is also taken by couples who are closely
related or older women planning to have children.

The prenatal testing (ultrasonography, amniocentesis, chorionic villus

sampling, maternal blood testing) allows early intervention such that the
development of the condition may be prevented or alleviated. In some
situations the family has to make choices of either terminating pregnancy or
prepare for a child with an untreatable genetic condition. The postnatal tests
on the other hand are done for testing genetic disorders in newborn infants.
Testing is also done on adults for heterozygote screening, late onset diseases
(before symptoms develop) and for decisions related to personalised drug
treatment. Now in the following section we shall discuss about the techniques
commonly used to separate nature and nurture in order to improve our
predictive abilities.

9.4 TECHNIQUES USED TO SEGREGATE

THE RELATIVE ROLE OF GENES AND
ENVIRONMENT
Two commonly used methods to separate nature (genes) and nurture
(environment) is adoption studies and twin studies. These studies also
improve our predictive abilities. In the former method biological parents share
nature but not nurture with their children while the latter is based on
comparison of monozygotic and dizygotic twins. Some of the long term studies
on twins and / adoptees include Colorado Adoption Project (CAP); Twin Early
Development Study (TEDS) and Minnesota study of twins reared apart. The
single most important conclusion of all such studies is that almost all traits
investigated have a genetic component. Let us now understand how these
studies are designed to generate useful information.

9.4.1 Twin Studies

In order to analyze the genetics of human characteristics, twin studies are one
of the commonly used methods. Twins are gift to science. They could be either
monozygotic or dizygotic. Monozygotic twins are formed when a single
fertilised egg splits into two during early embryonic development. They allow
us to see heredity in action. As expected these twins are genetically identical,
although they may differ epigenetically or due to rare somatic mutations. They
have identical sex – either both are males or females (Fig.9. 7). The tendency
to produce identical twins does not appear to run in families. The frequency of
monozygotic twinning in most ethnic groups is constant at about 4 twin pairs
per 1000 births.

The dizygotic (fraternal) twins arise when two eggs are fertilized by two
different sperms. Usually they develop their own placenta but proximity can
lead to fusion and sharing of one placenta. 167
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Source: gap.med.miami.edu deccanchronicle.com

Fig. 9.7: Monozygotic (identical) twin pairs.

The dizygotic twins share only 50% of their genes just like siblings. These
twins may be of the same sex or of different sexes (Fig.9.8) but unlike other
siblings they are of the same age and shared the same environment in the
mother’s womb. Majority of twins are dizygotic and the tendency to produce
them has a genetic component in addition to environmental factors. The
frequency of dizygotic twins varies in different populations. Among Japanese,
birth rate of dizygotic twins is approximately 3 pairs per 1000 births; it is about
7 pairs per 1000 births among North American Caucasians and roughly 40
pairs per 1000 births among Nigerians.

(Source:shutterstock.com, alamy stock photo)

Fig. 9.8: Dizygotic (fraternal) twin pairs.

Concordance is the To determine the relative contribution of genetic and environmental factors for
percentage of twin the observed variations, twin studies are quite informative. In these studies
pairs in which both comparison of monozygotic and dizygotic twins (same sex provide a better
twins have a
comparison) reared together are done to calculate concordance for a trait.
particular trait.
When both members of a twin pair exhibit the trait they are said to be
concordant; otherwise they are discordant. Concordance refers to the
percentage of twin pairs that are concordant (similar) for a trait. It is used to
make an assessment.

You know dizygotic twins share 50% of their genes as compared to identical
twins which have 100% of their genes in common, so genetically influenced
traits should exhibit higher concordance (but not 100%) in monozygotic twins
as compared to dizygotic pairs. At the same time discordance between
monozygotic twins is taken as an indicator of environmental effects, for
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instance the concordance for epilepsy is about 59% and rest of the variation is
due to environmental factors. If a trait exhibits 100% concordance for both
monozygotic and dizygotic twins then genetic factors are unimportant.

SAQ 4
Differentiate between monozygotic and dizygotic twins.

9.4.2 Adoption Studies

The study of adopted children is another technique used by geneticists to
analyze the effects of genes and environment for various characteristics.
Several children are separated from their biological parents soon after birth
due to different reasons (born to unmarried girls, economic condition, frequent
wars) and adopted by adults with whom they have no genetic relationship.
These adoptees and their adoptive parents do not have common genes
(nature) but they share an environment with each other (nurture). On the other
hand, adopted children have fifty percent of the genes in common with their
biological parents but they do not share the same environment with them.

The environments of biological and adoptive families should preferably be

independent in adoption studies but this assumption may not always be
possible because adoption agencies try to select a family that is similar to that
of the biological family. Thus, some of the similarity between adopted children
and their biological parents may be due to similar environments and not only
to common genetic factors. In addition to this, there is sharing of the same
environment during prenatal development between offspring and biological
mother. It is important that adoptees are not genetically related to the adoptive
parents and are not in regular touch with their biological parents.

The relative contribution of genes and environment is assessed by comparing

whether an adoptee resembles for a given characteristic (s) with the biological
parents or adoptive parents. For instance, if nature (genes) is why obesity
(measured as BMI; weight / height) runs in families than adoptive children will
be like their genetic parents; which is what is observed. The adoption
experiment also provides a direct test of nurture; if the body weight is
comparable to adopted parents then it is controlled largely by environment.

SAQ 5
Indicate the assumptions on which adoption studies are based.

The range of characters studied using twin and adoption techniques include
susceptibility to diseases, general learning abilities, memory, mood disorders,
reading disability, autism, smoking habit, hobbies, learning a second language
and schizophrenia. It is observed that heritability for cognitive abilities
increases with development.
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9.5 SUMMARY
 Traditional genetic techniques are difficult to apply to study human traits.
It is not possible to control mating; have long generation time, small
family size and the difficulty of separating genetic and environmental
influences.

 A pictorial representation of a family history that displays the inheritance

of one or more traits through several generations is called pedigree. The
person from whom the pedigree is initiated is known as proband.

 Autosomal dominant traits are transmitted by either parent to sons and

daughters; do not skip generation; generally an affected progeny has
one affected parent.

 Autosomal recessive traits appear with equal frequency in both sexes;

transmitted by either sex; tend to skip generation; affected children are
generally

 born to unaffected parents; their frequency increases in

consanguineous marriages.

 X-recessive traits affects predominantly males which they generally

inherit from asymptomatic carrier mothers; tends to skip generations;
never passed from father to son; an unaffected mother may have
affected male relatives.

 X-linked dominant traits appear in both males and females; more

frequently in females. They do not skip generations; affected men pass
the trait to all of their daughters but none of their sons. Heterozygous
women pass the trait to ½ of her progenies, irrespective of sex.

 Y-linked traits appear only in males and are passed from father to all
sons.

 Two commonly used methods to separate nature (genes) and nurture

(environment) is the adoption study and twin study.

 In twin method monozygotic (100% identical) and dizygotic twins (share

50% of the genes; same sex provide a better comparison) reared
together are compared to calculate concordance for a trait. When both
members of a twin pair exhibit the trait they are said to be concordant;
otherwise they are discordant.

 Higher concordance in monozygotic than dizygotic twins indicates a

genetic influence on the trait and less than 100% concordance in
monozygotic twins is due to environmental influences.

 In adoption method the relative contribution of genes and environment is

assessed by comparing whether an adoptee resembles for a given
170 characteristic (s) with the biological parents or adoptive parents.
Unit 9 Human Pedigree Analysis

 Similarities between adopted children and their biological parents are

indicative of genetic influence whereas if they resemble their adoptive
parents then environmental effect dominates.

9.6 TERMINAL QUESTIONS

1. Indicate the factors which complicate the task of studying inheritance of
human characteristics.

2. Predict the most likely mode of inheritance of the pedigree given below.
Defend your choice.

Source: Human Molecular Genetics by T. Strachan A. P. Reed

3. How are adoption method used to separate the effects of genes and
environment in humans?

4. What is genetic counselling? Indicate situations in which it is advisable

to seek guidance of a genetic counsellor.

5. Define concordance and what does high concordance in monozygotic as

compared to dizygotic twins signify.

6. Analyse the pedigree carefully and answer the following questions:

a) Predict the likely mode of inheritance of the trait.

b) What will be the phenotype of two boys and two girls born to III-b
and III-c?

Source: Assessment test bank for Introduction to Genetic analysis by Griffith et al. 171
Block 3 Genetic Basis of Development and Sex Determination

9.7 ANSWERS
Self-Assessment Questions
1. The person from whom the pedigree is initiated is called the proband
and is usually designated by an arrow.

2. X-linked recessive: (a) more males than females are affected. (b) Never
passed from father to son. (c) Affected sons are born to unaffected
mothers.

Autosomal recessive: (a) appears in both sexes with equal frequency.

(b) Transmitted by both parents to all offsprings. (c) The incidence of the
trait increases in consanguineous marriages.

3. i) b)

ii) c)

4. Monozygotic twins are formed when a single fertilised egg splits into two
during early embryonic development; are genetically identical; twin pairs
have identical sex – either both are males or females; The tendency to
produce identical twins does not appear to run in families; lower
frequency than dizygotic twins.

Dizygotic twins: (fraternal) twins arise when two eggs are fertilized by
two different sperms; they share only 50% of their genes just like other
siblings; may be of the same sex or of different sexes; Majority of twins
are dizygotic.

5. i) The foster parents and biological parents are not genetically

related.

ii) The environments of biological and adopted parents are

independent.

iii) Adoptees have no contact with their biological parents after birth.

Terminal Questions
1. Incomplete family records / small family size / long generation time /
controlled matings are not possible.

2. The most likely mode of inheritance is autosomal dominant.

Affects both sexes / transmitted by either sex / affected individual has at
least one affected parent / does not skip generations.

3. The relative contribution of genes and environment is assessed by

comparing whether an adoptee resembles for a given characteristic (s)
with the biological parents or adoptive parents. If it resembles biological
parents then the trait has a genetic basis otherwise environment plays a
major role.
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4. Genetic counselling is an educating process by providing information to

patients at risk about genetic disorders, their mode of inheritance,
diagnosis and available treatments.

Generally people seek counselling in case of marriages between

relatives; those with a family history of genetic disorder; couples with an
abnormal child, etc.

5. Concordance is the percentage of twin pairs that are concordant for a

trait. A higher concordance in MZ Vs DZ twins signifies greater genetic
influence on the trait.

6. (a) Cytoplasmic inheritance (transmitted from mother to all offsprings).

(b) None of the progeny will be affected.

9.8 FURTHER READINGS

1. Pierce, B. Genetics: A conceptual approach, 6th Ed. W.H. Freeman and
Company.

2. Plomin, R. Blueprint (2018); Penguin books.

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