Pedigree Analysis in Humans

Background Information
As geneticists are unable to manipulate the mating patterns of people, they must obtain inheritance
patterns of human traits through the analysis of the results of matings that have already occurred.
Information about the presence of a particular trait is gathered from family members. This information
is represented pictorially in a pedigree that indicates the presence or absence of a particular trait in a
family and the interrelationships of members of the family. Because the trait being investigated is
often a genetic defect, persons with the trait are generally referred to as ‘affected’ individuals and
those lacking the trait ‘unaffected’.

The collection of records can be difficult. Some members of a family may refuse to discuss or release
family documents. Others may refuse permission for information about themselves to be included in
pedigree analysis. Years ago, less information was recorded in some situations. For example, if a baby
was stillborn, the sex or presence of a condition may not have been recorded. The following figure is
an example of a family pedigree. The meanings of the various symbols are outlined in the legend
below the pedigree.

I
1 2

II
1 2 3 4 5

III
3
1 2 3 4-6 7 8 9

IV
1 2 3 4 5

LEGEND

Unaffected female Mating line

Unaffected male Consanguineous mating – some

degree of relationship

Affected female I Generation

II 3 Person three in generation II

Affected male

Female who has died Identical (monozygotic)

twins
Sex unknown

Three unaffected females

3
Analysing Pedigrees Non-identical (dizygotic) twins
What information are we aiming to gather from pedigree analysis? Basically two things:
 Is the trait dominant or recessive?
 Is the gene responsible for the trait located on an autosome or X chromosome?
 Note the at this stage of the pedigree analysis, the only sex chromosome we consider is the X
chromosome. Although the Y chromosome in humans is also a sex chromosome, it carries very few
genes and hence there are very few Y linked traits for consideration.

If effect, taking alternative answers to the two questions posed above, and combining the options, the
possible modes of inheritance are:
 Autosomal recessive
 Autosomal dominant
 X-linked recessive
 X-linked dominant

Consider the following pedigree and assume that the family have a trait previously unknown.

pedigree 1

pedigree 2 pedigree 3

pedigree 4

This family pedigree has several parts. That is, one can also consider many parts of the whole pedigree
to be pedigrees within their own right. If one considered pedigrees 1, 2 and 3, they are all non-
informative in terms of mode of inheritance of the trait. Each of the four modes of inheritance we have
considered could apply in each case. On the other hand, pedigree 4 is completely informative. It can
only be explained on the basis of autosomal dominant mode of inheritance. Because it is within one
family, we know the mode of inheritance will be identical in each of the pedigrees within the greater
pedigree. Given that, we are now in a position to assign genotypes that will be far more informative. It
was the birth of the daughter in the fourth generation within pedigree 4 that suddenly enabled the
family to have more accurate information about the trait within the family.

Procedure
Examine each of the pedigrees on the following pages and use your knowledge of Mendalian genetics
to suggest possible mode(s) of inheritance involved. All examples illustrated are of single gene
inheritance.
You will need to determine if the trait is inherited as a dominant or a recessive trait, and whether the
gene responsible is sex-linked (on the X-chromosome) or autosomal. In general, unless there is clear
evidence to the contrary, it is reasonable for you to conclude that any non-affected individual
entering the pedigree in later generations is homozygous at the gene locus involved.
Give full reasoning to support your decision for the most probable mode of inheritance for the trait in
each of the pedigrees. List your resons clearly.
In your answer you should also spell out why the pedigree cannot be other modes of inheritance.
(a) Schwartz-Jampel syndrome
(b) Cutaneous malignant melanoma
(c) Charcot-Marie-Tooth disease

(d) Heterotopia
 Answers
(a) Autosomal Recessive

Autosomal
- Fairly even number of males and females – each sex has same chance of being affected which
is not true for X-linked disorders because males, having no second X-chromosome to override
effects of a recessive allele are unprotected against X-linked recessive disorders

Recessive
- Skips generations
- Two unaffected parents (III4 and III5) produce affected children (IV6 and IV7) – if the trait were
dominant this wouldn’t be possible as both III4 and III5 would have to be homozygous
recessive, leaving no possibility of their children receiving an affected allele

Impossible to be X-linked
- If it were X-linked recessive, individuals IV4 and IV5 with genotypes of XRY and XRXr or
XRXR respectively (where XR denotes unaffected allele and Xr denotes affected allele) could
not produce an affected daughter (V7) as she would inherit the XR allele from her father,
dominating over any affected allele
- If it were X-linked dominant, I1 could not have an unaffected daughter (II4) as an affected
father will always pass on the disease to his daughter – occurs because she must inherit the
only X-chromosome that her father has, which carries the trait

(b) Autosomal Dominant

Can’t be autosomal recessive

- Would mean than II3 would have the genotype BB, where B represents non-affected allele and
b an affected allele – therefore her children could not be affected by the trair as they would all
inherit B, overriding effects of b received from their father, II 2

Can’t be X-linked recessive

- Would mean that III3 and III4 would have genotypes Xb Xb and XB Y respectively (where Xb
represents affected allele and XB the unaffected allele) – makes it impossible to have a
daughter with the trait (IV1 and IV2) as she must inherit XB from her father which would
override the Xb gene inherited from her mother

Can’t be X-linked dominant

- An affected father will always pass the trait on to his daughter – II 2 is affected but one of his
daughters (III2) is does not inherit it – he would have genotype X BY, meaning all daughters
would have to inherit the XB allele and therefore the trait

(c) X-linked recessive

X-linked recessive
- Considerably more males than females affected – female receiving recessive allele has the
chance to inherit dominant allele to prevent her from getting the trait, whereas male receiving
the recessive allele will definitely have the trait

Can’t be X-linked dominant

- Two unaffected parents produce an affected child - III 2 and III3 would have genotypes of Xb Xb
and Xb Y respectively, leaving no possibility of their children (IV3 and IV6) obtaining the XB
allele required to inherit the trait

Not likely to be autosomal

- Majority of those affected are male

Autosomal dominant imporssible

 - Individuals III2 and III3 must have genotype bb and therefore can’t produce affected children

Autosomal recessive impossible

- II5 mating with an unaffected homozygous male can’t have affected children – would be bb
and BB, each child inheriting Bb and therefore the unaffected phenotype

(d) X-dominant

X-linked dominant
- Affect father (III1) has passed the disease on to all of his daughters, who must inherit his
affected X-chromosome
- Two affected females have a non-affected father

Can’t be X-linked recessive

- Individual II1 would have to obtain the affected allele (and therefore inherit the trait) from his
mother, who would have a genotype of Xr Xr

Can’t be autosomal recessive

- III1 (genotype bb) and III2 (genotype BB) would be unable to produce affected offspring, as all
their children would have genotype Bb

Autosomal dominant also a possibility