What is pedigree analysis?

Overview and Definition

Pedigree analysis involves the construction of family trees that can be used to
trace inheritance of a trait over several generations. It is a graphical
representation of the appearance of a particular trait or disease in related
individuals along with the nature of the relationships.

Standardized symbols are used in pedigree charts. Male individuals are
designated by squares, and female individuals are denoted by circles. Symbols for
individuals affected by a trait are shaded, while symbols for unaffected
individuals are not. Heterozygous carriers are indicated by shading of half of the
symbol, while carriers of X-linked recessive traits have a dot in the middle of
the symbol. Matings are indicated by horizontal lines linking the mated
individuals. The symbols of the individuals who are offspring of the mated
individuals are linked to their parents by a vertical line intersecting with the
horizontal mating line.

The classic way to determine the mode of inheritance of a trait in animals is
to conduct experimental matings of large numbers of individuals. Such experimental
matings between humans are not possible nor ethical, so it is necessary to infer
the mode of inheritance of traits in humans through the use of pedigrees. Large
families with good historical records are the easiest to analyze. Once a pedigree
is established, it can be used to determine the likely mode of inheritance of a
particular trait and, if the mode of inheritance can be determined with certainty,
to determine the risk of the trait’s appearing in offspring.

Typical Pedigrees

There are four common modes of inheritance detected using pedigree
analysis: autosomal dominant, autosomal recessive, X-linked dominant, and X-linked
recessive. Autosomal traits are governed by genes found on one of the autosomes
(chromosomes 1–22), while the genes that cause X-linked traits are found on the X
chromosome. Males and females are equally likely to be affected by autosomal
traits, whereas X-linked traits are never passed on from father to son but can be
passed from father to daughter, and all affected males in a family received the
mutant allele from their mothers.

The pattern of autosomal dominant inheritance is perhaps the easiest type of
Mendelian
inheritance to recognize in a pedigree. A trait that appears
in successive generations and is found only among offspring where at least one of
the parents is affected is normally due to a dominant allele.

If neither parent has the characteristic phenotype displayed by the child, the
trait is recessive. For recessive traits, on average, the recurrence risk to the
unborn sibling of an affected individual is one in four. The majority of X-linked
traits are recessive. The hallmark of X-linked recessive inheritance is that males
are much more likely to be affected than females, because males are hemizygous,
that is, they possess only one X chromosome, while females have two X chromosomes.
Therefore, a recessive trait on the X chromosome will be expressed in all males
who possess that X chromosome, while females with one affected X chromosome will
be asymptomatic carriers unless their other X chromosome also carries the
recessive trait.

X-linked dominant traits are rare but distinctive. All daughters of an affected
male and an unaffected female are affected, while all sons of an affected male and
an unaffected female are unaffected. For matings between affected females and
unaffected males, the risk of having an affected child is one in two, regardless
of the sex of the child. Males are usually more severely affected than females.
The trait may be lethal in males. In the general population, females are more
likely to be affected than males, even if the disease is not lethal in males.

Usefulness

Pedigrees are important both for helping families identify the risk of
transmitting an inherited disease and as starting points for researchers in
identifying the genes responsible for inherited diseases. Mendelian ratios do not
apply in individual human families because of the small size. Pooling of families
is possible.

However, even using large, carefully constructed records, pedigrees can be
difficult to construct and interpret for several reasons. Tracing family
relationships can be complicated by adoption, children born out of wedlock, and
assisted reproductive technologies that result in children who may not be
genetically related to their parents. Additionally, people are sometimes hesitant
to supply information because they are embarrassed by genetic conditions.

Many traits do not follow clear-cut Mendelian ratios. Extensions and exceptions
to Mendel’s laws that can confound efforts to develop a useful pedigree are
numerous. In diseases with variable expressivity, some of the symptoms of the
disease are always expressed but may range from very mild to severe. In autosomal
dominant diseases with incomplete penetrance, some individuals who
possess the dominant allele may not express the disease phenotype at all. Some
traits have a high recurrent mutation rate. An example is achondroplasia, in which 85 percent of cases are due to new
mutations, where both parents have a normal phenotype. Traits due to
multifactorial inheritance have variable expression as a result of interactions of
the genes involved with the environment. Early-acting lethal alleles can lead to
embryonic death and a resulting dearth of expected affected individuals.
Pleiotropy is the situation in which a single gene controls several functions and
therefore has several effects; it can result in different symptoms in different
affected individuals. Finally, one trait can have a different basis of inheritance
in different families. For example, mutations in any one of more than four hundred
different genes can result in hereditary deafness.

Modern Applications

Genetic
counseling is one of the key areas in which pedigrees are
employed. A genetic counseling session usually begins with the counselor taking a
family history and sketching a pedigree with paper and pencil, followed by use of
a computer program to create an accurate pedigree. The Human Genome
Project has accelerated the number of genetic disorders that
can be detected by heterozygote and prenatal screening. A large part of the
genetic counselor’s job is to determine for whom specific genetic tests are
appropriate.

Although genetic tests for many disorders are now available, the genes involved
in many other disorders have yet to be identified. Therefore, most human gene
mapping utilizes molecular DNA markers, which reflect variation at noncoding
regions of the DNA near the affected gene, rather than biochemical, morphological,
or behavioral traits. A DNA marker is a piece of DNA of known size, representing a
specific locus, that comes in identifiable variations. These allelic variations
segregate according to Mendel’s laws, which means it is possible to follow their
transmission as one would any gene’s transmission. If a particular allelic variant
of the DNA marker is found in individuals with a particular phenotype, the DNA
marker can be used to develop a pedigree. The DNA from all available family
members is examined and the pedigree is constructed using the presence of the DNA
marker rather than phenotypic categories. This method is particularly useful for
late-onset diseases such as Huntington’s disease, as affected individuals may not
know they carry the deleterious allele until they are in their forties or fifties,
well past reproductive years. Although using DNA markers is a powerful method,
crossover in the chromosome between the marker and the gene can cause an
individual to be normal but still have the marker that suggests presence of the
mutant allele. Thus, for all genetic tests there is a small percentage of false
positive and false negative results, which must be factored into the advice given
during genetics counseling.

Key Terms




alleles


:

alternate forms of a gene locus, some of which may cause disease




autosomal trait

:

a trait that typically appears just as frequently in either sex because an autosomal chromosome, rather than a sex chromosome, carries the gene




dominant allele

:

an allele that is expressed even when only one copy (instead of two) is present




hemizygous

:

male humans are considered to be hemizygous for X-linked traits,
because they have only one copy of X-linked genes




heterozygous carriers

:

individuals who have one copy of a particular recessive allele that is expressed only when present in two copies




homozygote

:

an organism that has identical alleles at the same locus




recessive allele

:

an allele that is expressed only when there are two copies present




X-linked trait

:

a trait caused by a gene carried on the X chromosome, which has different patterns of inheritance in females and males because females have two X chromosomes while males have only one





Bibliography

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