Pedigree analysis - What are the patterns of autosomal inheritance?
What’s the probability of inheriting certain genetic disorders?
Pedigree analysis is usually quite helpful in answering this question.
Fortunately, a thorough understanding of human genetics isn’t required to do so.
Usually, an overview of classical hereditary suffices.
We’d like to provide you with this overview in two Chalk Talk episodes on pedigree analysis.
In addition, we’ll give you an example of a corresponding hereditary disorder for each
inheritance pattern, which will help you better understand the principles of inheritance.
But before we delve into the various patterns, let’s go through the basics:
Somatic cells that contain two sets of chromosomes are termed diploid.
Germ cells contain one set of chromosomes and are haploid.
During the fusion of two germ cells, maternal and paternal chromosomes combine to form a
new set of diploid chromosomes.
This new gene combination increases the gene pool of the population and leads to the formation
of new, visible traits.
Another important piece of information is that the genetic makeup of a trait, also termed
allele, doesn’t automatically result in the physical expression of the trait.
Therefore, a differentiation is made between the individual’s genotype and phenotype.
If maternal and paternal alleles for a particular trait are identical, then the term homozygous
is used.
In homozygotes, only one phenotype is possible.
If each parent provides a different allele for a specific trait, then the term heterozygous
is used.
Theoretically, there are two phenotypes that can be expressed in heterozygous individuals:
the maternal or the paternal phenotype.
The allele that finally determines the phenotype of the trait in a heterozygote is dominant
and is represented by an uppercase letter.
The trait of the allele that isn’t visible in the phenotype is termed recessive and represented
by a lowercase letter.
Another possibility is codominant alleles, in which both alleles are expressed simultaneously
leading to a mixed phenotype.
Codominance is a more complex pattern of expression; so, to keep things simple, we won’t look
into it any further.
The inheritance of traits is usually depicted using a pedigree chart.
In a family tree, each family member is represented by a particular symbol: circles for females
and squares for males.
The line connecting two symbols indicates a direct relationship.
Pedigree charts are read from top to bottom.
Therefore, the generation at the top is the first or parent generation and represented
by the Roman numeral I. Directly beneath this is the second generation, the children, represented
by the Roman numeral II.
This is followed by the grandchildren and so on.
If an individual is affected by the trait, their symbol is shaded with color.
We’ll be using the color purple for affected individuals, but there’s no general rule
on the use of a particular color.
The pattern of inheritance can be easily traced in the pedigree chart.
Let’s assume that both parents are heterozygous for a particular trait.
This gives four different potential allele combinations in the children.
Because the parental alleles are inherited independently of one another, these four combinations
are equally probable.
The chance that a child inherits their genotype is one out of four, which corresponds to one-quarter
or 25%.
Since it’s irrelevant which allele stems from the mother or the father, the child can
only inherit one of three different genotypes.
The heterozygous genotype “big A little a” or “little a big A” has a 50% chance
of being inherited.
The two homozygous genotypes, “big A big A” and “little a little a” each have
a 25% chance of being inherited.
OK, so that was a short review of the basics.
Let’s take a detailed look at autosomal inheritance.
Traits inherited independently of sex in families are located on chromosomes known as autosomes.
Autosomes are labeled with the chromosome numbers 1 to 22 and are present as pairs in
males and females.
First, let’s look at a simple case of a dominantly inherited allele.
We’re going to term this allele “big A”.
Once a dominant allele is present in the genotype, the trait is also expressed in the phenotype.
This means that for children with only one heterozygous parent with the genotype “big
A little a”, there’s a 50% chance that they’ll be affected.
All offspring inherit one allele from this individual; either the dominant “big A”
or the recessive “little a”.
Because “big A” is dominant and always asserted phenotypically, this doesn’t change
even if the other parent is unaffected, that is, has the “little a little a” genotype.
If both parents are heterozygous for the trait, then the probability of inheriting the dominant
“big A” allele from at least one of both parents is 75%.
However, there remains a 25% chance that they will have a child that doesn’t carry the
abnormal gene!
But if an affected parent is homozygous for the dominant “big A big A” genotype, then
all offspring will carry the gene and express the phenotype.
One example of an autosomal dominant inheritance pattern is Marfan syndrome, which is a connective
tissue disease resulting in impaired microfibril synthesis.
It leads to multiple pathological changes in various organs, especially the heart.
Other characteristic manifestations include tall stature and hyperelastic joints.
Marfan syndrome is a mutation of the fibrillin-1 gene on chromosome 15.
It occurs in approximately 1–2 per 10,000 individuals.
Around 75% of cases are hereditary, with the remaining caused by new spontaneous mutations.
Now, if we look at the autosomal inheritance of a recessive allele, “little a”, predicting
which individual is affected is somewhat complicated.
As only homozygous individuals with the genotype “little a, little a” exhibit the phenotype
for the trait, heterozygous individuals can pass the allele to their children unnoticed
without exhibiting the trait.
In regard to mutations, they’re considered carriers or also genetic carriers.
In a pedigree, they’re represented by a dot in the middle of a symbol.
A recessive trait or disorder can skip several generations such that the trait isn’t phenotypically
expressed before it reappears.
If one parent is unaffected but the other is either a carrier or affected, then none
of the children will be affected.
This is because the dominant allele from the healthy parent is always expressed in the
phenotype.
However, there’s a 50% chance that each child of a carrier is also a carrier.
Children of an affected parent are always carriers.
Affected individuals or disorders in the second generation can only occur when both parents
carry the recessive allele “little a”.
If both parents are carriers, that is, heterozygous, their children have a 25% chance of being
homozygous and affected.
With the genotype “little a little a”, they’re affected; whereas with the genotype
“big A big A”, they’re unaffected.
The probability that any children from these parents will be a carrier is 50%.
If one parent is a carrier and the other parent is affected, then all of the children in the
second generation are at least carriers.
The probability of a child being affected is 50%: All of the children inherit a recessive
allele, namely “little a” from the affected parent, and have a 50% chance of inheriting
an additional recessive allele “little a” from the carrier parent.
An example of autosomal-recessive inheritance is cystic fibrosis.
It’s the most common hereditary autosomal recessive condition in individuals of northern
European descent.
Cystic fibrosis is caused by a mutation in the CFTR gene on chromosome 7.
The CFTR gene codes for a chloride channel protein in cell membranes.
A mutation of the CFTR gene leads to the production of hyperviscous secretion in the body’s
exocrine glands.
This results in a chronic productive cough, exocrine pancreatic insufficiency, and malabsorption.
Cystic fibrosis is grouped into different classes according to the type of point mutation,
in which a single amino acid of the channel protein is substituted or absent.
The different levels of severity depend on the amino acid affected.
In the US, the prevalence of cystic fibrosis is approximately 1 in 3,300 individuals.
The heterozygote frequency in the US is 1 in 25 or 4 %.
So, let’s wrap it up for dominant and recessive autosomal patterns.
Do you want to check if you’ve remembered everything in this episode?
Then stay put for the quiz!