Pedigree Analysis – Part 1: Autosomal Inheritance Patterns
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Pedigree Analysis – Part 1: Autosomal Inheritance Patterns

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!

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