Pedigree analysis: What are the patterns of sex-linked inheritance?
In the previous Chalk Talk episode, we focused on autosomal or non-sex linked inheritance
patterns. They affect any trait whose genes are located on autosomes. Autosomes are the
chromosomes 1 to 22 of which two copies of each are present in males and females.
Sex-linked inheritance usually involves traits whose genes are located on the sex chromosomes,
that is, chromosome 23. In addition, all traits encoded in mitochondrial DNA follow a sex-linked
mode of inheritance as mitochondria are usually inherited exclusively from the mother. In
this episode, we’ll be focusing on why these patterns of inheritance depend on the sex
of the affected individual and also potentially on the sex of the children.
Let’s first look at chromosome 23:
In the cell, chromosome 23 is quite special as a diploid set of chromosomes. If we look
at the condensed form of chromosome 23 during mitosis, we can see a double X-shaped chromosome
in females and an X and a Y shaped chromosome in males. Although it’s been scientifically
proven that the Y chromosome carries very little genetic information, it isn’t exactly
known what type of information is stored on the Y chromosome. By the way: To date, there
are no known gene defects inherited via the Y chromosome. That’s why we won’t be taking
a look at Y-linked inheritance in this episode.
Let’s look at a simple case of X-linked inheritance, the dominant alleles. As for
autosomal dominant inheritance, each dominant allele “big A” demonstrates the corresponding
trait in the phenotype. However, the chance of passing on the allele on the X chromosome
to the next generation differs from that of autosomal dominant inheritance:
If the father possesses the allele “big A” and the mother is homozygous with the
genotype “little a little a”, then all sons won’t inherit the allele “big A”
and are unaffected. This is because the father always passes on the Y chromosome to his son.
In contrast, all daughters will be affected as they inherit both one maternal and paternal
X chromosome. However, if the mother is an affected heterozygote
with the genotype “big A little a”, then all offspring have a 50% chance of inheriting
the “big A” allele and being affected. If the mother possesses the genotype “big
A big A”, all offspring will be affected.
There are very few X-linked dominant disorders. One of these is Alport syndrome. In approximately
80% of cases, it’s caused by a mutation in the collagen gene on the X chromosome.
Since collagen is a component of the basement membrane, this mutation mainly leads to dysfunctions
of the glomerulus, the inner ear, and the eye. Although the condition is quite rare,
it’s the most common cause of hereditary nephritis.
On the other hand, if an X-linked allele is recessive, a differentiation needs to be made
between affected individuals that manifest the trait and those that only pass on the
gene, which are termed carriers. As shown in the first episode, carriers are marked
by a dot within the symbol in the pedigree. Carriers are heterozygous, which means that
in addition to the allele with the trait, they also have a dominant allele that doesn’t
express the trait. That’s why in X-linked recessive inheritance, only females can be
carriers. Males possessing the recessive allele always express the trait, because there’s
no genetic material on the Y chromosome to compensate for a recessive allele on the X
chromosome. To illustrate this, carriers of the genotype “big A Y” and “little a
Y” are called hemizygotes.
All daughters of a carrier mother have a 50% chance of being a carrier themselves, whereas
each son has a 50% chance of being affected. However, if the father is affected, then his
daughters will be carriers, whereas his sons won’t inherit the allele and are, therefore,
unaffected. The offspring of an affected male and a female
carrier with the genotype “big A little a” have, regardless of their sex, a 50%
chance of inheriting the genotype “little a little a” or “Y little a” and, therefore,
become affected. While male offspring are otherwise unaffected, each female child is,
at least, a carrier. This is because both the X and Y chromosomes inherited from the
father promote manifestation of the maternal recessive allele. So, the probability is based
on the maternally inherited allele. If both parents exhibit the phenotype of the
X-linked recessive gene, then all their children will be affected.
X-linked recessive disorders mainly affect male individuals. One example is Duchenne
muscular dystrophy, which occurs in approximately one in 3,500 male newborns. It’s caused
by a dystrophin gene defect on the X chromosome. Without functional dystrophin, muscle cells
are not adequately anchored to the extracellular matrix. As a result, several clinical features
start to develop in affected individuals between the ages of three and five. These include
muscle cell fiber death, subsequent replacement with connective and adipose tissue, and hypertrophy
of remaining muscle cells.
An additional sex-linked pattern of inheritance is mitochondrial inheritance. Phenotypically
expressed gene defects arising from mitochondrial DNA are, in fact, rare. Furthermore, mitochondrial
inheritance doesn’t follow the laws of chromosomal inheritance. So, we’ll only comment on two
important aspects of this type of inheritance:
The mitochondria of female gametes are located in the cytoplasm, just like in somatic cells.
In contrast, the mitochondria of sperm are arranged in the form of a cuff, spiraling
around the central part of the tail. Therefore, during gamete fusion, the mitochondria of
sperm aren’t transferred to the oocyte. In other words, all offspring inherit their
mitochondrial DNA exclusively from the maternal gamete. So, mitochondrial mutations are passed
on solely from mothers equally to all the offspring of both sexes.
Despite this clear line of inheritance, it’s not possible to reliably predict the chance
of inheriting a mitochondrial mutation. The reason behind this is actually quite simple:
Nuclear DNA mutations are easier to manifest than errors in mitochondrial DNA. Although
almost all the genetic information of human cells is encoded on nuclear DNA, the number
of chromosomes in the nucleus is comparatively small with only 46. In contrast, there are
over a thousand copies of mitochondrial DNA within a single cell, which are not all damaged
in case there’s a mutation. The ratio of intact to defective mitochondrial DNA then
determines whether the genetic defect is phenotypically visible and if so, the degree of severity.
Since mitochondria are randomly distributed to daughter cells during cell division, the
new cells cover a wide range of phenotypical variance. Some of these germ cells provide
the basis for healthy offspring, whereas others result in severely affected offspring.
An example of a mitochondrial inherited condition is MERRF syndrome, which is the acronym for
Myoclonic Epilepsy with Ragged Red Fibers. In approximately 80% of cases, this extremely
rare form of myopathy is caused by a point mutation in the mitochondrial DNA. Affected
individuals develop neurological manifestations ranging from myoclonic jerks, generalized
seizures and cerebellar ataxia to dementia.
OK. So, now we’ve introduced you to the classical patterns of inheritance in two Chalk
Talk episodes. To distinguish these in a pedigree chart, a simple scheme can be used:
First, you need to ask yourself whether the affected offspring are predominantly male.
If the answer is yes, then you’re most likely looking at an X-linked recessive trait. A
Y chromosome, in contrast to the X chromosome, can’t phenotypically dominate a recessive
allele.
But even if male offspring aren’t affected more than females, you still need to take
a more detailed look at the affected offspring: The next question to ask is whether all of
them have an affected mother. If yes, then ask whether all of their daughters are also
affected, whereas the sons are unaffected. If all of these questions can be answered
with yes, the pattern indicates X-linked dominant inheritance. The father always passes down
the unaffected Y chromosome to his sons and the affected allele on the X chromosome to
his daughters.
If one or several of the questions are answered with no, the inheritance pattern is autosomal.
In this case, you need to determine whether each affected child has at least one affected
parent. Then the inheritance pattern is autosomal dominant. If the trait skips one or more generations,
then the pattern of inheritance is autosomal recessive.
Would you like to put this information into practice? Then stay put for the quiz.