Modes of inheritance in monogenic disorders Flashcards
In humans, as in many organisms, the expression of a particular genetic trait often
depends on many genes acting in concert. For some, however ?
A particular
genotype at a single locus (in other words, a single allele) is primarily responsible
for the genetic character: this character is then said to be Mendelian (if
chromosomal) or more generally monogenic (which would include
mitochondrial characters as well)
What does the genotype describe ?
The genotype describes the combination of alleles for an organism, or its genetic constitution (as distinguished
from its physical appearance, the phenotype)
In a single-gene or monogenic disorders, what causes the phenotype ?
- Genetic variation.
- Environmental factors.
- Epigenetic effects (independent of the base sequence of the DNA).
- Stochastic factors
If a Mendelian trait (or disease) is manifested in the heterozygote (which carries both the mutant and normal, or wild-type, allele) then it is said to ?
It is said to be dominant
If the character is instead only expressed in the homozygote, it is said to be?
Recessive
If two phenotypes expressed by two different alleles are simultaneously displayed by the heterozygote, then they
are said to be ?
Co-dominant (example, the AB blood type)
What is aneuploidy ?
Due to loss of one chromosome or to the presence of an extra one is lethal in most cases, due to gene dosage issues
In the case of aneuploidy occurring to the X chromosomes, what happens ?
A potential imbalance in the two sexes is dealt with by the inactivation of one of the two sex chromosomes in females (X-inactivation)
How is X-inactivation achieved ?
X-inactivation is achieved by silencing of essentially one entire X
chromosome which becomes condensed (Barr body)
The choice of which
chromosome to inactivate, either the paternal or the maternal one, is made?
Early in the embryo, randomly in each cells. After the decision is made all the cells deriving from subsequent division will maintain that pattern, giving rise to mosaicism: the female will be a genetic mosaic with clones expressing a maternal allele and other expressing the paternal one, and this
affects X-linked disorders in females
What is the proband ?
The proband is a person serving as the starting point for the genetic study of a family
Explain the autosomal dominant inheritance?
In this type of disorders the disease locus is present on one of the autosomes and is manifested in heterozygotes
In autosomal dominant inheritance, what would be the chance of each child developing the disease ?
Each child would have a 50% chance of
developing the disease (in the most common
case where only one parent carries the mutation,
and is heterozygous for it)
Explain the autosomal recessive inheritance ?
In this type of disorders the disease locus is on one of the autosomes and is manifested in homozygotes
In autosomal recessive inheritance, what would be the chance of each child developing the disease ?
Each child would have a 25% chance of
developing the disease (in the most common
case where both parents are carriers for the
mutation, and are heterozygous for it)
What is compound heterozygotes ?
In the case of frequent disorders, there are generally several variant mutant alleles in the population, and the disease might
manifest with two allelic mutations in heterozygote form
What is true homozygotes?
In the case of rare disorders, usually affected individuals carry the same mutant allele
In the case of rare disorders, usually affected individuals carry the same mutant allele, which they have inherited by ?
Parents who are close relatives
Explain X-linked recessive inheritance ?
In this type of disorders the disease locus is on the X chromosome and is manifested in all males and in homozygous females
In the case where the father is affected and the mother is not a carrier, each child
would have? (X-linked recessive inheritance)
A 0% chance of developing the disease
In the case where the father is not affected and the mother is a carrier, each child would have? (X-linked recessive inheritance)
A 0% chance of
developing the disease if female, and 50%
if male
In the case where the father is affected and the mother is a carrier, each child would have? (X-linked recessive inheritance)
A 50% chance, irrespective of gender, of developing the disease
Explain X-linked dominant inheritance?
In this type of disorders the disease locus is on the X chromosome and is manifested in all males and in heterozygotes
females
In the case where the father is affected, who will be affected? (X-linked dominant inheritance)
In the case where the father is affected, no
sons will be affected, but all the daughters
will
In the case where the mother is affected, who will be affected? (X-linked dominant inheritance)
In the case where the mother is affected,
50% of the children will be affected, regardless of gender
What are pseudoautosomal regions? and what do they do ?
- The X and Y chromosomes bear largely different
sequences but carry essentially identical sequences near
the telomeres - These pseudoautosomal regions recombine during meiosis (there is one obligate crossover in the major pseudoautsomal region) and behave like autosomes for inheritance
Briefly explain Y-linked inheritance ?
Y-linked inheritance concerns only males. But given that
only 31 genes (mostly involved in male specific functions)
are present on the Y chromosome, it is very rare
How would Y chromosomes be eliminated ?
Because harmful mutations cannot be eliminated on the Y chromosome by recombination, evolutionary pressure
has lead to a reduction in size of this chromosome to
delete accumulated deleterious changes
Where is the Mitochondrial DNA is only inherited from?
The mother, not the father
However, mothers can transmit the disease ?
Equally to sons and daughters
MtDNAs within a cell can be?
Identical (homoplasmy) or mixed (heteroplasmy) when both normal and
mutant copies are present.
Because rapid shifts in heteroplasmy are observed, a bottleneck hypothesis has been proposed which suggests?
That during early development germline cells pass through a
stage where they contain very few mtDNAs (bottleneck). The chance that normal or
mutant mtDNAs might be over-represented at the bottleneck stage will affect final ratio in the mature egg
What’s an issues with determine inheritance?
- If a pedigree is small determining the mode of inheritance can be difficult
- One way to get around this is to look at the same disorder in different families and determine the
segregation ratio in children overall. But this assumes that the same genetics (genes, alleles, etc) are at
play in the different families - Another issue is that by focussing only on affected families there will be an intrinsic bias in the
genotypes examined, unless there is an independent way to identify healthy carriers (which is now being
increasingly provided by exon sequencing)
What are some issues with determining inheritance?
- If a pedigree is small determining the mode of inheritance can be difficult
- Locus heterogeneity
- Allelic and phenotypic heterogeneity
What is Penetrance ?
Penetrance is defined as the proportion of individuals of a specified genotype that show the expected
phenotype (for example the proportion of individuals with a monogenic disorder allele that will express the
disease)
What is non- penetrance ?
Dominant disorders sometimes have variable penetrance and can skip a generation
What is Variable expression?
Variable expressivity refers to the degree in which a genotype is phenotypically expressed
What is Imprinting ?
Imprinting describes the fact that mutant alleles can be transmitted by either sex but are expressed only when coming form either the mother or the father (there are examples of both kinds). This is due to epigenetic effects,
and the suppressed allele is referred to as the imprinted allele
What is genetic anticipation?
The phenotype
varies in different generations in a directional manner,
becoming more severe and potentially with earlier onset
Several human syndrome exist (collectively known at telomere
syndromes), where?
The replication of telomeric DNA is defective,
due to the mutation in various genes. As a consequence telomeres will shorten in successive generations, leading to earlier onset of diseases
and greater severity of symptoms
