3. Mendelian Inheritance I (Classic Modes of Mendelian Inheritance) Flashcards
Ter or * =
STOP CODON
A standardised system of nomenclature:
What does
c.
g.
p.
m.
r.
stand for in genetic nomenclature?
Interpret this sequence.
What is the sequence for Coding DNA?
What is the sequence for Genomic DNA?
Protein
* DNA mutations that affect the corresponding protein
* Three letter abbreviation is preferred
* “_.” nomenclature:
* Begins with the affected _____ ______
* Uses amino acid position in the protein chain
p
amino acid
Where are codon numbers written?
What is the sequence for protein?
What are silent mutations?
What are missense mutations?
What are nonsense mutations?
What are Intronic mutations?
Indels
* Use ____ for deletions and ins for insertions
* The _______ position or amino acid symbol comes first
del
nucleotide
Indels
* Use del for deletions and _____ for insertions
* The nucleotide position or amino acid symbol comes first
ins
Duplications
* Use “____” to indicate a duplication event
dup
- Mutation nomenclature is always written from the perspective of the NORMAL sequence
List an example:
What makes us different/ unique? (3)
- Normal genetic variation
- How?
- Mutation
- Genetic drift
- Natural selection
- Learn about mutations and their consequences
What is a mutation?
How do mutations occur? (2)
Mutations can be _______ or ______.
somatic
germline
What are somatic mutations?
What are germline mutations?
What are Static variants?
- No change when passed to offspring
- Examples:
- Point mutations (single nucleotide substitutions)
- Deletion / Insertion mutations
- Splice site mutations
What are dynamic variants?
- Potential to change when passed to offspring
- Example:
- Trinucleotide repeats (TNR
Types of mutations:
Point mutations
* Single nucleotide _______
* occur in _____ than 1% of the population
* more than 1% of the population = polymorphism
substitutions
less
Examples of point mutations: (3)
- Silent mutations
- Nonsense mutations
- Missense mutations
What is the effect of silent mutations? (2)
- No effect on amino acid sequence
- Can influence kinetics of protein folding
What is the effect of missense mutations? (3)
- Nature of the amino acid substitution
- Location (conserved or non-conserved region of the gene)
- Folding of the protein
What is the effect of missense mutations? (2)
- Conversion of a codon into a stop codon
- No protein (Nonsense Mediated Decay) or
premature termination of protein with altered
function (truncated
Multiples of three → ____ _____ mutation
in frame
NOT multiples of three → _______ mutations
frameshift
Impact of Indels: (2)
- Insertion of __ bp or multiples of 3bp
- Extra amino acids in the protein
- Insertion ≠ 3bp or ≠ to multiple of 3bp results in a frameshift during ________
- Altered protein sequence 3’ of the mutation
- Possible introduction of a stop codon
- Altered or _______ protein function
3
translation
abolished
What are Splice site mutations? (2)
- Prevention of correct splicing
- Intron retention
- Inappropriate splicing
- Exon skipping
What is a Family Pedigree?
A pedigree is a genetic representation of a family tree that indicates the relationships between family members and illustrates the inheritance of a trait or disease through several generations.
Why draw a Family Pedigree? (6)
- Step 1 of genetic counselling
- gathering info PEDIGREE
- Advantages of a family pedigree: (5)
Easy to read
Fast
Permanent and clear record of family genetic info
Combines medical data and biological relationships
Use of standardized symbols
Collection of family history
Produce a three-generation pedigree that
includes: (7)
- Patient’s first, second and third degree relatives
- Information on maternal and paternal relatives
- Representation of “full” and “half” relationships
- Affected and unaffected individuals
- Date of collection and name of collector
- Legend or key
- Indication for referral
Collection of family history
Information to be collected:
Pedigree Symbols
* Gender: (3)
Pedigree Symbols:
Relationship:
Pedigree Symbols:
Relationship:
CONSANGUINITY
Pedigree Symbols:
* Multiple Relationship:
Pedigree Symbols:
* Offspring:
Pedigree Symbols:
* Offspring (to save space):
Pedigree Symbols:
* Siblings:
Pedigree Symbols:
* Twins :Non-Identical / Dizygotic Twins
Pedigree Symbols
* Twins :
Identical / Monozygotic Twins
Pedigree Symbols
* Pregnancy Related Symbols:
Pedigree Symbols
* Adoption:
Pedigree Symbols:
- Deceased Individuals
- Separation / Divorce
Pedigree Symbols:
* Trait / Disease Expression:
Pedigree Symbols:
* Trait / Disease Expression:
RECESSIVE CONDITIONS
Pedigree Symbols:
* Trait / Disease Expression:
X-LINKED CONDITIONS
Pedigree Symbols:
* Extras:
Proband symbol:
Consanguinity with cousins:
Adoption:
What is Mendelian inheritance? (4)
- Mendelian inheritance is a type of biological
inheritance that follows the principles originally
proposed by Gregor Mendel - Mendel’s Principles of Heredity
- Inheritance patterns for single gene disorders
- These rules for inheritance patterns are used
continuously in genetics practice
What is single-gene inheritance?
What is an autosomal dominant gene?
How are dominant genes passed on? (5)
- There are two copies of every autosomal gene
- Both copies of the gene function to produce a product
(i.e.protein) - One copy of each gene is passed to a child from their
mother and the other from the father - Dominant mutation on one gene, will produce the
condition despite the working copy - (Only 1 copy needed to express the condition
- There are 2 copies of each gene
- If only one allele ______
i.e. Paternal - Phenotype to _______
- Allele 1 (Paternal) is dominant to allele 2 (maternal)
mutated
manifest
How is the probability of inheritance determined?
Punnet square for one parent affected:
Punnet square for both affected parents:
What is achondroplasia? (5)
- Form of short-limbed dwarfism
- Mutation in the FGFR3 gene
- Cartilage not converted to bone
- Breathing problems, recurrent ear infections etc.
- Double are lethal
Other examples of achondroplasia: (4)
Neurofibromatosis type 1
Huntington disease
Familial hypercholesterolaemia
Inherited predisposition to some cancer
What is the pedigree for an autosomal dominant family?
- Genetic conditions can occur due to several different kinds of alterations in the genetic information.
- The first kind includes chromosomal abnormalities that can either be _____ or _______.
- Multifactorial, mitochondrial and epigenetic disorders are classified as non-Mendelian disorders where there
is a more complex genetic basis than a single gene mutation that gives rise to the condition. - But the focus for this lecture is Mendelian disorders, also known as single gene disorders, particularly
Autosomal recessive conditions which are caused by ______ gene mutations that exhibit a significant effect on
gene function and are responsible for the phenotype (clinical manifestations) of the condition. A genetic
disorder that is caused by a gene mutation on an autosome is said to show autosomal dominant or autosomal recessive inheritance, whereas a genetic disorder caused by a gene mutation on one of the sex chromosomes is said to show ______-_______ inheritance.
structural
numerical
single
sex-linked
What is an autosomal recessive trait?
When do autosomal recessive disorders manifest? (4)
- Autosomal recessive disorders manifest only when a mutant allele is present in double dose. So, what
that means is that, for an individual to present with an autosomal recessive condition, they need to have
two faulty genes which can also be referred to as homozygosity. - Individuals who are heterozygous for the same mutant allele, meaning that they have one faulty gene,
usually show no features of the disorder and are referred to as carriers. - Parents of a child with an autosomal recessive condition are referred to as obligate carriers of the
condition. - So to simply explain the slide; The two chromosomes on the left with a purple highlight that represents
a mutation represents an individual with a homozygous mutation present with clinical manifestations of
an autosomal recessive disorder, whilst the two chromosomes on the left with the purple (which
represents a mutation) and the yellow (which represents a normal functioning gene) represents an
individual with the same heterozygous mutation which display no clinical features of an autosomal
recessive condition and are only carriers of a heterozygous mutation
Genetic Risks
What happens when two carriers of the same recessive gene have a baby?
These are the potential outcomes: (3)
Autosomal recessive pedigree
Pedigree characteristics: (4)
Examples of autosomal recessive
conditions: (6)
- Cystic fibrosis
- Sickle cell anaemia
- Oculocutaneous albinism
- Spinal muscular atrophy
- Tay-Sachs disease
- Thalassaemias
What is cystic fibrosis?
Cystic fibrosis is a genetic disorder that often affects multiple organ systems of the body. Cystic fibrosis is characterized by abnormalities affecting certain glands
(exocrine) of the body especially those that produce mucus. Saliva and sweat glands may also be affected. Exocrine glands secrete substances through ducts, either internally (e.g., glands in the lungs) or externally (e.g., sweat glands). In cystic fibrosis, these secretions become abnormally thick and can clog up vital areas of the body causing inflammation, obstruction and infection.
What is Spinal muscular atrophy (SMA)?
Spinal muscular atrophy (SMA) is a group of inherited neuromuscular disorders characterized by loss of nerve cells in the spinal cord called lower motor neurons or
anterior horn cells. Lower motor neurons originate in the brainstem or the spinal cord and relay nerve impulses from upper motor neurons, located in the brain, to the muscles they control. The loss of lower motor neurons leads to progressive muscle weakness, muscle wasting (atrophy) and low muscle tone (hypotonia) that is typically more pronounced in muscles closest to the trunk of the body (proximal muscles) such as the shoulders, hips and back
What is Consanguinity?
What does the double horizontal line indicate?
- The double horizontal (mating) line in the fourth generation indicates consanguinity between the affected female’s (who’s in the 5th generation) parent
- Some populations in the world preferentially practice consanguineous marriage due to ______ or _______
traditions. - Generally, a consanguineous marriage is defined as a union between two individuals related as second
cousins or closer. - Consanguinity rates vary from one population to another due to culture, religion, and/or geography.
- The highest rates of consanguinity in human populations occur in the Middle East, Northern Africa, and West Asia. In these populations, consanguineous marriages can account for ____-_____ of all marriages.
- Research of consanguineous marriages in these populations reveal several social and cultural benefits, such as more stable marital relationships, greater compatibility with in-laws, lower _____ _____ rates,
lower divorce rates, and the familial maintenance of any landholdings. - The prevalence of autosomal recessive disorders in the offspring of first cousins has shown to be higher
than background population risk. For example, if we take a child born first cousins 1/16 of their genome will
be _________ because they have parents from a common ancestors. In cases of inbreeding, we know that
there are regions where both copies of the genome are the same. The child will have significant regions of
homozygosity, scattered across their genome, and if a pathogenic allele lay in any of those regions, the child
will be affected by a recessive condition.
cultural or religious
20%-50%
domestic violence
homozygous
How can the degree of relatedness among individuals in each population be calculated? (4)
- The degree of relatedness among individuals in each population can be calculated using the inbreeding
coefficient which represents the chances of two alleles being identical-by-descent (IBD), which simply means
the chances of having two alleles descending from a common ancestor, at a specific locus. - If we look at the images, for instance, the proportion of shared genes amongst first degree relatives which
includes parents, siblings, children and in cases of dizygotic twins is 1/2 or 50%. The chance of homozygosity
in siblings and dizygotic twins is 1/4/25%. - For second-degree relatives which includes half-siblings, uncles/aunts, nieces/nephews, and double-first
cousins, they have a 1/4 proportion of shared genes. The chances of homozygosity is an 1/8 or 12.5% - And lastly for third-degree relatives (first-cousins, half-uncle/aunts, half-nieces/nephews) they are an 1/8 of
their genes. The chance of homozygosity is 1/16 or 6.25%. - Consanguinity increases the overall chance that two alleles at any locus in an individual are identical by
descent from the common ancestor(s) of the two parent in the population. The closer the relationship
between the two parents, the higher the proportion of homozygosity in the offspring and the greater the
risk for recessive genetic diseases to occur in these offspring.
What is the founder effect? (4)
- The founder effect is a phenomenon that is defined as a decrease of genetic variation in the population due
to a population bottleneck followed by a random genetic drift. - A population bottleneck refers to an event that drastically reduces the size of a population. This could be due
to famine, disease, war, or migration. - This would result in a smaller population than the original one which would increase inbreeding and result in
low genetic variation within the new population. - If original founders of a population carried mutated alleles, due to the restricted number of members in the
population, the founders were forced to breed amongst themselves, therefore, increasing the frequency of
carriers and affected individuals of an autosomal recessive condition in the populatio
What are some examples of the founder effect? (3)
- A genetic condition may become common within a population because all individuals are descended from a small number of ancestors, with one or more ancestors having had, or were carriers of the condition
- Different population groups have associated genetic conditions due to the founder effect. This table provides us with a breakdown of several population groups and common genetic conditions found within those groups.
- In summary, populations that practice consanguinity or were established through founder effect have a
higher prevalence of autosomal recessive conditions because of smaller population pools and lack of genetic
variation
What if one parent is affected and the other
parent is a carrier: pseudo-dominance
Other concepts in autosomal recessive conditions: (3)
- Locus heterogeneity
- Compound heterozygosity
- Heterozygous advantage
What is 1. Locus heterogeneity?
What is 2. Compound heterozygosity?
What is Heterozygote advantage?
Dosage: the ___ chromosome has > genes than the ___ chromosome
X
Y
Random X-inactivation =
For interest:
Barr body- an X chromosome inactivated by a
process called ________.
lyonization
What is the The Callico cat?
What is Skewed X-inactivation?
X-linked inheritance
- Genetic conditions caused by _______ in genes found on the X chromosome
mutations
Who is affected in both cases?
Biological females:
- mostly unaffected
- referred to as ‘carriers’
- sons are at 50% risk
Biological males:
- affected
- all daughters are obligate carriers
What is Duchenne Muscular Dystrophy (DMD)?
DMD pedigree:
What is Haemophilia?
Haemophilia pedigree:
Who is affected in both cases?
Biological females:
- affected
- 50% risk to all children
Biological males:
- more severely affected
- some conditions are lethal in males
- 100% of daughters and 0% of sons will be
affected
What is Rett syndrome? (4)
- Inherited in an X-linked dominant manner
- Impaired brain development and functioning
- Disordered movement and severe congitive impairment
- Mostly affects girls as it is lethal in boys
What is Y-linked inheritance?
Who is affected from Y-linked inheritance?
