Extension Of Mendelian Genetics Flashcards
Describe recessive lethal alleles
-Unlikely to be observed in the population
- consider homozygous null mutations in a pathway such as glycolysis
- Glycolysis is an essential pathway almost all biological life forms on earth
- therefore complete loss of glycolysis is likely to be lethal
Another example might be genes encoding histone proteins
-DNA in chromosomes need their histones
Describe homozygous dominant lethal
-Agouti is wild type (normal) mouse
- One “Y” elbow mutation = yellow mouse
- yellow is a dominant trait
-two “Y”ellow mutations= lethal
So the end result is 2/3 and 1/3 ratios when two heterozygous (yellow mice) mate (AA^y xAA^x)
Give an example of the 1/3 and 2/3 ratio homozygous dominant in humans
-Achondroplasia (autosomal dominant; a form of dwarfism)
- Recall, FGFR3 “gain of function” mutation
- Let A be the normal allele
- Let A* be the mutation which causes achondroplasia
So, the surviving children (on average) 1/3 of possibilities are of normal stature, and 2/3 have dwarfism. Inheritance of two FGFR3 mutations causes fetal or perinatal lethality
Explain the phenomena of Dominant alleles; delayed age of onset
- Consider Huntington’s disease(HD)-a lethal allele, if the patient lives long enough to succumb to the disorder
- If patient doesn’t die of something else, the HD will inexorably be lethal
Give 2 examples of dominant disease alleles in the homozygous state
Typically are not found (the disease alleles are already very rare; so it’s extremely rare that they will come together in two individuals)
Example 1: Familial hypocholesterolemia
-AD (heterozygous) adult onset consequences of high cholesterol
-AD(homozygous) childhood onset consequences of high cholesterol
Example 2: Achondroplasia
- AD(heterozygous) dwarfism
- AD (homozygous) lethal during fetal development, or perinatal period
Explain how a phenotype May be influenced by many factors
- Sometimes a trait is influenced strongly by a specific allele (these are Mendelian traits) allele 8s said to have high penetrance
- Sometimes traits are influenced by many different genes
- However, modifier genes may alter the trait
- Environmental exposures May influence a trait
- For some traits, many genes and combination of environmental exposures may act together to affect a trait-multifactoral traits
What are Mendelian traits?
When a trait is strongly influenced by a specific allele then these traits are Mendelian
The allele is said to have high penetrance
What is genetic epistle is?
- One gene may be called epistemic to another if it masks the trait of that other gene
- Allows scientists to attempt to arrange genes into pathways (common function and order of effect)
- Genes that act downstream are called epistemic
- Genes that are masked (downstream) are called hypostatic
Explain an example of epistasis
-Consider a cell signaling pathway that controls morphology(blobs and projections)
Gene A arrests blobs which form on the cell
Gene B causes blobs to form projections
A loss of function of gene A would be expected to block formation of both blobs and projections
If a different mutation in gene B( such as gain of function) is found that allows projections to form in the absence of gene A function, then we expect that gene B. Functions after gene A
What is the Bombay phenotype?
A woman is found to be type O
Her husband is type A
But her children inherit type B from her (no hanky-pinky is going on)
-Mother passes on type B
- There is no father involved
- And she inherited type B from her mother
Therefore something else is going on
Explain the Bombay phenotype
-People with Bombay phenotype (blood type) do not create the precursor carbohydrate, so they can be neither A nor B, even if the alleles that control the addition of the sugars are functional for them
In the Bombay Phenotype, the H substance itself cannot be made, so the carbohydrate cannot be matured. Therefore, the person may be neither A nor B (and functionally appears as they type O)
Genetically, type B (mom in previous example
Of course, this is very rare in human populations
What is pleiotropy ?
Marfan syndrome as an example
- Many features of the phenotype May be observed that are all caused by (somehow) the sane mutation (same allele)
- Marfan syndrome(fibrillin) and connective tissue problems
- Single gene disorder affects multiple organ systems
- Chest wall deformity
- Tall stature
- Risk of heart disease
- Eye lens subluxation
Describe X-linkage in humans
Females are XX
-The ovum can Contribute only an X to a zygote
Males are XY
- the sperm can contribute either an X or a Y to a zygote
How much chromosomes does a human have?
46 chromosomes (44 autosomal chromosomes, come in pairs
What chromosome determines the sex?
Sex is determined by the X chromosome
A gamete from a female (ovum) May only be X(female is XX)
A gamete from a male (sperm) May be X or Y (this is because the male is XY)
Why is the X chromosome so big compared to the Y chromosome?
There are more than 1,000 genes on the X chromosome
- some are required for formation of the female sex - Most genes on the X chromosome are for “other” functions
Only a few genes are on the Y chromosomes
- Most control the formation of the male sex and spermatogenesis
- Very little for other functions(some intersting exceptions)
What is X-inactivation?
During embryonic development, one of the few X chromosomes is deactivated (called X-inactivation) to ensure that males and females have balanced gene expression (a few genes escape this; genes that control formation of the female phenotype)
Describe the pairing of X and Y chromosomes
They pair up during mitosis and meiosis
They must be controlled to ensure appropriate
Psuedoautosomal regions of X and Y allow pairing during mitosis and meiosis
Give an X-linkage example
Hemophilia A or B
Bleeding disorder; improper hemostasis
-blood clots fail to form; or form too slowly
Many components are in this pathway
We will focus on Hem A and Hem B which are are both X-linked
Mom of a male is an affected carrier of the mutation
Mostly occurs in males(likely to be more severe in males x*Y)
If seen in females, likely to be seen less severe in females
What is the royal bleeding disorder?
Hemophilia
What is the recurrence risk for the X-linked recessive disorder, hemophilia with a normal father and carrier mother?
- 50% of daughters may be carriers, 50% of daughters may be normal
- 50% of sons may be affected, 50% of sons may be normal
Each conception event is independent
1/4 risk that a child may be affected
What is the recurrence risk for the X-linked recessive disorder, hemophilia with an affected father and normal mother?
All daughters of an affected father must be carriers of the mutant allele
A son may not inherit an X-linked mutation from his father
None of his children affected
What is the recurrence risk for the X-linked recessive disorder, hemophilia with an affected father and a carrier mother?
Each conception is independent event, but on average:
50% of daughters may be carriers; 50% of daughters may be affected
50% of sons may be affected; 50% of sons may be normal
What does it mean to be hemizygous?
Due to XY sex determination
A typical male may not be homozygous for anything on the X chromosome
Males only have one X chromosome
Males with hemophilia are hemizygous for a mutant gene
Females have two copies of the X chromosome
Describe sex influenced inheritance
Some traits are influenced by the sex of the animal(person) who has the allele
- Male pattern baldness
- More extreme in males but can still be observed in females
- the effect is thought to be exerted by testoserone
- Lots of disease examples in humans
Describe sex-limited inheritance
Feathers in the do,entice fowl(hen vs cock)
-hens don’t have the characteristic long feathers
Milk production in a dairy cow
-bulls don’t have make milk
What are conditional mutations?
Temperature sensitivity as an example
A Himalayan rabbit and a Siamese catBoth show dark fur color on snout, ears, and paws. These patches are due to effect of a temperature-sensitive allele responsible for pigment production
What is anticipation?
Triple repeat expansion disorders
- Simple sequence repeats(SSR) in the genome tend to change over generations
- SSR is di, tri, tetra
Examples: (AT repeats, CGG repeat)
-A child is likely to have the same number of repeats as his or her parents; but sometimes they change a little bit over generations
-These are most polymorphic areas of the genome
What causes myotonic dystrophy?
Caused by a triplet repeat expansion in the DMPK gene
The expansion doesn’t affect the DMPK gene itself, instead, the expansion affects how many other genes are processed (and therefore expressed) in the tissues where it is expressed (the muscle )
Autosomal dominant transmission
Describe the Myotonic dystrophy phenotype
Myotonic dystrophy has a pleiotropic phenotype
Characterized by wasting of the muscles, cataracts, heart conduction defects, endocrine changes, and myotonia
-Imability to relax muscle(myotonus) leads to muscle weakness and other symptoms
What is myotonia?
Is reduced ability to relax after muscle contraction
What is myoclonus?
A quick, involuntary muscle jerk
Describe myotonic dystrophy as an example of anticipation
- As repeat gets longer, it becomes more unstable, and can expand more.
- In successive generations:
- Age of disorder onset can decrease and…
- Severity of the disorder can increase
