Lecture 12 Flashcards
Why are some alleles more common in certain populations?
The founder effect and the heterozygote advantage
What is the Founder Effect?
The loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population
What is a Heterozygote Advantage?
A single copy of a disease allele confers an advantage. E.g. sickle cell anemia
What can’t physicians use to diagnose genetic crosses of their patients?
Mendelian Crosses
What do Physicians use to predict heredity of rare disease?
Family histories or pedigrees
What did Polygamy lead to?
Rare alleles from small groups to be widely spread
What is the Propositus?
The first case of a disease that comes to the attention of a doctor
What are the characteristics of an Autosomal recessive disorder in a pedigree?
The parents are unaffected (usually)
It can affect both males and females
Entire generations can be unaffected
More frequency when there is inbreeding
What is the inheritance of PKU?
Autosomal Recessive
What occurs in PKU?
There is a defect in Phenylalanine hydroxylase, a liver enzyme
Causes buildup of phenylalanine & phenylpyruvic acid in the body which affects the development of neurons
What can manage PKU?
Low protein diet
What are the characteristics of pedigrees with autosomal Dominant disorders?
Generally the disease appears in the parental generation
Tends to appear in every generation
Affected progeny includes males and females
What causes Pseudoachondroplasia?
Mutation in the COMP gene that affects the structural integrity of Cartilage. It is a dominant allele and the allele that causes it is homozygous lethal
What causes Achondroplasia?
Mutation in the FGFR3 that is a regulator of bone development. Also homozygous lethal
What is the inheritance of Piebald spotting?
Autosomal Dominant
What occurs in Piebald spotting?
It affects the migration of melanocytes from dorsal to ventral
What is Penetrance?
The proportion of percentage of individuals with a specific allele or allele combination (genotype) that display the corresponding phenotype
When can we say something is fully penetrant?
When all individuals with this genotype manifest the phenotype
When can we say incomplete penetrance?
An allele for which a phenotype manifests is less than 100%
Why would the same genotype not always give rise to the same phenotype?
Environment factors e.g. nutrients, exposure to UV light, altitude
Influence of other alleles/genes
Stochastic events e.g. X inactivation
What is Expressivity?
The degree to which a given allele influences the phenotype in an individual. It describes the intensity of the phenotype
What is the dominance of Polydactyly?
Autosomal dominant
What are the characteristics of X linked disorders?
Males are more common than females
No transmission from father to son
Daughters of affected males are carriers
Affected females have affected fathers and carrier mothers
What does is Pseudodominant?
In X-linked genes, disease causing recessive alleles in a hemizygous organism/cell
What is Hemophilia?
The inability to make fibrin which is used in clotting
What is the difference between Hemophilia A and B?
Hemophilia A patients have a mutation in the F8 gene
Hemophilia B patients have a mutation in the F9 gene
What is another way that females can have an X-linked disease?
If the X chromosome carrying the wild type allele become deactivated early on in embryogenesis functional mosaicism can occur where the whole organism is mostly the mutated X-chromosome
What are the characteristics of X-linked dominant mutations?
A female heterozygote transmits to 1/2 of their children
Affected male will transmit to all daughters but not to sons
Affected females may be more common than males
No transmission from father to son
What is the inheritance of Fragile X syndrome?
X-linked dominant
What causes fragile X syndrome?
The non-coding region of the FMR1 gene has an increased number of CGG repeats which cause the gene to be turned off (via methylation)
What is the Dominance of fragile X syndrome due to?
Haploinsufficiency if the wild type allele
What are the 3 types of Mosaicism?
Repeat Length Mosaicism
Repeat Methylation Mosaicism
X-chromosome inactivation Mosaicism
What is Repeat Length Mosaicism?
Because full mutations are mitotically unstable some patients have a mixture of cells with repeat lengths ranging from permutation to full mutation
What is Repeat Methylation Mosaicism?
Some patients have a mixture of cells with and without methylation of CGG repeat
What causes repeat sequences in DNA?
Strand slippage of the newly synthesized strand which causes the replication machine to believe that it missed nucleotides so it goes back and synthesizes them
How do Trinucleotide expansions occur?
CAG next to CAG tend to attract to each other which cause the slippage
How does Fragile X syndrome occur?
There is an increased number of CGG nucleotides in the untranslated region which causes a loss of function of the gene because RNA binding is impaired
What is the cause of Huntington disease?
Increased CAG produces polyglutamine which give the gene new function through increased transcriptions
What is methylation?
When a Methyl group is added to a cytosine nucleotide and signals for the associated gene to be transcripted less
How does DNA methylation cause gene repression?
The methylation marks DNA for repression and this attracts proteins like MeCP2 which recruits other repression proteins that make DNA inaccessible
What occurs in Rett Syndrome?
In the X-linked dominant disease there is a mutation in the MeCP2 a DNA binding protein that regulates many genes which is critical for brain function and development. Only occurs in females because males die
