WEEK 4 (STUDY GROUP) Flashcards
mito disease affects organs with ____ and _____
high energy requirements and high metabolic
what are examples of signs of mito disease
affects nervous system (brain), muscle, heart muscle
what is progression of mito disease
step wise
describe mito dna
circular, continous, no 5 or 3 uncoding regions, nuclear proteins help make mito proteins BUT mito dna doesn’t impact nuclear DNA
homoplasmy vs heteroplasmy
homo is that all the mtdna is the same (either all wild or mutant) vs. hetero is a mixture of wild and mutant
bottleneck effect
there are variable amounts of mutant dna in each cell and each mitocondria; there is asymmetric segregation of mutant mtdna during cell division; variable amount is passed along; increased mutant dna is assoc. with severe disease
threshold effect
above a certain % of mutant dna means disease phenotype affect (different thresholds for different genes)
important mitocondrial functions that happen inside
TCA cycle in the matrix, oxidative phosphorylation on the inner membrane
if you suspect a mitochondrial disorder in oxidative phosphorylation what would be a sign
increased lactate (lactic acidosis) bc aerobic metabolism of pyruvate is not occurring
most of mtDNA inheritance – what does it look like for offspring and who can pass it down
any offspring can have it; only passed down through female
qualitative trait vs quantitative
Qualitative traits are those that have a defined cutoff; you either have a cleft lip, or you don’t. Quantitative traits vary in their intensity and do not lend themselves to the rigidity of categorizing a trait as present V absent. An example could be (qualitative) cleft lip v. (quantitative) Intelligence.
Define: epigenetics
The study of heritable changes in gene expression without a change in the actual DNA sequence
What is the role of epigenetic in cell-type specificity?
Between fertilization and implantation of the zygote: demethylation and loss of most epigenetic modifications (with the exception of imprinted regions) from the genome –> the zygote is now totipotent (has the potential to develop into every cell in the body)
During development, DNA methylation and histone modifications occur that gradually restrict the number of cell types a particular cell can become
What are the 2 primary types of epigenetic modifications?
DNA methylation, histone modifications
What are the 2 mechanisms in which epigenetic disorders cause disease? Give examples of each
- Pathogenic variants alter chromatin directly. Examples: beta thalassemia, fragile X syndrome, congenital limb malformation disorders, fascioscapulohumeral muscular dystrophy-1 (FSHD1)
- Pathogenic variants in genes that regulate the epigenetic machinery. Examples: Kabuki syndrome, fascioscapulohumeral muscular dystrophy-2 (FSHD2)
Monoallelic expression
when expression of a particular gene occurs from only one of two alleles.
Genomic imprinting
When only one of the two alleles at a particular locus are expressed, and this is dependent on the parent that that gene was inherited from.
Maternally imprinted
the gene is NOT expressed from the maternal allele, but instead is subject to silencing by DNA hypermethylation and other changes that reflect a closed chromatin conformation.
Paternally imprinted
the gene is NOT expressed from the paternal allele, but instead is subject to silencing by DNA hypermethylation and other changes that reflect a closed chromatin conformation
Imprinting control region (ICR)
Locus that determines and controls imprinting within a particular region, also called the imprinting center (IC)
Uniparental disomy (UPD)
The inheritance of both homologues of a particular chromosome from a single parent.
Heterodisomy
The inheritance of both grandpaternal chromosomes from one parent and a single chromosome from another, resulting in triomsy for that chromosome. ‘Trisomy rescue’ then occurs where one of the chromosomes is deleted early in the post-zygotic embryo to ensure the normal diploid number of chromosomes. Thus the individual is heterozygous for many alleles on that chromosome, but they are both from either the maternal or paternal lineage.
*It is possible for the single chromosome for the other parent to be kicked out, such that a person has both chromosomes from one parent.
Isodisomy
Is the result of ‘monosomy rescue’, in this instance, the post-zygotic embryo contains only a single copy of a particular chromosome, which undergoes duplication, such that each cell contains two exact copies of that chromosome. Thus the individual will be homozygous for all alleles on that chromosome.
Genomic imprinting and uniparental disomy disorders
Prader-Willi Syndrome (PWS) and Angelman syndrome (AS)
Both PWS and AS are caused by abnormalities at 15q11-13. This region contains several genes that are subject to genomic imprinting.
Prader: paternally expressed; maternally imprinted; paternal variants/deletions
Angelman: maternally expressed; paternally imprinted; maternal variants/deletions
