L3- Monogenic disorders Flashcards
what are monogenic disorders
disorders caused by defects in a single gene
= gain or loss of function
define penetrance
frequency of a genotype to show a certain phenotype
= depends on both genotype and environment
not all organims of a particular genotupe shpw a phenotype = due to envirnmental factors
penetrance can be ………
complete or incomplete
complete –> 100% ov genotype shows trait
incomplete –> less than 100% of genotype show trait
example: just because you have bRAC mutation which increases succeptibility to breast cancer does not mean youll have cancer
what percentage of offspring would a autosomal dominant gene cause - Aa against aa
50%
= always gain of function mutations
Autosomal dominant are traceable through generations
defone variable expressivity
variation in the phenotye of affected indiviuals
define co-dominance
2 alleles are both expressed in heterozygous state
= AB = both A and B alleles are seen
what type of mutations are autosomal recessive and why are these diseases harder to keep track of
loss of function mutations
= can skip generations due to ‘carriers’
define pseudodominance
reccessive allele LOOKs dominant due to 1 carrier crossed with a infected
= mimics dominant inheritance
this is opposed to the normal inheritance of 2 carriers = 25% chance of kids having disease
give one example of a heterozygote advantage
sickle cell trait
= HbA turn to HbS due to mutation in beta-globulin chain
provides advnatage against malaria
= red blood cells infected with malaria ‘sickle’ faster and are destroyed = not enough time for parasite to replicate inside
who does X-linked recessive disorders affect the most
males
= only takes a single muated X chromsome for men to cause disease
women have 2
‘loss of function mutations = due to protein or gene not being expressed propelry causing the disease
if it was ‘gain of function’ then it would be dominant = women would experience it too with just inheriting 1
describe how X-inactivation produces a mosaic of cells in heterozygous females for recsssive disorder
X-linked inactivation ‘silenes’ randomly one of the 2-X chromosomes
means that some cells express paternal X chromsome and others the maternal X chromosome
‘loss of function’ recssive disorder means that although some cells do not produce the desired protein OTHER cells in the tissue can compensate for this
= mild symptoms
‘gain of function’ dominant mutation would mean that despite only some of the cells in the tissue producing harmful proteins this would still affect./damage tissue
describe how and why X-lined recessive disorders could affect females - 2 reasons
- skewed/non-random inactivation of X-chromosme
= more than 50% of inactivated x-chromosomes are the ‘normal’ one
- numerical abnornamilities
= female has abnormal number of X-chromosomes
= Tuners syndrome with only 1 X = will always show symptoms in all cells
define hemizygous
only containing a SINGLE copy of a gene
= males will only have single copies of some X-chromososome genes
what is the name of the regions at the ends of X and Y chromosomes
PARs - Pseudoautosomal regions
= identical genes at the ends of both X and Y chromsomes that can recombine during male meioisis (sperm formation)
how do pseuodoautosomal regions (PARs) cause partial sex linkage and X-inactivation
sex chromsomes are fully sex-linked = genes on X chromsome only pass down through the X
BUT genes in PARs are shared between X and Y
= can be inherited from either parent through X or Y
‘partial’ sex linkage as although on sex chromosomes they behave like autosomes –> can recmobine and swap
= PARs escape X-inactivation –> still expressed on inactivated X
autosomnal pattern of inheritance of the genes on PARs
how do PARs affect genetic disorders inheritance
inheritance pattern looks autosomal
= defective genes in PARs can pass from father to son despite rececing a Y gene from father
affects males and females equally due to x-inactivation escape
what is the hardy weinberg principle
allelic frequencies will not change in population if conditions are met
= they are never met = its an ‘ideal’ state
what type of disorder is Duchenes muscuolar dystophy (DMD)
X-linked recessive monogenic disorder
what does DMD genes code for in duchenes muscular dystrophy and how is this affected in the disorder
DMD codes for ‘dystrophin’ protein
links actin cytoskeleton to plasma membrane and then to the outside connective tissue = stabilises msucle cell when contracting
deletions in the gene produce truncated or no protein
= sarcolemma becomes fragile and tears
= muscle wasting disease
what are trinucleotide repeat disorders
microsatelite region of genome —> repeats can expand due to polymerase slipping in DNA synthesis
come from a rare ‘founder’ mutation
severity gets worse due to increasing number of repeats in generations = ‘anticipiation’
what is anticipation
increasinging severity of symtpoms due to increasinging number of repeats
name 2 trinucletide repeat disorders
Fragile x syndrome = fragile site
Hungtintins = neurodegenerate disease
describe hungtintins disease
CAG repeat in hungtintin gene
= codes for run of glutamamine amino acids
in disease repeat is longer - neuron degeneration due to clumping of toxic protein
jerky involuntary movement
describe what happens in Fragile X syndrome- Trinucleotide repeat disorder
CGG rpeat in FMR1 gene
= longer repeat = hypermethylation of bottom of `X chromome preventing transcription
intelluctual disability and mental retardation
