Chapter 7 Flashcards
allele
version of a gene (could be many versions for the same gene), single dominant; 2+= dominant= polymorphic
locus
particular location on a chromosome (could be anything -band -many genes- or 1 gene
Single- gene disorder
- alleles at single locus determine if someone has the disorder or not
- 1 million live births=0.36%
- mendelian= because happen in babies with regular probabilities
How does a variant arise?
- nucleotide sequence has to be different
- mutation (not always bad)
- medical genetics (usually disease= alleles/ changes)
OMIM
- online Mendelian Inheritance in Man
- online database (relationship between genotype and phenotype)
- Mendelian
genotype
collection/specific allele of genotype
phenotype
physical result of the genotype (visual characteristics)
pedigree
-graphical representation of family tree
=shows single-gene disorder inheritance in families
-standard symbols
proband
first affected person (who comes to genetic counsellor and pedigree built around them= IS affected
sibs
siblings
sibship
collection of brothers and sister
First Degree
parents and siblings and children
Second degree
grandparents, parent’s siblings, neices/nephews, grandchildren and half siblings
Third degree
cousins
kindred
entire pedigree= collection of individuals
consultand
maybe affected but also relative of the proband
consaguinity
couples who have 1 or more ancestors in common
Autosomal Recessive
need to be homozygous for a mutant allele to show phenotype
Autosomal Dominant
need at least 1 dominant allele to show the phenotype
Pure dominance
same phenotype regardless of Aa or AA
incomplete dominance
alleles combine to give a mixed phentoype
x^a
x-linked recessive
x^A
x-linked Dominant
Factors that affect a pedigree
- some disorders not experienced at all, even though the genotype affects other members
- phenotype can vary between members of a family
different in expression can be caused by
- histone methylation
- penetrance
- expressivity
- age of onset
- lack of info ancestors my have passed it on
pyrotrophy
1 gene= multiple phenotypes
penetrance
individual has genotype. What is the probability it will be expressed. (all or nothing concept)
reduced penetrance
i.e.) methylated= not expressed
has genotype but doesn’t show phenotypes
Expressivity
Individuals look the same genotype =different severity of the phenotype
- -> variable expressivity (epigentics)
- two people with the same mutant genes= some common symptoms; others may differ
Factors that affect penetrance and expressivity
1) genetic background: Jeans can affect each other (interact)
2) environment: twins with the same genotypes still look different; it affects how the genotype correlates with their phenotypes
3) epigentics
Neurofibromatosis (NF1)
-pyrotrophy
-variable structure of genes= strength of the promoter
-one game= List of phenotypes
-disorder of the nervous system eyes skin
-benign tumour growths in skin and eye
-Cafe au lair spots (dark patches of pigmentation)
Sometimes mental retardation, Central nervous system tumours, cancer of the nervous system or muscle
NF1
- autosomal dominant
- penetrance 100% in adults (have mutation in gene all adults will show the phenotype
- diagnosing children is hard–> shows in adults
- variable expressivity not recognized therefore there is a lack of information and older individuals on the mutation may be spontaneous
- why are all siblings not affected?
- some are too young
- maybe they don’t have the gene itself
split-hand deformity
- reduced penetrance example
- looks autosomal recessive
Age of onset
-can arise at any time
-genetic disorder
-cogenital
=complicate pedigrees
genetic disorder
to do with genes
cogenital
Not necessarily genetics in a birth defect (abnormalities due to complications during delivery)
Lethal disorder
Early termination or miscarriage
Late onset dominant disorder
Parents died still weren’t showing the phenotype yet (NF1)
Genetic heterogeneity
Different mutations= same or similar phenotype
Three types: allelic, locus, and phenotypic
Allelic heterogeneity
Many mutant alleles in the population causing a phenotype (single gene) or a range of phenotypes
ex) CFTR= APPROX 1400 different mutant alleles for 1 gene
True homozygotes
Allelic heterogeneity
-Truely Homozygote for an allele
Compound heterozygote
Allelic heterogeneity
-an individual has two completely different alleles or two identical alleles to show that phenotype
Exceptions for allelic heterogeneity
-one known allele gives rise to specific phenotypes i.e. Sickle cell anemia
Within ethnic group= people get married= bring the same alleles
Locus heterogeneity
I.e. Retinitis pigmentosa -locus specific region on the chromosome 5 different Loci if mutated= x-linked -14 autosomally dominant= one mutated= this is autosomal -24 autosomal recessive
In total 43 loci that give rise to this
How? Disruption at variant Points in the metabolic pathways
phenotypic heterogeneity
- different mutations in the same gene= different disorders i.e. RET
- -Color problems, other thyroid cancer Colin and thyroid
LMNA -muscular dystrophy -cardiomyopathy Adipose tissue disorder Premature aging syndrome Neopathy
-all mutations in different parts of the same gene
autosomal recessive
only in homozygotes and compound heterozygotes -skips generations Aa/Aa= 75% affected; 25% unaffected aa/aa= 100% affected M/F equally affected
Consanguinity and Autosomal recessive condition
- both could be carriers of recessive alleles
- not as big of a risk as ppl imagine
- 1st cousins: 3-5% risk of abnormal offspring
- 3rd cousins- not really significant unrelated- 2-3% risk of abnormal offspring
Measuring consanguinity
F= co-efficient of inbredding
-probability that homozygotes got both alleles at a locus form the same ancestral source
parent-child bro-sis uncle niece 1st cousins 2x (1st cousins) 2nd cousins
1/4 1/4 1/8 1/8 1/16 1/8 1/64
Inbreeding (unrelated individuals)
- selection of mates in small population
- similar to consanguinity
Autosomal Dominant
- more than 1/2 of mendelian disorders
- problem for the entire kindreds because only need 1 allele to express phenotypes
- dangerous with homozygous than carrier (incomplete dominance)
- Aa/Aa= 1/4 unaffected; 3/4 affected; Aa/aa 50/50 (all pure dominance)
Incomplete Dominant Inheritance
ie) Achondroplasia
- dwarfism/norm intelligence
- 2 heterozygote can reproduce but homo offspring are severely affected don’t live past postnatal period
- AA more severe
- A/a survived
- aa normal= unaffected or penetrance/mutation in gamete
- non-inherited mutations contribution to Autosomal dominant disorders
denovo mutations
gamete of non homologous parent
- (mutation that developed later in parents)
- -> mutation could be early developmental (1 cell/ 2 cell stage)
- disorder happens because only 1 of 2 alleles at a locus needs to be defective
Autosomal dominant conditions only because of de novo mutations
- reduced fitness:
- -> inversion relation btw fitness and proportional of affected patients who got the defected gene as a new mutation
- -> all autosomal dominant genetic lethal diseases have to be new mutations
- -> because if normal fitness= disorder more likely to be inherited
Autosomal Conditions show up in 1 sex
- male limited precocious puberty
- boys develop secondary sexual characteristics at approx. 4 years old
- females are unaffected
- may be die to a mutation in LCGR (lutenizing hormone pathway)
x-linked inheritance
most genes on x–> male gets 1 female gets 2
- 1100 on X
- 40% can cause disease phenotypes (500- 450)
For the Sexes
females can be carriers (1 mom and 1 dad)
- male: gets an affected chromosome–> screwed
- males= hemizygous for any x gene
-x-linked dominant and recessive/ found out through phenotype in heterozygous females (x-inacticavtion can affect inheritance –> not all genes undergo inactivation)
x-linked recessive
higher in males than females because father gives ‘Y’
- cant be passed father to son
- heterzygous females usually unaffected because have a normal allele
Hemophila A
- x-linked recessive inheritance
- blood clotting disorder
- x^h(affected make)
- x^H/x^_ unaffected females usually heterozygous
- mom is xH xH if NO sons are affected
Red- Green Colour Blindness
- most x-linked are rare
- unlikely female to be homozygous unless parents are consanguineous
- 10% males have this (rare)
Manifesting Heterozygote
-rare female carrier to show the x-linked recessive phenotype
Factors: 1) skewes x-inactivation
2) disease-dependent
example of manifesting heterozygote
DMD- duchenne muscular dystrophy (protein)
- protein dystrophin surround cells
- normal female big cells with thick white lining
- affected male with no white lining
- heterozygote female: mixture therefore manifesting heterozygote
x-linked dominant
if expressed in heterozygotes
- no male to male inheritance
- father has condition= all daughters no sons affected
- if daughter unaffected to any son is affected then inheritance is autosomal–> father is affected
- inheritance in females= same as any autosomal dominant pattern
- in any female theres x-inactivation
x-linked dominant disorder with male lethality
pedigrees with affected daughters, normal daughters and normal sons all= proportions are 1:1;1
Rett Syndrome
- example of male lethality
- relatively normal until ~6months
- 6-18 neurological symptoms
- microcephaly–> most of the time only male showing this
RS males affected how?
- rare
- XXY Klinefelter’s Syndrome
- SRY genen recombined onto x= phenotypic male
- mosascism–> mutation in male early stage–> one mutant allele in subset
Mosaicism
- inheritance on an individual/tissue of at least 2 cell lines that are different genetically
- xinactivation/ mutations in early life (only daughter cell= mutations)
Pseudoautosomal inheritance
inheritance that happens in homologous regions of X&Y therefore can have male to male inheritance
Mosaicism in pedigrees
no affected parents/ people in earlier generations
A= spontaneous mutations (rare)
B= more reasonable–> germ line/ in father (mutation in)
somatic mosaicism
not inheritance: bunch of cells
–> mutation= won’t develop into cells only see it in muscle cells
germline mosaicism
- female: ~30 mitotic divisions that occur before the 1st meiosis
- male= 100s of mitotic divisions before 1st meiotic (increased possibility of mutation)
Unstable Repeat Expansions
- most mutations (polymorphs_ stably transmitted (all affected members of the family share the same inherited mutation)
- can be detected by sequencing (unstable repeat expansions –> new class of genetic disease)
unstable repeats
sequence of mutation can change 1 generation to the next
Repeat expansion
- in genes/ trinucleotide repeats because no frameshift mutation–> if frameshift–> early termination= stop codon (intron or UTR)
- 4/5 bp changes are known
WT alleles are polymorphic
- range of number of repeats= WT
- -decrease in the number of repeats= normal population
- increase in the number of repeats= increased risk of expansion and disease (gene expression)
Characteristic of UREDs
- > 12 URED known–> # of max repeat surpassed= neurological disorders
- inheritance patterns= dominant, recessive, x-linked
- shows anticipation
anticipation
slow increase of the phenotype= changes generation to generation= increase in size until it reaches the absolute max= more sever phenotypes
difference between UREDS
- length and base sequence of repeats (4/5 nucleotides)
- number of repeats in normal and fully affected individuals differs
- location of repeat unit inside a gene (intron 5’ UTR)
- parental bias= where expansion happens
examples of UREDS
- Huntington: Autosomal dominant (locus coding region)
- Fragile X: x-linked (5’ UTR)
- Myotonic Dystrophy: Autosomal dominant (3’ UTR)
Mechanism of Repeat Expansion
- strand slippage in replication
- can also happen if 2 strands don’t pair properly
- the replicated strand slips mismatched repeat unit loops out
resolving the loop
chop off loop, fix pathway
- (no mutation happens)
- -> if repair doesn’t work, loop stays inside cell, decrease in the number of repeats depending on which strand loops
repeat can happen in different parts of transcribed genes
-coding=exon
-noncoding= intron
-gene needs a promoter, transcriptional start site,
start codon (down stream in an exon) 5’ to 3’ UTR, stop codon introns
Class 1 UREDS
- transcption impaired
- repeat could insert between promoter and transcription start site, epigenetics etc
- on impair transcription
class 2 UREDs
- noncoding repeats inferred onto RNA causing RNA to act differently
- could prevent translation
- expanding repeat would result in clenching of RNA binding
CLASS 3 UREDS
coding region is impaired
Fragile X Syndrome
Class 1
-common form of moderate mental retardation
-x-linked inheritance
-50-60% penetrance in females
FMR1 gene–> CCG in 5’UTR > 200 copies when phenotypes happens
diagnosis: PCR (put primers on the region, CGH (measures +/- in test sample relative to the control FISH not the best
FMR1 GENE
- involved in the proper development of a a neuron
- FMRP= protein
- RNA-binding protein: suppression of mRNA targets (cytoskeletal structure, synaptic transmission and neuron maturation)
Repeat
6-50: WT
60-200 phenotype not shown but risl in offspring
>200 phenotype shown
CGH
1.0 ratio= control
1.5 ratio= trisomy
0.5 ratio= monosomy
for a female patient
-control is a male and vice versa
premutation
- risk of expansion to full phenotype depeds on repeat number in parent
- carriers at risk of other illness (dont show phenotype for fragile x, they could show a phenptype for some other disorder)
inheritance in males vs females
male: 50%
females= 25% due to x-inactivation
Friedreich Ataxia
-Class 1 AR -repeat in intron --> not close to the promoter and no methylation to stop transcription -happens before adolsecence -incoordination of limb movements -difficulty of speech -cardiomypathy -foot deformaties expansion on GAA trinucleotide in FRDA gene
FRDA GENE
FRIEDRICH ATAXIA CLASS 1 GAA repeat in intron 1 patients 100-1200 repeats higher the # more sever the phenotype repeats affect transcription of mRNA
Mytonic Dystrophy 1
AD Class 2
pleiotropic (1 gene influenses many unrelated phentoypic traits) of all YREDS
character: muscle weakness and wasting
-cardiac conduction defects
testicular atrophy
cataracts/ insulin resistence
every kid with a congential form has an affected mother
DMPK
MD1 -EXPANSION IF CTG IN 3'UTR NORMAL=5-30 carriers/premutation= 38-52 mild 50-80 severe >2000
Huntinton’s DiEASE
Class 3
AD -
passed from generation to generation 50% risk to children
homo and heterozygotes= similar traints
-variable age of onset
anticipation (only when trasmitted from father not mother
shows up in midlife -> loss of cognition/ personaluty changes/ death/
CAG expansion in HD coding region
normal is 40
