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CMMB Midterm 1 > Chapter 7 > Flashcards

Chapter 7 Flashcards

1
Q

allele

A

version of a gene (could be many versions for the same gene), single dominant; 2+= dominant= polymorphic

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2
Q

locus

A

particular location on a chromosome (could be anything -band -many genes- or 1 gene

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3
Q

Single- gene disorder

A
  • 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
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4
Q

How does a variant arise?

A
  • nucleotide sequence has to be different
  • mutation (not always bad)
  • medical genetics (usually disease= alleles/ changes)
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5
Q

OMIM

A
  • online Mendelian Inheritance in Man
  • online database (relationship between genotype and phenotype)
  • Mendelian
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6
Q

genotype

A

collection/specific allele of genotype

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7
Q

phenotype

A

physical result of the genotype (visual characteristics)

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8
Q

pedigree

A

-graphical representation of family tree
=shows single-gene disorder inheritance in families
-standard symbols

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9
Q

proband

A

first affected person (who comes to genetic counsellor and pedigree built around them= IS affected

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10
Q

sibs

A

siblings

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11
Q

sibship

A

collection of brothers and sister

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12
Q

First Degree

A

parents and siblings and children

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13
Q

Second degree

A

grandparents, parent’s siblings, neices/nephews, grandchildren and half siblings

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14
Q

Third degree

A

cousins

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15
Q

kindred

A

entire pedigree= collection of individuals

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16
Q

consultand

A

maybe affected but also relative of the proband

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17
Q

consaguinity

A

couples who have 1 or more ancestors in common

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18
Q

Autosomal Recessive

A

need to be homozygous for a mutant allele to show phenotype

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19
Q

Autosomal Dominant

A

need at least 1 dominant allele to show the phenotype

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20
Q

Pure dominance

A

same phenotype regardless of Aa or AA

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21
Q

incomplete dominance

A

alleles combine to give a mixed phentoype

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22
Q

x^a

A

x-linked recessive

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23
Q

x^A

A

x-linked Dominant

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24
Q

Factors that affect a pedigree

A
  • some disorders not experienced at all, even though the genotype affects other members
  • phenotype can vary between members of a family
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25
Q

different in expression can be caused by

A
  • histone methylation
  • penetrance
  • expressivity
  • age of onset
  • lack of info ancestors my have passed it on
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26
Q

pyrotrophy

A

1 gene= multiple phenotypes

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27
Q

penetrance

A

individual has genotype. What is the probability it will be expressed. (all or nothing concept)

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28
Q

reduced penetrance

A

i.e.) methylated= not expressed

has genotype but doesn’t show phenotypes

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29
Q

Expressivity

A

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
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30
Q

Factors that affect penetrance and expressivity

A

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

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31
Q

Neurofibromatosis (NF1)

A

-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

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32
Q

NF1

A
  • 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
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33
Q

split-hand deformity

A
  • reduced penetrance example

- looks autosomal recessive

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34
Q

Age of onset

A

-can arise at any time
-genetic disorder
-cogenital
=complicate pedigrees

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35
Q

genetic disorder

A

to do with genes

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36
Q

cogenital

A

Not necessarily genetics in a birth defect (abnormalities due to complications during delivery)

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37
Q

Lethal disorder

A

Early termination or miscarriage

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38
Q

Late onset dominant disorder

A

Parents died still weren’t showing the phenotype yet (NF1)

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39
Q

Genetic heterogeneity

A

Different mutations= same or similar phenotype

Three types: allelic, locus, and phenotypic

40
Q

Allelic heterogeneity

A

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

41
Q

True homozygotes

A

Allelic heterogeneity

-Truely Homozygote for an allele

42
Q

Compound heterozygote

A

Allelic heterogeneity

-an individual has two completely different alleles or two identical alleles to show that phenotype

43
Q

Exceptions for allelic heterogeneity

A

-one known allele gives rise to specific phenotypes i.e. Sickle cell anemia
Within ethnic group= people get married= bring the same alleles

44
Q

Locus heterogeneity

A 
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

45
Q

phenotypic heterogeneity

A
  • 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

46
Q

autosomal recessive

A 
only in homozygotes and compound heterozygotes 
-skips generations 
Aa/Aa= 75% affected; 25% unaffected 
aa/aa= 100% affected 
M/F equally affected
47
Q

Consanguinity and Autosomal recessive condition

A
  • 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
48
Q

Measuring consanguinity

A

F= co-efficient of inbredding

-probability that homozygotes got both alleles at a locus form the same ancestral source

49
Q 
parent-child 
bro-sis 
uncle niece 
1st cousins 
2x (1st cousins) 
2nd cousins
A 
1/4 
1/4
1/8
1/8
1/16
1/8
1/64
50
Q

Inbreeding (unrelated individuals)

A
  • selection of mates in small population

- similar to consanguinity

51
Q

Autosomal Dominant

A
  • 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)
52
Q

Incomplete Dominant Inheritance

A

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

53
Q

denovo mutations

A

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
54
Q

Autosomal dominant conditions only because of de novo mutations

A
  • 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
55
Q

Autosomal Conditions show up in 1 sex

A
  • 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)
56
Q

x-linked inheritance

A

most genes on x–> male gets 1 female gets 2

  • 1100 on X
  • 40% can cause disease phenotypes (500- 450)
57
Q

For the Sexes

A

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)

58
Q

x-linked recessive

A

higher in males than females because father gives ‘Y’

  • cant be passed father to son
  • heterzygous females usually unaffected because have a normal allele
59
Q

Hemophila A

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
60
Q

Red- Green Colour Blindness

A
  • most x-linked are rare
  • unlikely female to be homozygous unless parents are consanguineous
  • 10% males have this (rare)
61
Q

Manifesting Heterozygote

A

-rare female carrier to show the x-linked recessive phenotype

Factors: 1) skewes x-inactivation
2) disease-dependent

62
Q

example of manifesting heterozygote

A

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
63
Q

x-linked dominant

A

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
64
Q

x-linked dominant disorder with male lethality

A

pedigrees with affected daughters, normal daughters and normal sons all= proportions are 1:1;1

65
Q

Rett Syndrome

A
  • example of male lethality
  • relatively normal until ~6months
  • 6-18 neurological symptoms
  • microcephaly–> most of the time only male showing this
66
Q

RS males affected how?

A
  • rare
  • XXY Klinefelter’s Syndrome
  • SRY genen recombined onto x= phenotypic male
  • mosascism–> mutation in male early stage–> one mutant allele in subset
67
Q

Mosaicism

A
  • inheritance on an individual/tissue of at least 2 cell lines that are different genetically
  • xinactivation/ mutations in early life (only daughter cell= mutations)
68
Q

Pseudoautosomal inheritance

A

inheritance that happens in homologous regions of X&Y therefore can have male to male inheritance

69
Q

Mosaicism in pedigrees

A

no affected parents/ people in earlier generations
A= spontaneous mutations (rare)
B= more reasonable–> germ line/ in father (mutation in)

70
Q

somatic mosaicism

A

not inheritance: bunch of cells

–> mutation= won’t develop into cells only see it in muscle cells

71
Q

germline mosaicism

A
  • female: ~30 mitotic divisions that occur before the 1st meiosis
  • male= 100s of mitotic divisions before 1st meiotic (increased possibility of mutation)
72
Q

Unstable Repeat Expansions

A
  • 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)
73
Q

unstable repeats

A

sequence of mutation can change 1 generation to the next

74
Q

Repeat expansion

A
  • in genes/ trinucleotide repeats because no frameshift mutation–> if frameshift–> early termination= stop codon (intron or UTR)
  • 4/5 bp changes are known
75
Q

WT alleles are polymorphic

A
  • 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)
76
Q

Characteristic of UREDs

A
  • > 12 URED known–> # of max repeat surpassed= neurological disorders
  • inheritance patterns= dominant, recessive, x-linked
  • shows anticipation
77
Q

anticipation

A

slow increase of the phenotype= changes generation to generation= increase in size until it reaches the absolute max= more sever phenotypes

78
Q

difference between UREDS

A
  • 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
79
Q

examples of UREDS

A
  • Huntington: Autosomal dominant (locus coding region)
  • Fragile X: x-linked (5’ UTR)
  • Myotonic Dystrophy: Autosomal dominant (3’ UTR)
80
Q

Mechanism of Repeat Expansion

A
  • strand slippage in replication
  • can also happen if 2 strands don’t pair properly
  • the replicated strand slips mismatched repeat unit loops out
81
Q

resolving the loop

A

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
82
Q

repeat can happen in different parts of transcribed genes

A

-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

83
Q

Class 1 UREDS

A
  • transcption impaired
  • repeat could insert between promoter and transcription start site, epigenetics etc
  • on impair transcription
84
Q

class 2 UREDs

A
  • noncoding repeats inferred onto RNA causing RNA to act differently
  • could prevent translation
  • expanding repeat would result in clenching of RNA binding
85
Q

CLASS 3 UREDS

A

coding region is impaired

86
Q

Fragile X Syndrome

A

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

87
Q

FMR1 GENE

A
  • 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

88
Q

CGH

A

1.0 ratio= control
1.5 ratio= trisomy
0.5 ratio= monosomy
for a female patient
-control is a male and vice versa

89
Q

premutation

A
  • 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)
90
Q

inheritance in males vs females

A

male: 50%

females= 25% due to x-inactivation

91
Q

Friedreich Ataxia

A 
-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
92
Q

FRDA GENE

A 
FRIEDRICH ATAXIA CLASS 1 
GAA repeat  in intron 1 
patients 100-1200 repeats
 higher the # more sever the phenotype 
repeats affect transcription of mRNA
93
Q

Mytonic Dystrophy 1

A

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

94
Q

DMPK

A 
MD1 
-EXPANSION IF CTG IN 3'UTR 
NORMAL=5-30 
carriers/premutation= 38-52 
mild 50-80 
severe >2000
95
Q

Huntinton’s DiEASE

A

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

CMMB Midterm 1 (6 decks)

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