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Mutations and Polymorphisms Flashcards

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1
Q

What is a mutation?

A

any PERMANENT CHANGE in seq or arrangement of genomic DNA.

3 broad categories

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2
Q

What are genome mutations?

A

altered NUMBER of chromosomes. .. .(genome mutations are more common than chromosome mutations)

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3
Q

What are chromosome mutations?

A

altered STRUCTURE of chromosomes

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4
Q

What are gene mutations?

A

Altered INDIVIDUAL GENES

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5
Q

What are the origins of genomic mutations?

A

missegregation

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6
Q

What are the origins of chromosome mutations?

A

rearrangements

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7
Q

What are the origins of gene mutations?

A

DNA replication errors

DNA repair failure-DNA repair polymerases (3’-5’ exonuclease activity) do not have proof reading capacity.

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8
Q

What are the types of gene mutations?

A

Nucleotide substitutions(point mutations)
Deletions or insertions
Dynamic mutations

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9
Q

Where can mutations be on a gene?

A

Anywhere on a gene, coding or non-coding.
Promoter mutations are in non-coding regions and can be very dangerous b/c it will abolish transcription. Some mutations in non-coding regions do not pose much of a problem.

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10
Q

The effects of mutations can be different due to the type of mutation which are?

A

Selectively neutral
Beneficial
Deleterious

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11
Q

What types of effects can point mutations result in?

A
  1. Silent/synonymous-changed DNA but has not changed expression of the genetic code-protein synthesis is still the same.
  2. Missense-substitution of 1 aa by another. i.e. Glu(6)Val for sickle cell anemia
  3. Nonsense mutations-Premature termination codon-mRNA too small or truncated protein so will not see the gene product.
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12
Q

What do Nonsense mutations lead to?

A

Nonsense mediated mRNA decay
Unstable truncated protein
May also abolish the termination codon and allow translation until next termination codon is reached. So, either the mRNA or protein is too long->misfiling/degradation

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13
Q

What are the common RNA processing mutations?

A

they are commonly splicing mutations

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14
Q

What is a HotSpot of Mutation?

A

*Hotspot of mutation->CG doublets-methylated cytosine->deamination->thymine->T:A mutations.
Hotspots are regions prone to mutation.CpG doublets have a high freq of CG repeats that usually accumulate at 5’ region->cytosine is methylated leading to silencing of the gene. When cytosine is deaminated, it becomes uracil, a methylated uracil is not repaired in DNA b/c it is recognized as Thymine! so C replaced with T and G replaced with A leading to T:A mutations

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15
Q

What are In-frame deletions?

A

Small deletions and insertions in multiples of 3, so they do not affect the reading frame. Tend to be minor in their effect on the cell. Ex. Baker’s Muscular Dystrophy.

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16
Q

What are Frame-shift mutations?

A

small insertions/deletions in which the # of nucleotides added/removed are not multiples of 3 which changes the reading frame, leading to a diff protein and fxn. i.e. DMD very severe no dystrophin protein from frame shift.

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17
Q

What are large deletions and insertions?

A

Detected by southern blotting.
Large deletions are rare, DMD, NF1, a-thalassemia
Large Insertions are even rarer, LINE seas and Hemophilia A

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18
Q

What is the basis for deletions?

A

Aberrant recombination b/w silmilar or identical sequences-unequal crossing over, esp with repetetive seqs b/c they are predisposed to unequal crossing over which often lead to deletions or insertions.
Ex:Alu seqs in LDL receptor gene, famililal hypercholesterolemia, a-thalassemia

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19
Q

What are dynamic gene mutations?

A

Mutations expand during gametogenesis and interfere with gene expression.
Huntington’s, Fragile X, Friedreich’s ataxia, Myotonic dystrophy

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20
Q

What is the mutation rate of a gene equal to?

A

Number of new mutations/locus/generation.
Reasons for variation include: gene size, fraction of mutant allele showing the phenotype, age and gender of parent, mutational mechanism, mutational hotspots..ie, children with hemophilia have older fathers!

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21
Q

What are sex differences in mutation rates?

A

marked diffs in both sexes regarding timing and number of mitotic and meiotic divisions forming the gametes->diffs in freq and type of mutation

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22
Q

Mutation rates in oocyte?

A

longer the oocyte is in meiosis I/diplotene arrest, the higher chance of nondisjunction error. Females have a higher incidence of non-disjunction.
Ovum, 22 mitotic divisions in fetal life->primary oocyte enters meiosis I and arrested until ovulation.

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23
Q

What are mutation rates for sperm?

A

Point mutations are more common! Spermatogenesis, 30 mitotic divisions up to puberty->20-25 replication cycles/yr thereafter. Ex. Achondroplasia, Apert syndrome, MEN2A & 2B, Hemophilia B

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24
Q

Polymorphism

A

genetic diversity and individuality

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25
Q

What do promoter mutations result in?

A

Abolish transcription, incomplete mRNA/protein

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26
Q

What is it called when a mutation does not lead to a deleterious effect?

A

A variation in sequence rather than mutation

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27
Q

What are selectively neutral mutations?

A

Arise in non-coding sequence, does not change probability of survival,

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28
Q

Evolution leads to?

A

new nucleotide variation leading to genetic diversity and individuality

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29
Q

What are alleles?

A

Different versions of a particular DNA sequence at a locus.

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30
Q

What is genetic polymorphism?

A

when alleles are so common as to be seen in more than 1% of chromosomes in general population

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31
Q

What are rare variants?

A

Alleles with frequency of less than 1%-MOST DELETERIOUS MUTATIONS THAT LEAD TO DISEASE ARE RARE VARIANTS.

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32
Q

What are polymorphisms used for?

A

GENETIC MARKERS! Prenatal diagnosis, heterozygote detection, blood banking and tissue typing for transfusions, organ transplantations, provide genomic based personalized medicine, forensic application, gene mapping by linkage analysis or allelic association

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33
Q

What is a SNP (single nucleotide polymorphism)?

A

substitution of one or the other of 2 bases at one location. Most common! Once every 1kbp. HapMap is based on SNPs. Active research, may lead to a subtle change in disease susceptibility rather than directly causing a serious illness.

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34
Q

What is Indel?

A

Insertion-deletion polymorphisms. 2-100 nucleotides, SIMPLE-50% presence/absence of inserted or deleted segment.
MULTIALLELIC-variable # of a segment of DNA that is repeated in tandem at a location:
Microsatellite
Minisatellite

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35
Q

What are Microsattelites?

A

2-4 nucleotide repeats b/w 1 and a few dozen times.

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36
Q

What are STRP, short tandem repeat polymorphisms?

A

Different alleles due to differing #’s of repeated units. (micro satellites)

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37
Q

What are mini satellites, VNTRs?

A

Variable Number of Tandem Repeats. Due to insertion of varying #’s of copies of DNA, 10-100bp in length in tandem. No 2 related individuals share same allele. Each person has 2 VNTR at each locus, one from each parent, it’s our molecular fingerprint.

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38
Q

What is DNA fingerprinting?

A

simultaneous detection of # of mini satellite polymorphisms (VNTRs)

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39
Q

What are Copy Number Polymorphisms? CNP

A

Variation in # of copies of larger segments of genome. 200bp-2MB.
Simple/multiallelic
Typed by array CGH

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40
Q

What are some polymorphisms of medical significance?

A

ABO and RH blood groups-> blood transfusions.

Major histocompatibility Complex (MHC)->transplantation medicine

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41
Q

What are the antigens on the surface of RBC’s?

A

Antigen A, antigen B

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42
Q

What are the two corresponding antibodies on RBC’s?

A

Antibodies anti-A and anti-B in plasma

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43
Q

What are the four major phenotypes of blood?

A

O, A, B, AB

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44
Q

What is it called when RBC lack antigen A, but serum contains Anti-A?

A

Reciprocal relationship b/w antigens present on RBC an antibodies in serum.

45
Q

What is the molecular basis of the ABO blood system?

A

3 alleles, A, B,O of which A and B are codominant and O is recessive. Chrom 9.

46
Q

What is the protein called present on the RBC surface?

A

Protein called H antigen present on RBC surface.

47
Q

What do the A and B alleles code for?

A

The enzyme Glyosyl Transferase

48
Q

What does the enzyme coded by the A allele do?

A

Adds N-acetyl-galactosamine to H antigen.

49
Q

What does the enzyme coded by the B allele do?

A

Adds D-galactose to H antigen.

50
Q

What does the O allele code for?

A

a mutant protein that lacks Transferase activity.

51
Q

What is the molecular basis for the altered specificity b/w A and B?

A

4 nucleotide seq differences b/w A and B which leads to a change in aa’s and altered specificity of the enzyme.

52
Q

What is the molecular basis for the O allele?

A

single base-pair deletion–>frame shift mutation->no transferase activity

53
Q

When is DNA seq analysis for ABO blood group typing done?

A

Technical difficulties in serological analysis
Foresic investigations
Paternity testing
When there is cancer bc cancer interferes w/blood type/group . . . requires blood typing before transfusions

54
Q

What is the primary clinical importance of ABO system?

A

Blood transfusions
Tissue and organ translplantation
Hemolytic Disease of the New born may occur but is very mild condition

55
Q

What is a compatible combination of ABO system?

A

RBC of donor do not carry A or B antigens that correspond to antibodies in recipients serum. . . . .

56
Q

What is incompatible combination?

A

When a patient is type A, so has antibodies to Anti-B. Patient, A is given B blood which contains antigen B and antigen-antibody agglutination->hemolysis->Hb builds up and blocks vessels(esp liver) ->death

57
Q

What is the molecular basis for the Rh system?

A

Gene on chrom 1 codes for the antigen Rh-D–>Rh positive. Rh+ is dominant.
Mutant allele->nonfxn’l-> does not express the protein->Rh -

58
Q

What is the clinical significance of the Rh system?

A

Prob when Rh-neg woman carries a Rh+ fetus. 1st pregnancy, the mother is sensitized to Rh+ blood of the fetus during birth. In subsequent pregnancies, the mother’s anti-Rh+ Abs may cross the placental barrier to attack Rh+ RBCs of the fetus-Hemolytic Disease of the Newborn (HDN).

59
Q

What is the mechanism of hemolysis for HDN?

A

1st exposure, IgM will not cross placenta, but will regress and make memory B cells. Repeat exposure to the same antigen on next pregnancy will rapidly induce IgG which can cross the placent into fetal circulation and attack Rh+ antigen on fetal RBC’s. Antibody coated rbc’s are lysed by the reticuloendothelial system. Hydrops fetalis

60
Q

What are the clinical features of HDN?

A

Infant is jaundiced at birth or in 1st 24 hrs after birth, rapidly unconjugated bilirubin level, anemia, hepatosplenomegaly, and most severe hydrous fettles.

61
Q

How do you diagnose a HDN?

A

Indirect Coombs test and Direct antibody test

62
Q

What is the treatment for HDN?

A

transfusion with type O, Rh- fresh rbc’s.
intensive phototherapy
IV immunoglobulin

63
Q

How can HDN be prevented?

A

Administer Rh Immunoglobulin:

to all unsensitized Rh- women at 28 wks gestation and additional dose administered soon after birth if infant is Rh+.

64
Q

Where is the Major Histocompatibiity Complex, large cluster of genes located?

A

Short (p) arm of Chromsome 6

65
Q

What is Class I & II of MHC?

A

Human Leukocyte antigen (HLA) genes.

Encode proteins that are important for initiation of immune response->Present antigen to lymphocyte

66
Q

What is Class III of MHC?

A

Gene that codes for components of complement system

67
Q

What are the alleles assoc with HLA class I?

A

HLA-A,B,C. Present on all nucleated cells and platelets. Consists of 2 polypeptide subunits: a variable heavy alpha chain, and a nonpolymorphic beta2 micro globulin(encoded outside MHC on chrome 15).
Present peptides derived from intracellular proteins (Ex. viral antigens)

68
Q

What alleles are assoc with HLA class II?

A

HLA-DP, DQ,DR. On antigen-presenting cells like macs, dendritic cells, and B-cells.
Heterodimers of alpha and beta subunits.
Present peptides derived from exogenous proteins i.e. extracellular microbes

69
Q

T or F? HLA alleles and haplotypes have ethnic diffs for all the alleles?

A

TRUE

70
Q

The set of HLA alleles at different class I & II loci on a given chromosome form the?

A

haplotype

71
Q

HLA Alleles are codominant and close enough to be transmitted as?

A

a single block. not much shuffling. parent and child share only 1 haplotype; siblings have 25% chance to have matching haplotypes

72
Q

What is linkage disequilibrium?

A

restriction in diversity of haplotypes in a population (due to diffs in alleles and their freqs)

73
Q

How is linkage disequilibrium explained?

A

Low rate of meiotic recombination
Positive selection by environment
Historical facts like time when pop was founded, how many founders were there? how many immigration occurred?

74
Q

What is ankylosing spondylitis?

A

Autoimmune, chronic inflammatory disease of spine and sacroiliac joints.
Predisposed by certain alleles of HLA B27-peculiar assoc->HLA B27 was found to be more than 1 gene

75
Q

What are some disorders that show linkage disequilibrium with HLA genes?

A

Congenital Adrenal Hyperplasia- 21-a-Hydroxylase deficiency which tends to be immediate neighbor of HLA so when HLA genes are transferee as a block, so are the others.
Hemochromatosis(cys282Tyr in HFE) and HLA-A*0301

76
Q

Perfect match for HLA and blood groups seen in?

A

MZ twins. 100% success of transplantation without immunosuppressive therapy

77
Q

Solid organ transplantation?

A

HLA identical siblings 72% survival falls to 56% when donor sibling has only 1 haplotype common.

78
Q

Bone marrow transplantation?

A

Graft which contains immunocompetent lymphs can attack host->graft vs host disease (GVHD)

79
Q

What is population genetics?

A

quantitative study of distribution of genetic variation in populations. Concerned with genetic factors such as mutation and reproduction, Environmental/societal factors->selection and migration.
Provides info about disease genes common to pops which is required for clinical diagnosis, genetic counseling and determining allele freqs for risk calculations

80
Q

What is allele/gene frequency?

A

% of a given allele in a population. Sum of allele frees is 1 or 100%.

81
Q

What is genotype frequency?

A

measures the proportion of each genotype in a population.

82
Q

What is the Hardy-Weinberg principle?

A

ideal population, the freqs of alleles and genotypes do not change with the passage of generations.

83
Q

What is an ideal population?

A

No migration, no selection, random mating, and constant mutation rate.
Assumptions: population is large and random mating.

84
Q

Why are allelic frequencies constant overtime in an ideal population?

A
  1. There is no appreciable rate of mutation
  2. Inviduals with all genotypes are equally capable of mating and passing on their genes, i.e. there is no selection against any particular genotype
  3. There has been no significant immigration of individuals from a population with allele frequencies very different from the endogenous population
85
Q

What is the eqn for the Hardy-Weinberg Law?

A

Binomial expansion P^2 +2pq + q^2
p=dominant allele, normal
q=recessive allele, mutant
Genotype freqs expressed as ratios

86
Q

Do the freqs of p and q remain constant from generation to generation?

A

Yes!

87
Q

What is the Incidence, I of the disease in a population?

A

the frequency of a disease-causing allele (q)

88
Q

What is the incidence, I of an Autosomal Recessive disease, i.e. cystic fibrosis?

A

I =q^2

89
Q

What is the incidence, I of an autosomal Dominant disorder?

A

I=2pq + q^2 which is: I=2q, so q=I/2 since q, the recessive allele freq is negligible.

90
Q

What is the incidence of X-linked disorders?

A

(mainly males affected)Incidence=ppl affected=males=q (because males hemizygous) and p=1-q.
The genotype freqs in females can be estimated like in autosomal genes.

91
Q

What is the carrier frequency of a heterozygote female?

A

2pq

92
Q

What is the frequency for X-linked dominant?

A

Incidence, I = freq. of affected males = q, hence, p = 1-q.
Freq of affected heterozygote female =2pq
Freq of affected homozygote female = q^2

93
Q

What is Hardy-Weinberg equilibrium?

A

a population that demonstrates the basic features of hardy-weinberg law. By defn:
Large (no migration)
Random mating
Constant mutation rate (alleles lost by death, balanced by new mutation)
No selection for or against any genotype

94
Q

What factors can disturb H-W equilibrium?

A

Exceptions to random mating:
Statification-a population in which there are a # of subgroups that have remained relatively genetically separate(i.e. amish)
Effect on recessive disorder->excess of homozygotes in pop and a corresponding deficiency of heterozygotes.
Has no effect on freq of AD disease and
Only a minor effect on X-linked disease by increasing small # of females homozygous for mutant allele.

95
Q

What factors can disturb H-W equilibrium? Exceptions to random mating . . . WHAT IS ASSORTIVE MATING?

A

Choice of a mate because the mate possesses some particular trait, usually positive.
Clinical importance-tendency to choose partners with similar medical problems-increases the chances of 2 ppl carrying mutations in same disease locus.

96
Q

What factors can disturb H-W equilibrium? Exceptions to random mating . . . WHAT IS CONSANGUINITY AND INBREEDING?

A

increases the freq of an AR disease, disorders that may be rare an unusual.

97
Q

What factors can disturb H-W equilibrium? Exceptions to CONSTANT ALLELE FREQs:

A

Small populations-random events have a much greater effect in small populations-> allele freqs can fluctuate from generation to generation->GENETIC DRIFT
Possible consequence: 1 allele could be lost altogether and the other allele may become “fixed”

98
Q

What factors can disturb H-W equilibrium? Exceptions to Constant allele freqs: What is mutation and selection?

A

The frequency of an allele in a population reflects a balance b/w mutation rates and selection.
FITNESS is a measure of the # of offspring of affected persons who survive to reproductive age, compared with the appropriate control group.

99
Q

Exceptions to Constant allele freqs: What is mutation and selection?

A

if a mutant allele is just as likely to as a normal allele to be present in the next generation, f=1.
If an allele causes death or sterility, selection acts against it completely, f=0->genetic lethal

100
Q

What is the coefficient of selection,

(s)?

A

S is measure of loss of fitness.
Given by 1-f-> population of mutant alleles that are not passed on but due to selection.
eg. Achondroplastic dwarves have only 1/5th as many children compared to ppl of normal stature. Therefore, their avg. fitness, f=0.2 and the coefficient of selection, S=0.8

101
Q

Exceptions to Constant allele freqs: mutation and selection. WHAT DOES THE FREQUENCY OF AN ALLELE (q) IN A POPULATION REPRESENT?

A

A balance b/w the mutation rate (mu) of that gene and the effects of selection (s).
If mutation rate or effectiveness of the selection is altered, the allele frequency is expected to change and
the mutation rate (mu) at a locus must be sufficient to account for the proportion of mutant alleles lost by selection (s)

102
Q

Exceptions to Constant allele freq.s: mutation and selection . . .Autosomal recessive

A

Autosomal recessive->selection against harmful mutation is much less effective.
Only a small proportion of genes present in homozygotes are subject to selection. It takes many generations to reduce the allele freq of mutant allele appreciably b/c there are many copies of mutant allele in the heterozygous state with normal fitness.

103
Q

Exceptions to Constant allele freq.s: mutation and selection . . .Autosomal Dominant disorders

A 
if the disorder is deleterious but not lethal->contribute fewer than avg # of offspring-> f is REDUCED!
Mutation rate (mu)= q X s
104
Q

Exceptions to Constant allele freq.s: mutation and selection . . . X-linked disorders

A 
Mutation rate (mu)= 1/3 X q X s
Incidence is largely determined by the affected males; I=q. Also, males being homozygous contain 1/3rd of the x-linked gene pool.
Most X-linked disorders are recessive->selection occurs in homozygous males, not in asymptomatic heterozygous females.
GENETIC LETHALS-DMD, males do not reproduce (genetic lethals), hence 1/3rd of mutant alleles are lost in each generation so the mutant alleles must be replaced by recurrent new mutation
105
Q

Exceptions to Constant allele freq.s: mutation and selection . . .Migration and Gene flow: WHAT IS GENE FLOW?

A

the slow diffusion of alleles across a racial or geographical barrier.

106
Q

When does gene flow occur?

A

when alleles are introduced into a population as a consequence of migration with subsequent intermarriage. This will lead to a change in the relevant allele freqs. Ex: CCR5 cytokine receptor and its deletion allele delCCR5 is highest in western Europe and Russia and declines to a few in middle east and Indian subcontinent.
CF mutation delF508 and Z allele of Pi locus (a1-antitrypsin) highest in Scandanavia with declining frets across Europe; could be a consequence of Viking invasion in the past.

107
Q

How are ethnic diffs in genetic diseases explained?

A

Genetic drift including founder effect, Heterozygote advantage.
In small population there are marked changes in the allele freq from one generation to the next, DUE TO CHANCE disturbing the HW equilibrium.

108
Q

What is the founder effect?

A

Genetic drift explains the establishment of mutant alleles and the formation of a small population. If in a sub-population, one of the original founders happens to carry a relatively rare allele (defective), the allele may become fixed as a consequence of genetic drift=founder effect.
Tyrosinemia-Lac Saint Jean Quebec
High incidence of Huntington’s disease in Lake Maracaibo region, Venezuela

109
Q

What is the heterozygote advantage?

A

in some autosomal recessive disorders, the selection may increase the fitness of heterozygotes, compared to unaffected homozygotes. e.g. malaria endemic areas, heterozygous sickle trait are relatively immune to infection with Plasmodium falciparum. Unaffected homozygotes have severe anemia and prone to infection with the malarial parasite. In these communities, the freqs of heterozygotes tend to increase relative to those of normal and affected homozygotes

Genetics (12 decks)

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