Bioc L01 Mutations and Polymorphisms

Question 1

What’s a genotype?

Answer 1

The genetic constitution of an organism. It is the
summation of the entire DNA within the cell or organism.

Question 2

What’s a phenotype?

Answer 2

The observable traits/character of a cell or organism

Question 3

Can somatic cell mutations be passed on to the next generation?

Answer 3

No, only germline mutations can be passed on.

Question 4

What is a point mutation?

What is a Transition mutation?

What is a transversion mutation?

Answer 4

A single bp mutation

Transition: purine replaced by another purine or pyrimidine replaced by another pyrimidine

Transvertion: a purine is replaced by a pyrimidine or
vice versa.

Question 5

What type of mutation causes Hemophelia B?

How does the mutation cause the disease?

What gene/chromosome?

Answer 5

Point mutation in clotting factor gene.

A to G transition alters the binding of a key transcription factor needed for expression of the factor IX gene

X chromosome, males more affected

Question 6

How are mRNA splice sites and disease associated with point mutations?

Answer 6

A point mutation could remove a splite site cause an intron to be left in the mRNA, changing the protein.

Question 7

What is the inheritance pattern of Tay-Sachs?

What gene is affected and how?

What is the phenotype?

Answer 7

Tay-Sachs is autosomal recessive.

A point mutation in hexA gene alters mRNA splicing, causing intron 12 to be included in gene product.

Lack of hexosaminidase A leads to a build-up of GM2 ganglioside in neuronal lysosomes, causing neuron damage. Death before 5 years of age is inevitable.

Question 8

What is a missense mutation?

Answer 8

A point mutation that changes an amino acid in the final protein.

Question 9

What type of mutation causes Sickle Cell Disease? (state 2 features)

What is the inheritence pattern?

What’s a benefit of having one mutated allele?

Answer 9

A missense (point mutation) transversion (A to T)

Autosomal recessive, two mutated alleles needed for disease phenotype

Resistance to malaria.

Question 10

What is a nonsense mutation?

Answer 10

A mutation that introduces a stop codon resulting in a truncated protein.

Question 11

What are the traits of Neurofibromatosis Type I (NF1)?

What causes NF1?

Answer 11

Autosomal dominant disease with variable phenotypes including neurofibromas, cafe-au-lait spots, Lisch nodules in iris and more

Most cases caused by a nonsence mutation, adding a stop codon in the coding region. The shortened protein is unstable and readily degradeable.

Question 12

What is ß-Thalassemia?

How is ß-Thalassemia inherited and what type of mutation does it originate from?

Answer 12

Decrease in ß-globin, affects hemoglobin

Autosomal recessive, point mutations can affect transcriptional components of the gene, splice sites, aa sequence (missense, nonsense), and that stability of the proteint (nonsense, sometimes missense)

Question 13

What is a frameshift mutation?

Answer 13

Insertion/Deletion of 1-2 bp (or multiples)

Question 14

What is an in-frame mutation?

Answer 14

Insertion/Deletion of 3 bp (or multiples)

Question 15

What causes Infantile Tay-Sachs?

Answer 15

A 4 base insertion in the hexA gene, resulting in a frame shift and premature stop codon.

Question 16

What causes Cystic Fibrosis (CF)?

Answer 16

The most common mutation is a deletion of three nucleotides within the coding region (∆F508) of CFTR

Loss of a single aa (in-frame) prevents the chloride channel transporter from reaching plasma membrane.

Question 17

What causes a-thalassemia?

What is the normal number of functional a-globin proteins for non-affected individual?

When does the disease present and what are the different outcomes?

Answer 17

A large deletion from aberrent recombination. Homology in sequences of 2 functional alpha-globin genes and 1 non-functional alpha-globin gene on chromosome 16 can cause misalignment during recombination.

Result is one gamete will be missing a functional a-globin and one gamete will have an extra.

A normal individual will have 4 a-globin proteins, 2 from mom and 2 from dad, an individual with 3 is a silent carrier

Individuals with 2 or less will show symptoms:
2 copies: a-thalassemia: mild anemia, microcytosis
1 copy: HbH (ß₄) disease: moderaterly severe hemolytic anemia
0 copies: Hydrops fetalis (hypoxemia/edema
in the fetus) or Hb Bart’s

Question 18

What causes Charcot-Marie-Tooth disease (CMT)?

What is the phenotype?

Answer 18

70% caused by large insertion in PMP22, caused by misalignment during recombination

Additional copies and increased production of PMP22 causes demyelination.

Question 19

What are 6 effects of mutations on phenotype?

Answer 19

1. Lethal: (infantile tay-sachs)
2. Conditional mutations: manifestation depends on environment (G6PD deficiency)
3. Loss of Function: function of hene lost partially or completely (NF-1 and CF)
4. Gain of Function: either increased protein activity, new function gained or expressed in new location that has an afffect on cells in that location.
5. Dominant negative: Usually the result of a mutated protein interfering with the function of the protein made from its non-mutated allele counterpart.
6. Epigenetic changes: Not mutations but alterations to DNA such as methylation (silences transcription) alters phenotype w/out changing genotype

Question 20

What DNA residues get methylated?

Answer 20

Cytosines

Question 21

What was the Dutch “Hunger Winter”?

What of DNA alteration is this an example of?

Answer 21

Pregnant Dutch women in their 3rd trimester, starved by nazis during WWII, had babies with low birth weight (and remained small entire lives) and decreased risk of obesity.

Women who were starved “only” in their 1st trimester had children with an increased risk of obesity

Some of these effects persisted to the grandchildren of the starved women.

An example of cytogenetics (I think, because starvation wouldn’t cause mutations)

Question 22

How can epigenetics effect granchildren?

Answer 22

A pregnant mother can pass the traits to her developing fetus, the germ cells of the defeloping fetus can also be affected (grandchildren)

Question 23

How are polymorphisms different than mutations?

Answer 23

A polymorphism is a mutation with an occurence greater than or equal to 1%. (a mutation with higher occurence)

Polymorphisms generally do not affect health.

Question 24

What are the 4 main types of polymorphisms?

How are polymorphisms used in paternity tests?

Answer 24

1. SNPs: single nucleotide polymorphisms
2. STRPs: Short tandem repeat polymorphisms (microsatellites), 2-5bp
3. VNTRs: Variable Number of Tandem Repeats (minisatellites), 14-500bp
4. CNVs: Copy Number Variations, repeats >1000 to 2 million bp

Everybody has two polymorphism patterns, one maternal and one paternal. VNTR analysis is good at excluding possible fathers in a paternity test if the child shares no VNTR patterns.

Question 25

Which diseases discussed in lecture 1 are caused by point mutations?

Answer 25

• Hemophelia B
• Infantile Tay-Sachs
• Sickle Cell Disease
• NF-1
• ß-thalassemia

Question 26

Which diseases discussed in lecture 1 are caused by small deletions?

Answer 26

• Cystic Fibrosis

Question 27

Which diseases discussed in lecture 1 are caused by small insertions?

Answer 27

• Tay-Sachs (common variant)

Question 28

Which diseases discussed in lecture 1 are caused by large insertions?

Answer 28

• Charcot-Marie-Tooth disease

Question 29

Which diseases discussed in lecture 1 are caused by large deletions?

Answer 29

• a-thalassemia