04: Genetic Variations & Their Origins

Question 1

What is a polymorphism?

Answer 1

A genetic variation present in at least 1% of the population.

Question 2

What is a rare variant?

Answer 2

Genetic variation seen in less than 1% of the population.

Question 3

What is an allele?

Answer 3

Genetic variations present at a particular chomosome locus (chromosomal locaton).

Question 4

What are the various types of polymorphisms?

Answer 4

Single nucleotide polymorphisms, microsatellites, tandem repeats, copy number variants

Question 5

Explain the genetic basis behind blood type/blood group antigens.

Answer 5

• ABO: O, A, B, AB
  
  • Determined by glycosyltransferase gene on chromosome 9.
  • A and B are co-dominant, O recessive to add terminal sugars to H protein and surface of RBCs.
  • O is due to a 1bp deletion.
• Rh
  
  • Rh+ express the Rh-D antigen encoded on chromosome 1.
  • Rh- are homozygous for non-functional Rh-allele.
  • If mother Rh- and fetus Rh+, can lead to hemolytic disease of newborn; prevent with RhoGam (Rh Ig).

Question 6

For achondroplasia, describe:

1. Heritability
2. Incidence
3. Mutation
4. Phenotype

Answer 6

1. Autosomal dominant
2. 1/15,000-1/40,000
3. FGFR3 gain of function nucleotide 1138, codon 308 (G–>A or G–>C)
4. Shortening of limbs, frontal bossing, midface hypoplasia, lumbar lordosis, obstructive apnea, brainstem compression, hydrocephalus

Question 7

What is the genetic basis of alpha thalassemia?

Answer 7

On each chromosome 16, two copies of alpha chain for hemoglobin (arose by gene duplications). Can have deletions of one or both copies of the alpha gene on one or both chromosome 16s.

Deletions of one alpha gene more common in Mediterranean; deletions of both alpha genes more common in SE Asians.

Question 8

What is the genetic basis for almost half of all new mutations in Factor VIII?

Answer 8

Intragenic recombination resulting in inversions.

Causes ~45% of non-related Hemophilia A cases.

Question 9

Microdeletion syndromes (Angelman, Prader Willi) are often caused by what?

Answer 9

Genomic instability due to flanking repeat sequences.

Question 10

What is the genetic basis of trinucleotide repeat (NTR) expansions?

Answer 10

Slipped mispairing; replicating strand detaches inappropriately from template during replication, newly synthesized strand contains an extra repeat.

Question 11

What is genetic drift?

Answer 11

Fluctuation in gene frequency due to small size of breeding population.

Results in potential fixation or extinction of an allele.

Question 12

What is the founder effect?

Answer 12

High frequency of gene in distinct population, due to its introduction at a time when the population was small, and continued high frequency due to the population being closed.

Question 13

How do you calculate the frequency of a mutation?

Answer 13

1 = p² + 2pq + q²
1 = p + q

p = frequency of normal allele A
q = frequency of mutant allele a

q² is the number of people with the disease (aa) if recessive.
2pq is the number of carriers (Aa).

Note: This is for an autosomal recessive condition.

Question 14

What is Hardy Weinberg Equilibrium?

Answer 14

The assumption that allele frequencies remain constant from generation to generation under the following conditions:

1. Population is large
2. Mating is random
3. No selection for/against particular phenotype
4. Mutation rate constant; alleles lost by death replaced by de novo mutations
5. No immigration or emigration

Question 15

What is fitness?

Answer 15

The proportion of offspring that live to reproductive age of carriers versus controls.

1 = no advantage to carriers
0 = causes premature death

Question 16

What is CCR5 and what are its clinical implications?

Answer 16

Gene for a cell surface cytokine receptor necessary for HIV entry. 32 bp deletion is common; benign trait unless infected with HIV, and then it is advantageous.