Genetic Variability in Individuals and Populations

Question 1

Mutation Notation: Nucleotide change

Answer 1

Put the nucleotide number followed by what the mutation is. Ex: m.8393C>T (C was changed to a T) m indicates mitochondrial DNA and r is mRNA. g is genomic DNA, c is cDNA or coding

Question 2

Mutation Notation: Intron Mutation

Answer 2

Put IVS for intervening sequence to indicate in intron. Then use a “+” for forward from the 5’ splice site or a “-“ for backwards. Ex: g.IVS33+2T>A or g.IVS33-2A>T

Question 3

Mutation Notation: Deletion

Answer 3

Indicate which regions where deleted by the numbering. First nucleotide and last nucleotide deleted are listed. Ex: c.1257_1261delACGTC

Question 4

Mutation Notation: Insertion

Answer 4

Indicate the two nucleotide numbers the new insertion is in-between. Ex: c.1321_1322insGCGT

Question 5

Mutation Notation: Missense/nonsense

Answer 5

Put an X to indicate a stop codon or if it is an amino acid change, put the new amino acid that will be coded by the mutation. Ex: Gln43X or Gln43Arg

Question 6

Polymorphisms

Answer 6

Variant sequences (not necessarily deleterious) occurring at an allele frequency greater than 1%

Typical polymorphisms are:

1) Single nucleotide polymorphisms (SNPs; 2 alleles)
2) Simple insertions or deletions (indels; 2 alleles)
3) Short tandem repeat sequences (STRPs; 5 or more alleles)
4) Variable number tandem repeats (VNTR; 5 or more alleles)
5) Copy number polymorphisms (CNP; 2 alleles)

All are powerful mapping and identification tools, associating with disease risk. Polymorphisms impact the ability to transplant organs.

Question 7

ABO Bloodgroups

Answer 7

They are defined by a glycosyltransferase that adds either N-acetylgalactosamine residues (blood group A) or D-galactose residues (blood group B) or no sugars (blood group O) the H-antigen on RBCs. A and B are both dominant where O is recessive. It is possible to be type “AB” as well, thus A and B are co-dominant in that case. If you are type A, you make an antibody for type B. If you are type B, you make an antibody for type A. If you are type AB you don’t make any antibody and if you’re type O you make BOTH antibodies. This is crucial for transplant medicine because if your blood has the antibody for type A blood for example, if you had a transfusion with type A, your body would reject it. So, type O is the universal donor and type AB is a universal acceptor

Question 8

Rh Blood Groups

Answer 8

This refers to the rhesus factor that is expressed on RBCs. It is encoded on chromosome 1. Among different ethnic backgrounds, 17% of caucasians, 7% of african americans, and 0.5% of Japanese are (homozygous) Rh-. Rh- mothers are injected with anti-Rh Ig before and after giving birth. This is because if an Rh- mother has an Rh+ baby, the mother will build antibodies against the Rh+. Then, if she has another baby that is Rh+, it will attack the baby’s blood cells.

Question 9

Major Histocompatability Complex (MHC) Class I & II

Answer 9

Due to the close range of the gene involved the MHC cluster is inherited as a haplotype. The more MHCs one has in common with another, the greater the chance of the acceptance of that organ in a transplant. There are many MHC genes so the likelihood of 2 individuals having the same is rare. MHC defines expression of human lymphocyte antigen (HLA) A, B, C and HLA-DR, DP and DQ which (class I) define antigen presentation to CD8+ and (class II) CD4+ T cells, respectively. These hyper-variable genes are encoded on chromosome 6p. MHC class I molecules are expressed by all living cells, class II by professional antigen presenting cells. HLA matching is pivotal for organ transplantations and for preventing graft-versus-host-disease after bone marrow transplant. Disregarding crossing over, siblings have a 25% chance of sharing both alleles of the MHC haplotype and are thus better matching donors than parents. Only a limited number of haplotypes are found within a given ethnic group. In other words, combinations of alleles are acquired in coupling as a haplotype more frequently then by chance alone.

Question 10

Haplotype

Answer 10

A sequence of genes mapping in a very close proximity to one another that are generally inherited together (infrequently separated by crossing-over)

Question 11

p

Answer 11

It is the allele frequency. It denotes the allele frequency of the wild-type allele (allele frequency)

Question 12

q

Answer 12

It is the allele frequency. It denotes the allele frequency of the mutant allele

Question 13

q^2, p^2, 2pq

Answer 13

These are the genotype frequencies

Question 14

4 Conditions that must be met for Hardy-Weinberg

Answer 14

1) Large Population: Not influenced by chance fluctuations
2) Random Mating: No preference based on phenotype similarities
3) No mutation: No conversion of a “p” allele to a “q” allele
4) No selection: All genotypes are equally capable of mating and producing offspring

Question 15

Hardy-weinberg equilibrium for sex-linked diseases

Answer 15

For X-linked genes, the genotype frequency= allele frequency in MALES because there is only one X chromosome and thus only one allele. For example, with colorblindness, q=0.08 thus 8% colorblind males and 0.64% colorblind females in the population. Among females the carrier frequency is 2pq which is about 0.15 or 15% whereas there are NO CARRIERS in males

Question 16

3 Exceptions to the Hardy-Weinberg Equilibrium

Answer 16

1) Gene Flow: it is the slow movement of genes between populations. It is the process by which genes diffuse into a foreign population over time. For example, the CCR5 allele that confers protection against AIDS infection appears to be of celtic origin, yet it is currently prevalent among a wider array of Northwestern Europe populations and remains virtually absent among Africans.
2) Genetic Drift: Involved chance changes with the environment favoring a genetically defined subpopulation. Such as a hurricane wiping out a large set of the population leaving a higher number of mutants that then throw off the allele frequency now in this population making it much higher.
3) Founder Effect: Occurs when a small subpopulation with a different allele distribution breaks away from the general population.

Question 17

Define Fitness (f) and its relation to new mutation frequency.

Answer 17

In dominant disease, the fitness (f) of diseased individuals (or their ability to procreate) is generally less than 1. For a population in equilibrium, the new mutation rate (u) is u=sq with selection coefficient (a measure of selection against the mutant allele) s=1-f.

Example: achondroplasia patients have 20% fitness, s=0.8 and 80% of mutant alleles are due to mew mutations.

At f=0 the disorder is genetically lethal. Here, new mutations affect genotype frequencies directly; selection removes the mutant alleles in a single generation. Such diseases almost always arise as new mutations.

Question 18

Balanced Polymorphism

Answer 18

It is when forces exist to remove affected alleles from the population as well as to maintain them.

Question 19

Heterozygote Advantage

Answer 19

It is where the heterozygote favors viability over the homozygotes. A classic example is heterozygosity for sickle cell anemia which offers protection from malaria when compared to the homozygote.

Question 20

Describe the meaning and usage of ancestry information markers (AIMS)

Answer 20

They are used to show the relationship among different ethnic groups. African Americans and European Americans are very similar because they have common ancestors where as hispanic americans are not as similar because they come from many different origins. They can be useful when hardy-weinberg can’t be used as accurately due to other forces acting on the genes. AIMS is looking for markers that associate with different populations. They can show what groups other ethnic groups are most closely related to.