Lecture 2: Genetic Analysis in Humans

Question 1

What are the 5 main problems with carrying out genetic analysis in humans?

Answer 1

1. Cant do controlled matings
2. few progeny
3. long generation time
4. Few useful single gene variants
5. Analysis needs to be based on pedigrees (family trees)

Question 2

What is the consultand?

Answer 2

The person who comes tot he clinician and provides the information about themselves and their family in order to construct a pedigree

Question 3

How many generations are usually sufficient to build a pedigree and determine if any inheritance is occurring?

Answer 3

4

Question 4

What is typically seen in a pedigree when the mode of inheritance is autosomal dominant?

Answer 4

an affected individual is present in every generation

Question 5

What are three examples of autosomal dominant conditions?

Answer 5

Huntington’s disease
Familial Hypercholesterolaemia
Marfan Syndrome

Question 6

Why are autosomal dominant conditions less common in a population?

Answer 6

These conditions are often more deadly and will kill you resulting in the loss of the disease allele from a population

Question 7

What is typically seen in a pedigree when the mode of inheritance is autosomal recessive?

Answer 7

There isn’t an affected individual in every generation (but may see more in consanguinous relationships)

Question 8

What are three examples of autosomal recessive conditions?

Answer 8

Cystic Fibrosis
Sickle Cell Anaemia
Albinism

Question 9

If the consultand is the only affected individual in the pedigree, what mode of inheritance does this suggest? what might it also be?

Answer 9

mode of inheritance could be autosomal recessive

could also be spontaneous de novo mutation or developmental (i.e. not genetic/inherited)

Question 10

True or false: consanguinous relationships increase the frequency of recessive disorders?

Answer 10

True

Question 11

What would you expect to see in a pedigree for an X-linked recessive mode of inheritance?

Answer 11

affected males that skips generations

Question 12

What can be determined about carrier status from X-linked recessive pedigree?

Answer 12

Can determine obligate female carriers (all females in generations above the affected male must be carriers)

Question 13

What are manifesting carriers and how does this come about?

Answer 13

Manifesting carriers are females that are affected by an X-linked recessive condition.

Comes about due to random X-inactivation resulting dominant allele on other chromosome not being expressed so traits of the X-linked condition can be seen.

Question 14

Other than inherited single gene causing disorders, what may be other causes of disorders? (4)

Answer 14

• Chromosomal defect (rearrangement or aneuploidy)
• Not inherited (random/spontaneous mutation)
• Multifactorial (several genes)
• Mitochondrial

Question 15

True or false: mitochondria are inherited via the paternal line?

Answer 15

False: maternal inheritance

Question 16

What would you expect to see in a pedigree showing mitochondrial inheritance?

Answer 16

Mother affected and all mother’s children also affected as maternal inheritance

Question 17

What is heteroplasmy in mitochondria?

Answer 17

When an individual has two or more types of mitochondrial DNA. The assortment of cellular mitochondrial assortment into new cells during mitosis and meiosis is semi-random. Therefore some cells may have more of one type of mtDNA than another.

Question 18

How can heteroplasmy result in variable expression of mitochondrial disease?

Answer 18

If a cells contains a population of mutated and non-mutated mtDNA, semi-random assortment during cell division result in cells which may have predominantly normal mitochondria or mutated mitochondria

Question 19

Why can mitochondrial diseases be more harmful to males?

Answer 19

If a mitochondrial DNA mutation causes more harm to males but not females (neutral to females), since the mitochondria are inherited through the female line, this will not be selected out as females unaffected.

Question 20

Define penetrance

Answer 20

The proportion of people with the relevant genotype that show the phenotype/characteristic

Full penetrance = all people with genotype show phenotype

Question 21

Define expressivity

Answer 21

the degree to which an individual with the relevant genotype displays the characteristics of a condition

Question 22

If autosomal dominant inheritance is believed to be the mode of inheritance based on the pedigree but the parent of an affected individual is apparently unaffected, what could be the cause of this?

Answer 22

• not real parent (adoption)
  or
• parent has disease allele but unaffected due to reduced penetrance

Question 23

What can cause variable expressivity of disease?

Answer 23

• environmental influences (E.g. multiple sclerosis worsened by viral infection)
• presence of modifier alleles in genome

Question 24

What is the LOD score (z)

Answer 24

Log odds
- measures the likelihood that a disease gene and a molecular marker (VNTR/STR microsatellites) are linked (i.e. they are sufficiently close together that their recombination frequency is less than 0.5

Question 25

what does a LOD score (z) >3 mean?

Answer 25

likely that the disease gene and molecular marker are linked

Question 26

what does a LOD score (z) < -2 mean?

Answer 26

Unlikely that disease gene and molecular marker are linked

Question 27

How can LOD scores be used to map the locus of a disease gene?

Answer 27

Multiple molecular markers used on a particular chromosome, as the marker gets closer to the locus of the disease gene, the LOD score will increase and then begin to decrease as you move away from the locus.

Question 28

How is haplotype analysis used in gene mapping?

Answer 28

Take a number of affected individuals and identify haplotypes/markers that are associated with the disease gene using LOD scores.
By looking at overlapping haplotypes across a range of affected people you can narrow down the region/distance of the disease gene even further and identify the candidate genes within this region (sequenced to identify mutations)

Question 29

How do we know that a genetic change is responsible for the disease? (3)

Answer 29

Mutation is likely to have strong effects on the protein (nonsense, frameshift causing extensive missense, string missense, splice site mutations, deletions removing all or part of coding sequence)

Unrelated individuals with the same condition have mutations within the same gene

Mutations are not found in unaffected/non-carrier individuals