Discovery of Human Disease Genes

Question 1

Definition of monogenic disease

Answer 1

Mutation in 1 gene that is both necessary and sufficient to produce the clinical phenotype

Question 2

Definition of positional cloning

Answer 2

Used to locate the position of a disease associated gene on the chromosome

Question 3

Definition of cosegregation

Answer 3

Transmission of 2 or more linked genes on a chromosome to the same daughter cell leading to the inheritance by the offspring of these genes together

Question 4

Definition of recombination

Answer 4

2 chromosomes of a homologous pair exchange segments

Question 5

Definition of genetic linkage

Answer 5

DNA regions that are in close proximity are more likely to be coinherited

Question 6

Definition of non penetrance

Answer 6

Have the genotype associated with the disease but is not present in the phenotype

Question 7

Definition of phenocopies

Answer 7

Have the phenotype associated with the disease but do not have the genotype normally associated with the disease

Question 8

Definition of genetic heterogeneity

Answer 8

Mutations at 2+ loci that produce same/similar phenotypes

Question 9

Describe the spectrum of genetic disease

Answer 9

Most disease states and traits result from a combination of genetic and environmental factors

Question 10

What are the 2 key properties of monogenetic diseases

Answer 10

Mutation in 1 gene
-necessary and sufficient to produce clinical phenotype

Transmission seen in pedigrees (recessive/dominant)

Question 11

Why identify disease causing genes

5 reasons

Answer 11

• Molecular confirmation of clinical diagnosis
• Accurate carrier testing for individuals/couples
• Presymptomatic testing for adult onset conditions (HD)
• Prenatal diagnosis for pregnancies at high risk of a severe disorder
• Understand pathological mechanisms

Question 12

What is positional cloning

What are the 3 steps involved in this

Answer 12

Used to locate the position of a disease associated gene on the chromosome

Identification of multigenerational affected pedigree
Systematic evaluation of inheritance patterns across the genome
Mutational search within genomic areas cosegregating with disease

Question 13

Name the 3 monogenic inheritance patterns

Answer 13

Autosomal dominant
Autosomal recessive
X linked recessive

Question 14

What are the main properties of autosomal dominant diseases

• how many alleles are affected
• mode of transmission
• male to female ratios
• is transmission of disease from an unaffected individual possible

Answer 14

• Mutation in 1 allele => disease
• Vertical transmission
• Male : Female ratio affected is equal
• Male => male transmission possible
• Unaffected individuals => unaffected offspring unless mutation is spontaneous

Question 15

What are the main properties of autosomal recessive diseases

• how many alleles are affected
• male to female ratio

Answer 15

• Mutations in both alleles => disease
• Parents are carriers
• Male : Female ratio affected is equal
• Consanguinity may be present

Question 16

What are the main properties of X linked recessive
diseases

• how many mutated alleles are needed to be shown in the phenotype in both genders
• male to female ratio
• male => male transmission

Answer 16

• Mutation in 1 allele => diseased male
• Mutation in both alleles => diseased female
• Mutation in 1 allele in females => carrier
• Male : Female ratio is higher
• No male => male transmission

Question 17

What is recombination

What is genetic linkage

Answer 17

2 chromosomes of a homologous pair exchange segments

Recombination can occur at any location along the chromosome
DNA regions that are in close proximity are more likely to be coinherited

Question 18

How would you map genes with linkage relationships

Answer 18

Consider a series of variable loci across the genome and see if they are linked to the mutation locus

The higher the frequency of 2 alleles inherited together, the closer they are to each other

Question 19

How would you calculate the statistical likelihood for linkage
What can the LOD score tell you

Answer 19

LOD10 = log10 L(linkage)/L(no linkage)

LOD score >3 => linkage
LOD score linkage excluded

Question 20

How would you use the info found in linkage relationships

3 ways

Answer 20

• Identify genes within linkage intervals
• Assess genes as potential candidates based on biological functions
• Sequence genes in affected to identify causative mutations

Question 21

What are the 3 confounders in linkage analysis

Answer 21

Non penetrance
-Have genotype associated with disease but not present in phenotype

Phenocopies
-Have the phenotype associated with disease but don’t have the genotype normally associated with the disease

If the no of people in a pedigree is too small, LOD scores from many pedigrees can be added together but can lead to confounders due to genetic heterogeneity

Question 22

What can you do when the no people in a pedigree is too small in a linkage analysis

Answer 22

LOD scores from many pedigrees can be added together

Question 23

What are the uses of DNA and exome sequencing

Why is this possible

Answer 23

Both are more affordable

-leads to personalised care and identification of disease causing genes

Question 24

What are the 2 main uses of exomes

Answer 24

Causative mutations in monogenetic diseases found in exomes

Can catalogue all protein altering variation in an individual

Question 25

How would you use exomes to compare unrelated individuals to identify variants that cause disease

Answer 25

Take a small no of unrelated individuals with the same disease

Find the no of genes that they have in common

Eventually will isolate the 1 true mutation

Question 26

How would you analyse the true mutation from exome sequencing

Answer 26

The region containing the true mutation is sequenced, can identify what part => disease

Question 27

What are the pros and cons of exome sequencing in monogenetic diseases

Answer 27

Pros
-not reliant on ascertainmnet of large pedigrees

Cons
-major confounder = genetic heterogeneity