Lecture 49. Human Genetics - Pedigree Analysis

Question 1

What are the two types of genetic disease variation?

Answer 1

Simple Mendelian
Complex or multifactorial

Question 2

What are simple Mendelian diseases?

Answer 2

Tractable/Easy to investigate
Single gene mutation associated with disease
Disease due to a typically rare allele in the population ( 1 in >2000 individuals)
Readily defined pattern of inheritance

Question 3

What are some examples of simple Mendelian diseases?

Answer 3

Huntington’s disease, cystic fibrosis, Duchenne muscular dystrophy, BRCA1 breast cancer

Question 4

What are complex diseases?

Answer 4

Difficult to investigate
Allelic variation in multiple genes associated with disease
Cumulative affect of weakly expressed common alleles
Disease risk is typically influenced by non-genetic factors (environment, life-style and age)

Question 5

What are examples of complex diseases?

Answer 5

Various cancers, heart-related diseases, irritable bowel diseases, diabetes, Parkinsons, Alzheimers

Question 6

What is pedigree analysis?

Answer 6

Use of a diagram to summarise the inheritance of discrete trait (phenotype) in a family history

Question 7

What shape represents females in a pedigree chart?

Answer 7

Circle

Question 8

What shape represents males in a pedigree chart?

Answer 8

Square

Question 9

What shape represents an unknown sex in a pedigree chart?

Answer 9

Diamond

Question 10

What does a double line in a pedigree chart mean?

Answer 10

Mating between relatives

Question 11

What does a black oval mean in a pedigree chart?

Answer 11

Stillbirth or spontaneous abortion

Question 12

What represents generations in a pedigree chart?

Answer 12

Roman numerals

Question 13

Why do pedigree analysis?

Answer 13

Knowledge about simple ‘Mendelian’ traits
Ethical limits: controlled matings are not possible

Question 14

What are the limitations in a pedigree diagram?

Answer 14

Sampling: small family sizes per generation
Inaccurate & incomplete data: e.g false information about parentage or missing clinical records or phenotype data
Demographics: migration & intermating

Question 15

What are the aims of pedigree analysis?

Answer 15

Determine the mode of inheritance (sex-linked/autosomal or dominant/recessive)
Calculate the probability of an affected individual based on recent family history (e.g for genetic counselling)

Question 16

What is autosomal recessive inheritance?

Answer 16

If d denotes a disease allele, then dd denotes genotypes that are affected by the disease, whereas DD and Dd are disease-free
Disease will typically not occur in every generation
Affected individuals can be born to unaffected parents
Males and females equally affected

Question 17

What are two examples of autosomal recessive diseases?

Answer 17

Cystic fibrosis and Tay-Sachs disease

Question 18

What is autosomal dominant inheritance?

Answer 18

If D denotes a disease allele, then dd denotes genotypes that are disease free
In most cases DD will be lethal, so all diseased individuals will be heterozygous Dd
Disease will be found in every generation every affected individual has an affected parent
Males and females equally affected

Question 19

What are three examples of autosomal dominant diseases?

Answer 19

Huntington’s disease, hereditary retinoblastoma and achondroplasia

Question 20

What are examples of X chromosome sex-linked recessive diseases?

Answer 20

Haemophilia, red-green vision deficiency, Christianson syndrome, fragile X syndrome and Duchenne muscular dsytropy

Question 21

What are examples of Y chromosome sex-linked recessive diseases?

Answer 21

Y chromosome infertility and Swyer syndrome

Question 22

If a female carrier of an X-linked recessive inheritance disease and a normal male bred, what phenotypes would there offspring be?

Answer 22

Half of the males and females would be normal, half the daughters would be carriers and half the sons would be affected

Question 23

If an affected male of an X-linked recessive inheritance disease and a normal female bred, what phenotypes would there offspring be?

Answer 23

All the daughters will be carriers and none of the sons will be affected

Question 24

What are examples of X chromosome sex-linked dominant diseases?

Answer 24

Incontinentia pigmenti, Charcot-Marie tooth neuropathy, Coffin-Lowry syndrome and Hypophosphatemic rickets

Question 25

What are examples of Y chromosome sex-linked dominant diseases?

Answer 25

Unknown

Question 26

If an affected male of an X-linked dominant inheritance disease and a normal female bred, what phenotypes would there offspring be?

Answer 26

All the daughters will be affected and none of the sons will be affected

Question 27

If an affected female of an X-linked dominant inheritance disease and a normal male bred, what phenotypes would there offspring be?

Answer 27

Half of the males and females would be normal whilst the other half of both the males and females would be affected

Question 28

What can be ruled out if two affected parents have unaffected children?

Answer 28

Recessiveness (True for both autosomal and sex-linked traits)

Question 29

What can be rules out if unaffected parents have an affected child?

Answer 29

Dominance (True for both autosomal and sex-linked traits)

Question 30

What can be ruled out if unaffected parents have an affected daughter?

Answer 30

Dominance and X-linked recessive

Question 31

What can be ruled out if an affected woman has an unaffected son, OR an unaffected man has an affected daughter?

Answer 31

X-linked recessive

Question 32

What can be ruled out if an unaffected woman has an affected son, OR an affected man has an unaffected daughter?

Answer 32

X-linked dominance

Question 33

If a woman’s brother has died from Tay Sach’s Disease (autosomal recessive, lethal), but she is unaffected, what are the chances that she is a carrier?

Answer 33

2/3

Question 34

Assuming your Grandfather A is a carrier of an allele for a rare autosomal recessive disease, what’s the chance that YOU are also a carrier of this allele?

Answer 34

25%

Question 35

Name two molecular markers?

Answer 35

SSR and SNP

Question 36

What is SSR?

Answer 36

Simple Sequence Repeats
Microsatellites (2-4 basepair repeats)
Minisatellites (variable number tandem repeats or short tandem repeats)

Question 37

What is SNP?

Answer 37

Single Nucleotide Polymorphisms

Question 38

In SSR what do more sequence repeats equal?

Answer 38

Bigger PCR product

Question 39

In SSR what do fewer sequence repeats equal?

Answer 39

Smaller PCR product

Question 40

How does linkage mapping in SSRs take place?

Answer 40

1. Collect pedigree information from a family with history of a genetic disease, and also blood samples for DNA from living family members
2. Use PCR and gel electrophoresis to determine genotype of family members for several hundred SSR loci distributed throughout the genome (many on each chromosome)
3. Use statistical linkage analysis to identify SSRs that are linked (low recombination) to inheritance of the disease allele (defining a mapping interval or locus)
4. Identify new molecular markers from within the locus, and repeat the linkage analysis with additional families to resolve a narrower map interval