L26 Genetics of Complex Diseases

Question 1

What is a polygenetic disease?

Answer 1

A disease caused by two or more genes

Question 2

What is a multifactorial disease?

Answer 2

A disease caused by genetics and environmental factors

Question 3

What is being defined here: ‘The inheritance and expression of a phenotype being determined by the cumulative action of multiple genes at multiple loci.’

Answer 3

A polygenetic disease.

I thought this was multifactorial disease…?

Question 4

True or false: Genes involved with multifactorial disease are viewed as being dominant or recessive to each other.

Answer 4

False.

Because each involved gene contributes to the final phenotype and environmental factors also play a role, the multiple genes in multifactorial disease are not viewed as being dominant or recessive to each other.

Question 5

True or false: Genes that contribute to multifactorial diseases segregate in a Mandelian manner, but the phenotype they produce does not.

Answer 5

True

Question 6

Monogenetic or polygenetic:

Has a single strong, highly penetrant phenotype.

Answer 6

Monogenetic

Question 7

Monogenetic or polygenetic:

Very common.

Answer 7

Polygenetic

Question 8

Monogenetic or polygenetic:

Has less penetrant phenotypes

Answer 8

Polygenetic

Question 9

Monogenetic or polygenetic:

Not dominated by one gene, though a gene could increase susceptibility.

Answer 9

Polygenetic

Question 10

Monogenetic or polygenetic:

Dominated by one gene, but expression of this gene is regulated by modifier genes that affect the severity of the phenotype.

Answer 10

Monogenetic

Question 11

What is ‘penetrance’, with relation to genetics?

Answer 11

Penetrance is the fraction of cases carrying a given gene that manifests in a specified phenotype

Single gene disorders are fully penetrant; multifactorial disorders have a low penetrance.

Question 12

Monogenetic or polygenetic:

Hypertension, obesity, schizophrenia, Alzheimer’s , asthma, diabetes mellitus, MS, coronary artery disease, Crohn’s disease, autism, cancer, migraine, arthritis

Answer 12

Polygenetic

Question 13

Why is it important to study the genetics of multifactorial disease?

Answer 13

• Identify individuals with an increased risk of disease
• Identify targets for better therapy
• Untangle complexity of gene-environment interactions
• Multifactorial disease affects 60% of the population

Question 14

What is ‘liability threshold’ when referring to genetic disease?

Answer 14

Some diseases seem to be polygenic, but do not show the typical bell-shaped distribution with its associated severity of disease. Instead, disease symptoms seem to be related to a liability threshold within a distribution that must be passed before the disease is expressed.

Question 15

How is heritability quantified?

Answer 15

A number between 0 and 1.

0 = no genetic influence

1 = high genetic influence

High heritability does not mean the phenotype is solely determined by genetics - environment may still have an effect.

Question 16

True or false: Dizygotic twins are genetically identical.

Answer 16

False. Dizygotic twins share roughly 50% of their genes.

Monozygotic twins are genetically identical.

Question 17

Twins are often studied as part of concordance studies. What is concordance?

Answer 17

Probability (%) that twins (identical or non-identical) will both have the disease, given that one of the pair has the disease.

Question 18

How are concordance studies used to estimate the heritability of a disease?

Answer 18

Difference between the % concordance in dizygotic twins versus monozygotic twins = estimate of heritability

Question 19

Define ‘allele’.

Answer 19

One of a number of alternative forms of the same gene.

Question 20

What are SNPs?

Answer 20

Single nucleotide polymorphisms

DNA sequence variations that occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered at the same genetic location between different chromosomes (either within an individual or between individuals)

Question 21

To be considered a SNP, the variation must occur in what percent of the population?

Answer 21

More than 1%

Question 22

SNPs are responsible for what percentage of human genetic variation?

Answer 22

~90%

Question 23

True or false: Most SNPs have no effect on protein function.

Answer 23

True.

Question 24

Why are SNPs useful in genetic research?

Answer 24

SNPs can act as biological markers that help us identify genes associated with disease.

They can be used to map haplotypes.

Question 25

Define ‘haplotypes’.

Answer 25

Disease-linked genomic loci that are physically linked on a chromosome and segregate together.

Question 26

What is GWAS?

Answer 26

Genome-wide association study.

Compare patient DNA to non-patient DNA to identify disease-specific SNPs.

Question 27

True or false: Chromosomal disorders are usually de novo, but can be inherited.

Answer 27

True

Question 28

Trisomies, deletions, duplications, translocations are all types of what kind of disorder?

Answer 28

Chromosomal disorders

Question 29

What term is being defined:

‘presence of an abnormal number of chromosomes in a cell’

Answer 29

Aneuploidy

Humans should have 46 chromosomes

Question 30

Triple X syndrome is an example of chromosome aneuploidy. What is it?

Answer 30

Additional sex chromosome

47 chromosomes

XXX

Affects 1 in 1000

Question 31

Klinefelter syndrome is an example of chromosome aneuploidy. What is it?

Answer 31

Additional sex chromosome

47 chromosomes

XXY

Affects 1 in 1000

Question 32

XYY syndrome is an example of chromosome aneuploidy. What is it?

Answer 32

Additional sex chromosome

47 chromosomes

XYY

Affects 1 in 1000

Question 33

Turner syndrome is an example of chromosome aneuploidy. What is it?

Answer 33

Missing sex chromosome

45 chromosomes

Xo

Affects 1 in 2000-5000

Question 34

Why is chromosome aneuploidy almost always deleterious (harmful)?

Answer 34

Because it results in genetic imbalance, interfering with normal genome function.

Question 35

What are autosomal chromosomes?

Answer 35

Non-sex chromosomes

22 pairs of autosomal chromosomes

Question 36

What is trisomy-21?

Answer 36

Down’s syndrome

Affects 1 in 800-1000

Question 37

What is trisomy-18?

Answer 37

Edward syndrome

Affects 1 in 6000

Question 38

What is trisomy-13?

Answer 38

Patau syndrome

Affects 1 in 10,000

Question 39

What is DiGeorge syndrome?

Answer 39

Chromosome deletion.

Deletion of band 11.2 on long arm of chr 22.

~3 Mb deleted, containing ~45 genes

Prevalence: 1:4000
Risk: 0.025% in population

Cardiac defects, facial dysmorphia, thymic aplasia, cleft palate, hypocalcaemia, learning difficulties, T-cell immunodeficiency

Question 40

What is meiotic nondisjunction?

Answer 40

During gamete formation the chromosomes should split and give a chromatid to each daughter.

nondisjunction is failure of chromatids to separate during meiotic division. Results in a gamete with 2 chromatids and a gamete with none. Leads to trisomy and monosomy diseases, such as Down’s syndrome (trisomy-21)