WEEK 3 (STUDY GROUP)

Question 1

Locus

Answer 1

position of an allele on a chromosome

Question 2

Allele

Answer 2

variant DNA sites at a particular locus

Question 3

Hemizygous

Answer 3

only one allele because only one chromosome (e.g. X in males, deletions)

Question 4

Mendel’s three laws

Answer 4

1. Segregation
2. Independent Assortment
3. Dominance

Question 5

Law of segregation

Answer 5

Equal probability that an allele will be transmitted to offspring

Question 6

Law of independent assortment

Answer 6

Transmission of alleles at different loci is independent (linked genes an exception)

Question 7

Law of dominance

Answer 7

A dominant allele completely masks the effect of a recessive allele

Question 8

First degree relative

Answer 8

parents, siblings, children

Question 9

Second degree relative

Answer 9

shares a quarter of genes (grandparents, aunts/uncles, nephews/nieces, grandchildren)

Question 10

Third degree relative

Answer 10

cousins, great-grandparents, great-grandchildren

Question 11

Genotype

Answer 11

alleles present at one or more loci

Question 12

Phenotype

Answer 12

clinical, biochemical, physiological, or morphological characteristics of an individual

Question 13

Phenocopy

Answer 13

presence of a particular phenotype, NOT due to the same inherited genotype

Question 14

Penetrance

Answer 14

proportion of individuals with a genotype that exhibit disease phenotype

Question 15

Variable expressivity

Answer 15

individuals with disease-associated allele are all affected, although with variable clinical presentation (e.g. age of onset, severity)

Question 16

Autosomes

Answer 16

Non-sex chromosomes, 44 (22 from mother, 22 from father)

Question 17

Autosomal dominant inheritance

Answer 17

a dominant allele completely masks the effect of a recessive allele

Question 18

Autosomal dominant pedigrees x3

Answer 18

1. every generation has affected individuals
2. unaffected family do not transmit phenotype to their children
3. males and femals BOTH affected and BOTH sexes transmit disorder

(with exceptions)

Question 19

Exceptions to autosomal dominant rules x2

Answer 19

1. De novo variants

2. incomplete penetrance (skip generations)

Question 20

Recurrence risk x3

Answer 20

1. likelihood of two individuals having an affected child.
2. Independent for each pregnancy
3. Differs by sex for x-linked disorders

Question 21

Genetic fitness

Answer 21

probability of an individual transmitting their genetic material to the next generation compared to the average probability of the population (e.g. lethality in early age = 0 vs. no effect on reproduction until old age = 1)

Question 22

Autosomal recessive inheritance

Answer 22

disease only manifests when disease-associated alleles are present on BOTH chromosomes

Question 23

Autosomal recessive pedigrees x4

Answer 23

1. typically occurs in single generation
2. parents are asymptomatic carriers
3. males and females both affected
4. alleles tend to be rare in populations*

Question 24

Compound heterozygosity

Answer 24

two different disease-associated alleles in the same gene maternally AND paternally inherited (e.g. both parents heterozygote)

Question 25

Consanguinity consequences x2

Answer 25

increased likelihood to
1. have rare variants that are recessive

2. to inherit same disease-associated allele from both parents

Question 26

Founder effects

Answer 26

increase likelihood to inherit same disease-associated allele from both parents due to reproductive isolation of population (e.g. islands)

Question 27

Selective advantage

Answer 27

variant that causes a recessive disease in homozygous state can be maintained in population at high levels if heterozygous state offers some benefit (e.g. sickle cell, CF)

Question 28

Nettie Stevens

Answer 28

discovered sex chromosomes. NOT Thomas Hunt Morgan

Question 29

X vs. Y gene content

Answer 29

~900 vs. 55 genes (important for male sex determination/characteristics)

Question 30

X-inactivation

Answer 30

dosage compensation due to increase in gene-rich X. Clonal process (i.e. every daughter cell will have same X inactivated)

Question 31

X-linked dominant pedigrees x3

Answer 31

1. Looks similar to autosomal dominant, every generation has affected individuals BUT
2. affected males DON’T have affected sons
3. ALL daughters of affected mails are affected

Question 32

Male lethality pedigree

Answer 32

due to lack of X-inactivation in males. Only affected females, multiple miscarriages.

Question 33

X-linked recessive pedigrees x4

Answer 33

1. generally, females not affected
2. allele is never transmitted directly from father to son, but allele transmitted to all daughters
3. allele transmitted through multiple carrier females
4. isolated cases often due to de novo variants

Question 34

Exception to Mendel’s 2nd law (Independent Assortment)

Answer 34

Linked genes. Due to recombination in meiosis, genetic material closer together is more likely to be inherited together.

Question 35

Massively parallel DNA sequencing (NGS)

Answer 35

probes designed complementary to exonic coding regions, aligned using reference genome.

Question 36

Gene panel

Answer 36

probes designed to specific genes known to be implicated in a particular disease

Question 37

Exome seuqencing

Answer 37

All known genes in genome are sequenced, broadly applicable to all genetic disorders

Question 38

Full genome sequencing

Answer 38

ALL regions, including introns. For SNVs (single nucleotide variants), indels, structural variants, STRs (short tandem repeats)

Question 39

Heritability

Answer 39

proportion of variability in a trait caused by genetic factors

Question 40

Equation for heritability

Answer 40

H^2 = Vg / (Vg + Ve);; Vg is variance due to genetics and Ve is due to environment

Question 41

Method used to traditionally calculate heritability

Answer 41

Twin studies – phenotypic concordance among identical (MZ) twins is compared to concordance among non-identical (DZ twins). Because they share the ‘same environment’ the difference in phenotype is attributed to genetics

Question 42

What is additivity

Answer 42

Additivity is where many variants each individually contribute to overall trait variation

Question 43

Threshold model

Answer 43

Threshold model: an individual has disease if the collective effects of each additive allele, along with the environmental component, cross a certain ‘threshold’

Question 44

Quantitative trait

Answer 44

Quantitative trait: genetics and environment both contribute additively to a continuous measure (e.g. height, LDL, blood pressure, etc.)

Question 45

How is recurrence risk calculated

Answer 45

By comparing distribution of a quantitative trait among general population to affected family members, we can estimate where this threshold is and calculate recurrence risk

Question 46

How does Genome Wide Assoc. Study work and its goal?

Answer 46

Compares cases (eg. people who have heart disease) to control (eg. people who don’t have heart disease) and compare their allele frequency to see if they are associated with certain diseases.

Question 47

What is polygenic risk score

Answer 47

estimate of disease risk calculated from genotypes at many different GWAS-derived risk loci

Question 48

Duchene muscular dystrophy – what type of disease? What gene?

Answer 48

X linked recessive disorder; genotype phenotype correlation. Variant in DMD which codes for dystrophin (needed in muscles). Out of frame variant = severe disease. In frame (eg. missense) = mild disease (Becker muscular dystrophy). Females at increased risk of dilated cardiomyopathy – an eg of how females can be lowkey affected even as a carrier in a recessive x linked disease.

Question 49

X linked dominant

Answer 49

X-linked dominant disorders are caused by mutations in genes on the X chromosome, one of the two sex chromosomes in each cell. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).

Question 50

X linked recessive

Answer 50

X-linked recessive disorders are also caused by mutations in genes on the X chromosome. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission). Affected males –> Affected daughters.

Question 51

Alport syndrome – what type of disease? What gene?

Answer 51

X linked dominant. Variant in COL4A5 which affects collagen fibers. Genotype phenotype correlation – truncating (frameshift, deletion, premature stop) is more severe than missense, dominant negative.

Question 52

Oral facial digital syndrome type I

Answer 52

X linked dominant. Variant in OFD 1. Male lethality during development, so only females affected mostly. (except disproved– case study on some males were born w it because of in frame variant)

Question 53

PCDH assoc. epilepsy

Answer 53

Female restricted disorder, males are carriers. Those without mutation can create protocadherin and communicate; males with carrier don’t make the protein but can still communicate; female carriers have a mix of normal protocadherin and mutated version, so cells can’t communicate.

Question 54

Example of x inactivation escape artists?

Answer 54

Cdls (cornelia de lange) and SMCI A assoc epilepsy

Question 55

46, XY disorder of sex development

Answer 55

Y linked disorder, SRY gene depleted so patients have XY chromosome but are female presenting

Question 56

Why are clinical features typically more severe in males than females who carry a pathogenic variant in a gene
associated with X-linked dominant inheritance?

Answer 56

Males have only one X chromosome while females have two. In general, random X chromosome inactivation
predicts that 50% of the female’s cell’s will express the unaltered allele and generate functional protein.

Question 57

What is gene dosage?

Answer 57

Refers to the number of copies of a particular gene, of particular importance for the X chromosome as females
have two copies of the X chromosome to males 1.

Question 58

3. Why is the usefulness of the terms ‘dominant’ and ‘recessive’ debatable for X-linked disorders?

Answer 58

A significant proportion (if not majority) of females that carry X-linked pathogenic variants have some features of
the disorder, though they are normally much milder, or may only present a subset of the features.

Question 59

4. What is skewed X-inactivation?

Answer 59

Skewed X-inactivation can occur when the one X-chromosome is preferentially inactivated, This can happen if
there is a cell survival or proliferative disadvantage for those cells expressing the X chromosome with the altered
allele. Thus, it is a common for female carrier to show skewed X-inactivation (the pathogenic variant is
preferentially inactivated) for certain disorders including immunodeficiencies and intellectual disabilities.

Question 60

5. Why are there so many more genes associated with disease that occur on the X chromosome and compared to the
   Y?

Answer 60

The X chromosome has ~900 genes to the Y chromosomes ~55.