Module B: Mendelian Genetics

Question 1

What are the four forms of monogenic inheritance?

Answer 1

autosomal dominant

autosomal recessive

X-linked

mitochondrial

Question 2

Other than monogenic inheritance, what are two other forms of inheritance?

Answer 2

chromosomal

multifactorial

Question 3

What is haploinsufficiency? (2)

Answer 3

one allele has mutation leading to decreased expression (i.e. quantity) of protein

phenotype occurs because homeostasis is intolerant of decrease in that gene product

Question 4

Gain-of-function mutations are typically attributed to what form of inheritance?

Answer 4

autosomal dominant

Question 5

Loss-of-function mutations are typically attributed to what form of inheritance?

Answer 5

autosomal recessive

Question 6

Describe “loss-of-function” mutations in the context of autosomal recessive inheritance. (3)

Answer 6

most enzyme deficiencies do not manifest deleterious phenotype unless enzyme activity is <10% of normal

heterozygotes have 50% of normal activity and are asymptomatic

homozygotes have near 0% activity

Question 7

Describe the relationship between X-linked recessive inheritance in females and X-inactivation. (2)

Answer 7

1 of the 2 X chromosomes is inactivated

in daughters inheriting mutant allele, 50% of cells will inactivate mutant chromosome and express normal, and 50% will do vice versa

Question 8

List the characteristics of mitochondrial inheritance. (4)

Answer 8

vertical inheritance pattern

children of affected men not affected

all children of affected women affected, but to varying degrees

tends to affect tissues most dependent on oxidative metabolism (brain, muscle, etc.)

Question 9

In the context of mitochondrial inheritance, what is heteroplasmy?

Answer 9

affected individuals in mitochondrial inheritance have a mixture of mutant and normal mitochondria, which is responsible for variable expressivity observed in mitochondrial inheritance

Question 10

What is incomplete penetrance? Give two examples.

Answer 10

fraction of people with genotype of interest who show some manifestation of the genotype

100% penetrance = everyone who inherits the mutation gets the disease

50% (incomplete) penetrance = half of those with the mutation get the disease

Question 11

Give an example of a disease for which penetrance is age-dependent.

Answer 11

Huntington’s disease

Question 12

Define mosaicism.

Answer 12

presence of cells with different genetic makeups in a single individual

Question 13

Define gonadal mosaicism. (2)

Answer 13

mutation occurs in gamete-producing (usually sperm) cell

causes unaffected individual to have children with an autosomal dominant disorder, giving appearance of recessive inheritance

Question 14

How would an autosomal dominant disease arise in a child with no family history of that disease?

Answer 14

may result from new mutation that arises in parental germ cell

Question 15

Are point mutations more common in male or female germ cells?

Answer 15

far more common in male germ cells

Question 16

What is the most common point mutation?

Answer 16

C to T change at CG dinucleotide in DNA strand

Question 17

CG dinucleotides are sites for

Answer 17

cytosine methylation

Question 18

Deamination of methylcytosine yields

Answer 18

thymine

Question 19

What is a copy number mutation?

Answer 19

variation in number of copies of genes is much greater than previously thought

Question 20

How do copy number mutations occur? (2)

Answer 20

when regions of DNA with similar sequences next to each other on a chromosome (i.e. long tandem repeats) mispair during meiosis

crossover then causes duplication of gene on chromosome and deletion on other chromosome

Question 21

Describe the basis of red green colorblindness in the context of copy number mutations. (4)

Answer 21

red light and green light genes located next to each other on X chromosome

very similar in sequence

if red gene accidentally pairs with green gene, then crossover occurs

one chromosome w/ 3 color vision genes, other w/ only 1

Question 22

Copy number variants are most commonly detected by

Answer 22

CMA

Question 23

What are triplet repeat expansions? What is their genetic significance? (2)

Answer 23

genes containing segments of repeated trinucleotides

genes with larger numbers of repeats may be unstable during DNA replication in meiosis, leading to expansion of the repeated segment

Question 24

Describe the relationship between triplet repeat expansions and the number of repeats. (2)

Answer 24

if the number of repeats exceeds a threshold number → nonfunctional gene → disorder

if increased number of repeats but under threshold → risk for further expansion, but asymptomatic → “premutation”

Question 25

Most of the known disorders associated with triplet repeat expansions belong to what grouping of disorders?

Answer 25

neurologic disorders

Question 26

Define anticipation.

Answer 26

autosomal dominant disorders become more severe or manifest earlier or both as it is passed down through generations

Question 27

What is a possible reason for anticipation?

Answer 27

ascertainment bias = children with more severe phenotypes are more likely to come to medical attention, leading to discovery of mildly affected parent

Question 28

Describe the relationship between triplet repeat expansion and anticipation.

Answer 28

disorders from triplet repeat expansion may show anticipation if expansion of repeat causes more severe phenotype

Question 29

(T/F) Anticipation and triplet repeat expansion are independent of sex.

Answer 29

False. For a disorder, both triplet repeat expansion and anticipation may be more associated with one sex.

Question 30

What is imprinting?

Answer 30

parent-of-origin specific expression of a gene (i.e. only one allele is preferentially expressed, instead of both)

Question 31

Give an example of a disease associated with imprinting.

Answer 31

Angelman syndrome

Question 32

What causes Angelman syndrome?

Answer 32

caused by mutations that inactivate UBE3A gene, which is only expressed from the maternal allele (paternal allele is imprinted and not expressed)

Question 33

Explain the relationship between a genetic mutation in a paternal UBE3A allele and imprinting.

Answer 33

if you inherit mutant UBE3A from father, you will not be affected (i.e. have Angelman syndrome) because the paternal allele is imprinted/not expressed

Question 34

What is uniparental disomy?

Answer 34

both chromosomes of a pair are inherited from the same parent (a rare phenomenon)

Question 35

Describe the phenotype associated with uniparental disomy.

Answer 35

usually, uniparental disomy is inconsequential, but if there’s an imprinted region or a duplication involved, it might lead to a disorder

Question 36

How can uniparental disomy be detected? (2)

Answer 36

examining polymorphic loci on the chromosome by using an SNP array

all loci will have the same allele (complete lack of heterozygosity)

Question 37

What is variable expression?

Answer 37

idea that some genetic conditions can cause multiple phenotypic effects, which vary among individuals

Question 38

Give an example of a disease that is associated with variable expression.

Answer 38

neurofibromatosis type I

Question 39

What causes neurofibromatosis type I?

Answer 39

mutations in NF1 gene

Question 40

What are some underlying causes for variable expression? (3)

Answer 40

environmental factors

differences in genetic background (modifier genes)

differences in specific mutation that causes the disease (allelic heterogeneity, severe vs. mild mutations)

Question 41

Differentiate between penetrance and variable expression.

Answer 41

penetrance = all or none, either you have the disease or you don’t

variable expression = extent to which disease manifests

Question 42

What are the two forms of genetic heterogeneity?

Answer 42

locus heterogeneity

allelic heterogeneity

Question 43

Define locus heterogeneity.

Answer 43

mutations in different genes (i.e. loci) cause the same phenotype

Question 44

Define allelic heterogeneity.

Answer 44

single gene disorders caused by many different mutations in the same gene

Question 45

Give an example of locus heterogeneity.

Answer 45

mutations in LDLR, ARH, ApoB, and PCSK9 all lead to high LDL cholesterol

Question 46

Give an example of allelic heterogeneity.

Answer 46

more than 600 mutations in CFTR cause cystic fibrosis

Question 47

What is gene frequency?

Answer 47

fraction (b/w 0 and 1) of all alleles at a single locus in a population

Question 48

What is the nomenclature/convention associated with the Hardy-Weinberg equilibrium?

Answer 48

frequency of normal allele symbolized by “p”

frequency of mutant allele symbolized by “q”

Question 49

What does the Hardy-Weinberg distribution/equilibrium state?

Answer 49

if there are two alleles (A and a) in a population w/ frequencies p and q:

frequency of AA homozygotes = p²

frequency of aa homozygotes = q²

frequency of Aa heterozygotes = 2pq

Question 50

How are X-linked conditions factored into the Hardy-Weinberg equilibrium?

Answer 50

for X-linked conditions, mutant gene frequency (q) is same as disease frequency in males

carrier frequency in females calculated using 2pq

Question 51

What are the two assumptions underlying Hardy-Weinberg genotype proportions?

Answer 51

random mating

all genotypes are equally likely to survive

Question 52

What are three types of mating that lead to non-random mating (a deviation from the Hardy-Weinberg equilibrium)?

Answer 52

assortative mating

inbreeding

consanguinity

Question 53

What is assortative mating?

Answer 53

choosing mates because of characteristics which have a genetic component

Question 54

What is positive assortative mating?

Answer 54

people with similar characteristics tend to mate (e.g. tall people mating with tall people)

Question 55

What is negative assortative mating?

Answer 55

people with different characteristics tend to mate (e.g. blond-haired people preferring to mate with brown-haired people)

Question 56

What is inbreeding?

Answer 56

choosing mates from within a small group such defined by ethnicity or geography

Question 57

What is consanguinity?

Answer 57

mating within a family (relatives closer than 6 steps removed)

Question 58

In the context of the Hardy-Weinberg equilibrium, what is the ultimate outcome of non-random mating?

Answer 58

increases frequencies of homozygotes in the population, above what Hardy-Weinberg would predict

Question 59

Give four deviations from the Hardy-Weinberg equilibrium.

Answer 59

non-random mating

selection/differential survival

mutations and gene frequencies

population movements/random variations

Question 60

What is fitness?

Answer 60

survival of individuals with given genotype compared to population as a whole

Question 61

Selection is rapid and slow for which conditions?

Answer 61

rapid for X-linked or autosomal dominant (early manifestation, therefore early exposure to selection)

slow for autosomal recessive (heterozygotes do not manifest the trait)

Question 62

What is the founder effect?

Answer 62

mutations for recessive traits brought into small population by a few founders will lead to higher frequencies for those alleles in the population, generations later

Question 63

What is heterozygote advantage?

Answer 63

heterozygotes have higher relative fitness than either the homozygous dominant or homozygous recessive genotype

Question 64

In the context of new mutations, how must mutant alleles be maintained at a constant frequency in the population? (2)

Answer 64

balance losses from selection against allele with new mutations

since selection acts more strongly on dominant or X-linked traits, mutation rates for the genes that cause such traits must be high