Patterns of Inheritance Lecture Oct 4

Question 1

Single trait genes are often called what?

Answer 1

Mendelian traits - they appear in roughly fixed proportions

Question 2

The great majority of human health problems are caused by what?

Answer 2

complex genetic diseases

Question 3

what is a locus?

Answer 3

a segment of DNA at a specific location

if the segment contains a gene then the DNA segment is the gene locus

Question 4

what is a polymorphism?

How does that differ from a mutation?

Answer 4

a polymorphism is another work for a variant - it’s just another version of an allele

a polymorphism is not considered a mutation unless the variant refers to a NEW genetic change in a faily and/or to a disease-causing allele

Question 5

What will the typical frequency of a wildtype allele be?

How about a polymorphic allele?

a mutant?

Answer 5

wiltype allele frequency will be greater than 50%

a polymorphic allele will be observed in 1-5%

A mutant is in less than 1%

Question 6

Why can a mutation in a non-coding region still result in disease?

Answer 6

80% of the non-coding regions of the human genome contain areas that regulate expression of genes (often gene switches)

Question 7

What does homozygous mean? Heterozygous? Hemizygous? Compound heteroxygous?

Answer 7

Homozygous: an individual’s two alleles are functionally identical at a specific locus

Heterozygous: the alleles are functionally different

Hemizygous: a special situation when an individual has only on eallele of a gene (as it is for males in X-linked disorders)

Compound Heterozygous: when an individual has two heterogenous recessive alleles at a particular locus (which can lead to disease - as it does in sickle cell anemia and cystic fibrosis)

Question 8

What is a pedigree? A kindred?

Answer 8

a pedigree is a graphical representation of the family tree, using standard symbols
a kindred is the extended family depicted in the pedigree

Question 9

WHat is a proband? A consultand? Can they be the same person?

Answer 9

the proband is the first affected person who is brought to clinical attention (and there can be multiple probands); all other family members are analyzed in relation to the proband; there is another term, consultand, that refers to the person who brings the phenotype to clinical attention (this can be an affected or unaffected individual)

Question 10

What must couples share to be comsidered consanguineous?

Answer 10

One or more ancestors in common - typically we say it has to be within 2 generations, so same grandparents

Question 11

As a genetic term, what does fitness mean?

Answer 11

fitness is a genetics term that refers to the measure of the impact of a condition or genotype on reproduction and is defined by the number of offspring of affected individuals who survive to reproductive age, compared with an appropriate control group

Question 12

What does the arrow point to on a pedigree?

Answer 12

the proband

Question 13

Inheritance patterns depend on two factors, which are?

Answer 13

1. Dominant or recessive?
2. On an autosome or sex chromosome?

Question 14

How does the inheritance for autosomal and x-linked diseases differ by gender?

Answer 14

Autosomal disorders GENERALLY affect males and females equally

x-linked disorders are far more common in males because they are hemizygous for genes on the x chromosomes, unlike females who can be heterozygous or homozygous

Question 15

What causes mosaicism in females?

Answer 15

Females randomly inactivate one of their x chromosomes in order to control gene dosing.

but which x is inactivated is random, so the phenotype may only be expressed in a subset of cells, resulting in mosaicism

If the female is heterozygous for a disease allele in an x-linked recessive disease, females may demonsrtate an attenuated phenotype compared to males due to mosaicism

Question 16

Most recessive diseases involve a ___-of-function mutation.

Answer 16

a loss of function

the mutations in both alleles eliminates gene function

Question 17

What is the difference between an autosomal dominance disease that displays PURE DOMINANCE compared to SEMIDOMINANCE?

Answer 17

Pure dominance occurs when both homozygotes and heterozygotes show an identical severity of phenotype. THIS RARELY HAPPENS.

More commonly, a disease is semidominant - it is more severe in homozygotes than heterozygotes

Question 18

What does it mean when an autosomal dominant inheritance is codominant?

Answer 18

When two different variant alleles are expressed together (like ABO blood group)

Question 19

What does it mean to say that a mutant gene demonstrates “reduced penetrance?”

Answer 19

Penetrance is the probability that a mutant gene will have any phenotypic expression (the percentage of individuals demonstrating SOME disease phenotype.

It the percentage is less than 100%, then the mutant gene has reduced penetrance

Question 20

What does it mean to say a mutatnt gene has variable expresivity?

Answer 20

Expressivity is the severity of the expression of the phenotype among individuals with the same disease-causing phenotype

so if the severity among people who have the same genotype, it is said to have variable expressivity

Question 21

How does neurofibromatosis display variable expressivity?

Answer 21

It’s an autosomal dominant disease and always exerts some kind of disease phenotype in heteroxygotes and homozygotes (100% penetrance)

However, the severity of the disease varies greately (some people only get cafe au lait spots or iris nodules while others develop lethal spinal cord tumors)

This is variable expressivity

It does this because there are different possible mutations in the NF1 gene

Question 22

How can age of onset affect analysis of a pedigree?

Answer 22

FOr a genetic disorder that results in fetal lethality, the inheritance pattern may be obscured by requence miscarriages and reduced fertility

In dominant disorders with late onsets, the inheritance pattern could be obscured by the fact that some family members died of other causes before the onset would have occur. Or the children are too young to have developed the disease phenotype - this is how it is in Huntington Disease

Question 23

Describe allelic heterogeneity.

what are two disease examples?

Answer 23

When a loci can containe multiple mutant alleles within a population

Note that different combinations of mutant alleles can have a large impact on disease severity

Cystic fibrosis is an example, as is phenylketonuria

Question 24

Describe locus heterogeneity.

Answer 24

This is when a disease phenotype can be cause by mutations in distinctly different genes

This makes it difficult to determine the causative gene

Examples inlude retinitis pigmentosa and hyperphenylalanemias

Question 25

Describe phenotypic heterogeneity.

Examples?

Answer 25

In some genes, different mutations in the SAME GENE can cause DIFFERENT DISEASES.

The RET gene is an example (encodes a tyrosine kinase)

One mutation causes Hirschsprung disease

Another mutation causes endocrine cancers

A third mutation will cause both Hirschsprung disease and endocrine cancers.

Question 26

For an autosomal recessive disease, what is the liklihood of developing the phenotype for a child with the following parent combinations?

R/r x R/r

R/r x r/r

r/r x r/r

Answer 26

R/r x R/r; in this case the likelihood of an r/r offspring is 25%

R/r x r/r; in this case the likelihood of an r/r offspring is 50%

r/r x r/r; in this case the likelihood of an r/r offspring is 100%

Question 27

What does it mean to say that an autosomal recessive disorder is sex influenced?

Give an example.

Answer 27

Usually autosomal recessive disorders show the same frequency in males and females

However, sometimes one sex actually ends up having a higher frequency

An example is hemochromatosis which is an iron metabolism disorder that occurs much more often in men even though it’s an autosomal recessive disorder.

THey think this can eithe rbe due to reduced iron intake in women, loss of iron in menstruation, or lower alcohol intake in women

Question 28

Why are autosomal recessive disorders more likely to appear in children of consanguineous parents?

Answer 28

The parents are related and therefore more likely to be carriers of the disease allele and more likely to pass it on to their kids

Question 29

What is inbreeding and how is it different from consanguinity?

Give an example of a disease that is common in inbreeding.

Answer 29

Inbreeding is at the population - it describes a situation where individuals from a small, isolated population tend to choose mates from within the same population

THey may be unrelated, but they typically share a lot of gene alleles from ancestors and thus increase the chances that the two individuals are heterozygous for the same recessive alleles

This is why Tay-Sachs is so much more common in Ashkenazi Jews

Question 30

How does one diagnose Tay sachs?

Answer 30

Look in the retina to see if they have a cherry spot (a red spot surrounded by white from the abnormal storage of ganglioside in retinal neurons)

Question 31

In terms of autosomal dominant inheritance, risk and severity depend on two things, which are…

Answer 31

whether one or both parents are affected

whether the trait is strictly dominant of incompletely dominant (reduced penetrance)

Question 32

For an autosomal dominant trat, what are the liklihoods of a child expressing the phenotype if they have these parent combinations?

C/d/ x d/d

D/d x D/d

Answer 32

parents are D/d x d/d, risk if 50%
parents are D/d x D/d, risk is 75%

this assumes complete dominance

Question 33

Why is the D/D genotype rare?

Answer 33

Matings between affected parents are often rare and sometimes the D/D genotype is embryonic lethal

this is because two copies of a dominant mutant allele tend to be mroe severe than one
(semidominance)

Question 34

How does achondroplasia exhibit incomplete dominance?

Answer 34

Acondroplasia is an incomplete dominant skeletal disorder

Marriage between two affected individuals is common

homoxygotes tend to show a mroe severe phenotype and often the children therefore show a more severe phenotype and don’t survive post-natally

familial hypercholesterolemia is another example

Question 35

Sometimes autosomal dominant disorders can arise from spontaneous new mutations. WHat two places can these new mutations come from? WHich is the most common?

Answer 35

these mutations most commonly arise in the gametes of the parents (sperm, eggs), such that the parents are normal but they pass on a mutant allele; the likelihood of new mutations rises dramatically with the age of the parents (an example is Down Syndrome)

at a much lower frequency, new mutations can occur in the early stage embryo of the proband

Question 36

What’s an example of a sex-limited autosomal dominant disorder?

Answer 36

Male-limited precocious puberty

This is an autosomal dominant disorder, but it only occurs in males

they end up entering puberty at 4 years of age.

Question 37

What is required to differentiate a sex-limited autosomal disease from an X-linked disorder?

Answer 37

You have to show direct evidence of father to son transmission (or mapping of causative genes to an autosome)

Question 38

If a mutation has a freater effect on fitness, is it more likely to be observed as an inherited mutation or observed thorugh a new mutation?

Answer 38

It would be throuh a new mutation more often because if the mutaition affects fitness, affected individuals are less likely to be able to pass on their genes.

Question 39

What does it mean to say that DUchennes Muscular Dystropy displays mosiacism in female carriers?

Answer 39

Depending on what cells ianctivate which x chromosome, female carriers will exhibit mosic expression

so some of their muscle cells will have dystrophin expression and others wont

Their affected sons won’t express dystrophin anywhere.

Question 40

What distinguishes x-linked dominant diseases from x-linked recessive diseases?

Answer 40

It all depends on the phenotype of heteroxygous females

If it’s consistently expressed in carrier, then the disease is dominant. If not, recessive.

This determination is often hard to make due to mosaicism in female heteroxygotes.

Question 41

Hemophilia A is a classic X-linked recessive disease.

If a hemophiliac male mates with a wild type female, what is the likelihod that thier sons will have the disease? How about their daughters?

Answer 41

None of the sons will have the disease because they ahve to get the Y frm their dad and their mom only has wild type Xs.

Because the daughters have to get the mutant X from the dad and one normal X from the mom, all the daughters will be oblifate carriers of the disease

Question 42

Why are homozygous x-linked recessive females rare?

What is one example of it actually happening?

Answer 42

The homozygous phenotype is often too severe and embryonic lethal.

X-linked color blindness is an example of it actually happening, though - usually through consanguinity.

Question 43

What are some conditions where manifesting heteroxygotes are observed for x-linked recessive inheritance?

Answer 43

color blindness

hemophilia A

hemophilia B

Duchennes muscular dystrophy

Wisckott-Aldrich

Question 44

What are some ways a manifesting heterozygote can come about?

Answer 44

X-inactivation patterns are established very early in development, so if a portion of mutant genes are expressed in early early cells, then through development you may end up with a much greater than 50% proportion of cells with the mutant allele in heteroxygous females

also, a tissue may be particularly sensitive to even a 50% expression - this is the case for fragile X syndrome

Question 45

Is the phenotype in manifesting female heterosygotes less or more severe than in males?

Answer 45

less

Question 46

For X-linked dominant diseases, what is the inheritance pattern for chlidren of affected males?

For affected females?

Answer 46

Affected males will have all affected daughters and NO affected males.

Affected daughters will have the same patern of autosomal dominance when it comes to passing it along to their kids.

Question 47

Why is the heteroxygote female often less severe than hemizygous males in x-linked dominant inheritance?

Answer 47

It displays semidominance

Question 48

Why do some x-linked dominant diseases only display clinical cases in females?

Answer 48

because the disease is lethal in males (and in the very rare female homozygote for that matter(

An example is Rett Syndrome

Question 49

Why do new mutations account for a signifcant share of x-linked mutant alleles?

where is the source for these new mutations?

Answer 49

there is a strong selective pressure against the survival of mutant alleles in this case, so the affected hemixygous males don’t survve long enough to pass on their genes.

the male sperm lineage is the most common source of these new mutations - males have a higher mutation rate than females.

Question 50

Are Y-linked disorders always recessive or dominant?

What do they usually involve phenotypically speaking?

Answer 50

They have to be dominant by definition.

THey usually involve verious forms of infertility/reproductive abnormalities (for obvious reasons).

They also obviously only affect males.

Question 51

Describe MUTATIONAL mosaicism.

Answer 51

This is the mosaicism that can occur in early development, such that a clone of cells developes from a single mutation

these cells then go on to form a tissue or part of a tissue that is abnormal

this can occur in either the germline OR somatic cells

they often present as childhood cancers and developmental disorders

Question 52

If a male has two affected children, but NO persona lmutaiton in his somatic cells, what does that suggest?

Answer 52

he must have been a mosaic for a new mutation in his germline.

Question 53

What is an unstable repeat expansion disorder?

Examples?

Answer 53

The mutation can change from one generation to the next, getting worse and worse phenotypically

this happens when there are usntable triplet repeat expansions

this happens in huntingoton disease, fragile a, myotonic dystrophy and friedrich ataxia

Question 54

Describe maternal inheritance trhough the mitochondrial genome.

Answer 54

Segregation of mitochondria during cell replication is random and some daughter cells can receive more mitochondira than most.

Thus, a mutation in mitochondrial DNA may or may not be trnanmitted to the daughter cell and the number of mutant mitochondria within a cell will vary. This is why mitochondrial disorders demonstrate such a wide range of severity.

You only inherit your mitochondrial genome from the egg - so from the mother.

Question 55

Describe transgenerational epigenetic inheritance,

Answer 55

this is NOT gene-based ,but it’s inheritable through multiple generations

we think that the underlying mechanism is through small non-coding RNAs and/or methylation/adetylation of the chromatin structure

Question 56

What happened here?

Answer 56

There must have been a mutation in the germ cell of the generation 2 parents (likely the male), which then conferred the mutation to one of the generation 3 sons.

This must be autosomal dominant as well because the Gen3 affected male then had a son and a duaghter who are affected

Question 57

What is this?

Answer 57

Autosomal recessive

the gen2 parents must both be heterozygous carriers

Question 58

What’s represented by the double line?

Answer 58

consanguinity

the gen 3 pair are both carriers for the allele and therefore have an affected child

autosomal recessive

Question 59

What is this?

Answer 59

autosomal dominant

Question 60

What is this?

Answer 60

male precocious puberty

it’s an autosomal dominant gene

although it looks like it might be sex-linked, notice that affected males pass it onto sons - this wouldn’t happen in x-linked

Question 61

What is this?

Answer 61

x-linked recessive

Men are affected

Daughters of affected males are carriers, but sons of affected males are not affected

Question 62

What unusual situation does this show?

Answer 62

This is an x-linked recessive disease that has homozygous affected females - x-liked blindness

Question 63

What is this?

Answer 63

x-linked dominant

the daughters of affected males will always be affected, but sons won’t be

Offspring from affected females will have a 50% - as in autosomal dominant

Question 64

What is this?

Answer 64

This is an x-linked dominance trait wiht male lethality (and female homozygote lethality probably)

Only females will be affected because the hemizygous males die as embryos.

Rett SYndrome will be like this

Question 65

What is this?

Answer 65

This is a pedigree of a mitochondrial DNA inheritance

notice that offspring of affected females will ALL be affected, but none of the offspring of affected males will be affected