Genetics 3

Front 1

Who manifests an AUTOSOMAL RECESSIVE Inheritance?

Back 1

Homozygous for 2 mutant alleles (a/a)
(A/a or AA) don't manifest dz

Front 2

What are 5 common examples of autosomal recessive dz?

Back 2

Cystic fibrosis
Tay-sachs
Sickle cell anemia
Congenital deafness
PKU (phenyketonuria)

Front 3

What is "horizontal transmission" - as relates to autosomal recessive criteria?

Back 3

DZ typically appears in only ONE generation and in only ONE Sibship

Front 4

Do people with autosomal recessive inheritance typically have affected parents?

Back 4

NO
-and equal numbers of males and f/m affected

Front 5

Siblings of an affected autosomal recessive individual have what chance of also being affected?

Back 5

1/4 - Parents are A/a and A/a
AA
Aa
Aa
aa

Front 6

Why is Consanguinity genetically unfavorable?

Back 6

Can increase risk of person having autosomal recessive dz as well as many other genetic disorders

Front 7

If child is from heterozygous parents for autosomal recessive dz, and is normal, what is chance is AA or Aa

Back 7

AA is - 1/3
Aa is 2/3
*Aa is not 1/2
**see next slide for calculation

Front 8

How do you determine sibling carrier frequency for heterozygous parents for autosomal recessive dz (unaffected)

Back 8

P(II-a = Aa)/[P(II-1 = AA) + P(II-1 = Aa)
--> Aa = (1/2)/[1/4+1/2] = 2/3

Front 9

What is the Hardy Weinberg theory?

Back 9

The sum of the frequency of the dominant alleles and the frequency of the recessive alleles equals one

Front 10

What are the 4 hardy Weinberg assumptions?

Back 10

1. Random mating
2. Constant mutation rate
3. No selection
4. No random fluctuation of gene frequencines due to migration or other causes

Front 11

What is the equation for the Hardy Weinberg?

Back 11

(p+q)^2 = 1^2
P^2 + 2pq + q^2 = 1
AA +Aa +aA + aa = 100%

Front 12

What is the likelihood someone is a carrier if the frequency of the disease (aa) is 1/10,000?

Back 12

then q^2 = 1/10,000 and
q = 1/100
p = 99/100
*Carrier frequency is 2pq or 2(99/100)(1/100) = 1.98 or ~2%

Front 13

In estimating disease allele frequency, how would you estimate frequence of disease?

Back 13

frequency of dz = q^2

Front 14

In estimating disease allele frequency, how would you estimate frequence of disease allele?

Back 14

frequency of dz allele = square root (2q)
-see example calculation

Front 15

What are key questions to consider when counseling for Autosomal Recessive Disorders?

Back 15

1. Prob father is carrier?
2. Prob. mother is carrier
3. If both carriers, what is prob. child will have autosomal recessive DZ?

Front 16

Make sure can look at pedigree chart and estimate overall risk to child

Back 16

Be able to look at chart to determine

Front 17

Is it appropriate to use the Hardy Weinberg equation w/ Cosanguinity?

Back 17

No

Front 18

Know the rationale behind estimation of probabilities using H-W

Back 18

P(II-3) is Aa = 1/2
P(III-3) is Aa = 1/2*1/2 = 1/4
**look at tree

Front 19

What is the probability equation that a child is effected when consanguinity?

Back 19

(child chance aa)(mother chance of being carrier)(father chance of being carrier) probabilities of being
**again, take a look at the tree and equation

Front 20

Offspring of first degree relative have what % risk of having a child with a disability?

Back 20

40%!!!

Front 21

What accounts for the increased frequency of consanguinity among parents of children w/ RARE autsomal recessive disorders?

Back 21

The probability that 2 individuals might be carriers for the mutant allele increases if both have inherited the allele from a common ancestor (consanguintiy), whereas if dz rare, the prob. that 2 individuals who are carriers for gene will marry is rare

Front 22

What is nice about recognizing Autosomal Dominant Inheritance?

Back 22

The genotype of only those individuals who are UNAFFECTED is UNAMBIGOUS

Front 23

What assumption should we make about Autosomal Dominant inheritance?

Back 23

Assume that an individual who is homozygous for the DZ allele is rare -- vast majority of affected individual have genotype Aa

Front 24

How do you estimate the frequency of the dz allele for autosomal dominant inheritance?

Back 24

Req affected indiv. ~2pq ~ 2q
*p = dz allele frequency

Front 25

What is one exaple of an autosomal dominant disorder?

Back 25

Dentinogenesis
-freq. affected individuals = 1/8000
2p = 1/8000, p= 1/16000

Front 26

What is key to remember about X-linked recessive disorders?

Back 26

Gene causing DZ on X chromosome
**Individuals who have ONLY abnormal copies of the gene are affected

Front 27

Male vs. Female X-linked recessive disorders
Male?

Back 27

Only one X chromosome, so a SINGLE abnormal copy of gene = DZ

Front 28

Male vs. Female X-linked recessive disorders
Female?

Back 28

TWO X CHROMOSOMES
-affected ONLY IF BOTH alleles abnormal

Front 29

What are 2 examples of X-linked disorders?

Back 29

Hemophilia A
Duchenne Muscular Dystrophy

Front 30

Is there Male to male transmission of X-linked recessive disorders?

Back 30

No

Front 31

All daughters of an affected male (x-linked recessive disorder) are?

Back 31

Heterozygous

Front 32

what % of sons of a carrier f/m are affected? x-linked recessive

Back 32

50%

Front 33

what % of daughters of a carrier f/m are carriers? (x-linked recessive)

Back 33

50%

Front 34

What is the DZ?
-X-linked recessive!
-affected boys normal for first year or two of life, but then develop musc. weakness 3-5 years
-confined to wheelchair by 12 years
- unlikely to survive beyond age 20- genetically lethal, and death due to cardiac failure?

Back 34

Duchenne muscular dystrophy

Front 35

How do most mutations occur for Duchenne muscular dystrophy since it is genetically lethal?

Back 35

X-linked recessive and 1/3 are NEW mutations

Front 36

Frequency of affected males with X-linked recessive inheritance =?

Back 36

DZ allele freq. (males are always affected if they are carriers)

Front 37

What is the frequency of carrier f/ms X-lined recessive rare?

Back 37

~2q or about 2X freq affected males

Front 38

Where are most of the mutant alleles w/ rare, recessive X-linked disorder?

Back 38

1/3 of mutant alleles in males
2/3 of mutant alleles in carrier f/ms

Front 39

What is the numerical diff. between affected f/m and affected males?

Back 39

q^2 vs. q (males much higher)

Front 40

What are 3 ways a f/m can be affected by an X-linked recessive inheritance DZ?

Back 40

1. Homozygous for mutant allele
-common Dz allele
-consanguinity
2. F/m Hemizygous for the X chromosome
3. X-inactivation (Lyonization)

Front 41

What does it mean for a f/m to be "Hemizygous" for the X chromosome?

Back 41

If a f/m has only one X chromosome or a DELETION in part of the X chromosome and if there is a muation in the remaining copy of the gene, then the f/m is affected

Front 42

What are reasons for f/m hemizygosity?

Back 42

Turner Syndrome
Deletion or Translocation

Front 43

What is X-inactivation? (Lyon hypothesis)

Back 43

Males and f/m produce similar quantities of gene products for genes on the X chromosome (yet males have only a single X while f/ms have 2 X chromosomes)

Front 44

Explain the Lyon Hypothesis?

Back 44

In f/m SOMATIC cells, ONLY ONE X CHROMOSOME IS ACTIVE
- Other X is condensed and inactive

Front 45

When is it believed that inactivation occurs?

Back 45

Early in EMBRYONIC LIFE

Front 46

How is it believed that X-inactivation occurs?

Back 46

RANDOM X-inactivation in each somatic cell
- can be either the maternally or paternally inherited X chromosome
- Once X-inactivation has occurred, all descendants of the CELL will have the same X-inactivated

Front 47

In what kind of cells does X-inactivation occur?

Back 47

Theory says that it is SOMATIC cells only

Front 48

Results of X-inactivation:
F/m DO NOT produce more gene product than males since product is only produced from the active X chromosome

Back 48

Dosage compensation

Front 49

Results of X-inactivation:
f/m have diff. combos of genes active in various cells?

Back 49

Mosaicism

Front 50

Results of X-inactivation:
Variability of expression among HETEROZYGOUS F/m from entirely NORMAL to FULL MANIFESTATION

Back 50

believed it is due to skewed X-inactivation

Front 51

Going w/ X-inactivation theory, what might observe with Duchenne musc. dystrophy for carrier f/m?

Back 51

Positive and negative stained cells reflecting X-inactivation

Front 52

B/c several x-linked recessive disorder such as DMD are quite lethal in affected males, what is occuring since the dz freq. is constant even though most males don't live long enough to reproduce?

Back 52

Dz kept at constant freq. by high rate of new mutations

Front 53

Diff. between X-linked dominant and X-linked recessive disorder?

Back 53

f/ms are now affected if they only have one copy b/c now only need ONE abnormal copy of gene to be affected

Front 54

What are examples of X-linked dominant disorders (2)

Back 54

1. X-linked Hypophasphatemic rickets
2. Ornithine Transcarbamylase (OTC)

Front 55

X-linked dominant criteria:
affected males w/ unaffected mates will have?

Back 55

all UNAFFECTED sons
all daughters will be obligate HETEROZYGOTES and AFFECTED

Front 56

X-linked dominant criteria:
all offspring of affected f/ms (who are most likely are heterozygous) have what risk of being affected?

Back 56

50%

Front 57

X-linked dominant criteria:
affected f/ms vs males?

Back 57

affected f/ms twice as common as affected males

Front 58

How are f/ms with X-linked dominant dz affected compared to males?

Back 58

b/c of Lyoniztion, usually less severely affected

Front 59

For a rare, X-linked dominant disorder, what is the ration of affected f/m to affected males?

Back 59

approximately 2:1
(2q:q)

Front 60

What is the DZ?
-x-linked dom.
-lethal in males b/4 birth, los of milestones
-microcephaly
-seizures
-characteristic wringing or flapping of hands and arms

Back 60

Rett Syndrome