Biology 211 Spring 2017

Lecture 3

January 19th 2017

 Probability Exercise
Sickle cell disease, at an organismal level, is defined as an autosomal
recessive disorder because one copy of HbA produces enough normal
hemoglobin to prevent anemia.

At the cellular level, regarding blood cell shape, the phenotype of the
sickled red blood cell is incompletely dominant because heterozygotes can
display some sickled red blood cells (RBCs) in low-oxygen environments.

Finally, regarding hemoglobin at the molecular level, there is

codominance. In heterozygotes, both HbA and HbS alleles are expressed.

2
If two people with sickle cell trait have children, what is the chance that a child will have
normal RBCs in both high- and low-oxygen environments?

What is the chance that a child will have sickle cell disease?

Write the possible genotypes in the Punnett square.

3
If two people with sickle cell trait have children, what is the chance that a child will have
normal RBCs in both high- and low-oxygen environments?

What is the chance that a child will have sickle cell disease?

Write the possible genotypes in the Punnett square.

HbA HbS

HbA
HbA/HbA HbA/HbS

HbS
HbS/HbA HbS/HbS

Normal RBCs in high- and low-oxygen environments

HbA/HbA 1/4 (25%)

Sickle cell disease

HbS/HbS 1/4 (25%)

4
What is the chance that a child will carry the HbS gene but not have sickle cell disease?

What are the chances that these parents will have three children who are homozygous
for normal RBCs?

5
What is the chance that a child will carry the HbS gene but not have sickle cell disease?

What's the genotype for this phenotype = HbS/HbA 2 X 1/4 = 1/2

What are the chances that these parents will have three children who are homozygous
for normal RBCs?

Genotype of each child = Independent event

multiply the probabilities of all independent events

(1/4) X (1/4) X(1/4) = 1/64 = 1.56%

6
What are the chances that these parents will have two children with sickle cell trait
and one with sickle cell disease? (Show your work.)

In the cross above, if you know that the child does not have sickle cell disease, what is
the chance that the child has sickle cell trait?

7
What are the chances that these parents will have two children with sickle cell trait
and one with sickle cell disease? (Show your work.)

Again all independent events

(1/2) X (1/2) X (1/4) = 1/16 = 6.25%

In the cross above, if you know that the child does not have sickle cell disease, what is
the chance that the child has sickle cell trait?

Because you have eliminated the possibility of a child having sickle cell disease
(HbS/HbS) then there are only 3 possibilities and of the three remaining possible
genotypes 2 of the 3 would have sickle cell trait (HbA/HbS) therefore the probability is
2/3 = 66.67%

8
Multiple couples living in a small village in the eastern African lowlands, all of whom are
heterozygous for the HbS allele, have 500 children among them. Of these children, 139
are homozygous for HbA, 279 are heterozygous for HbS, and 82 suffer from sickle cell
disease. Are these data statistically significant? Explain using a chi-square statistical
analysis test.

9
Multiple couples living in a small village in the eastern African lowlands, all of whom are
heterozygous for the HbS allele, have 500 children among them. Of these children, 139
are homozygous for HbA, 279 are heterozygous for HbS, and 82 suffer from sickle cell
disease. Are these data statistically significant? Explain using a chi-square statistical
analysis test.

State TESTABLE hypothesis as null hypothesis

Null hypothesis: The genotype frequencies represent a simple Mendelian

inheritance of the two alleles HbA and HbS

10
Multiple couples living in a small village in the eastern African lowlands, all of whom are
heterozygous for the HbS allele, have 500 children among them. Of these children, 139
are homozygous for HbA, 279 are heterozygous for HbS, and 82 suffer from sickle cell
disease. Are these data statistically significant? Explain using a chi-square statistical
analysis test.

HbA HbS

Calculating expected HbA

HbA/HbA HbA/HbS
500 children HbS
HbA/HbA = 1/4 X 500 = 125 HbS/HbA HbS/HbS
HbA/HbS = 1/2 X 500 = 250
Hbs /HbS = 1/4 X 500 = 125

11
Multiple couples living in a small village in the eastern African lowlands, all of whom are
heterozygous for the HbS allele, have 500 children among them. Of these children, 139
are homozygous for HbA, 279 are heterozygous for HbS, and 82 suffer from sickle cell
disease. Are these data statistically significant? Explain using a chi-square statistical
analysis test.

12
Multiple couples living in a small village in the eastern African lowlands, all of whom are
heterozygous for the HbS allele, have 500 children among them. Of these children, 139
are homozygous for HbA, 279 are heterozygous for HbS, and 82 suffer from sickle cell
disease. Are these data statistically significant? Explain using a chi-square statistical
analysis test.

2 = 1.57 + 3.36 +14.79 = 19.72

Degrees of freedom or d.f. equals the number of independent events one

3 possible genotypes 1 = 2

so d.f. is 2

13
Multiple couples living in a small village in the eastern African lowlands, all of whom are
heterozygous for the HbS allele, have 500 children among them. Of these children, 139
are homozygous for HbA, 279 are heterozygous for HbS, and 82 suffer from sickle cell
disease. Are these data statistically significant? Explain using a chi-square statistical
analysis test.

2 19.72 with 2 d.f.

p > 0.005

reject the null hypothesis

therefore these alleles are not following

a Mendelian inheritance pattern

14
 Overview

Cytoplasmic Inheritance
Pedigree Analysis
Conditional Probability
Endosymbiosis
Additional Endosymbiosis Evidence
Cytoplasmic Inheritance
Rules of non-Mendelian inheritance for mtDNA and cpDNA:

Ratios typical of Mendelian segregation do not occur because

meiotic segregation is not involved.

Reciprocal crosses usually show uniparental inheritance because

zygotes typically receive cytoplasm only from the mother.

Genotype and phenotype of offspring is same as mother.

Paternal leakage occurs at low levels and usually is transient;

mechanisms that degrade paternal mtDNA/cpDNA exist.

Heteroplasmy (mixture of mtDNA/cpDNA organelles with different

DNA substitutions) results in rare cases.
Examples of mitochondrial inheritance:

Mutant [poky] Neurospora possess altered mtDNA cytochrome

complements that lead to slow growth.

[poky] phenotype is inherited with the cytoplasm.

protoperitheca (sexual mating type)

conidia
(asexual mating type)

Fig. 23.10, Reciprocal crosses of poky and wild-type Neurospora.

Examples of maternally inherited human mtDNA defects:

Lebers hereditary optic neuropathy (LHON), OMIM-535000

Mid-life adult blindness from optic nerve degeneration.

Mutations in ND1, ND2, ND4, ND5, ND6, cyt b, CO I, CO II, and
ATPase 6 inhibit electron transport chain.

Kearns-Sayre Syndrome, OMIM-530000

Paralysis of eye muscles, accumulation of pigment and

degeneration of the retina, and heart disease.
Deletion of mtDNA tRNAs.

Myoclonic epilepsy & ragged-red fiber disease (MERRF), OMIM-

545000

Spasms and abnormal tissues, accumulation of lactic acid in the

blood, and uncoordinated movement.
Nucleotide substitution in the mtDNA lysine tRNA.

Most individuals with mtDNA disorders possess a mix of normal and

mutant mtDNA, therefore severity of diseases varies depending on
the level of normal mtDNA.
Cytoplasmically inherited characteristics
frequently exhibit extensive phenotypic
variation because cells and individual offspring
contain various proportions of cytoplasmic
genes.
http://bmj-sti.highwire.org/content/77/3/158.full
Examples of non-Mendelian inheritance:

Variegated-shoot phenotypes in four oclocks

Mixed chloroplasts
White/green

Mutant chloroplast
White
non-photosynthetic

Normal chloroplast
Green
photosynthetic

Fig. 23.8b
Experiments by Carl Correns
introduced concepts of non-nuclear
chromosomal inheritance.

Carl Correns used pollen from 4o clock

plants with white, green, and
variegated leaf patterns to fertilize
seeds from white, green, and
variegated plants. The progeny
displayed the same color leaves as the
seed plant, regardless of the leaf
pattern exhibited by the pollinating
plant. The ratio of these phenotypes
did not conform to the phenotypic
ratio predicted by Mendelian
inheritance laws.
Exceptions to maternal inheritance:

Heteroplasmy, mice show paternal DNA present at 1/10,000 the

level of maternal DNA.

Occurs when mtDNA from sperm leak into egg cytoplasm at the
time of fertilization.

In these cases, maternal and paternal mtDNA can recombine!

Paternal inheritance of chloroplasts commonly occurs in some plants

(e.g., gymnosperms).

www.sciencemusings.com/
 Pedigree analysis
Following patterns of inheritance
(especially in humans) can be
done by generating pedigrees

What does the inheritance

pattern tell us about gene
function/activity

Inheritance patterns:
X vs autosomal linkage
Dominance vs recessive
phenotypes

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Pedigree
symbols and
conventions

Proband person being

studied
Propositus male
Proposita - female

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 Generation and individual
identification
Roman numerals for generation
Numbers for individuals

31
 Cousinhood: terminology of relatedness

Note: diamonds are used here because the term cousin leaves the sex of an individual unspecified

Mange and Mange (1990) Genetics: Human Aspects 221.F13

 Assumptions with disease causing
mutations

For rare conditions (which most genetically

inherited diseases are rare):
-Unless information in the pedigree indicates
otherwise, affected individuals for a dominantly
inherited trait are usually heterozygous
-Unless information in the pedigree indicates
otherwise, for recessively inherited diseases, most
unrelated individual will not be carriers

33
There are no disease genes
All genes are normally used by the organism (so far)
Each somatic cell contains 2 copies of all autosomal genes
The function of genes can be impaired or modified by mutations in
such a way to cause a phenotype associated with a disease

34
 Pedigree analysis: autosomal recessive

A/a A/a

a/a A/a a/a A/a

Typically:
Parents are unaffected
Affected progeny include both males and females
Phenotype is rare in general population
Phenotype is often revealed by consanguineous unions.
recall that siblings share 1/2 of their alleles
first-cousins share 1/8 of their alleles
Mendelian ratios are rarely observed in families because the sample size is very small

35
Pedigree analysis: autosomal recessive

36
 Recessive alleles with a disease phenotype

OMIM chr
Cystic fibrosis 219700 7
Tay-Sachs disease 303800 15

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

37
 Pedigree analysis: autosomal Dominant

Typically:
Phenotype occurs in every generation
Affected parents transmit phenotype to both sons and daughters
On average, half the children of affected individuals show phenotype
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 Dominant alleles with a phenotype

OMIM chr
Huntingtons disease 143100 4
Polydactylly - postaxial, typeA1 174200 7
Brachydactyly 112500 2&5
Piebaldism 172800 4

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

39
 X-linked dominant
Affected female transmits to 50% male and
female progeny
Affected male transmits to 100% daughters,
0% sons.

40
 Examples of X-linked Dominant Inheritance

OMIM Chromosome
Hypophosphatemic rickets 307800 X
CHARCOT-MARIE-TOOTH DISEASE 302800 X

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

41
 X-linked recessive

Females are carriers, males are affected

Carrier female will transmit to 50% of sons

(affected) and to 50% of daughters (carriers)

Affected male cannot transmit to sons but 100%

of daughters are carriers.

42
 Examples of X-linked Recessive Inheritance

OMIM Chromosome
HEMOPHILIA A 306700 X
Cowchock syndrome 310490 X
ICHTHYOSIS 308100 X
Color blindness 303800 X

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

43
 Y-Linked Inheritance is transmitted
paternally
Traits on the Y chromosome are only
found in males, never in females

The fathers traits are passed to all

sons.

Dominance is irrelevant: there is

only 1 copy of each Y-linked gene
(hemizygous).

44
 Y-linked traits

Most Y linked genes are involved in

spermatogenesis
Hemizygous
Mutations therefore can cause sterility and
are unlikely to be passed down

45
 Mitochondrial DNA inheritance
(non-Mendelian)

Typically:
Inheritance only through maternal line
Affected females transmit mtDNA to all progeny
Affected males do not transmit mtDNA or the disease phenotype

e.g., Leber hereditary optic neuropathy (LHON)

221.F12
Lets solve a pedigree
Start with the 4 most common Mendelian inheritance patterns
Autosomal Dominant
X-Linked Dominant
Autosomal Recessive
X-Linked Recessive
1st Question
Does this trait skip generations?
2nd Question
Do Unaffected parents have affected offspring?
3rd Question
Do Unaffected mothers have affected sons?
1st Question
Does this trait skip generations?
2nd Question
Do Unaffected fathers have affected daughters?
 In rare autosomal recessive diseases, when consanguinity is involved, those individuals in
the direct line of descent within the family are considered to be carriers and those
individuals from outside the family are considered homozygous normal unless there is
evidence to the contrary.
Mendelian traits in humans

56
Mendelian traits in humans
Tongue rollers carry a dominant gene R. Non-tongue
rollers are homozygous recessive (rr).

D If you have a Widow's Peak, you have at least one

dominant gene. No downward point of the hairline,

D and you are homozygous recessive (ww).

Dr
If the lobe is attached directly to the head, the
individual is homozygous recessive, and the ee
genotype is present.

Some individuals can bend the last joint of the

thumb backwards at about a 45 degree angle.

D
These individuals are homozygous for a

r recessive gene, hh,

The dominant gene, B, causes the terminal bone of

the little finger to angle toward the fourth (ring) finger.
Individuals whose little fingers are straight possess
the homozygous recessive condition, bb.

57
Mendelian traits in humans
Tongue rollers carry a dominant gene R. Non-tongue
rollers are homozygous recessive (rr).

T? W? ? ?
If you have a Widow's Peak, you have at least one
dominant gene. No downward point of the hairline,
and you are homozygous recessive (ww).

ee If the lobe is attached directly to the head, the

?
individual is homozygous recessive, and the ee

E? genotype is present.

Some individuals can bend the last joint of the

thumb backwards at about a 45 degree angle.

B?
These individuals are homozygous for a

hh
?
recessive gene, hh,

The dominant gene, B, causes the terminal bone of

the little finger to angle toward the fourth (ring) finger.
Individuals whose little fingers are straight possess
the homozygous recessive condition, bb.

58
 Penetrance and expressivity

Variable phenotypes can be caused by a number of factors

Allelic variation
Gene expression variability
Modifier genes
Epigenetic effects
Environmental factors
Genetic and environmental interactions
http://www.nature.com/scitable/topicpage/same-
genetic-mutation-different-genetic-disease-
phenotype-938

http://www.healthknowledge.org.uk/public-
health-textbook/disease-causation-
diagnostic/2d-genetics/basic-genomic-
concepts
Penetrance and expressivity apply to all types of inheritance patterns,
i.e. the mutant phenotype can be dominant, recessive, autosomal or
sex-linked, [but is specific to nuclear not mitochondrial inheritance]
expressivity
The degree that a given genotype is expressed phenotypically in one individual.

Polydactyly: extra digits in the hand

Common variations on the basic growth pattern of the hand.
Many forms including
o a small extra bump on the side of the hand,
o a finger which widens to end in two fingertips,
o an extra finger which dangles by a thin cord from the hand,
o a hand which looks normal except that it has a thumb and five fingers

http://www.e-hand.com/hw/hw024.htm
 penetrance
The percentage of individuals with a specific genotype that exhibit the expected
phenotype.

autosomal dominant trait

with
incomplete penetrance

There is ample evidence for autosomal dominant inheritance:

The disease is passed from the father (II-3) to the son (III-5), this never happens with X-linked traits.
The disease occurs in three consecutive generations, this never happens with recessive traits.
Males and females are affected, with roughly the same frequency.
However, II-1 does not express the disease. He must have inherited the mutant allele because he
passed it on to two children, III-1 and III-3. II-1 is a classical example of incomplete penetrance, he
has the allele for the disease but he does not exhibit the phenotype.

http://www.uic.edu/classes/bms/bms655/lesson4.html
221.F13
 Calculating risks in pedigree
analysis

?
HEXA; 606869

Niemann Pick Disease #257220

http://www.nytimes.com/2005/06/03/science/03gene.html?pagewanted=2&ei=5090&en=efcc603583e17b54&ex=1275451200&
63
partner=rssuserland&emc=rss
 Statisitical Probability Rule:
Independent events
"AND" or Intersections are Independent Events

Two events are independent if the occurrence of one does not change
the probability of the other occurring.

An example would be rolling a 2 on a die and flipping a head on a coin.

Rolling the 2 does not affect the probability of flipping the head.

If events are independent, then the probability of them both occurring is

the product of the probabilities of each occurring.

Specific Multiplication Rule: Only valid for independent events

P(A and B) = P(A) * P(B)

64
 Statistical Probability Rules:
mutual exclusion is additive
"OR" or Unions: Mutually Exclusive Events
Two events are mutually exclusive if they cannot occur at the same
time. Another word that means mutually exclusive is disjoint.
If two events are disjoint, then the probability of them both occurring
at the same time is 0

If two events are mutually exclusive, then the probability of either

occurring is the sum of the probabilities of each occurring.
Specific Addition Rule: Only valid when the events are mutually
exclusive.

P(A or B) = P(A) + P(B)

65
Calculating risks in pedigree
analysis
I

II

III

66
 Example: an autosomal
recessive affliction
d) If III.1 and III.7 had
a child, what is the
probability that their
child will be
affected?

67
 Probability in Pedigrees

I
1 2 3 4

II
1 2 3 4 5 6

1) What is the probability that III 2 and III3

III are both heterozygous (carriers) ?
1 2 3 4

IV 2) What is the probability that IV 1 will be

1 homozygous (affected) ?
 Conditional Probability
Given that you have an individual with a black coat color what is the probability
that the individual is a heterozygote?

69
 Probability in Pedigrees

I
1 2 3 4

II
1 2/3 2 3 4 5 2/3 6

1) What is the probability that III 2 and III3

III are both heterozygous (carriers) ?
1 1/2 2 3 1/2 4 (2/3 X 1/2) X (2/3 X 1/2) = 1/9 =0.111

IV 2) What is the probability that IV 1 will be

1 homozygous (affected) ?
1/9 X 1/4 = 1/36 = 0.028
 Probability in Pedigrees

I
1 2 3 4

II
1 2 3 4 5 6
1) What is the probability that III 2 and III3
III are both heterozygous (carriers) ?
1 2 3 4
2) What is the probability that IV 2 will be
homozygous (affected) ?
IV
1 2
 Probability in Pedigrees

Now there is evidence that

both III 2 and III 3 are NOT
I both carriers
1 2 3 4 So P(A|B) = P(B|A) X P(A)
P(B)
II
1 2 3 4 5 6
1) What is the probability that III 2 and III3
III are both heterozygous (carriers) ?
1 2 3 4
2) What is the probability that IV 2 will be
homozygous (affected) ?
IV
1 2
 Probability in Pedigrees

A = both parents are carriers = BC

B = one normal child = 1N

P(B|A) = P(1N|BC) = (3/4)

I P(A) = p(BC) = (2/3 X 1/2) X (2/3 X 1/2) = 1/9
P(B) = P(1N) = P(B|A) + P(B|A) = (3/4 X 1/9 ) + (8/9 X 1)
1 2 3 4
P (A|B) = 3/4 X 1/9 = 3/36
(1/9 X 3/4) + (8/9 X 1) 3/36 + 32/36

II = 0.083/0.973 = 0.085

1 2/3 2 3 4 5 2/3 6
1) What is the probability that III 2 and III3
III are both heterozygous (carriers) ?
1 1/2 2 3 1/2 4 0.085
2) What is the probability that IV 2 will be
homozygous (affected) ?
IV
1 2 0.085 X 0.25 = 0.021
Recitation
 Pedigree Analysis: Hyperpigmentation of Eyelids

Is this recessive or dominant trait?

Using H to signify the dominant allele and h for the recessive,

what are the genotypes of these individuals?
75
Based upon the above pedigree what is the most likely pattern of inheritance for this trait?

Give two reasons why you think this.

If proband III 2 were to have children what is the probability he would pass the trait to a
son?

What is the probability he would pass the trait to a daughter?

Write in the genotypes for all of the members of this pedigree that you are able.
 Pedigree Analysis: Fish Odor Syndrome (#602079)

An inborn error of metabolism accompanied by fish-like body odor results

from a mutation in dimethylglycine dehydrogenase that causes a deficiency of
dimethylglycine dehydrogenase.

What are three clues that this is a recessive trait?

Let ff stand for the trait. What are the genotypes of all of the
members of the pedigree?
77
Based upon the above pedigree, what type of inheritance does this disease display? (1 Pt)

b) Does this disease follow Mendels laws of inheritance (why/why not)? (2 Pts)

c) Would you expect III 1 to pass this trait to any of her children? Why? (2 Pts)

d) Would you expect III 2 to pass this trait to any of his children? Why? (2 Pts)
Given the above pedigree what is the probability that II 2 and II 3 are both
heterozygous?
Show your work. (10 pts)
Answers
 Pedigree Analysis: Hyperpigmentation of Eyelids

Hh hh

hh Hh hh Hh hh

hh hh

hh Hh Hh hh Hh hh hh

Is this recessive or dominant trait?

Dominant
Using H to signify the dominant allele and h for the recessive,
what are the genotypes of these individuals?
81
 XaY XAXA

XAY XAXa

XaY

Based upon the above pedigree what is the most likely pattern of inheritance for this trait?
sex-linked recessive
Give two reasons why you think this.
Recessive - Affected parent has no affect children, Sex linked - affected only males
If proband III 2 were to have children what is the probability he would pass the trait to a
son?
0%
What is the probability he would pass the trait to a daughter?
100%

Write in the genotypes for all of the members of this pedigree that you are able.
 Pedigree Analysis: Fish Odor Syndrome (#602079)

An inborn error of metabolism accompanied by fish-like body odor results

from a mutation in dimethylglycine dehydrogenase that causes a deficiency of
dimethylglycine dehydrogenase.

Ff Ff Ff Ff

ff
ff ff

ff ff

What are three clues that this is a recessive trait?

Trait not seen in every generation
Two unaffected parents have affected offspring
Two affected parents have only affected offspring

Let ff stand for the trait. What are the genotypes of all of the
members of the pedigree?
83
Based upon the above pedigree, what type of inheritance does this disease display? (1 Pt)
Mitochondrial or organelle maternal inheritance

b) Does this disease follow Mendels laws of inheritance (why/why not)? (2 Pts)
No, only females pass the trait on and they pass it on to all of their children

c) Would you expect III 1 to pass this trait to any of her children? Why? (2 Pts)
Yes, all of her children will inherit her organelles in the ovum

d) Would you expect III 2 to pass this trait to any of his children? Why? (2 Pts)
No, human males do not pass organelles onto the next generation

I also accepted autosomal dominant IF & ONLY IF the lack of affected children of II-4 were explained
adequately.
Given the above pedigree what is the probability that II 2 and II 3 are both
heterozygous?
Show your work. (10 pts)
P ( A| B) = P( B | A) * P(A)
P(B)

P ( Both II 2 & II 3 are carriers given 3 normal children V) =

P (3 normal children given Both II 2 & II 3 are carriers) * P (Both II 2 & II 3 are carriers)
/ P( 3 normal children V)

P (3 normal children given Both IV 1 & IV 2 are carriers) = (3/4) 3 = 0.422

P (Both IV 1 & IV 2 are carriers) = (2/3*2/3) = (4/9) = 0.444
P( 3 normal children V) = ((3/4)3 *(4/9)+(1*5/9)) = ((0.187)+ (0.555)) = 0.742

P ( Both IV 1 & IV 2 carriers given 3 normal children ) = (0.422)*(0.444)/ ((0.187)+ (0.555)) =

= 0.187/0.742
= 0.252
0.0279

100% * 0.252 = 25.2%