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Chapter 05

Lecture Outline
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Several factors must be understood to predict the

phenotype of offspring from their genotype.

Mendelian inheritance patterns involve genes that

Includes dominant/recessive relationships

gene interactions, sex, environment
Directly influence the outcome of an organisms traits
Obey Mendels laws

Most genes in eukaryotic species follow a

Mendelian pattern of inheritance

However, there are many that dont



In this chapter we will discuss additional (even

bizarre) patterns of inheritance that deviate from a
Mendelian pattern

Maternal effect and epigenetic inheritance

Involve genes in the nucleus

Genotype of offspring does not directly govern

phenotype as predicted by Mendel

Extranuclear inheritance

Involves genes in organelles other than the nucleus




Maternal effect refers to an inheritance pattern for

certain nuclear genes in which the genotype of
the mother directly determines the phenotype of
her offspring

Surprisingly, the genotypes of the father and

offspring themselves do not affect the phenotype of
the offspring

This phenomenon is due to the accumulation of

gene products that the mother provides to her
developing eggs

The first example of a maternal effect gene was

discovered in the 1920s by A. E. Boycott

He was studying morphological features of the

water snail, Limnaea peregra

In this species, the shell and internal organs can be

arranged in one of two directions

Right-handed (dextral)
Left-handed (sinistral)
The dextral orientation is more common and dominant
The snails body plan curvature depends on the cleavage
pattern of the egg immediately after fertilization

Figure 5.1 describes Boycotts experiment




Reciprocal cross

Same genotype, but different


A 3:1 phenotypic ratio would

be predicted by a Mendelian
pattern of inheritance

Figure 5.1

The 3:1 phenotypic ratio

shows up in the next


Alfred Sturtevant later explained the incongruity

with Mendelian inheritance

Snail coiling is due to a maternal effect gene that exists

as dextral (D) and sinistral (d) alleles

The phenotype of the offspring depended solely on the

genotype of the mother

His conclusions were drawn from the inheritance

patterns of the F2 and F3 generations


Reciprocal cross

F1 mothers are Dd
The dominant allele,
D, caused ALL the F2
offspring to be dextral

F2 mothers include 3 with

the D allele and 1 with the
d allele
This explains this 3:1 ratio

Figure 5.1


Thus, in this example

DD or Dd mothers produce dextral offspring

dd mothers produce sinistral offspring

The phenotype of the progeny is determined by

the mothers genotype NOT by her phenotype

The genotypes of the father and offspring do not affect

the phenotype of the offspring


The non-Mendelian inheritance pattern of

maternal effect genes can be explained by the
process of oogenesis in female animals

Maturing animal oocytes are surrounded by maternal

cells that provide them with nutrients
These nurse cells are diploid, whereas the oocyte
becomes haploid

In the example of Figure 5.2a

A female is heterozygous for the snail-coiling maternal

effect gene
The haploid oocyte received the d allele in meiosis


The gene products are a reflection of the genotype of the mother

They are transported to the cytoplasm of the oocyte where they
persist for a significant time after the egg has been fertilized
Thus influencing the early developmental stages of the embryo

Figure 5.2a


D gene products cause egg cleavage that

promotes a right-handed body plan

Figure 5.2b


d gene products
cause egg cleavage
that promotes a lefthanded body plan

Even if the egg is fertilized

by sperm carrying the
D allele
The sperms genotype is
irrelevant because the
expression of the sperms
gene would be too late

Figure 5.2b


Figure 5.2c

Remarkably, the orientation of

the cleavage plane in the
earliest stages of development
carries through to the adult


Maternal effect genes encode RNA and proteins

that play important roles in the early steps of

For example-Cell division, Cleavage pattern, Body Axis


Accumulation of maternal effect gene products

before fertilization allows these steps to proceed
very quickly after fertilization
Therefore defective alleles in maternal gene effects
tend to have a dramatic effect on the phenotype of
the individual

In Drosophila, geneticists have identified several dozen

maternal effect genes

These have profound effects on the early stages of development



Epigenetic inheritance refers to a pattern in which

a modification occurs to a nuclear gene or
chromosome that alters gene expression

Epigenetic changes are caused by DNA and

chromosomal modifications

However, the expression is not permanently changed

over the course of many generations
That is because the DNA sequence does not change

These can occur during oogenesis, spermatogenesis or

early embryonic development

We will look at Dosage Compensation and

Genomic Imprinting

Dosage Compensation

The purpose of dosage compensation is to offset

differences in the number of active sex

Dosage compensation has been studied extensively

in mammals, Drosophila and Caenorhabditis elegans

Depending on the species, dosage compensation

occurs via different mechanisms

Refer to Table 5.1



Dosage compensation is not well understood in

some species, such as birds and fish
In birds, the sex chromosomes are the

Z, a large chromosome containing many genes

W, a microchromosome containing few genes
Males are ZZ; females are ZW

It appears that the Z chromosome in males does not

undergo condensation like one of the X
chromosomes in female mammals

Different studies have shown variation in gene expression

of some Z-linked genes in male and female birds
May lack a general mechanism, but some compensation
may occur on specific genes


Dosage compensation in mammals

In 1949, Murray Barr and Ewart Bertram identified a

highly condensed structure in the interphase nuclei
of somatic cells in female cats but not in male cats

This structure became known as the Barr body (Figure


In 1960, Susumu Ohno correctly proposed that the

Barr body is a highly condensed X chromosome
In 1961, Mary Lyon proposed that dosage
compensation in mammals occurs by the
inactivation of a single X chromosome in females

Dosage compensation in mammals

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Tim Davis / Photo Researchers

(b) A calico cat

The Barr body in a human


The black and orange

mosaic pattern is due to
an X-linked gene that can
occur as an orange or
black allele

Figure 5.3


The mechanism of X inactivation, also known as

the Lyon hypothesis, is schematically illustrated in
Figure 5.4

The example involves a white and black variegated

coat color found in certain strains of mice
Mouse with
patches of
black and
white fur

A female mouse has inherited two X chromosomes

One from its mother that carries an allele conferring white coat
color (Xb)
One from its father that carries an allele conferring black coat
color (XB)


The epithelial cells

derived from this
embryonic cell will
produce a patch of
white fur

At an early stage of
embryonic development

While those from

this cell will produce
a patch of black fur

Figure 5.4


During X chromosome inactivation, the DNA

becomes highly compacted

When this inactivated X is replicated during cell


Most genes on the inactivated X cannot be expressed

Both copies remain highly compacted and inactive

X inactivation is passed along to all future somatic cells

Another example of variegated coat color is found

in calico cats

Refer to Figure 5.3b


The Lyon Hypothesis Put to the Test

Experiment 5A

In 1963, Ronald Davidson, Harold Nitowsky and

Barton Childs set out to test the Lyon hypothesis at
the cellular level
To do so they analyzed the expression of a human
X-linked gene

The gene encodes glucose-6-phosphate dehydrogenase

(G-6-PD), an enzyme used in sugar metabolism


Biochemists had found that individuals vary with

regard to the G-6-PD enzyme

This variation can be detected when the enzyme is

subjected to gel electrophoresis

One G-6-PD allele encodes an enzyme that migrates very


Another allele encodes an enzyme that migrates more


The fast enzyme

The slow enzyme

The two types of enzymes have minor differences in their


These do not significantly affect G-6-PD function


Figure 5.5 illustrates the mobility of G-6-PD proteins

from various individuals
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Heterozygous Hemizygous


Slow G-6-PD
Fast G-6-PD

Direction of

Heterozygous adult females produce both types of

Hemizygous males produce either the fast or the slow type

The Hypothesis

According to the Lyon hypothesis, an adult

female who is heterozygous for the fast and
slow G-6-PD alleles should express only one of
the two alleles in any particular somatic cell and
its descendants, but not both

Testing the Hypothesis

Refer to Figure 5.6


Figure 5.6


The Data
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All cells



Slow G-6-PD
Fast G-6-PD

Ronald G. Davidson, Harold M. Nitowsky, and Barton Childs. Demonstration of Two Populations of Cells in the Human Female Heterozygous for Glucose-6-Phosphate
Dehydrogenase Variants. PNAS. 50 (1963) f. 2, p. 484. Courtesy Harold M. Nitowsky. Reproduced with author permission.


All nine clones expressed one of

the two types of G-6-PD enzyme,
not both

Interpreting the Data

These epithelial cells were used
to generate the nine clones (as
described in steps 2 to 4)

The heterozygous
woman produced
both types of
G-6-PD enzymes

All cells


Clones 2, 3, 5, 6, 9 & 10
expressed only the slow
Clones 4, 7 & 8 expressed
only the fast type

9 10

Slow G-6-PD
Fast G-6-PD

Ronald G. Davidson, Harold M. Nitowsky, and Barton Childs. Demonstration of Two Populations of Cells in the Human Female Heterozygous for Glucose-6-Phosphate
Dehydrogenase Variants. PNAS. 50 (1963) f. 2, p. 484. Courtesy Harold M. Nitowsky. Reproduced with author permission.


Interpreting the Data

These results are consistent with the hypothesis


X inactivation has already occurred in any given

epithelial cell
This pattern of inactivation is passed to all of the cells


X Inactivation in Mammals Depends

on Xic, Xist, Tsix and Xce

Researchers have found that mammalian cells can count their

X chromosomes and allow only one of them to remain active

Additional X chromosomes are converted to Barr bodies

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Sex Chromosome Number of

Barr bodies

Normal female


Normal male


Turner syndrome (female)


Triple X syndrome (female)


Klinefelter syndrome (male)



The genetic control of inactivation is not entirely

understood at the molecular level

However, a short region on the X chromosome termed

the X-inactivation center (Xic) plays a critical role

For inactivation to occur, each X chromosome must

have a Xic region (Figure 5.7)
The Xic region contains a gene named Xist (for Xinactive specific transcript)

The Xist gene is only expressed on the inactive X

It does not encode a protein

It codes for a long RNA, which coats the inactive X chromosome

Other proteins will then bind and promote chromosomal
compaction into a Barr body


A gene designated Tsix also plays a role in

chromosome choice

It is located in the Xic region, overlaps Xist, and is

expressed in the opposite direction of Xist
Tsix is Xist spelled backwards
It is expressed only during early embryonic development
It encodes an RNA complementary to Xist RNA
X chromosomes carrying a Tsix mutant are preferentially
inactivated in females



Figure 5.7


The process of X inactivation can be divided into

three stages



The chosen X chromosome is inactivated


One of the X chromosomes is targeted for inactivation

The inactivated X chromosome is maintained as such during

future cell divisions

Refer to Figure 5.8


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The Barr body is

replicated and
both copies
remain compacted

Figure 5.8


A few genes on the inactivated X chromosome are

expressed in the somatic cells of adult female

These genes escape the effects of X inactivation

They include

Pseudoautosomal genes

Dosage compensation in this case is unnecessary because

these genes are located on both the X and Y chromosomes

Up to a quarter of X genes in humans may escape full


The mechanism is not understood

May involve loosening of chromatin in specific regions



Genomic imprinting is a phenomenon in which a

segment of DNA is marked and the effect is
maintained throughout the life of the organism
inheriting the marked DNA

Imprinted genes follow a non-Mendelian pattern of


Depending on how the genes are marked, the offspring

expresses either the maternally-inherited or the
paternally-inherited allele

Not both

This is termed monoallelic expression


Lets consider the following example in mice:

The Igf-2 gene encodes a growth hormone called insulinlike growth factor 2

Imprinting results in the expression of the paternal but not

the maternal allele

The paternal allele is transcribed into RNA

The maternal allele is not transcribed

Igf-2- is a loss-of-function allele that does not express a

functional Igf-2 protein

A functional Igf-2 gene is necessary for a normal size

This may cause a mouse to be dwarf depending on whether it

inherits the mutant allele from its father or from its mother

Refer to Figure 5.9


Figure 5.9

Reciprocal crossGenotypes are


Normal Size



At the cellular level, imprinting is an epigenetic

process that can be divided into three stages

1)Establishment of the imprint during gametogenesis

2) Maintenance of the imprint during embryogenesis and in
the adult somatic cells
3) Erasure and reestablishment of the imprint in the germ

These stages are described in Figure 5.10

The example also considers the imprinting of the Igf2 gene


Both male and female

mice express the Igf2
in their somatic cells

Female mouse
inactive alleles

Figure 5.10

Male mouse transmits

transcriptionally active
Transcribed into mRNA
in the somatic cells of
offspring; But half yield
defective proteins


Thus genomic imprinting is permanent in the somatic

cells of an animal

However, the marking of alleles can be altered from

generation to generation

Genomic imprinting occurs in several species

including insects, mammals and flowering plants

It may involve

A single gene
A part of a chromosome
An entire chromosome
Even all the chromosomes from one parent

It can be used for X inactivation in some species


Imprinting and DNA Methylation

Genomic imprinting must involve a marking process

At the molecular level, the imprinting of several

genes is known to involve an imprinting control
region (ICR) located near the imprinted gene

The ICR is methylated either in the oocyte or sperm

Not both

The ICR contains binding sites for one or more

transcription factors that regulate the imprinted gene
For most genes, methylation causes inhibition of

Both parents inherit one methylated and

one unmethylated gene, which is
maintained in somatic cells

Methylation is
removed in gamete
forming cells

Haploid female gametes transmit

an unmethylated DMR

Figure 5.11

Methylation in male
gamete cells only

Haploid male gametes transmit

a methylated DMR


To date, imprinting has been identified in dozens of mammalian genes

Genomic imprinting can influence human diseases.


Imprinting plays a role in the inheritance of certain human

diseases such as Prader-Willi syndrome (PWS) and
Angelman syndrome (AS)

PWS is characterized by

AS is characterized by

Reduced motor function

Small hands and feet

Hyperactivity and thinness

Unusual seizures
Repetitive symmetrical muscle movements
Mental deficiencies

Most commonly, PWS and AS involve a small deletion in

chromosome 15

If it is inherited from the mother, it leads to AS

If it is inherited from the father, it leads to PWS


Researchers have discovered that this region contains

closely linked but distinct genes

AS results from the lack of expression of a single gene,


These are maternally or paternally imprinted

UBE3A encodes a protein that regulates protein degradation

The paternal copy is silenced

PWS results (most likely) from the lack of expression of a

single gene, designated SNRNP

SNRNP encodes a small nuclear ribonucleoprotein polypeptide N

which is part of a complex that controls gene splicing
The maternal copy is silenced



Figure 5.12



Extranuclear inheritance refers to inheritance

patterns involving genetic material outside the

The two most important examples are due to
genetic material within organelles

Mitochondria and chloroplasts

These organelles are found in the cytoplasm

Therefore, extranuclear inheritance is also termed

cytoplasmic inheritance

The genetic material of mitochondria and

chloroplasts is located in a region called the nucleoid

The genome is composed of a single circular

chromosome containing double-stranded DNA

Refer to Figure 5.13

A nucleoid can contain several copies of the chromosome

An organelle can contain more than one nucleoid

Chloroplasts tend to have more nucleoids per

organelle than mitochondria
Refer to Table 5.3


Besides variation in copy number, the sizes of

organellar genomes also vary greatly among
different species

There is a 400-fold variation in the size of mitochondrial

There is also a substantial variation in size of chloroplast

In general, mitochondrial genomes are

Fairly small in animals

Intermediate in size in fungi and protists
Fairly large in plants

Although plants and algae can show substantial variation in size


The main function of mitochondria is oxidative


A process used to generate ATP (adenosine triphosphate)

The genetic material in mitochondria is referred to as mtDNA

The human mtDNA consists of only 17,000 bp (Figure 5.15)

Oxygen is consumed during ATP synthesis

ATP is used as an energy source to drive cellular reactions

It carries relatively few genes

rRNA and tRNA genes

13 polypeptides that function in oxidative phosphorylation

Note: Most mitochondrial proteins are encoded by genes in

the nucleus

These proteins are made in the cytoplasm, then transported into the


Ribosomal RNA genes

Necessary for synthesis of proteins

inside the mitochondrion

Transfer RNA genes

NADH dehydrogenase subunit genes (7)
Cytochrome b gene
Cytochrome c oxidase subunit genes (3)
ATP synthase subunit genes (2)
Noncoding DNA

Function in oxidative phosphorylation

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12S rRNA


16S rRNA




Figure 5.14



The main function of chloroplasts is photosynthesis

The genetic material in chloroplasts is referred to as cpDNA

The cpDNA of tobacco plant consists of 156,000 bp

It is typically about 10 times larger than the mitochondrial genome of

animal cells

It carries between 110 and 120 different genes

rRNA and tRNA genes

Many polypeptides that are required for photosynthesis

As with mitochondria, many chloroplast proteins are encoded

by genes in the nucleus

These proteins contain chloroplast-targeting signals that direct them

from the cytoplasm into the chloroplast


Maternal Inheritance

Carl Correns discovered that pigmentation in

Mirabilis jalapa (the four oclock plant) shows a nonMendelian pattern of inheritance

Leaves could be green, white or variegated (with both

green and white sectors)

Correns determined that the pigmentation of the

offspring depended solely on the maternal parent and
not at all on the paternal parent

This is termed maternal inheritance

different than maternal effect

Refer to Figure 5.15


Figure 5.15


In this example, maternal inheritance occurs because the

chloroplasts are transmitted only through the cytoplasm of
the egg

The pollen grains do not transmit chloroplasts to the offspring

The phenotype of leaves can be explained by the types of

chloroplasts found in leaf cells
Green phenotype is the wild-type

White phenotype is the mutant

Due to normal chloroplasts that can make green pigment

Due to a mutation that prevents the synthesis of the green

A cell can contain both types of chloroplasts

A condition termed heteroplasmy

In this case, the leaf would start out all green


Figure 5.16 provides a cellular explanation for the

variegated phenotype in Mirabilis jalapa

Consider a fertilized egg that inherited two types

of chloroplast

Green and white

As the plant grows, the chloroplasts are

irregularly distributed to daughter cells

Sometimes, a cell may receive only white chloroplasts

Such a cell will continue to divide and produce a white sector

Cells that contain only green chloroplasts or a

combination of green and white will ultimately produce
green sectors

Figure 5.16


The Pattern of Inheritance of

The pattern of inheritance of mitochondria and
chloroplasts varies among different species
Heterogamous species

Produce two kinds of gametes

Female gamete Large

Provides most of the cytoplasm to the zygote

Male gamete Small
Provides little more than a nucleus

In these species, organelles are typically (but not

always) inherited from the mother
Table 5.4 describes various inheritance patterns


The Pattern of Inheritance of


Species with maternal inheritance may, on

occasion, exhibit paternal leakage
The paternal parent occasionally provides
mitochondria through the sperm

In the mouse, for example, 1-4 paternal mitochondria

are inherited for every 100,000 maternal mitochondria
per generation of offspring


Human Mitochondrial Diseases

Occurs in two ways

Human mtDNA is transmitted from mother to offspring via the

cytoplasm of the egg

Therefore, the transmission of human mitochondrial diseases follows a

strict maternal inheritance pattern

Mitochondrial mutations may occur in somatic cells

Accumulate as a person ages

Mitochondria are very susceptible to DNA damage

High oxygen consumption leads to free radicals

Mitochondrial DNA has very limited repair abilities

Over 200 human mitochondrial diseases have been


These are typically chronic degenerative disorders affecting cells

requiring high levels of ATP such as nerve and muscle cells
See Table 5.5


Human Mitochondrial Diseases


Human Mitochondrial Diseases

Heteroplasmy is an important factor in

mitochondrial disease
Cells can contain a mixed population of
Some may carry disease causing mutation while
others do not

As cells divide some cells may receive a high ratio of

mutant to normal mitochondria
Disease may occur when the ratio of mutant to
normal mitochondria exceeds a threshold value
Symptoms may vary widely within a given family

The Endosymbiosis Theory

The endosymbiosis theory describes the evolutionary

origin of mitochondria and chloroplasts

These organelles originated when bacteria took up

residence within a primordial eukaryotic cell

chloroplasts originated as cyanobacterium

mitochondria originated as Gram-negative nonsulfur purple bacteria
During evolution, the characteristic of the intracellular bacterial cell
gradually changed to that of the organelle

The endosymbiotic origin of organelles is supported

by several observations

These include

Organelles have circular chromosomes (like bacteria)

Organelle genes are more similar to bacterial genes than to those
found within the nucleus


The eukaryotic cell

was now able to

Figure 5.17

The eukaryotic cell

was now able to
synthesize greater
amounts of ATP

The bacterial cells

may have gained a
more stable
environment with
more nutrients


The Endosymbiosis Theory

During the evolution of eukaryotic species, most genes

originally found in the bacterial genome have been lost or
transferred to the nucleus

Most gene transfer occurred early in chloroplast and

mitochondrial evolution
The gene transfer has primarily been unidirectional

From the organelles to the nucleus

In addition, gene transfer can occur between organelles

Certain genes in nucleus are more similar in sequence to known

bacterial genes
About 1500 genes transferred to nuclear genome

Between two mitochondria, two chloroplasts or a mitochondrion and a


The biological benefits of gene transfer remain unclear