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Chapter 05

Lecture Outline
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INTRODUCTION

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
and
Obey Mendels laws

Most genes in eukaryotic species follow a


Mendelian pattern of inheritance

However, there are many that dont

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INTRODUCTION

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

Mitochondria
Chloroplasts

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5.1 MATERNAL EFFECT

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
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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


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Cross

and

Reciprocal cross

Same genotype, but different


phenotype

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
generation

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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

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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

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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

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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

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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

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D gene products cause egg cleavage that


promotes a right-handed body plan

Figure 5.2b

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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

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Figure 5.2c

Remarkably, the orientation of


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

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Maternal effect genes encode RNA and proteins


that play important roles in the early steps of
embryogenesis

For example-Cell division, Cleavage pattern, Body Axis


orientation

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

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5.2 EPIGENETIC INHERITANCE

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
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Dosage Compensation

The purpose of dosage compensation is to offset


differences in the number of active sex
chromosomes

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


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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

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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


5.3a)

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
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Dosage compensation in mammals


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Barr
body

Tim Davis / Photo Researchers

(b) A calico cat

The Barr body in a human


nucleus

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

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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)

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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

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During X chromosome inactivation, the DNA


becomes highly compacted

When this inactivated X is replicated during cell


division

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

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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

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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


quickly

Another allele encodes an enzyme that migrates more


slowly

The fast enzyme

The slow enzyme

The two types of enzymes have minor differences in their


structures

These do not significantly affect G-6-PD function

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


from various individuals
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Heterozygous Hemizygous
female
male

Hemizygous
male
Origin

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

Direction of
migration

Heterozygous adult females produce both types of


enzymes
Hemizygous males produce either the fast or the slow type
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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


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Figure 5.6

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The Data
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All cells
1

Clones

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.

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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
1

Clones
3

Clones 2, 3, 5, 6, 9 & 10
expressed only the slow
type
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.

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Interpreting the Data

These results are consistent with the hypothesis


that

X inactivation has already occurred in any given


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

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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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Phenotype

Sex Chromosome Number of


Composition
Barr bodies

Normal female

XX

Normal male

XY

Turner syndrome (female)

X0

Triple X syndrome (female)

XXX

Klinefelter syndrome (male)

XXY

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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


chromosome
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

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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

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Promotes
compaction
Prevents
compaction

Figure 5.7

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The process of X inactivation can be divided into


three stages

Initiation

Spreading

The chosen X chromosome is inactivated

Maintenance

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

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A few genes on the inactivated X chromosome are


expressed in the somatic cells of adult female
mammals

These genes escape the effects of X inactivation

They include

Xist
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


inactivation

The mechanism is not understood

May involve loosening of chromatin in specific regions

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5.3 GENOMIC IMPRINTING

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


inheritance

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


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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


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Figure 5.9

Reciprocal crossGenotypes are


identical

Normal Size

Dwarf

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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
cells

These stages are described in Figure 5.10

The example also considers the imprinting of the Igf2 gene

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Both male and female


mice express the Igf2
in their somatic cells

Female mouse
transmits
transcriptionally
inactive alleles

Figure 5.10

Male mouse transmits


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

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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


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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
transcription
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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

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

Genomic imprinting can influence human diseases.


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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


Obesity
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

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Researchers have discovered that this region contains


closely linked but distinct genes

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


UBE3A

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

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Deletion
inherited
from
mother

Figure 5.12

Deletion
inherited
from
father

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5.4 EXTRANUCLEAR
INHERITANCE
Extranuclear inheritance refers to inheritance

patterns involving genetic material outside the


nucleus
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
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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
Note:

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
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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


genomes
There is also a substantial variation in size of chloroplast
genomes

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

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The main function of mitochondria is oxidative


phosphorylation

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
mitochondria

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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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tRNAPhe

tRNAPro

12S rRNA
tRNAVal

tRNAThr
tRNAGlu

16S rRNA
tRNALeu
tRNAIle
tRNAGln
tRNAMet

tRNALeu
tRNASer
tRNAHis

tRNATrp
tRNAAla
tRNAAsn
tRNACys
tRNATyr

tRNAArg
tRNAGly
tRNASer

Figure 5.14

tRNAAsp tRNALys

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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

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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

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Figure 5.15

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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
pigment

A cell can contain both types of chloroplasts

A condition termed heteroplasmy


In this case, the leaf would start out all green

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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
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Figure 5.16

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The Pattern of Inheritance of


Organelles
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
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The Pattern of Inheritance of


Organelles

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

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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


identified

These are typically chronic degenerative disorders affecting cells


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

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Human Mitochondrial Diseases

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Human Mitochondrial Diseases

Heteroplasmy is an important factor in


mitochondrial disease
Cells can contain a mixed population of
mitochondria
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
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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

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The eukaryotic cell


was now able to
undergo
photosynthesis

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

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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


chloroplast

The biological benefits of gene transfer remain unclear


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