Dr.

Marie Serena McConnell

Mendelian inheritance patterns involve genes that

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

Linkage can be considered as non-Mendelian

inheritance

Patterns of inheritance that deviate from a

Mendelian pattern:
Maternal effect and epigenetic inheritance
Involve genes in the nucleus

Extranuclear inheritance
Involves genes in organelles other than the nucleus
Mitochondria
Chloroplasts

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
This phenomenon is due to the accumulation of
gene products that the mother provides to her
developing eggs

7-4

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 7.1 describes Boycotts experiment

7-5

Reciprocal cross

A 3:1 phenotypic ratio would

be predicted by a Mendelian
pattern of inheritance

Figure 7.1

7-6

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) alelles

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

7-7

Parental
generation
DD

dd

dd

DD

F1 generation
Dd
All dextral
F2 generation

Dd
All sinistral
Males and females

1 DD

2 Dd
1 dd
All dextral
Cross to each other

F3 generation

Males and females

3 dextral

1 sinistral

Note that the phenotype of each generation

depends on the maternal genotype of the
previous generation

DD or Dd mothers produce dextral offspring

dd mothers produce sinistral offspring

The phenotype of the progeny is determined by

the mothers genotype NOT phenotype

The genotypes of the father and offspring do not affect

the phenotype of the offspring
7-9

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 7.2

7-11

D gene products cause egg cleavage that

promotes a right-handed body plan

Figure 7.2

7-12

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 7.2

7-13

Maternal effect genes encode RNA or proteins that

play important roles in the early steps of
embryogenesis

For example

Cell division
Cleavage pattern

In Drosophila, geneticists have identified several

dozen maternal effect genes

These have profound effects on the early stages of

development (later lecture will deal with this in detail)

7-14

Epigenetic inheritance refers to a pattern in which

a modification occurs to a nuclear gene or
chromosome that alters gene expression
However, the expression is not permanently changed
over the course of many generations

Epigenetic changes are caused by DNA and

chromosomal modifications
These can occur during oogenesis, spermatogenesis or
early embryonic development
7-15

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 7.1
7-16

7-17

Barr body is a highly

condensed X
chromosome

The mechanism of X inactivation, also known as

the Lyon hypothesis, is schematically illustrated in
Figure 7.4

The example involves a white and black variegated

coat color found in certain strains of mice

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)

7-20

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 will produce a
patch of black fur

Figure 7.4

7-21

During X chromosome inactivation, the DNA

becomes highly compacted
Most genes on the inactivated X cannot be expressed

When this inactivated X is replicated during cell

division
Both copies remain highly compacted and inactive

In a similar fashion, X inactivation is passed along

to all future somatic cells

Another example of variegated coat color Is found

in calico cats
Refer to Figure 7.3b

7-22

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

7-23

Biochemists had found that individuals vary with

regards to the G-6-PD enzyme
This variation can be detected when the enzyme is
subjected to agarose gel electrophoresis
One G-6-PD allele encodes an enzyme that migrates very
quickly
The fast enzyme

Another allele encodes an enzyme that migrates slowly

The slow enzyme

The two types of enzymes have minor differences in their

structures
These do not significantly affect G-6-PD function

7-24

Figure 7.5 illustrates the mobility of G-6-PD proteins

from various individuals

Thus heterozygous adult females produce both types of

enzymes
Hemizygous males produce either the fast or the slow type
7-25

 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

7-26

Figure 7.6

7-27

The Data

7-28

Interpreting the Data

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

All nine clones expressed one of

the two types of G-6-PD enzyme,
not both
Clones 2, 3, 5, 6, 9 & 10
expressed only the slow
type
Clones 4, 7 & 8 expressed
only the fast type

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

7-29

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

7-30

Genomic imprinting is a phenomenon in which

expression of a gene depends on whether it is
inherited from the male or the female parent

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

7-39

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

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

The paternal allele is transcribed into RNA

The maternal allele is not transcribed

Igf-2m is a mutant allele that yields a defective protein

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

inherits the mutant allele from its father or mother

7-40

Cross: Homozygous normal male (Igf-2 Igf-2) X

homozygous mutant female (Igf-2m Igf-2m)
Offspring are heterozygous (Igf-2 Igf-2m)
They have inherited an Igf-2 allele from their father

This allele is expressed yielding a functional protein

The mouse grows to a normal size

Reciprocal cross: Homozygous mutant male (Igf-2m Igf-2m)

X homozygous normal female (Igf-2 Igf-2)
Offspring are heterozygous (Igf-2 Igf-2m)
They have inherited an Igf-2m allele from their father

This allele is expressed yielding a defective protein

The mouse has a dwarf phenotype

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 7.10

The example also considers the imprinting of the Igf-2

gene

Both male and female

mice express the Igf-2
in their somatic cells

Female mouse
transmits
transcriptionally
inactive alleles

Erasure and Reestablishment

During gametogenesis, the
imprint is erased; it is
reestablished depending on the
sex of the animal

Male mouse transmits

transcriptionally active
alleles
m
m

Transcribed into mRNA

in the somatic cells of
offspring; But yields
defective proteins

Genomic imprinting is permanent in somatic cells

It may involve

However, the marking of alleles can be altered from

generation to generation

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

Imprinting is the reason that parthenogenesis ("virgin

birth") does not occur in mammals. Two complete
female genomes cannot produce viable young
because of the imprinted genes.

 Failure

to inherit several
nonimprinted genes on the
father's chromosome #15 causes
a human congenital disorder
called Prader-Willi syndrome.
Failure to inherit one
nonimprinted gene (UBE3A) on
the mother's chromosome #15
causes Angelman syndrome.
Failure of imprinting in somatic
cells may lead to cancer.

 The

cancerous cells of a
malignancy called Wilms tumor
and many cases of colon cancer
have both copies of the IGF2 gene
expressed (where only one, the
father's, should be).
Reduced methylation and hence
increased expression of protooncogenes can lead to cancer,
while
increased methylation and hence
decreased expression of tumor
suppressor genes can also do so.

Genomic imprinting must involve a marking process

At the molecular level, the imprinting of several

genes is known to involve differentially methylated
regions (DMRs)
These are located near the imprinted genes
They are methylated either in the oocyte or sperm
Not both

They contain binding sites for one or more transcriptional

factors

For most genes, methylation at a DMR results in

inhibition of gene expression
Methylation could
Enhance the binding of proteins that inhibit transcription
and/or
Inhibit the binding of proteins that enhance transcription

Because of this, imprinting is usually described as

a process that silences gene expression by
preventing transcription
However, sometimes methylation activates specific genes

Lets consider two imprinted genes in humans,

H19 and Igf-2
They lie close to each other on human chromosome 11
Appear to be controlled by the same DMR

This DMR

Is ~ 2000 bp
Contains binding sites for proteins that regulate the transcription
of both genes
Is highly methylated on the paternally inherited chromosome

Methylation silences the H19 gene

and activates the Igf-2 gene

Only binds to
unmethylated
DMR

Only binds to
methylated
DMR

H19 gene Igf-2 gene

activated silenced

H19 gene Igf-2 gene

silenced
activated

Example of methylation patterns in somatic cells and gametes of male and

female offspring
Maternal
chromosome

Paternal
chromosome

Female
Offspring

Haploid female gametes transmit

an unmethylated DMR

Maternal
chromosome

Paternal
chromosome

Male
Offspring

Haploid male gametes transmit

a methylated DMR

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

However, the biological significance of genomic imprinting is

still a matter of speculation

Imprinting does play a role in the inheritance of certain

human diseases such as Prader-Willi syndrome (PWS) and
Angelman syndrome (AS)
PWS is characterized by
Reduced motor function
Obesity
Mental deficiencies

AS is characterized by

Hyperactivity
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
These are maternally or paternally imprinted

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

UBE3A

The gene is paternally imprinted (silenced)

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

single gene, designated SNRNP

The gene is maternally imprinted (silenced)

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

15 15
PW gene
AS gene

Deleted region that

includes both the AS
and the PW genes

PW gene
silenced
in egg
AS gene
silenced
in sperm

PW
AS

PW
AS

PW
AS

Fertilized Fertilized
egg
egg

Angelman syndrome

The offspring does not carry an

active copy of the AS gene.

PW
AS

Prader-Willi syndrome

The offspring does not carry an

active copy of the PW gene

Silenced allele
Expressed allele

Extranuclear inheritance refers to inheritance

patterns involving genetic material outside the

nucleus
The two most important examples: mitochondria and
chloroplasts
These organelles are found in the cytoplasm
Extranuclear inheritance = cytoplasmic inheritance

The genetic material of mitochondria and

chloroplasts is located in a region called the nucleoid
Refer to Figure 7.13

The genome is composed of a single circular

chromosome containing double-stranded DNA

In general, mitochondrial genomes are

Fairly small in animals
Intermediate in size in fungi, algae and protists
Fairly large in plants

Nuclear encoded genes in red

The main function of mitochondria is oxidative

phosphorylation
A process used to generate ATP (adenosine triphosphate)
ATP is used as an energy source to drive cellular reactions

The genetic material in mitochondria is referred to as mtDNA

The human mtDNA consists of only 17,000 bp (Figure 7.14)
It carries relatively few genes
rRNA and tRNA genes
13 genes 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

Necessary for synthesis of proteins

inside the mitochondrion
Function in oxidative phosphorylation

The main function of chloroplasts is photosynthesis

The genetic material in chloroplasts is referred to as cpDNA

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

The cpDNA of tobacco plant consists of 156,000 bp

It carries between 110 and 120 different genes
rRNA and tRNA genes
Many genes 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

Genes designated
ORF (open
reading frame)
encode
polypeptides with
unknown
functions

A genetic map of the tobacco chloroplast genome

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

Refer to Figure 7.16

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
Due to normal chloroplasts that can make green pigment

White phenotype is the mutant

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 be green

Figure 7.17 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

Mutations that yield defective mitochondria are

expected to make cells grow much more slowly

Boris Ephrussi and his colleagues identified

Saccharomyces cerevisiae mutants that have such
a phenotype
These were called petites because they formed small
colonies on agar plates
Wild-type strains formed larger colonies

Biochemical and physiological evidence indicated

that petite mutants had defective mitochondria

Genetic analyses showed that petite mutants are

inherited in different ways
Two main types of mutants were identified
1. Segregational mutants
Have mutations in genes located in the nucleus
Segregate in a Mendelian manner in meiosis
Refer to Figure 7.18a

2. Vegetative mutants
Have mutations in genes located in the mitochondrial genome
Show a non-Mendelian pattern of inheritance
Refer to Figure 7.18b

Yeast come in two mating types: a and

Thus, Euphressi was able to cross yeast belonging to two different
strains

Segregational mutant

Nuclear and mendelian

Zygote then

meiosis

Each resulting tetrad

shows a 2:2 ratio of
wild-type to petite
This result is typical of
Mendelian inheritance

Euphressi discovered two types of vegetative petites

Neutral and Suppressive

Zygote then

Each resulting tetrad

shows a 4:0 ratio of
wild-type to petite

meiosis

Zygote then

These results contradict the normal

2:2 ratio expected for the segregation
of Mendelian traits

meiosis

Each resulting tetrad

shows a 0:4 ratio of
wild-type to petite

Blue and red indicate mendelian segregation of nuclear genes

Researchers later found that

Neutral petites lack most of their mitochondrial DNA
Suppressive petites lack only small segments of mtDNA

When two yeast cells are mated, offspring inherit

mitochondria from both parents

Figure 7.18

Progeny have both wild type

and neutral petite mitochondria
They display a normal
phenotype because of the wild
type mitochondria

Progeny have both wild type and suppressive

petite mitochondria
So how come only petite colonies are produced?
Two possibilities
i. Suppressive petite mitochondria could
replicate faster than wild-type mitochondria
ii. Recombination between wild-type and
petite mtDNA may ultimately produce defects
in the wild-type mitochondria

The unicellular alga Chlamydomonas reinhardtii is

a model organism
It contains a single chloroplast
Occupies ~ 40% of the cells volume

Most strains are sensitive to the antibiotic

streptomycin (sms)

In 1954, Ruth Sager identified a mutant that was

resistant to streptomycin (smr)

Like yeast, Chlamydomonas can be found in two

mating types
mt+ and mt

Mating type is due to nuclear inheritance

It segregates in a 1:1 manner

Sager and her colleagues discovered that

resistance to streptomycin was not inherited in a
Mendelian manner

smr was inherited from the mt+ parent but not from the mt
parent

In subsequent studies, they mapped several

genes, including the smr gene, to the chloroplast
chromosome

Because the
mt+ strain was
smr

Because the
mt+ strain was
sms

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 of the zygote

Male gamete Small

Provides little more than a nucleus

In these species, organelles are typically inherited from the

mother

Species with maternal inheritance may, on

occasion, exhibit paternal leakage
The paternal parent 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 mtDNA is transmitted from mother to offspring via

the cytoplasm of the egg

Several human mitochondrial diseases have been

discovered
These are typically chronic degenerative disorders affecting the
brain, heart, muscles, kidneys and endocrine glands

Example: Lebers hereditary optic neuropathy (LHON)

Affects the optic nerve
May lead to progressive loss of vision in one or both eyes
LHON is caused by mutations in several different mitochondrial
genes

MATERNAL INHERITANCE OF MITOCHONDRIAL DNA MUTATIONS

The endosymbiosis theory describes the

evolutionary origin of mitochondria and chloroplasts
These organelles originated when bacteria took up
residence within a primordial eukaryotic cell
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
undergo
phtosynthesis

The eukaryotic cell

was now able to
synthesize greater
amounts of ATP

During the evolution of eukaryotic species, most genes

originally found in the bacterial genome have been lost or
transferred to the nucleus
Modern day mitochondria and chloroplasts have lost most of the genes
still found in present-day cyanobacteria and purple bacteria

The gene transfer has primarily been unidirectional

From the organelles to the nucleus

In addition, gene transfer can occur between organelles

Between two mitochondria, two chloroplasts or a mitochondrion and a
chloroplast

The biological benefits of gene transfer remain unclear