NON-MENDELIAN

INHERITANCE
INTRODUCTION
 Mendelian inheritance patterns involve genes that
 Directly influence the outcome of an organism’s traits
and
 Obey Mendel’s laws
 Most genes in eukaryotic species follow a
Mendelian pattern of inheritance
 However, there are many that don’t

 Indeed, linkage can be considered as non-

Mendelian inheritance
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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

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

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7.1 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 snail’s body plan curvature depends on the cleavage pattern

of the egg immediately after fertilization

 Figure 7.1 describes Boycott’s experiment

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 Reciprocal cross

A 3:1 phenotypic ratio would

be predicted by a Mendelian
pattern of inheritance

Figure 7.1
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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) 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

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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 7.1
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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 mother’s genotype NOT 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 7.2a

 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 7.2
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 D gene products cause egg cleavage that
promotes a right-handed body plan

Figure 7.2
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 d gene products
cause egg cleavage
that promotes a left-
handed body plan

Even if the egg is fertilized

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

Figure 7.2
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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, etc.

 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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7.2 EPIGENETIC INHERITANCE
 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

(methylation)and chromosomal modifications
 These can occur during oogenesis, spermatogenesis or
early embryonic development

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Dosage Compensation
 Dosage compensation is the process by which
organisms equalize the expression of genes between
members of different sexes.

 It 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

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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
7.3a)
 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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 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)

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The epithelial cells
derived from this
embryonic cell will
produce a patch of
At an early stage of
white fur embryonic development

While those from

this will produce a
patch of black fur

Figure 7.4
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 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

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The Lyon Hypothesis Put to the Test
Experiment 7A
 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
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

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 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

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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 7.6

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Figure 7.6
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The Data

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 All nine clones expressed one of
Interpreting the Data the two types of G-6-PD enzyme,
not both
These epithelial cells were used
to generate the nine clones Clones 2, 3, 5, 6, 9 & 10
(as described in steps 2 to 4) 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

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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 cell’s
progeny

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X Inactivation 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

Sex Chromosome Number of

Phenotype Composition Barr bodies
Normal female XX 1
Normal male XY 0
Turner syndrome (female) X0 0
Triple X syndrome (female) XXX 2
Klinefelter syndrome (male) XXY 1

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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 7.7, slide 7-35)
 The Xic region contains a gene named Xist (for X-
inactive 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
 It is expressed only during early embryonic development
 It encodes an RNA complementary to Xist RNA
 Termed antisense RNA (where Xist RNA is the sense RNA)

 Tsix antisense RNA is believed to bind to Xist sense RNA

and inhibit its function
 In other words, TsiX RNA prevent X chromosome inactivation
 The choice of which X is inactivated involves a complex interplay
between Xist and Tsix
 The exact mechanism is not understood

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 A second region termed the X chromosome
controlling element (Xce) affects the choice of the X
chromosome to be inactivated
 Xce is close to and may even overlap Xic
 Xce may bind proteins that regulate the genes of the Xic

 A female heterozygous for different Xce alleles will

have a skewed X-inactivation
 The X chromosome that carries a strong Xce allele is
more likely to remain active than one with a weak Xce
allele

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 Promotes
compaction

Prevents
May regulate the transcription of
compaction
the Xic region
Thereby influences the choice of
the active X chromosome
Figure 7.7

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Genomic Imprinting
 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

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 Let’s consider the following example in mice:
 The Igf-2 gene encodes a growth hormone called insulin-
like growth factor 2
 A functional Igf-2 gene is necessary for a normal size

 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-2m is a mutant allele that yields a partially defective

protein
 This may cause a mouse to be dwarf depending on whether it
inherits the mutant allele from its father or mother
 Refer to Figure 7.9

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 At the cellular level, imprinting is an epigenetic
process that can be divided into three stages

 Establishment of the imprint during gametogenesis

 Maintenance of the imprint during embryogenesis and in
the adult somatic cells
 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 Igf2 gene

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Both male and female
mice express the Igf2
in their somatic cells

Male mouse transmits

transcriptionally active
Female mouse alleles
transmits
transcriptionally Transcribed into mRNA
inactive alleles in the somatic cells of
offspring; But yields
defective proteins

Figure 7.10
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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 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

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 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, this is not always the case
 Refer to Figure 7.11

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 Let’s 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

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 Igf-2 gene
silenced

Only binds to
unmethylated
H19 gene
DMR
activated

Only binds to H19 gene Igf-2 gene

methylated silenced activated
DMR

Figure 7.11a
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7.3 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
 Refer to Figure 7.13
 The genome is composed of a single circular
chromosome containing double-stranded DNA
 Note:
 A nucleoid can contain more than one chromosome
 An organelle can contain more than one nucleoid

 Chloroplasts tend to have more nucleoids per

organelle than mitochondria
 Refer to Table 7.3

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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, algae and protists
 Fairly large in plants

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 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

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 Necessary for synthesis of proteins
inside the mitochondrion

Function in oxidative phosphorylation

Figure 7.14
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 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

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

Figure 7.15 A genetic map of the tobacco chloroplast genome

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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 of the zygote

 Male gamete  Small

 Provides little more than a nucleus

 In these species, organelles are typically inherited

from the mother

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 The Pattern of Inheritance of
Organelles
 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

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Human Mitochondrial Diseases
 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

 Several human mitochondrial diseases have been

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

 Example: Leber’s 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
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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 The eukaryotic cell
phtosynthesis was now able to
synthesize greater The bacterial cells
amounts of ATP may have gained a
more stable
environment with
more nutrients

Figure 7.20
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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
 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

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