Part06 Non-Mendelian inheritance: epigenetic inheritance etc (I)

Part06

Non-Mendelian inheritance: epigenetic inheritance etc (I)

YK Jang

Genetics

ContentsSo far we learned about molecular mechanisms responsible f

or how to modulate chromatin structure and function

Chromatin modulation including histone modifications and DNA methylation is one major molecular basis of non-Mendelian inheritance

In this part, we’ll take a look at general examples of Non-Mendelian inheritance:

(1) Maternal effect, (2) epigenetic inheritance (X-inactivation, genomic imprinting, cancer development), & (3) extranuclear 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

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

INTRODUCTION

• In this chapter we will discuss additional (even bizarre = very strange) patterns of inheritance that deviate*(=divert) 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


*to change what you are doing so that you are not following an expected plan, idea so on

• 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


(1) MATERNAL EFFECT

We’ll begin by considering genes that have a maternal effect


• 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, Lymnaea 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

Reciprocal cross

Figure 7.1

A 3:1 phenotypic ratio would be predicted by a Mendelian pattern of inheritance

Pattern deviating from Mendelian pattern

D is dominant to d (dextral is dominant to si

nistral)

Many combinations of crosses produced results that could not be explained by a Mendelian pattern of inheritance

How can we explain the unusual

results?

Alfred Sturtevant proposed the idea that snail coiling is due to a maternal effect gene (D or d

allele)

Figure 7.1

F1 mothers are Dd

This explains this 3:1 ratio

This ratio corresponds to the genotypes of the F2 females, which were the mothers of F3 (F2 mothers include 3 with the D allele

and 1 with the d allele)

Reciprocal cross

F1 mothers are Dd

The dominant allele, D, caused ALL the F2 offspring to be dextral, even if the offspring’

s genotype was dd


• 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 t

he phenotype of the offspring


• Q: How to explain this phenomenon?• The non-Mendelian inheritance pattern of materna

l effect genes can be explained by the process of oogenesis in female animals– Maturing animal oocytes are surrounded by maternal c

ells that provide them with nutrients– These nurse cells are diploid, whereas the oocyte beco

mes 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

Figure 7.2

The gene products are a reflection of the genotype of the mother Namely, the nurse cells produced both D and d gene products

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

In this way, the gene products of the nurse cells, which reflect the genotype

of the mother, influence the early developmental stages

Figure 7.2

A female with DD or Dd alleles will transmit D gene productsD gene products cause egg cleavage that promotes a right-h

anded body plan

Now we understand the relationship between oogenesis and maternal effect genes. Let’s reconsider the topic of snail coiling

Figure 7.2

Finally, a dd mother will contribute only d gene products

d gene products cause egg cleavage that promotes a left-hand

ed 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

• 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

determination

• Accumulation before fertilization allows these steps to proceed very quickly just 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 (*See next supplementary slides)• These have profound effects on the early stages of development

Axis Establishment of Drosophila

• Maternal effect (egg-polarity) genes– Encode for cytoplasmic determinants that initi

ally establish the axes of the body of Drosophila ( 배발생 초기에 body axes 의 구축에 필요한 세포질성 결정인자를 포함함 )

Ref: Campbell Biology, Ch21

Supplement

Q: The effect of the bicoid gene (a maternal effect gene)?

• Flies with the bicoid mutation (maternal effect gene)– Do not develop a body axis correctly ( 비정상적인 체축 )

Head

Wild-type larva

Tail Tail

Mutant larva (bicoid)Drosophila larvae with wild-type and bicoid mutant phenotypes. A mutation in the mother’s bicoid gene leads to tail structures at both ends (bottom larva). The numbers refer to the thoracic and abdominal segments that are present.

(a)

T1 T2T3

A1 A2 A3 A4 A5 A6 A7A8

A8A7 A6 A7

A8

Tail

Figure 21.14a

Bicoid 돌연변이는 머리 - 꼬리 말단부위 모두에 꼬리 구조를

형성함


Supplement

Gradients of bicoid mRNA and Bicoid protein

(b) Gradients of bicoid mRNA and Bicoid protein in normal egg and early embryo.

Translation of bicoid mRNAFertilization

Nurse cells Egg cell

bicoid mRNA

Developing egg cell

Bicoid mRNA in mature unfertilized egg

100 µm

Bicoid protein inearly embryo

Anterior end

1

2

3

Figure 21.14b

The bicoid mRNA produced in nurse cells transports to egg cell

The bicoid mRNAs are localized at the anterior end of the egg

After fertilization, the mRNA is translated.

Bicoid protein is one of several morphogens involved in a

xis specification


Supplement

• 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 (can be changed due to its dynamics but stable)– Epigenetic changes in particular gene can affect permanently the

phenotype of the individual– However, epigenetic modifications are not permanent because they do not

change the actual DNA sequence– For example, a gene may undergo epigenetic changes that inactivate it for

the lifetime when this individual makes gametes, the gene may become activated in offspring

• Epigenetic changes are caused by DNA and chromosomal modifications

– These can occur during most cellular and organismal processes including oogenesis, spermatogenesis or early embryonic development, cancer development, stem cell differentiation

(2) EPIGENETIC INHERITANCENow we are discussing on non-Mendelian inheritance

• The purpose of dosage compensation is to offset differences in the number of active sex chromosomes

• (“Offset ( 상쇄하다 )” means that it has an opposite effect so that the situation remains the same)

• 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

Dosage Compensation

We’ll examine two examples of epigenetic inheritance: dosage compensation and genomic imprinting

We’ll focus on

this

animals carrying their babies in a skin pocket (캥거루와 같은 유대류 )

Living organism that have both male and female organs (암수한몸 )

• 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

– When the expression of nine Z-linked genes were examined, at least six genes showed expression levels that were similar in males and females

– Alternatively, dosage compensation may occur if either/or

• Genes on the Z chromosome in male are down-regulated 50%• Corresponding genes in the female could be up-regulated twofol

d

• 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 (Fig. 7.3 a)

• In 1960, Susumu Ohno correctly proposed that the Barr body is a highly condensed X chromosome

• Based on these two lines of study, in 1961, Mary Lyon proposed that dosage compen

sation in mammals occurs by the inactivation of a single X chromosome in females– Liane Russell also proposed the same theory at about th

e same time

DNA staining with a DNA-specific dye,

DAPI

X chromosome staining with a X-specific probe

(yellow color)

Fig. 7.3a

Tortoiseshell or calcio cat with the mottled fur color

“Twin spots in fly

Mystery of the presence or absence of sweat glands in female skin

• In humans, mosaicism can be observed in a recessive X-linked mutation that prevents the development of sweat glands

• A woman who is heterozygous for this trait has patches of normal skin and patches of skin lacking sweat glands

(1) (2) (3)

(4)

Which of them belongs to phenotype caused by X chromosome inactivation?

Fig. 7.3b

• 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 c

olor (Xb)• One from its father that carries an allele conferring black coat col

or (XB)

Figure 7.4

At an early stage of embryonic development

The epithelial cells derived from this

embryonic cell will produce a patch of

white fur

While those from this will produce a patch of black fur

This top of this figure represents a mass of several cells that compose the early embryo. Initially, both X chromosomes are active

The mechanism of X chromosome

inactivation

• 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

(=cell memory)

• 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

• 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

The Lyon Hypothesis Put to the Test

• 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

• 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

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

– “Adult female mammals contain one active X chromosome”

Testing the Hypothesis

– Refer to Figure 7.6

Figure 7.6

TissueSmall skin samples taken from a woman who was heterozygous for the fast and slow alleles of G-6-PD

A clone includes mitotic descendants derived from

a single mother cell

The Data

Interpreting the Data All nine clones expressed one of the two types of G-6-PD enzyme, not both

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

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

• 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 (=Epigenetic inheritance)

Interpreting the Data

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

Phenotype

Sex Chromosome Composition

Number of 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

Molecular mechanism of X inactivation?

• 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)

• The Xic region contains a gene named Xist (for X-inactive specific transcript)– The Xist gene is only expressed on the inactive X chro

mosome– 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 second region termed the X chromosome controlling element (Xce) affects the choice of the X chromosome to be inactivated– This choice occurs during embryonic development and is

maintained in all subsequent cell divisions

– Researchers speculate that Xce serves as a binding site for proteins that regulate the expression of genes in the Xic, such as Xist or Tsix

– Genetic variation in Xce that enhances Xist expression would tend to promote Barr body formation, whereas Xce variation that enhances Tsix expression would tend to prevent X inactivation

• 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

Figure 7.7: The Xic region of the X chromosome

Promotes compaction

Prevents compaction

May regulate the transcription of the TsiX gene

Thereby influences the choice of the active X chromosome

• The process of X inactivation can be divided into three stages– Initiation

• One of the X chromosomes is targeted to be inactive

– Spreading• The chosen X chromosome is inactivated

– Maintenance• The inactivated X chromosome is maintained as such during

future cell divisions


Figure 7.8: The function of the Xic locus during X chromosome inactivation

The Barr body is replicated and both

copies remain compacted

Initiation: Occurs during embryonic development. The number of X-inactivation centers (Xics) are counted and one of the X chromosome remains active and the other is targeted for inactivation

Spreading: Occurs during embryonic development. It begins at the Xic and progresses toward both ends until the entire chromosome is inactivated. The Xist gene encodes an mRNA that coats the X chromosome and promotes its compaction into a Barr body

Maintenance: Occurs from embryonic development through adult life. The inactivated X chromosome is maintained as such during subsequent cell divisions.

• 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– SmcX encodes histone demethylase which has activity f

or removing methylation on histone tails (Published in Cell Journal (2006))

– Pseudoautosomal genes• Dosage compensation in this case is unnecessary because thes

e genes are located both on the X and Y

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

– This is termed monoallelic expression

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

• However, the biological significance of genomic imprinting is still a matter of speculation (not much understood yet)

Take one example

Dwarf mouseNormal size mouse

VS

Ref: Biology, 7th ed by Campbell, Chapter 15: Fig. 15.17

Genomic imprinting of the mouse Igf2 gene results in generation of dwarf mouse

An example of genomic imprinting in the mouse

• 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 defective protein

• This may cause a mouse to be dwarf depending on whether it inherits the mutant allele from its father or mother



Figure 7.9: An example of genomic imprinting in the mouse

Dwarf littermates

Normal-size littermates

– 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

– Establishment of the imprint during gametogenesis– Maintenance of the imprint during embryogenesis and in t

he adult somatic cells– Erasure and reestablishment of the imprint in the germ ce

lls

• These stages are described in Figure 7.10– The example also considers the imprinting of the Igf-2 ge

ne

Figure 7.10

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

m

m

Both male and female mice express the Igf-2 in their somatic cells

Male mouse transmits transcriptionally active

allelesFemale mouse transmits

transcriptionally inactive alleles

Transcribed into mRNA in the somatic cells of offspring; But yields defective proteins

during gametogenesis

Heterozygous femaleHeterozygous male

Imprinting results in the expression of the paternal but not the maternal allele

• Thus genomic imprinting is permanent in the somatic cells of an animal– However, the marking of alleles can be altered from

generation to generation (Dynamic)

• Genomic imprinting occurs in several species including mammals, insects and plants

• It may involve – A single gene– A part of a chromosome– An entire chromosome– Even all the chromosomes from one parent

• 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

Imprinting and DNA Methylation

• 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

• 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 o

f both genes• Is highly methylated on the paternally inherited chromosome

– Methylation silences the H19 gene

and activates the Igf-2 gene

Figure 7.11a

Only binds to unmethylated

DMR H19 gene activated

Igf-2 gene silenced

Only binds to methylated

DMRH19 gene silenced

Igf-2 gene activated

Role of DNA methylation in the imprinting process

Figure 7.11b Methylation patterns in somatic cells and gametes of male and female offspring (Igf-2 allele with methylated DMR can express mRNA for that gene)

Paternal chromosome

Maternal chromosome

Female Offspring

Male Offspring

Haploid female gametes transmit an unmethylated DMR

Haploid male gametes transmit a methylated DMR

Paternal chromosome

Maternal chromosome

The Igf-2 gene is always silenced

The Igf-2 gene is always expressed

• 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– UBE3A encodes a protein called EA-6P that transfers small ubiquitin

molecules to certain proteins to target their degradation – The gene is paternally imprinted (silenced)

• PWS results (most likely) from the lack of expression of a single gene, designated SNRNP – SNRNP encodes a small nuclear ribonucleoprotein which is a compl

ex that controls gene splicing • This protein is necessary for the synthesis of critical proteins in the brain

– The gene is maternally imprinted (silenced)

Figure 7.12: The role of imprinting in the development of Angelman and Prader-Willi syndromes

• 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 cyto

plasmic inheritance


(3) EXTRANUCLEAR INHERITANCE

Non-Mendelian 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

• 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


Fig. 7.13: Nucleoids within (a) mitochondria and (b) chloroplasts

(a) (b)

• 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 ge

nomes– There is also a substantial variation in size of chloroplast g

enomes

• In general, mitochondrial genomes are– Fairly small in animals – Intermediate in size in fungi, algae and protists– Fairly large in plants


• 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 mi

tochondria


Figure 7.14: A genetic map of human mtDNA

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 a

nimal 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 fr

om the cytoplasm into the chloroplast


Figure 7.15 A genetic map of the tobacco chloroplast genome

Genes designated ORF (open

reading frame) encode

polypeptides with unknown functions

• Carl Correns discovered that pigmentation in Mirabilis jalapa (the four o’clock plant) shows a non-Mendelian pattern of inheritance – Leaves could be green, white or variegated (with both gree

n and white sectors)


Maternal Inheritance in the Four-o’clock Plant

• 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


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 pigme

nt

– 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



Figure 7.17

• 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 col

onies on agar plates– Wild-type strains formed larger colonies


The Petite Trait in Yeast

>Studies in yeast and Chlamydomonas provided genetic evidence for extranuclear inheritance of mitochondria and chloroplasts. >Here we’ll discuss the petite trait in yeast.

• 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



Figure 7.18

• Yeast come in two mating types: a and – Thus, Euphressi was able to cross yeast belonging to two different stra

ins

Zygote then meiosisEach resulting tetrad shows a 2:2 ratio of wild-type to petite

This result is typical of Mendelian inheritance


Figure 7.18

• Euphressi discovered two types of vegetative petites – Neutral and Suppressive

Zygote then meiosis

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

Zygote then meiosis

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

These results contradict the normal 2:2 ratio expected for the segregation of

Mendelian traits

• 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



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

Figure 7.18

• The pattern of inheritance of mitochondria and chloroplasts varies among different species– Heterogamous species (reproduced by

two different gametes, sperm & egg)• 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


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


The Pattern of Inheritance of Organelles

• Human mtDNA is transmitted from mother to offspring via the cytoplasm of the egg– Therefore, the transmission of human mitochondrial diseases follow

s a strict maternal inheritance pattern

• Several human mitochondrial diseases have been discovered– These are typically chronic degenerative disorders affecting the brai

n, 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 gen

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

Human Mitochondrial Diseases

Homework (I)• You have a female snail that coils to the right, but you do not kn

ow its genotype. You may assume that right coiling (D) is dominant to left coiling (d). You also have male snails at your disposal of known genotype.

How would you determine the genotype of this female snail? In your answer, describe your expected results depending on whether the female is DD, Dd, or dd.

Homework (II)• In the experiment of figure 7.6 (as mentioned in

the previous slide), why does a clone of cells produce only one type of G-6-PD enzyme?

• What would you expect to happen if a clone was derived from an early embryonic cell?

• Why does the initial sample of tissue produce both

forms of G-6-PD?

1. Genetics (Analysis & Principles), 2nd ed by Robert Brooker, Chapter 072. Biology, 7th ed by Campbell, Chapter 15: Fig. 15.17

References

Part06 Non-Mendelian inheritance: epigenetic inheritance etc (I)

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