LECTURE PRESENTATIONSFor CAMPBELL BIOLOGY, NINTH EDITION

Jane B. Reece, Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minorsky, Robert B. Jackson

© 2011 Pearson Education, Inc.

Lectures byErin Barley

Kathleen Fitzpatrick

The Chromosomal Basis of Inheritance

Chapter 15

Mendelian inheritance has its physical basis in the behavior of chromosomes

• Mendel’s “hereditary factors” were genes• today we can show that genes are located on chromosomes• the chromosome theory of inheritance states:

– Mendelian genes have specific loci (positions) on chromosomes

– chromosomes undergo segregation and independent assortment

F1 Generation

All F1 plants produceyellow-round seeds (YyRr).

Meiosis

Metaphase I

Anaphase I

Metaphase II

R R

R R

R R

R R

R R R R

r r

r r

r r

r r

r r r r

Y Y

Y Y

Y Y

Y Y

Y Y Y Y

y y

y y

y y

y y

yy y y

Gametes

LAW OF SEGREGATIONThe two alleles for each gene separate during gamete formation.

LAW OF INDEPENDENTASSORTMENT Alleles of genes on nonhomologous chromosomes assort independently during gamete formation.

1

2 2

1

1/41/4

1/41/4YR yr Yr yR

• the behavior of chromosomes during meiosis accounts for Mendel’s laws of segregation and independent assortment

F1 Generation

All F1 plants produceyellow-round seeds (YyRr).

Meiosis

Metaphase I

Anaphase I

Metaphase II

R R

R R

R R

R R

R R R R

r r

r r

r r

r r

r r r r

Y Y

Y Y

Y Y

Y Y

Y Y Y Y

y y

y y

y y

y y

yy y y

Gametes

LAW OF SEGREGATIONThe two alleles for each gene separate during gamete formation.

LAW OF INDEPENDENTASSORTMENT Alleles of genes on nonhomologous chromosomes assort independently during gamete formation.

1

2 2

1

1/41/4

1/41/4YR yr Yr yR

• the behavior of chromosomes during meiosis accounts for Mendel’s laws of segregation and independent assortment

F2 Generation

3Fertilization recombines the R and r alleles at random.

Fertilization results in the 9:3:3:1 phenotypic ratio in the F2 generation.

An F1 F1 cross-fertilization

9 : 3 : 3 : 1

LAW OF SEGREGATION LAW OF INDEPENDENTASSORTMENT

3

Morgan’s Experimental Evidence: Scientific Inquiry• the first solid evidence associating a specific gene with a

specific chromosome came from Thomas Hunt Morgan - an embryologist

• Morgan’s experiments with fruit flies (Drosophila melanogaster) provided convincing evidence that chromosomes are the location of Mendel’s heritable factors

• several characteristics make fruit flies a convenient organism for genetic studies

– they produce many offspring – a generation can be bred every two weeks– they have only four pairs of chromosomes

• Morgan recorded wild type (or normal) phenotypes that were common in the fly populations

– traits alternative to the wild type are called mutant phenotypes

Drosophila mutations-white eyes (ABC gene mutation)-wingless (Wnt mutation)-curly winged, short winged (vestigial)-forked bristles-ebony color, yellow color

Correlating Behavior of a Gene’s Alleles with Behavior of a Chromosome Pair

• in one experiment, Morgan mated male flies with white eyes (mutant) with female flies with red eyes (wild type)

– the F1 generation all had red eyes

– the F2 generation showed the 3:1 red:white eye ratio– but only males had white eyes

All offspringhad red eyes.

PGeneration

F1

Generation

F2

Generation

F2

Generation

F1

Generation

PGeneration

Eggs

Eggs

Sperm

Sperm

XX

XY

w

w

ww w

w

ww w

w

w

w

w

w

ww w

RESULTS

EXPERIMENT

CONCLUSION

• Morgan determined that the white-eyed mutant allele must be located on the X chromosome

• Morgan’s finding supported the chromosome theory of inheritance

The Chromosomal Basis of Sex

• in many organisms there is a chromosomal basis of sex determination

• XX/XY determination – humans and most mammals and some insects– humans – Y determines the male– fruit flies – 2 X’s determine the

female• XX/XO determination – some

rodents & insects– females = XX– males = XO (absence of a second

sex chromosome)

Parents

orSperm

or

Egg

Zygotes (offspring)

44 XY

44 XX

22 X

22 Y

22 X

44 XX

44 XY

22 XX

22 X

(a) The X-Y system

(b) The X-0 system

The Chromosomal Basis of Sex• ZW determination – birds, some reptiles

and some insects– ZW = female

• W chromosome possesses sex determining genes

– ZZ = male• UV determination – some plants and algae

– U = female gametophytes– V = male gametophytes

• haplo-diploid system – bees and ants– diploid = female and sterile males– haplo = males (from unfertilized eggs)– so the queen and control gender

76 ZW

76 ZZ

32 (Diploid)

16 (Haploid)

(c) The Z-W system

(d) The haplo-diploid system

The Chromosomal Basis of Sex

• in humans and other mammals XX/XY determination– a larger X chromosome and a

smaller Y chromosome for males

• one X chromosome is inactivated in females

The Chromosomal Basis of Sex

• the Y chromosome – significantly lower numbers of genes vs. X chromosome (1846 vs. 454)– most of them are responsible for sex

determination and development of male reproductive structures

– the SRY gene on the Y chromosome codes for a protein that directs the development of male anatomical features

• BUT the ends of the Y chromosome have regions that are homologous with corresponding regions of the X chromosome = pseudoautosomal regions

• a gene that is located on either sex chromosome is called a sex-linked gene

• genes on the Y chromosome are called Y-linked genes

• genes on the X chromosome are called X-linked genes

• X chromosomes have genes for many characters unrelated to sex– whereas the Y chromosome mainly encodes genes

related to sex determination– e.g. SRY gene

The Chromosomal Basis of Sex

• X-linked genes follow specific patterns of inheritance• for a recessive X-linked trait to be expressed

– a female needs two copies of the allele (homozygous)– a male needs only one copy of the allele (hemizygous)

• X-linked recessive disorders are much more common in males than in females

X-linked Genes

Eggs Eggs Eggs

Sperm Sperm Sperm

(a) (b) (c)

XNXN XnY XNXn XNY XNXn XnY

Xn Y XN Y YXn

Xn Xn

XN

XN

XN XNXNXn XNY

XNY

XNY XNY

XnY XnYXNXn XNXn

XNXnXNXN

XnXn

• Some disorders caused by recessive alleles on the X chromosome in humans

– Color blindness (mostly X-linked)– Duchenne muscular dystrophy– Hemophilia A and B

X Inactivation in Female Mammals• the coloration of a calico cat is the physical

manifestation of a phenomenon called X-inactivation

• X-inactivation or lyonization process in mammalian females is where one of the two X chromosomes in each cell is randomly inactivated – in marsupials – always the paternally

derived X• prevents the female from having twice as

many X chromosome gene products as a male = dosage compensation

• the inactive X condenses into a Barr body

Early embryo:

X chromosomes

Allele fororange fur

Allele forblack fur

Two cellpopulationsin adult cat:

Cell division andX chromosomeinactivation

Active XInactive X

Active X

Black fur Orange fur

X Inactivation in Female Mammals• X inactivation begins at embryonic

development – occurs in the inner cell mass of the blastocyst

• once a specific X chromosome is inactivated – that one will remain inactive throughout its lifetime– will also be inactivated in all cellular

progeny• inactivation is an epigenetic change

– high methylation of DNA and low acetylation of histones

– methylation results in the packaging of the X chromosome into heterochromatin

– DNA is now a transcriptionally inactive structure

• reversed in female germ cells undergoing meiosis

Early embryo:

X chromosomes

Allele fororange fur

Allele forblack fur

Two cellpopulationsin adult cat:

Cell division andX chromosomeinactivation

Active XInactive X

Active X

Black fur Orange fur

X Inactivation in Female Mammals• active X chromosome is called Xa• inactive one is designated Xi• if multiple X chromosomes are present (i.e. 3 vs. 2) – only one X chromosome is

still Xa– default state is the inactive form

• hypothesis: an autosomally-encoded “blocking factor” binds to the Xa chromosome and prevents its inactivation– sequence in the chromosome known as the XIC – X inactivation center– sequence is bound to these factors - prevents inactivation??

• another hypothesis: the XIC of the the Xi chromosome produces a non-coding RNA called Xist RNA– coats the Xi chromosome inactivation

X Inactivation in Female Mammals

• despite the fact that the X chromosome is inactivated – there are genes on Xi that ESCAPE inactivation– these genes are also found on the Y chromosome of

males– so there is dosage compensation between the two

chromosomes

• Mosaicism – two or more populations of cells with different genotypes within a single organism

• most common forms rise from errors in the first few mitotic divisions of a fertilized zygote

– mitotic crossing over!– Source of genetic variation in asexually reproducing organisms– Can occur in sexually reproducing organisms– Takes place during interphase (G1)

• other mosaicisms – result from non-disjunction during meiosis and produce trisomies

• true mosaicism should NOT be confused with X-inactivation!!!– all the cells in this cat have the same genotype BUT a different X is active in

different cells

Mosaicism

• each chromosome has hundreds or thousands of genes (except the Y chromosome)

• genes located on the same chromosome that tend to be inherited together are called linked genes

Linked genes tend to be inherited together because they are located near each other on the same chromosome

P Generation (homozygous)

Wild type(gray body, normal wings)

b b vg vg b b vg vg

Double mutant(black body,vestigial wings)

How Linkage Affects Inheritance• Morgan did other experiments with fruit flies to see how linkage

affects inheritance of two characters• Morgan crossed flies that differed in traits of body color and wing size• found a higher percentage of parental phenotypes in the offspring• concluded that these genes do not assort independently

– body color and wing size are inherited together– reasoned that they were on the same chromosome

P Generation (homozygous)

Wild type(gray body, normal wings)

F1 dihybrid(wild type)

Testcrossoffspring

TESTCROSS

b b vg vg

b b vg vg

b b vg vg

b b vg vg

Double mutant(black body,vestigial wings)

Double mutant

Eggs

Sperm

RESULTS

PREDICTED RATIOS

Wild type(gray-normal)

Black-vestigial

Gray-vestigial

Black-normal

b vg b vg b vg b vg

b b vg vg b b vg vg b b vg vg b b vg vg

965 944 206 185

1

1

1

1

1

0

1

0

If genes are located on different chromosomes:If genes are located on the same chromosome and parental alleles are always inherited together:

:

:

:

:

:

:

:

:

:

b vg

How Linkage Affects Inheritance• Mated true-breeding wild type

flies with gray bodies and normal wings (b+b+vg+vg+) with mutants with black bodies and short, vestigial wings (bbvgvg)

• all F1 offspring looked like parents and were heterozygotes

P Generation (homozygous)

Wild type(gray body, normal wings)

F1 dihybrid(wild type)

Testcrossoffspring

TESTCROSS

b b vg vg

b b vg vg

b b vg vg

b b vg vg

Double mutant(black body,vestigial wings)

Double mutant

Eggs

Sperm

RESULTS

PREDICTED RATIOS

Wild type(gray-normal)

Black-vestigial

Gray-vestigial

Black-normal

b vg b vg b vg b vg

b b vg vg b b vg vg b b vg vg b b vg vg

965 944 206 185

1

1

1

1

1

0

1

0

If genes are located on different chromosomes:

If genes are located on the same chromosome and parental alleles are always inherited together:

:

:

:

:

:

:

:

:

:

b vg

How Linkage Affects Inheritance

• performed a test-cross of female F1 with true-breeding male mutants (bbvgvg)

– expected a 1:1:1:1 ratio of dominant to recessive

• most offspring looked like the parents

• only possible if the b and vg genes are linked and did not sort independently during meiosis

• in other words – the gametes made by the P generation contained a chromosome with the b+ allele AND the vg+ allele together on the same chromosome

Most offspring

F1 dihybrid femaleand homozygousrecessive malein testcross

or

b+ vg+

b vg

b+ vg+

b vg

b vg

b vg

b vg

b vg

• however, nonparental phenotypes were also produced– so body color and wing size were not always linked

genetically and were recombined as a result of crossing over or genetic recombination

Gametes from green-wrinkled homozygousrecessive parent (yyrr)

Gametes from yellow-rounddihybrid parent (YyRr)

Recombinant offspring

Parental-type

offspring

YR yr Yr yR

yr

YyRr yyrr Yyrr yyRr

Recombination of Unlinked Genes: Independent Assortment of Chromosomes

• offspring with a phenotype matching one of the parental phenotypes = parental types

• offspring with nonparental phenotypes (new combinations of traits) = recombinant types, or recombinants

• a 50% frequency of recombination is observed for any two genes on different chromosomes

Recombination of Linked Genes: Crossing Over

Testcrossparents

Replicationof chromosomes

Gray body, normal wings(F1 dihybrid)

Black body, vestigial wings(double mutant)

Replicationof chromosomes

Meiosis I

Meiosis II

Meiosis I and II

Recombinantchromosomes

Eggs

b vg

b vg

b vg

b vg

b vg

b vg

b vg

b vg

b vg

b vg

b vg

b vg

b vg

b vgb vg

b vg

bvg b vgb vg

b vg

Spermb vg

• MEIOSIS I: crossing over between the homologous chromosomes of the female parent produces new combinations of alleles (b+ vg and b vg+)

• at the end of MEIOSIS II: some of the gametes will be parental and some are recombinants

Testcrossoffspring

965Wild type

(gray-normal)

944Black-

vestigial

206Gray-

vestigial

185Black-normal

Sperm

Parental-type offspring Recombinant offspring

Recombinationfrequency

391 recombinants2,300 total offspring

100 17%

b vg b vgb vgb vg

b vg b vg b vg b vg

b vg

Eggs

Recombinantchromosomes

bvg b vg b vg b vg

New Combinations of Alleles: Variation for Normal Selection

• recombinant chromosomes bring alleles together in new combinations in gametes

• random fertilization increases even further the number of variant combinations that can be produced

• this abundance of genetic variation is the raw material upon which natural selection works

Mapping the Distance Between Genes Using Recombination Data: Scientific Inquiry

• Alfred Sturtevant, one of Morgan’s students, constructed a genetic map, an ordered list of the genetic loci along a particular chromosome

• Sturtevant predicted that the farther apart two genes are, the higher the probability that a crossover will occur between them and therefore the higher the recombination frequency

• in other words the farther apart two genes are the more likely they will be unlinked or “broken up” by crossing over

• a linkage map is a genetic map of a chromosome based on recombination frequencies

• distances between genes can be expressed as map units; one map unit, or centimorgan, represents a 1% recombination frequency

• map units indicate relative distance and order, not precise locations of genes

Mapping the Distance Between Genes Using Recombination Data: Scientific Inquiry

Chromosome

Recombinationfrequencies

9% 9.5%

17%

b cn vg

RESULTS• b-vg recombination frequency = 17%• b-cn recombination frequency = 9%

• genes that are far apart on the same chromosome can have a recombination frequency near 50%– such genes are physically linked by being on the same

chromosome - but genetically unlinked– they behave as if found on different chromosomes

Mutant phenotypes

Shortaristae

Blackbody

Cinnabareyes

Vestigialwings

Browneyes

Long aristae(appendageson head)

Gray body

Red eyes

Normalwings

Redeyes

Wild-type phenotypes

104.567.057.548.50

• Sturtevant used recombination frequencies to make linkage maps of fruit fly genes

• using methods like chromosomal banding - geneticists can develop cytogenetic maps of chromosomes

• Cytogenetic maps indicate the positions of genes with respect to chromosomal features

• in nondisjunction -pairs of homologous chromosomes do not separate normally during meiosis– as a result, one gamete receives two of the same type of

chromosome, and another gamete receives no copy

Abnormal Chromosome Number

Meiosis I

Nondisjunction

Meiosis I

Meiosis II

Nondisjunction

Non-disjunction

Gametes

Number of chromosomes

Nondisjunction of homo-logous chromosomes inmeiosis I

(a) Nondisjunction of sisterchromatids in meiosis II

(b)

n 1 n 1n 1 n 1 n 1n 1 n n

• Aneuploidy results from the fertilization of gametes in which nondisjunction occurred– offspring with this condition have an abnormal number of a

particular chromosome• a monosomic zygote has only one copy of a particular

chromosome– e.g. XO = Turner’s syndrome

• a trisomic zygote has three copies of a particular chromosome– e.g. 3 chromosome 21 = Down’s syndrome

• Polyploidy is a condition in which an organism has more than two complete sets of chromosomes– Triploidy (3n) is three sets of chromosomes– Tetraploidy (4n) is four sets of chromosomes

• polyploidy is common in plants - but not animals• polyploids are more normal in appearance than aneuploids• large-scale chromosomal alterations in humans and other

mammals often lead to spontaneous abortions (miscarriages) or cause a variety of developmental disorders– plants tolerate such genetic changes better than animals do

Down Syndrome (Trisomy 21)• alterations of chromosome number and

structure are associated with some serious disorders

• some types of aneuploidy appear to upset the genetic balance less than others - resulting in individuals surviving to birth and beyond

• Down syndrome is an aneuploid condition that results from three copies of chromosome 21

• it affects about one out of every 700 children born in the United States

• the frequency of Down syndrome increases with the age of the mother, a correlation that has not been explained

Aneuploidy of Autosomal Chromosomes

Aneuploidy of Sex Chromosomes

• Nondisjunction of sex chromosomes produces a variety of aneuploid conditions– Klinefelter syndrome is the result of an extra chromosome in a

male, producing XXY individuals – most common aneuploidy• also known as 47,XXY• 1:500 1:1000 live births• non-disjunction between X and Y chromosomes during meiosis I in

spermatogenesis• most are asymptomatic• hypogonadism (decreased endocrine function NOT size)and sterility• gynecomastia• reduced muscle mass, coordination and strength as kids• taller than average• higher incidence (vs. normal males) of breast cancer, autoimmune diseases and

osteoporosis

Aneuploidy of Sex Chromosomes

– Monosomy X, called Turner syndrome - produces X0 females

• also known as 45, X• all of part of the second X chromosome is absent (e.g.

deletion of the p arm)• 1 in 2,000 to 5,000 births• sterile – non-working ovaries• short stature, webbing in the neck, low hairline, low wet • congenital heart disease, hypothyroidism, diabetes,

visual problems, many autoimmune diseases, specific cognitive problems

• it is the only known viable monosomy in humans

Aneuploidy of Sex Chromosomes

– 48,XXYY and 48,XXXY – 1 in 18,000 to 50,000 live births

– 49,XXXXY 1 in 85,000 to 100,000 births

Alterations of Chromosome Structure

• breakage of a chromosome can lead to four types of changes in chromosome structure

– Deletion removes a chromosomal segment

– Duplication repeats a segment

– Inversion reverses orientation of a segment within a chromosome

– Translocation moves a segment from one chromosome to another

(a) Deletion

(b) Duplication

(c) Inversion

(d) Translocation

A deletion removes a chromosomal segment.

A duplication repeats a segment.

An inversion reverses a segment within a chromosome.

A translocation moves a segment from onechromosome to a nonhomologous chromosome.

A B C D E F G H

A B C E F G H

A B C D E F G H

A B C D E F G H B C

A B C D E F G H

A D C B E F G H

A B C D E F G H M N O P Q R

GM N O C H FED A B P Q R

Gene Duplications and Deletions• both can arise from unequal crossing over during meiosis• often results between repetitive sequences shared

between them• duplication can also result from replication slippage

– DNA polymerase dissociates and reattaches at an incorrect position – copies the same strand of DNA again

• these are not necessarily bad things

• cri du chat (“cry of the cat”) - results from a specific deletion of a section of chromosome 5 (p arm)– a child born with this syndrome is mentally retarded and has a catlike cry

– individuals who are missing the entire chromosome 5 usually die in infancy or early childhood

http://ghr.nlm.nih.gov/condition/cri-du-chat-syndrome

Translocation

• reciprocal translocations involve the exchange of material between non-homologous chromosomes

• crossing over between non-homologous chromosomes

• 1 to 625 newborns• usually harmless because they are

localized to the somatic cell

Balanced translocation

Normal chromosome 9

Normal chromosome 22

Reciprocal translocation

Translocated chromosome 9

Translocated chromosome 22(Philadelphia chromosome)

Translocation

• some translocations may be associated with increased chances of cancer

– Philadelphia chromosome– associated with Chronic Myelogenous

Leukemia– creates two fused genes BCR-Abl

fusion protein– speeds up the cell cycle

• but increased miscarriages can result in affected individuals

• can occur due to errors in mitosis in somatic cells

– limited to the affected cell type– e.g. CML and Philadelphia chr

• can also occur in germline cells during meiosis

– all cellular progeny affected

Translocation

• can occur due to errors in mitosis in somatic cells – limited to the affected cell type

• can also occur in germline cells during meiosis– cellular progeny will be affected if the gametes are altered

Some inheritance patterns are exceptions to standard Mendelian inheritance

• there are two normal exceptions to Mendelian genetics

• one exception involves genes located in the nucleus• the other exception involves genes located outside the

nucleus• in both cases, the sex of the parent contributing an

allele is a factor in the pattern of inheritance– Genetic Imprinting– Organelle Genes

Genomic Imprinting

• for a few mammalian traits, the phenotype depends on which parent passed along the alleles for those traits

• such variation in phenotype is called genomic imprinting

• genomic imprinting involves the silencing of certain genes that are “stamped” with an imprint during gamete production

• not a big deal as long as the active chromosome has a “normal” gene allele

(a) Homozygote

Paternalchromosome

Maternalchromosome

Normal Igf2 alleleis expressed.

Normal Igf2 alleleis not expressed.

Normal-sized mouse(wild type)

Mutant Igf2 alleleinherited from mother

Mutant Igf2 alleleinherited from father

Normal-sized mouse (wild type) Dwarf mouse (mutant)

Normal Igf2 alleleis expressed.

Mutant Igf2 alleleis expressed.

Mutant Igf2 alleleis not expressed.

Normal Igf2 alleleis not expressed.

(b) Heterozygotes – imprinted gene comes from mother

• it appears that imprinting is the result of the methylation (addition of —CH3) of the DNA– addition of CH3 to cysteine nucleotides– can result in transcriptional inactivation– the methylation pattern is passed on to progeny

through meiosis• genomic imprinting is thought to affect only a small

fraction of mammalian genes• most imprinted genes are critical for embryonic

development

Genomic Imprinting

Inheritance of Organelle Genes• extranuclear genes (or cytoplasmic genes) are found in organelles in the

cytoplasm• mitochondria, chloroplasts, and other plant plastids carry small circular DNA

molecules• extranuclear genes are inherited maternally because the zygote’s cytoplasm

comes from the egg• the first evidence of extranuclear genes came from studies on the inheritance of

yellow or white patches on leaves of an otherwise green plant

• Some defects in mitochondrial genes prevent cells from making enough ATP and result in diseases that affect the muscular and nervous systems – inheritance pattern is non-Mendelian – Maternal

– only the egg contributes mitochondria to the embryo

– e.g. mitochondrial myopathy• type of myopathy associated with abnormal mitochondria• muscle tissue shows “ragged red” fibers with mild

accumulations of glycogen• muscle weakness results• numerous types of MMs known

– e.g. Leber’s hereditary optic neuropathy• mitochondrial dysfunction results in the degeneration of

retinal ganglion cells (neurons in the retina)• loss of central vision