Chapter 15

The Chromosomal Basis of Inheritance

Updated November 2008

Overview: Locating Genes on Chromosomes

Genes Are located on chromosomes Can be visualized using certain

techniques

Figure 15.1

Concept 15.1: Mendelian inheritance has its physical basis in the behavior of chromosomes

Several researchers proposed in the early 1900s that genes are located on chromosomes

The behavior of chromosomes during meiosis was said to account for Mendel’s laws of segregation and independent assortment

The chromosome theory of inheritance states that

Mendelian genes have specific loci on chromosomes

During meiosis chromosomes undergo: Segregation Independent assortment

Meiosis

Homologous chromosomes during meiosis account for the segregation of alleles at each locus to different gametes

Nonhomologous chromosomes account for independent assortment of alleles

0.5 mm

Meiosis

Metaphase I

Anaphase I

Metaphase II

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.

14

yr 1 4Yr1

4 YR

3 3

F1 Generation

14

yR

R

R

R

R

RR

R

R R R R

R

Y

Y

Y Y

Y

YY

Y

YY

YY

yr r

rr

r r

rr

r r r r

y

y

y

y

y

y y

yyyy

All F1 plants produceyellow-round seeds (YyRr)

1

2 2

1

Morgan’s Experimental Evidence: Scientific Inquiry

Thomas Hunt Morgan In early 20th century, first geneticist to

associate a specific gene with a specific chromosome

Provided convincing evidence that chromosomes are the location of Mendel’s heritable factors

Morgan’s Choice of Experimental Organism

Morgan worked with fruit flies Because they breed at a high rate A new generation can be bred every two

weeks They have only four pairs of

chromosomes (3 pairs of autosomes & 1 pair of sex chromosomes)

And they are cheap and easy to get!

Morgan’s Flies

Morgan first observed and noted Wild type (normal) phenotypes that were

common in the fly populations Traits alternative to the wild type

Are called mutant phenotypes

Figure 15.3

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 Morgan determined that the white-eyed

mutant allele must be located on the X chromosome

Fig. 15-4c

EggsF1

CONCLUSION

Generation

Generation

P XX

w

Sperm

XY

+

+

++ +

Eggs

Sperm+

++ +

+

GenerationF2

w

w

w

ww

w

w

w

ww

w

w

w

ww

Morgan’s discovery

that transmission of the X chromosome in fruit flies correlates with inheritance of the eye-color trait Was the first solid evidence indicating

that a specific gene is associated with a specific chromosome

(Morgan and his lab did a lot of fascinating fly research. He won a Nobel Prize in 1933.)

Concept 15.2: Sex-linked genes exhibit unique patterns of inheritance

• In humans and some other animals, there is a chromosomal basis of sex determination

The Chromosomal Basis of Sex

In humans and other mammals, there are two varieties of sex chromosomes: a larger X chromosome and a smaller Y chromosome

Only the ends of the Y chromosome have regions that are homologous with the X chromosome

The SRY gene on the Y chromosome codes for the development of testes

SRY gene

The sex determining gene on the Y chromosome

Individuals with the SRY gene develop the generic embryonic gonads into testes

The SRY triggers a cascade of biochemical, physiological and anatomical features

Key in developmental biology

Females are XX, and males are XY Each ovum contains an X

chromosome, while a sperm may contain either an X or a Y chromosome

Other animals have different methods of sex determination

Fig. 15-6a

(a) The X-Y system

44 + XY

44 + XXParents

44 + XY

44 + XX

22 +X

22 + X

22 + Yor

or

Sperm Egg

+

Zygotes (offspring)

Different systems of sex determination are found in other organisms

Figure 15.9b–d

22 +XX

22 +X

76 +ZZ

76 +ZW

16(Haploid)

16(Diploid)

(b) The X–0 system

(c) The Z–W system

(d) The haplo-diploid system

Inheritance of Sex-Linked Genes

The sex chromosomes have genes for many characters unrelated to sex

A gene located on either sex chromosome is called a sex-linked gene

In humans, sex-linked usually refers to a gene on the larger X chromosome

Sex-linked genes follow specific patterns of inheritance

For a recessive sex-linked trait to be expressed A female needs two copies of the allele A male needs only one copy of the allele

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

Fig. 15-7

(a) (b) (c)

XNXN XnY XNXn XNY XNXn XnY

YXnSpermYXNSpermYXnSperm

XNXnEggs XN

XN XNXn

XNY

XNY

Eggs XN

Xn

XNXN

XnXN

XNY

XnY

Eggs XN

Xn

XNXn

XnXn

XNY

XnY

Some disorders caused by recessive alleles on the X chromosome in humans: Color blindness Duchenne muscular dystrophy Hemophilia

X Inactivation in Female Mammals

In mammalian females, one of the two X chromosomes in each cell is randomly inactivated during embryonic development

The inactive X condenses into a Barr body

If a female is heterozygous for a particular gene located on the X chromosome, she will be a mosaic for that character

Fig. 15-8

X chromosomes

Early embryo:

Allele fororange fur

Allele forblack fur

Cell division andX chromosomeinactivationTwo cell

populationsin adult cat:

Active XActive X

Inactive X

Black fur Orange fur

X inactivation

Involves modification of the DNA by attachment of methyl (-CH3) groups to cytosine nucleotides on the X chromosome that will become Barr body

Discovered a gene XIST (X-inactive specific transcript) which is only active on the Barr body chromosome

Concept 15.2: Linked genes tend to be inherited together because they are located near each other on the same chromosome

Each chromosome has hundreds or thousands of genes

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

How Linkage Affects Inheritance: Scientific Inquiry

Morgan did other experiments with fruit flies To see how linkage affects the

inheritance of two different characters Morgan crossed flies

That differed in traits of two different characters

Fig. 15-9-4

EXPERIMENTP Generation (homozygous)

RESULTS

Wild type(gray body,normal wings)

Double mutant(black body,vestigial wings)

b b vg vg

b b vg vg

Double mutantTESTCROSS

b+ b+ vg+ vg+

F1 dihybrid(wild type)

b+ b vg+ vg

Testcrossoffspring Eggs b+ vg+ b vg b+ vg b vg+

Black-normal

Gray-vestigial

Black-vestigial

Wild type(gray-normal)

b vg

Sperm

b+ b vg+ vg b b vg vg b+ b vg vg b b vg+ vg

PREDICTED RATIOS

If genes are located on different chromosomes:

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

1

1

1

1

1 1

0 0

965 944 206 185

:

:

:

:

:

:

:

:

:

According to independent assortment, this should produce 4 phenotypes in a 1:1:1:1 ratio

Morgan determined that

Body color and wing shape are usually inherited together because the genes are on the same chromosomes

Genes that are close together on the same chromosome are linked and do not assort independently

Parentsin testcross

b+ vg+

b vg

b+ vg+

b vg

b vg

b vg

b vg

b vg

Mostoffspring

X

or

Genetic Recombination and Linkage

Unlinked genes are either on separate chromosomes or are far apart on the same chromosome and assort independently

Genetic recombination is the production of offspring with new combinations of traits Parental types – phenotype matches one of

the parents Recombinant types (or recombinants)

Recombination of Unlinked Genes: Independent Assortment of Chromosomes

When Mendel followed the inheritance of two characters He observed that some offspring have

combinations of traits that do not match either parent in the P generation

Gametes from green-wrinkled homozygousrecessive parent (yyrr)

Gametes from yellow-roundheterozygous parent (YyRr)

Parental-type offspring

Recombinantoffspring

YyRr yyrr Yyrr yyRr

YR yr Yr yR

yr

Linked? Dependent?

Recombinant offspring Are those that show new combinations of the

parental traits When 50% of all offspring are recombinants

Geneticists say that there is a 50% frequency of recombination

The two genes are on different nonhomologous chromosomes

Independent and not linked

Unlinked genes randomly assort at metaphase I of meiosis

They follow the independent probability rules And is multiplication Or is addition

If these rules don’t seem to apply, the genes are probably linked

Recombination of Linked Genes: Crossing Over

Morgan discovered that genes can be linked But due to the appearance of

recombinant phenotypes, the linkage appeared incomplete

They tend to move together through meiosis and fertilization

But not completely or we would see the ratio 1:1:0:0

Morgan proposed that

Some process must occasionally break the physical connection between genes on the same chromosome

Crossing over of homologous chromosomes was the mechanism

Linked genes exhibit recombination frequencies less than 50%

Animation: Crossing OverAnimation: Crossing Over

Linkage Mapping: Using Recombination Data: Scientific Inquiry A genetic map

Is an ordered list of the genetic loci along a particular chromosome

Can be developed using recombination frequencies

A linkage map Is the actual map of a chromosome

based on recombination frequencies

Fig. 15-10a

Testcrossparents

Replicationof chromo-somes

Gray body, normal wings(F1 dihybrid)

Black body, vestigial wings(double mutant)

Replicationof chromo-somes

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+ vg

b vg+

b vg

Recombinantchromosomes

Meiosis I and II

Meiosis I

Meiosis II

Eggs Sperm

b+ vg+ b vg b+ vg b vgb vg+

Fig. 15-10b

Testcrossoffspring

965Wild type

(gray-normal)

944Black-

vestigial

206Gray-

vestigial

185Black-normal

b+ vg+

b vg b vg

b vg b+ vg

b vg

b vg

b+ vg+

Spermb vg

Parental-type offspring Recombinant offspring

Recombinationfrequency =

391 recombinants2,300 total offspring

100 = 17%

b vg

b+ vg b vg+

b vg+

Eggs

Recombinantchromosomes

Linkage Maps

The farther 2 genes are, the higher the probability that a crossover will occur between them

Therefore, the higher the recombination frequency

The relative distance is expressed as map units called centimorgans

RESULTSRecombination

frequencies

Chromosome

9% 9.5%

17%

b cn vg

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

Multiple crossing over

The recombination frequencies in our mapping example are not quite additive: 9% (b-cn) + 9.5% (cn-vg) > 17% (b-vg). This results from multiple crossing-over

events. A second crossing over “cancels out” the first

and reduces the observed number of recombinant offspring.

Genes father apart (for example, b-vg) are more likely to experience multiple crossing-over events.

Realistically...

Some genes on a chromosome are so far apart that a crossover between them is virtually certain

If genes are far enough apart, they appear to be on different chromosomes So what’s the recombination frequency?

In fact, Mendel’s pea seed color & flower color were on the same chromosome

Genes located far apart on a chromosome are mapped by adding the recombination frequencies between the distant genes and the intervening genes.

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

Figure 15.8

Mutant phenotypes

Short aristae

Black body

Cinnabareyes

Vestigialwings

Brown eyes

Long aristae(appendageson head)

Gray body

Redeyes

Normalwings

Redeyes

Wild-type phenotypes

IIY

I

X IVIII

0 48.5 57.5 67.0 104.5

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

Concept 15.4: Alterations of chromosome number or structure cause some genetic disorders

Large-scale chromosomal alterations Often lead to spontaneous abortions or cause

a variety of developmental disorders When nondisjunction occurs

Pairs of homologous chromosomes do not separate normally during meiosis

Gametes contain two copies or no copies of a particular chromosome

Fig. 15-13-3

Meiosis I

Nondisjunction

(a) Nondisjunction of homologous chromosomes in meiosis I

(b) Nondisjunction of sister chromatids in meiosis II

Meiosis II

Nondisjunction

Gametes

Number of chromosomes

n + 1 n + 1 n + 1n – 1 n – 1 n – 1 n n

Aneuploidy

Results from the fertilization of gametes in which nondisjunction occurred

Is a condition in which offspring have an abnormal number of a particular chromosome

Types of aneuploidy

If a zygote is trisomic It has three copies of a particular

chromosome (2n + 1) If a zygote is monosomic

It has only one copy of a particular chromosome (2n – 1)

If the organism survives, usually leads to a distinct phenotype

Polyploidy

Is a condition in which there are more than two complete sets of chromosomes in an organism

Figure 15.13

Polyploidy

Common in the plant kingdom Plays a large role in the evolution of

plants Less common in animals, but more

common in fish and amphibians Triploid (3n), tetraploid (4n), etc. Polyploids are more nearly normal

than aneuploids

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 a segment within a

chromosome Translocation moves a segment from one

chromosome to another

Fig. 15-15

DeletionA B C D E F G H A B C E F G H(a)

(b)

(c)

(d)

Duplication

Inversion

Reciprocaltranslocation

A B C D E F G H

A B C D E F G H

A B C D E F G H

A B C B C D E F G H

A D C B E F G H

M N O C D E F G H

M N O P Q R A B P Q R

Human Disorders Due to Chromosomal Alterations

Alterations of chromosome number and structure Are associated with a number of serious

human disorders

However, most are fatal and embryos abort long before birth

Down Syndrome

Is usually the result of an extra chromosome 21, trisomy 21

Affects 1 in 800 – 1000 (wiki) children born in US

Older women (35+) at higher risk of giving birth

Can be diagnosed before birth by fetal testing

Figure 15.15

Down Syndrome - Symptoms

Characteristic facial features and short stature

Heart defects Mental retardation Increased risk of respiratory infections,

leukemia & Alzheimer’s Most are sexually underdeveloped and

sterile

Aneuploidy of Sex Chromosomes

Nondisjunction of sex chromosomes Produces a variety of aneuploid

conditions

Next slide has a partial list from the Biol&160 (101) book

Klinefelter syndrome

Is the result of an extra chromosome in a male, producing XXY individuals

1 in 500 (wiki) male births Male sex organs, but abnormally small testes

and are sterile Although extra X is inactivated, some breast

enlargment and other female characteristics are common

Normal intelligence Napoleon & George Washington probably had

Klinefelter syndrome

Others Males (XYY)

tend to be taller Trisomy X (XXX)

1 in 1,000 (wiki) births produces healthy females

Turner syndrome (X or X0) 1 in 2,500 girl births (wiki) Only viable monosomy in humans Phenotypically female but are sterile

Disorders Caused by Structurally Altered Chromosomes

Cri du chat Is a disorder caused by a deletion in

chromosome 5 Mentally retarded, small heads with

unusual facial features Cry like a distressed cat

Certain cancers

Are caused by translocations of chromosomes

This is chronic myelogenous leukemia (CML)

Figure 15.16

Normal chromosome 9Reciprocal

translocation

Translocated chromosome 9

Philadelphiachromosome

Normal chromosome 22 Translocated chromosome 22

Concept 15.5: Some inheritance patterns are exceptions to the standard chromosome theory

Two normal exceptions to Mendelian genetics involve Genes located in the nucleus

Genomic imprinting Genes located outside the nucleus

Inheritance of organelle genes

Genomic Imprinting - Mammals

The phenotypic effects of certain genes depend on which allele is inherited from the mother and which is inherited from the father

Imprinted genes are not expressed Imprinting occurs during the formation

of gametes

Genomic Imprinting

Imprints are transmitted to all body cells during development

Maternally imprinted, means on the paternal allele is expressed (& visa versa)

Patterns are specific for each species

Fig. 15-18a

Normal Igf2 alleleis expressed

Paternalchromosome

Maternalchromosome

(a) Homozygote

Wild-type mouse(normal size)

Normal Igf2 alleleis not expressed

Igf2 – Insulin like growth factor

Fig. 15-18b

Mutant Igf2 alleleinherited from mother

Mutant Igf2 alleleinherited from father

Normal size 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

Imprinting and Methylation

It appears that imprinting is the result of the methylation (addition of –CH3) of DNA

Genomic imprinting is thought to affect only a small fraction of mammalian genes

Most imprinted genes are critical for embryonic development

Aberrant imprinting is associated with abnormal development & certain cancers

Inheritance of Organelle Genes

Extranuclear genes (or cytoplasmic genes) are genes 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

Croton dioicus

Mutations to mitochondrial DNA

Some diseases affecting the muscular and nervous systems Are caused by defects in mitochondrial

genes that prevent cells from making enough ATP

Other mitochondrial mutations may contribute to diabetes, heart disease, and other disease of aging

You should now be able to:

1. Explain the chromosomal theory of inheritance and its discovery

2. Explain why sex-linked diseases are more common in human males than females

3. Distinguish between sex-linked genes and linked genes

4. Explain how meiosis accounts for recombinant phenotypes

5. Explain how linkage maps are constructed

6. Explain how nondisjunction can lead to aneuploidy

7. Define trisomy, triploidy, and polyploidy8. Distinguish among deletions,

duplications, inversions, and translocations

9. Explain genomic imprinting10. Explain why extranuclear genes are not

inherited in a Mendelian fashion