Chapter 15

The Chromosomal Basis of

Inheritance

Rob Swatski

Associate Professor of Biology

HACC – York Campus

1

Overview: Genes and Chromosomes

We know Mendel’s “hereditary factors” are genes

We know genes are located on chromosomes in specific regions (loci)

- Fluorescent “tagging”

2

Mitosis & meiosis were first described in the late 1800’s

The chromosome theory of inheritance:

- Mendelian genes have specific loci on chromosomes

- Chromosomes undergo segregation & independent assortment

Chromosome behavior during meiosis accounts for Mendel’s laws

3

P Generation

Gametes

Meiosis

Fertilization

Yellow-round seeds (YYRR)

Green-wrinkled seeds ( yyrr)

All F1 plants produce yellow-round seeds (YyRr)

y

y

y

r

r

r

Y

Y

Y R

R R

4

0.5 mm

Meiosis

Metaphase I

Anaphase I

Metaphase II

Gametes

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

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

1 4 yr 1 4 Yr 1 4 YR

3 3

F1 Generation

1 4 yR

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 r r

r r

r r

r r

r r r r

y

y

y

y

y

y y

y y y y

All F1 plants produce yellow-round seeds (YyRr)

1

2 2

1

5

F2 Generation

3 Fertilization 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 INDEPENDENT ASSORTMENT

3

6

Morgan’s Experimental Evidence

• The 1st solid evidence associating a specific gene with a specific chromosome came from the embryologist, Thomas Hunt Morgan

• Morgan’s experiments with fruit flies provided convincing evidence that Mendel’s heritable factors are located on chromosomes

7

Why Fruit Flies?

- Fast breeding rate & lots of offspring

- New generation produced every 2 weeks

- The have only 4 pairs of chromosomes

8

Wild type (normal) phenotypes were common in the fly populations

Traits alternative to the wild type are called mutant phenotypes

wild type mutant

9

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

In one mating experiment, Morgan crossed:

- male white eyes (mutant) with female 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

- The white-eyed mutant allele must be on the X chromosome

Morgan’s finding supported the chromosome theory of inheritance

10

All offspring had red eyes.

P Generation

F1 Generation

F2 Generation

RESULTS

EXPERIMENT

11

F2 Generation

P Generation

Eggs

Eggs

Sperm

Sperm

X w

CONCLUSION

X X Y

w

w w w

w

w w w

w

w

w

w

w

w w w

F1 Generation

12

The Chromosomal Basis of Sex

In humans & other mammals, there are 2 varieties of sex chromosomes:

- larger X chromosome

- smaller Y chromosome

Only the ends of Y chromosomes are homologous with corresponding regions of the X chromosomes

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

X

Y

13

(a) The X-Y system: females are XX and males are XY

44 + XY

44 + XX

Parents

44 + XY

44 + XX

22 + X

22 + X

22 + Y or

or

Sperm Egg

+

Zygotes (offspring)

14

(b) The X-0 system (insects)

22 + XX

22 + X

(c) The Z-W system (birds, fishes, insects) - Sex chromosomes are present in the egg (not sperm)

76 + ZW

76 + ZZ

X0

15

(d) The haplo-diploid system (bees & ants) - No sex chromosomes

32 (Diploid)

16 (Haploid)

16

Inheritance of Sex-Linked Genes

Sex-linked gene: a gene that is located on either sex chromosome

- in humans, this usually refers to x-linked genes, which are genes located on the X chromosome

(there are few Y-linked genes)

- X chromosomes have genes for many characters unrelated to sex

17

X-linked genes follow specific patterns of inheritance

For a recessive sex-linked trait to be expressed:

- A female needs 2 copies of the allele (XnXn) = homozygous

- A male needs only 1 copy of the allele (XnY) = hemizygous

Sex-linked recessive disorders are much more common

in males than in females – why? 18

(a) (b) (c)

XNXN XnY XNXn XNY XNXn XnY

Y Xn Sperm Y XN Sperm Y Xn Sperm

XNXn Eggs XN

XN XNXn

XNY

XNY

Eggs XN

Xn

XNXN

XnXN

XNY

XnY

Eggs XN

Xn

XNXn

XnXn

XNY

XnY

Transmission of Sex-Linked Recessive Traits

19

Sex-linked recessive disorders in humans include:

- Color blindness

- Duchenne muscular dystrophy

- Hemophilia

20

X Inactivation in Female Mammals

In female mammals, 1 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

21

X chromosomes

Early embryo:

Allele for orange fur

Allele for black fur

Cell division &

X chromosome inactivation

2 cell populations in adult cat:

Active X

Active X Inactive X

Black fur Orange fur

22

Each chromosome has 100’s or 1000’s of genes

(except for the Y chromosome)

Linked genes: located near each other on the same chromosome

- Linked genes are usually inherited together

23

How Linkage Affects Inheritance

Morgan experimented with fruit flies to see how linkage affects the inheritance of 2 characters

He crossed flies that differed in:

- body color & wing size

24

P Generation (homozygous)

Wild type (gray body, normal wings)

F1 dihybrid (wild type)

Testcross offspring

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

EXPERIMENT

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

25

Conclusion:

body color & wing size are usually inherited together in specific combinations

(parental phenotypes)

These genes do not assort independently & Morgan reasoned that they were on the same chromosome

26

Most offspring

F1 dihybrid female & homozygous recessive male in testcross

or

b+ vg+

b vg

b+ vg+

b vg

b vg

b vg

b vg

b vg

Results: a much higher % of parental phenotypes than would be expected by independent assortment 27

However, non-parental phenotypes were also produced

Understanding this result involves exploring genetic recombination

- the production of offspring with combinations of traits different from either parent

Both findings of Mendel & Morgan relate to the chromosomal basis of recombination

28

Recombination of Unlinked Genes: Independent Assortment of Chromosomes

Mendel observed that combinations of traits in some offspring differ from either parent

- Parental types: offspring with a phenotype matching 1 of the parental phenotypes

- Recombinant types (recombinants): offspring with non-parental phenotypes (new combinations of traits)

A 50% frequency of recombination is observed for any 2 genes on different chromosomes

29

YyRr

Gametes from green- wrinkled homozygous recessive parent ( yyrr)

Gametes from yellow-round heterozygous parent (YyRr)

Parental- type

offspring

Recombinant offspring

yr

yyrr Yyrr yyRr

YR yr Yr yR

30

Recombination of Linked Genes: Crossing Over

Morgan discovered that genes can be linked, but the linkage was incomplete (as shown by the appearance

of recombinant phenotypes)

Morgan proposed that some process must sometimes break the physical connection between genes on the

same chromosome

= the crossing over of homologous chromosomes

31

Testcross parents

Replication of chromo- somes

Gray body, normal wings (F1 dihybrid)

Black body, vestigial wings (double mutant)

Replication of 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

Recombinant chromosomes

Meiosis I and II

Meiosis I

Meiosis II

Eggs Sperm

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

Crossing-over

32

Testcross offspring

965 Wild type

(gray-normal)

944 Black-

vestigial

206 Gray-

vestigial

185 Black-

normal

b+ vg+

b vg b vg

b vg b+ vg

b vg

b vg

b+ vg+

Sperm b vg

Parental-type offspring Recombinant offspring

b vg

b+ vg b vg+

b vg+

Recombination frequency =

391 recombinants

2,300 total offspring 100 = 17%

Eggs

Recombinant chromosomes

33

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

New Combinations of Alleles: Variation for Normal Selection

34

Genetic Maps

Alfred Sturtevant, one of Morgan’s students, constructed a genetic map: an ordered list of loci

along a particular chromosome

Sturtevant predicted that:

the farther apart 2 genes are, the higher the probability that a crossover will occur between them & therefore the higher the recombination frequency

35

Linkage Maps

Genetic map of a chromosome based on recombination frequencies

Distances between genes expressed as map units:

1 map unit (centimorgan)

= 1% recombination frequency

Map units indicate relative distance & order, not precise locations of genes

36

RESULTS

Recombination frequencies

Chromosome

9% 9.5%

17%

b cn vg

37

Genes that are far apart on the same chromosome can have a recombination frequency near 50%

Such genes are physically linked, but genetically unlinked, & behave as if found on different

chromosomes

38

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

Using methods like chromosomal banding, geneticists can develop cytogenetic maps of chromosomes

- Indicate positions of genes with respect to chromosomal features

39

Mutant phenotypes

Short aristae

Black body

Cinnabar eyes

Vestigial wings

Brown eyes

Red eyes

Normal wings

Red eyes

Gray body

Long aristae (appendages on head)

Wild-type phenotypes

0 48.5 57.5 67.0 104.5

A partial linkage map of a Drosophila chromosome 40

Large-scale chromosomal alterations often lead to spontaneous abortions (miscarriages) or cause a

variety of developmental disorders

Plants tolerate such genetic changes better than animals do

Alteration of Chromosome Number or Structure Cause Some Genetic

Disorders

41

Abnormal Chromosome Number

Nondisjunction: pairs of homologous chromosomes do not separate normally during meiosis

- As a result, one gamete receives 2 of the same type of chromosome & another gamete receives no copy

42

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 + 1 n – 1 n – 1 n – 1 n n

43

Aneuploidy: results from the fertilization of gametes in which nondisjunction occurred

- offspring have an abnormal number of a particular chromosome

Monosomic zygote: has only 1 copy of a particular chromosome

Trisomic zygote: has 3 copies of a particular chromosome

44

Polyploidy: organism has more than 2 complete sets of chromosomes

- Common in plants, but not animals

- Polyploids are more normal in appearance than aneuploids

- Triploidy (3n): 3 sets of chromosomes

- Tetraploidy (4n): 4 sets of chromosomes

45

Alterations of Chromosome Structure

Breakage of a chromosome can lead to 4 types of changes in chromosome structure:

- Deletion: removes a chromosomal segment

- Duplication: repeats a segment

- Inversion: reverses the orientation of a segment within a chromosome

- Translocation: moves a segment from 1 chromosome to another

46

(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 one chromosome 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

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

47

Human Disorders Due to Chromosomal Alterations

Some types of aneuploidy have higher survival rates, resulting in individuals surviving to birth & beyond

These survivors have a set of symptoms (syndrome) characteristic of the type of aneuploidy

48

Down Syndrome (Trisomy 21)

Aneuploidy due to 3 copies of chromosome 21

- affects 1 out of every 700 US children

- frequency increases with mother’s age…

49

50

Aneuploidy of Sex Chromosomes

Due to nondisjunction of sex chromosomes

Klinefelter syndrome: results from an extra X chromosome in a male, producing XXY individuals

Monosomy X (Turner syndrome): produces sterile X0 females

- the only known viable monosomy in humans

51

Klinefelter Syndrome 52

Turner Syndrome 53

Disorders Caused by Structurally Altered Chromosomes

Cri du chat syndrome: due to a specific deletion in chromosome 5

- mental retardation, catlike cry

- individuals usually die in infancy or early childhood

54

Disorders Caused by Structurally Altered Chromosomes

Certain cancers are caused by translocations of chromosomes

- Chronic myelogenous leukemia (CML)

55

Normal chromosome 9

Normal chromosome 22

Reciprocal translocation

Translocated chromosome 9

Translocated chromosome 22 (Philadelphia chromosome)

56

There are 2 normal exceptions to Mendelian genetics

1. One involves genes located inside the nucleus (genomic imprinting)

2. The other involves genes located outside the nucleus (extranuclear genes)

In both cases, the sex of the parent contributing an allele is a factor in the pattern of inheritance

57

Genomic Imprinting

For a few mammalian developmental traits, phenotype depends on which parent passed along

those alleles

- this phenotype variation is called genomic imprinting

- involves the silencing of certain genes that are “stamped” with an imprint during gamete

production

- due to the methylation (addition of –CH3) of cysteine nucleotides of DNA

58

Normal Igf2 allele is expressed

Paternal chromosome

Maternal chromosome

(a) Homozygote

Wild-type mouse (normal size)

Normal Igf2 allele is not expressed

Genomic imprinting of the mouse Igf2 gene 59

Mutant Igf2 allele inherited from mother

Mutant Igf2 allele inherited from father

Normal size mouse (wild type)

Dwarf mouse (mutant)

Normal Igf2 allele is expressed

Mutant Igf2 allele is expressed

Mutant Igf2 allele is not expressed

Normal Igf2 allele is not expressed

(b) Heterozygotes 60

Inheritance of Organelle Genes

Extranuclear (cytoplasmic) genes: found in organelles in the cytoplasm

- mitochondria, chloroplasts, & 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

61

62

Some defects in mitochondrial genes prevent normal ATP

synthesis

- result in diseases that affect the muscular &

nervous systems

- mitochondrial myopathy

63

64

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by Rob Swatski, 2013

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