Lecture 14 – The Chromosomal Basis of

Inheritance

In this lecture… • Linking Meiosis and Punnet Squares

– Sex-linked traits

• X inactivation

• Linkage

• Altering chromosome structure

– Polyploidy and aneuploidy

• Epigenetics

Linking Meiosis and Punnet Squares

How did we first figure out where genes were on chromosomes?

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

• Fruit flies are great model organisms

– Only four pairs of chromosomes

Morgan’s Contributions

• Confirmed the chromosomal theory of inheritance: genes are located on chromosomes

• Discovered gene linkage

Wild type

• Morgan noticed certain traits were much more common in flies

• These traits he called wild type (as in much more likely to be found in the wild)

Wild-type Mutant

Morgan’s experiments • 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

Figure 15.4

All offspring had red eyes.

P Generation

F1 Generation

F2 Generation

F2 Generation

F1 Generation

P Generation

Eggs

Eggs

Sperm

Sperm

X

X

X Y

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w w w

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w w w

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RESULTS

EXPERIMENT

CONCLUSION

Sex-linked traits

• Only males had the white eyes

• Why did the males get the short end of the stick?

• Color-blindness is a sex-linked trait

– Genes for sex-linked traits are carried on the sex chromosomes

– More specifically, it is an X-linked trait

Sex-linked traits • There are about 1,000 sex-linked genes

– These genes are found only on the sex chromosomes

• These genes are on the X chromosome, but not on the Y

– A female with XX will have two copies of an X-linked gene

– A male with XY will have one copy of an X-linked gene

Male Female Male

Why are men more susceptible to some genetic diseases?

• If the male receives a defective copy of a sex-linked gene/alelle, he has no functional copy as a backup

• Therefore, he has whatever disease is associated with that defective allele

Sex Chromosomes • X chromosome have genes for many

characters unrelated to sex, whereas the Y chromosome mainly encodes genes related to sex determination

• Female is the default sex?

More about the sex chromosomes

• Autosomes vs. sex chromosomes

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

• Each ovum contains an X chromosome, while a sperm may contain either an X or a Y chromosome

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

Sex determination in other animals

• X and Y are not the only way to determine sex

Punnet Squares and X-linked genes

• 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)

Figure 15.7

Eggs Eggs Eggs

Sperm Sperm Sperm

(a) (b) (c)

XNXN XnY XNXn XNY XNXn XnY

Xn Y XN Y Y Xn

Xn Xn

XN

XN

XN XN XNXn XNY

XNY

XNY XNY

XnY XnY XNXn XNXn

XNXn XNXN

XnXn

Transmission of X-linked recessive traits

Punnet Squares and X-linked genes

• A couple goes to a genetic counselor, wondering about the possibility of their children inheriting X-linked colorblindness. The man is colorblind, but the woman is not, and does not have a history of it in her family. What is the probability that:

– Their first child will be female

– Their sixth child will be female

– Their female children will be colorblind

– Their male children will be colorblind

Genetic disorders caused by defective X-linked genes

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

– Color blindness (mostly X-linked)

– Duchenne muscular dystrophy

– Hemophilia

• 30% of cases are spontaneous

Hemophilia and the Queen • Britain’s Queen Victoria was a carrier for hemophilia

• She passed the allele to royal households across Spain, Germany and Russia

• Called “the royal disease”

Aneuploidy in the sex chromosomes

• Aneuploidy: having an unusual number of chromosomes

• Sometimes, you can get aneuploidy involving extra sex chromosomes – XXY, XXX, XYY

• However, someone with an XY genotype can have a female phenotype if the SRY gene is damaged

• Similarly, someone with XX genotype can be phenotypically male if the SRY gene is translocated onto the X – In 1996, a test based on a molecular probe for SRY was

used to ensure that potential competitors for the women's Olympic events in Atlanta had no SRY gene

X aneuploidies • Monosomy X, called Turner syndrome, is the

absence of an X in females (XO) – The only known viable monosomy in humans – Incomplete development at puberty – Short height – Infertility

• Kleinfelter Syndrome is the presence of an extra X in males (XXY) – Gynecomastia – Abnormal body proportions – Infertility

• Male XYY Syndrome

X inactivation in female mammals • 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

Barr Bodies in Calico Cats

Are there male calico cats?

Linked Genes • Linked genes are genes that tend to be

inherited together

– They are located very close to each other on a chromosome

– They are unlikely to be separated during homologous recombination and independent assortment

Homologous recombination during meiosis “can cause alleles previously on the same chromosome to be separated and end up in different daughter cells. The farther the two alleles are apart, the greater the chance that a

recombination event may occur between them, and the greater the chance that the alleles are separated.”

Linkage maps • The first chromosome maps were linkage

maps

• A linkage map shows the positions of known genes relative to each other in terms of recombination frequency – The greater the frequency of recombination

between two genes, the farther apart they are

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

Calculating recombination frequencies

• Recombination frequency is the frequency with which a single chromosomal crossover will take place between two genes during meiosis

A miniature linkage map

A cow linkage map

Uses of linkage maps

• 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

• Linkage maps won’t tell you exactly where a gene is located on a chromosome

Damaging chromosomes • Damaging or altering chromosome structure

can lead to genetic disorders – Removing or adding a chromosome

– Deleting part of a chromosome

– Translocating part of a chromosome

• Alteration of chromosome structure is the main culprit behind spontaneous abortions in humans

• Plants can withstand largescale chromosome alteration better than animals

Aneuploidy (again) • Aneuploidy is a result of nondisjunction

– Chromosomes fail to separate during meiosis

• As a result, one gamete receives two of the same type of chromosome, and another gamete receives no copy

Aneuploidy in humans

• Aneuploidy occurs in 1 in 160 live births

• Most aneuploidies result in spontaneous abortion

• Most common error is trisomy 16 – not possible to survive

• Risk of aneuploidy increases with the age of the mother

Aneuploidy in humans • Trisomy 21

– Down syndrome – Small chin, round face, almond-shaped

eyes, shorter limbs, high risk for heart defects

• Trisomy 18 – Edwards syndrome – Small head, small jaw, cleft palate, clenched hands, heart

defects • Trisomy 13

– Patau syndrome – Heart defects, kidney defects mental

retardation, polydactylyl, cyclopia, abnormal cranial development

Polyploidy vs. Aneuploidy

• 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

• Polyploids are more normal in appearance than aneuploids

• ‘Odd’ polyploids are usually sterile

Polyploidy in plants • Polyploidy is common in ferns and flowering

plants

– 30-70% of plants are polyploid

• Polyploidy gives an opportunity for greater heterozygosity

– Instead of two alleles with diploids, polyploids can have n number of alleles

– Some polyploid plants have larger fruit

Seedless fruit • Some varieties of seedless fruit are triploid

• Odd-numbered polyploids are usually sterile, and produce no seeds

Triploid Tetraploid Hexaploid Octaploid

Apple, banana, oranges, watermelon

Apple, cotton, potato, cabbage, peanut

Wheat, oats, kiwi, chrysanthemum

Strawberry, sugarcane

Seedless…animals?

Polyploidy in yeast

• Some years ago, yeast underwent genome duplication

• They received an extra copy of their genome and became polyploid

• The extra genome had no evolutionary selective pressure on it, and could evolve in any random direction

• Yeast evolved alcohol fermentation in that extra genome copy

Alteration 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

Diseases due to chromosome alterations

• The syndrome cri du chat (“cry of the cat”), results from a specific deletion in chromosome 5

• A child born with this syndrome is mentally retarded and has a catlike cry; individuals usually die in infancy or early childhood

• Certain cancers, including chronic myelogenous leukemia (CML), are caused by translocations of chromosomes

Figure 15.16

Normal chromosome 9

Normal chromosome 22

Reciprocal translocation

Translocated chromosome 9

Translocated chromosome 22 (Philadelphia chromosome)

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

Hold on…

• Genomic imprinting is a bit of an archaic term

• Most genes have some sort of imprinting

• Today, genomic imprinting is called epigenetics

How epigenetics works

• One of the main determinants of whether a gene is expressed is where it is physically located in the genome

– Euchromatin is DNA bound loosely with protein, and is often expressed

– Heterochromatin is DNA bound up tightly with protein, and is rarely expressed

• Parental experiences can compress or unwind DNA

How epigenetics works

• What determines how the tightly the DNA is wound?

– Methylation (addition of –CH3 to nucleotides) produces euchromatin

• Studying methylation patterns it the basis of a new field of biology called epigenomics

Angelman’s syndrome and Prader-Willi Syndrome

• Caused by improper epigenetic regulation on chromosome 15

• Normally, one chromosome is expressed while the homologous chromosome is silenced through demethylation

• In Angelman’s syndrome, the maternal copy is lost through chromosomal deletion while the paternal copy is silenced – Symptoms: developmental delay, speech impediment, seizures, very

happy personality

• In Prader-Willi syndrome, the paternal copy is lost through chromosomal deletion while the maternal copy is silenced – Symptoms: developmental delay, short

stature, weak muscles, excessive and unsatisfied hunger

Inheritance of cell organelles

• Mitochondria, chloroplasts, and plastids are inherited from the mother

– The sperm is not big enough to hold all the organelles

• You can trace your maternal line through your mitochondrial genome

• Some defects in mitochondrial genes prevent cells from making enough ATP and result in diseases that affect the muscular and nervous systems

Vocabulary

• Wild-type • SRY gene • Hemophilia • Sex-linked trait • Barr body • Linkage maps • Aneuploidy

– Down syndrome, Edwards syndrome, Patau syndrome

– Turner syndrome, Kleinfelter syndrome

• Polyploidy – In yeast and plants

• Chromosomal alterations – Deletion, duplication,

inversion, translocation

• Methylation • Euchromatin • Heterochromatin • Epigenetics

– Angelman’s syndrome and Prader-Willi syndrome