chromosomes and human genetics chapter 11. chromosomes & cancer some genes on chromosomes...

Chromosomes andHuman Genetics

Chapter 11

Chromosomes & Cancer

• Some genes on chromosomes control cell growth and division

• If something affects chromosome structure at or near these loci, cell division may spiral out of control

• This can lead to cancer

Philadelphia Chromosome

• First abnormal chromosome to be

associated with a cancer

• Associated with a chronic leukemia

– Overproduction of white blood cells

A Reciprocal Translocation1 2

6

13 15

19 20

Chromosome 9

and chromosome

22 exchanged

pieces

An Altered Gene

• When the reciprocal translocation occurred, a gene at the end of chromosome 9 fused with a gene from chromosome 22

• This hybrid gene encodes an abnormal protein that stimulates uncontrolled division of white blood cells

Genes

• Units of information about heritable

traits

• In eukaryotes, distributed among

chromosomes

• Each has a particular locus

– Location on a chromosome

Homologous Chromosomes

• Homologous autosomes are identical in length, size, shape, and gene sequence

• Sex chromosomes are nonidentical but still homologous

• Homologous chromosomes interact, then segregate from one another during meiosis

Alleles

• Different molecular forms of a gene

• Arise through mutation

• Diploid cell has a pair of alleles at each

locus

• Alleles on homologous chromosomes

may be same or different

Sex Chromosomes

• Discovered in late 1800s

• Mammals, fruit flies

– XX is female, XY is male

• In other groups XX is male, XY female

• Human X and Y chromosomes function

as homologues during meiosis

Human Karyotype

1 2 3 4 5 6 7 8 9 10 11 12

13 14 15 16 17 18 19 20 21 22 XX (or XY)

Sex Determination

XX

XY

XX

XY

X X

Y

X

sex chromosome combinations possible in new individual

Y

X

sperm

X

X

eggs

Female germ cell Male germ cell

The Y Chromosome

• Fewer than two dozen genes identified

• One is the master gene for male sex

determination

– SRY gene (Sex-determining region of Y)

• SRY present, testes form

• SRY absent, ovaries form

Effect of YChromosome

10 weeks

Y present

Y absent

7 weeks

birth approaching

appearance of structuresthat will give rise toexternal genitalia

appearance of “uncommitted” duct system

of embryo at 7 weeks

Y present

Yabsent

testis

ovary

testes ovaries

The X Chromosome

• Carries more than 2,300 genes

• Most genes deal with nonsexual traits

• Genes on X chromosome can be expressed in both males and females

Discovering Linkage

homozygous dominant female

recessive male

Gametes:

XX X Y

All F1 offspring have red eyes

x

heterozygous male

heterozygousfemale

One cross

Discovering Linkage

homozygous recessive female

dominantmale

Gametes:

XX X Y

F1 offspring

x

recessive males

heterozygousfemales

Half are red-eyed females, half are white-eyed males

Reciprocal cross

Discovering Linkage

• Morgan’s crosses showed relationship

between sex and eye color

• Females can have white eyes

• Morgan concluded gene must be on the

X chromosome

Full Linkage

xAB ab

50%AB

50%ab

All AaBb

meiosis, gamete formation

Parents:

F1 offspring:

With no crossovers, half of the gametes have one parental genotype and half have the other

AB

ab

AB

ab

ab

AB

Incomplete Linkage

Parents:

F1 offspring

Unequal ratios of four types of gametes:

All AaCc

x

meiosis, gamete formation

AC acA

C AC

AC

ac

ac

Ac

aC

ac

Most gametes have parental genotypes

A smaller number have recombinant genotypes

Crossover Frequency

Proportional to the distance that

separates genesA B C D

Crossing over will disrupt linkage between

A and B more often than C and D

Linkage Mapping in Humans

• Linkage maps based on pedigree analysis through generations

• Color blindness and hemophilia are very closely linked on X chromosome – Recombination frequency is 0.167%

Pedigree

• Chart that shows genetic connections

among individuals

• Standardized symbols

• Knowledge of probability and Mendelian

patterns used to suggest basis of a trait

• Conclusions most accurate when drawn

from large number of pedigrees

Fig. 11.9, p. 178

male

female

marriage/mating

Individual showing trait being studied

sex not specified

generationI,II, III, IV...

offspring in order of birth, from left to right

I

II

III

IV

V

6 7

12

5,56,6

5,56,6

5,56,6

5,56,6

5,56,6

5,56,6

6,65,5

6,65,5

5,66,7

6,66,6Gene not expressed in this carrier.

Pedigree for Polydactly

I

II

III

IV

V

6 7

12

5,5 6,6

5,5 6,6

5,5 6,6

5,5 6,6

5,5 6,6

5,5 6,6

6,6 5,5

6,6 5,5

5,6 6,7

6,6 6,6*Gene not expressed in this carrier.

*

malefemale

Genetic Abnormality

• A rare, uncommon version of a trait

• Polydactyly

– Unusual number of toes or fingers

– Does not cause any health problems

– View of trait as disfiguring is subjective

Genetic Disorder

• Inherited conditions that cause mild to

severe medical problems

• Why don’t they disappear?

– Mutation introduces new rare alleles

– In heterozygotes, harmful allele is masked,

so it can still be passed on to offspring

Autosomal Recessive Inheritance Patterns

• If parents are

both

heterozygous,

child will have a

25% chance of

being affected

Galactosemia

• Caused by autosomal recessive allele

• Gene specifies a mutant enzyme in the pathway that breaks down lactose

LACTOSE GALACTOSEGALACTOSE-1-PHOSOPHATE

GALACTOSE-1-PHOSOPHATE

enzyme 1 enzyme 2 enzyme 3

+glucose intermediate

in glycolysis

Autosomal Dominant Inheritance

Trait typically appears in every generation

Huntington Disorder

• Autosomal dominant allele

• Causes involuntary movements, nervous system deterioration, death

• Symptoms don’t usually show up until person is past age 30

• People often pass allele on before they know they have it

Acondroplasia

• Autosomal dominant allele

• In homozygous form usually leads to stillbirth

• Heterozygotes display a type of dwarfism

• Have short arms and legs relative to other body parts

X-Linked Recessive Inheritance

• Males show disorder more than females

• Son cannot inherit disorder from his father

Examples of X-Linked Traits

• Color blindness– Inability to distinguish among some of all

colors

• Hemophilia– Blood-clotting disorder

– 1/7,000 males has allele for hemophilia A

– Was common in European royal families

Fig. 11.12b, p. 181

I

II

III

IV

V

VI

Albert Victoria

Fragile X Syndrome

• An X-linked recessive disorder

• Causes mental retardation

• Mutant allele for gene that specifies a

protein required for brain development

• Allele has repeated segments of DNA

Duplication

• Gene sequence that is repeated several

to hundreds of times

• Duplications occur in normal

chromosomes

• May have adaptive advantage

– Useful mutations may occur in copy

Duplication

normal chromosome

one segment repeated

three repeats

Inversion

A linear stretch of DNA is reversed

within the chromosome

Translocation

• A piece of one chromosome becomes attached to another nonhomologous chromosome

• Most are reciprocal

• Philadelphia chromosome arose from a reciprocal translocation between chromosomes 9 and 22

Translocation

chromosome

nonhomologous chromosome

reciprocal translocation

Deletion

• Loss of some segment of a chromosome

• Most are lethal or cause serious disorder

Polyploidy

• Individuals have three or more of each type of chromosome (3n, 4n)

• Common in flowering plants

• Lethal for humans– 99% die before birth

– Newborns die soon after birth

Nondisjunction

n + 1

n + 1

n - 1

n - 1chromosome alignments at metaphase I

nondisjunction at anaphase I

alignments at metaphase II anaphase II

Down Syndrome

• Trisomy of chromosome 21

• Mental impairment and a variety of additional defects

• Can be detected before birth

• Risk of Down syndrome increases dramatically in mothers over age 35

Fig. 11.18, p. 185

inci

den

ce

per

1,0

00 b

irth

s

20

15

10

5

020 25 30 35 40 45

mother's age

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 23

Turner Syndrome

• Inheritance of only one X (XO)

• 98% spontaneously aborted

• Survivors are short, infertile females– No functional ovaries

– Secondary sexual traits reduced

– May be treated with hormones, surgery

Klinefelter Syndrome

• XXY condition• Results mainly from nondisjunction in

mother (67%)• Phenotype is tall males

– Sterile or nearly so– Feminized traits (sparse facial hair,

somewhat enlarged breasts)– Treated with testosterone injections

XYY Condition

• Taller than average males

• Most otherwise phenotypically normal

• Some mentally impaired

• Once thought to be predisposed to criminal behavior, but studies now discredit

Phenotypic Treatments

• Symptoms of many genetic disorders

can be minimized or suppressed by

– Dietary controls

– Adjustments to environmental conditions

– Surgery or hormonal treatments

Genetic Screening

• Large-scale screening programs detect affected persons

• Newborns in United States routinely tested for PKU– Early detection allows dietary intervention

and prevents brain impairment

Prenatal Diagnosis

• Amniocentesis

• Chorionic villus sampling

• Fetoscopy

• All methods have some risks

Fig. 11.19, p. 186Karyotype analysis

Fetal cells

Centrifugation

Growth for weeks in culture medium

Removal of about 20 ml of amniotic fluid containing suspended cells that were sloughed off from the fetus

A few biochemical analyses with some of the amniotic fluid

Quick determination of fetal sex and analysis of purified DNA

Biochemical analysis for the presence of alleles that cause many different metabolic disorders