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Chromosomes andHuman Genetics

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

Reciprocal translocation

Causes chronic myelogenous leukemia

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

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

Karyotype Preparation - Stopping the Cycle

Cultured cells are arrested at metaphase by adding colchicine

This is when cells are most condensed and easiest to identify

Karyotype Preparation

Arrested cells are broken open Metaphase chromosomes are fixed

and stained Chromosomes are photographed

through microscope Photograph of chromosomes is cut up

and arranged to form karyotype diagram

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)

Figure 12.4Page 197

Karyotype Diagram

Sex Determination

eggs sperm

female(XX)

male(XY)

Figure 12.5Page 198

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

testes ovaries

Figure 12.6Page 199

Membrane Proteins

Protein pump across

bilayer

Protein channel

across bilayer

Protein pump

Recognition protein

Receptor protein

extracellular environment

cytoplasm

lipid bilayer

Figure 4.4Page 57

Androgen Insensitivity Syndrome Disease characteristics: (AIS) typically

includes evidence of feminization; and abnormal secondary sexual development in puberty, and infertility.

Cause: Gene for testosterone recognition malfunctions (recognition protein doesn’t work)

“Genetic males” are feminized

“Women with AIS look and feel like typical women, and in every practical, social, legal, and everyday sense they are women, even though congenitally they have testes and XY chromosomes, and can never bear children. The fact that a "woman" has AIS and is genetically a "male" is often not discovered until puberty, when she does not start to menstruate and a gynecological examination reveals the syndrome.”

Beauty queen Janel Bishop, Miss Teen USA 1991, suffers from AIS.

http://transwoman.tripod.com/ais.htm

Androgen Deprivation The “Guevedoces” of the Dominican

Republic Reports from isolated villages asserted that

”children appearing to be girls turned into men at puberty.” (Urological Sciences Research Foundation)

http://www.usrf.org/news/010308-guevedoces.html

Male Pseudohermaphrodites “These children appeared to be girls at

birth, but at puberty these 'girls' sprout muscles, testes, and a penis. For the rest of their lives they are men in nearly all respects …. Their underlying pathology was found to be a deficiency of the enzyme, 5-alpha Reductase. “

From the American Journal of Medicine (Am. L. Med. 62: 170-191, 1977)

6. And for the rest of their lives, the guevedoces resemble the other Dominican men in all respects except:* Beard growth is scanty.* There is no hairline recession.* None has acne.* The prostate remains small

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 have red eyes

1/2 1/2

generation:

XX X Y

xGametes:

Figure 12.7Page 200

Linkage Groups

Genes on one type of chromosome Fruit flies

4 homologous chromosomes 4 linkage groups

Not all genes on chromosome are tightly linked

Full Linkage

50% AB 50% ab

All AaBb

meiosis, gamete formation

Parents:

F1 offspring:

Equal ratios of two types of gametes:

Figure 12.8aPage 201

Incomplete Linkage

Parents:

F1 offspring:

Unequal ratios of four types of gametes:

All AaCc

meiosis, gamete formation

AC acA

parental genotypes

recombinant genotypes

Figure 12.8bPage 201

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

In-text figurePage 201

Linkage Mapping in Humans Linkage maps based on pedigree analysis

through generations

Color blindness and hemophilia are very closely linked on X chromosome

Pedigree Symbols

female

marriage/mating

Individual showing trait being studied

sex not specified

generationI, II, III, IV...

offspring in order of birth, from left to right

Pedigree for Polydactyly

5,5 6,6

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

galactose-1-phosphate

enzyme 2

lactose galactose

enzyme 1

+glucose

galactose-1-phosphate

enzyme 3

intermediatein 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

Achondroplasia

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

Achondroplasia

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

Royal Hemophilia

http://www.people.virginia.edu/~rjh9u/roylhema.html

A Pedigree of Hemophilia in the Royal Families of Europe Selected members of the pedigree I-1 = King George III III-1 and III-2 = Prince Albert and Queen Victoria IV-5 and IV-6 = Alice of Hesse and Ludwig IV of Hesse V-13 and V-14 = Alix and Nicholas II (Tsar of Russia) VI-16 = Alexei VIII-1 = Prince Charles

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

Fragile X Syndrome

http://www.tokyo-med.ac.jp/genet/index-e.htmo

Photomicrograph Fragile X Chromosome

Hutchinson-Gilford Progeria

Mutation causes accelerated aging

No evidence of it running in families

Appears to be dominant

Seems to arise as spontaneous mutation

Usually causes death in early teens

Hutchinson-Gilford Progeria

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

segments G, H, I become inverted

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

Philadelphia Chromosome

http://gslc.genetics.utah.edu/units/disorders/karyotype/reciprocal.cfm

Philadelphia Karyotype

http://gslc.genetics.utah.edu/units/disorders/karyotype/reciprocal.cfm

Translocation

one chromosome

a nonhomologouschromosome

nonreciprocal translocation

Deletion

Loss of some segment of a chromosome Most are lethal or cause serious disorder

Aneuploidy

Individuals have one extra or less chromosome

(2n + 1 or 2n - 1) Major cause of human reproductive

failure Most human miscarriages are

aneuploids

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 - 1chromosome alignments at metaphase I

nondisjunction at anaphase I

alignments at metaphase II anaphase II

Figure 12.17Page 208

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

Trisomy 21

Non-disjunction

Karotype Trisomy 21

Mother’s Age

Age = 35

Incidence/100

0births

Bow with Down’s Syndrome

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

Monosomy(Having only one X chromsome per cell)

Turner’s Syndrome

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

Klinefelter Syndrome

http://www.tokyo-med.ac.jp/genet/index-e.htmo

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

Amniocentesis

Pedigree Analysis

Preimplantation Diagnosis

Used with in-vitro fertilization

Mitotic divisions produce ball of 8 cells

All cells have same genes

One of the cells is removed and its genes

analyzed

If cell has no defects, the embryo is implanted in

uterus

Preimplant Diagnosis

http://www.layyous.com/book/book%20images/Untitled-196b.jpg

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