Chromosomes and Human 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 (CML)
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
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
Karyotype Diagram
10
11
12
13
14
15
16
17
18
19
20
21
22
XX (or XY)
Figure 12.4 Page 197
Sex Determination
female (XX)
male (XY)
eggs
sperm
X X
x
x
Y X
X X XX
X XX
Y
Figure 12.5 Page 198
XY
XY
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
appearance of structures that will give rise to external genitalia
appearance of uncommitted duct system of embryo at 7 weeks
Effect of Y Chromosome
7 weeks Y present Y absent Y present Y absent
testes 10 weeks
ovaries
ovary testis
Figure 12.6 Page 199
birth approaching
Membrane ProteinsRecognition
protein extracellular environment
Receptor protein
lipid bilayer cytoplasm Protein pump across bilayer Protein channel across bilayer Protein pump Figure 4.4 Page 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 doesnt 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.
http://transwoman.tripod.com/ais.htm
Beauty queen Janel Bishop, Miss Teen USA 1991,
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.
Map
From the American Journal of Medicine (Am. L. Med. 62: 170-191, 1977)
From the American Journal of Medicine (Am. L. Med. 62: 170-191, 1977)
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 Gametes: X X x
recessive male
All F1 have red eyes Gametes: X 1/2 1/2 X x X Y
1/2
1/4 1/2 1/4 1/4 1/4
F2 generation:
Figure 12.7 Page 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
B Parents: AB F1 offspring: A x A a
b
a b ab
B
All AaBb
meiosis, gamete formation
Equal ratios of two types of gametes:
a b
Figure 12.8a 50% AB 50% ab
Page 201
Incomplete Linkage
AC Parents: F1 offspring: C C All AaCc meiosis, gamete formation A A x a c c ac
Unequal ratios of four types of gametes:
A C c
a c
A C
parental genotypes
recombinant genotypes
Figure 12.8b
Page 201
Crossover Frequency
Proportional to the distance that separates genes
A B C D
Crossing over will disrupt linkage between A and B more often than C and D
In-text figure Page 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
male female marriage/mating
offspring in order of birth, from left to right
Individual showing trait being studied
sex not specified
I, II, III, IV... Figure 12.9a Page 202
generation
Pedigree for Polydactyly
I
female
male
II 5,5 6,6 III
*
5,5 6,6
6 7
6,6 5,5 5,5 6,6 5,5 6,6 5,5 6,6
12
6,6 5,5 5,6 6,7
IV
5,5 6,6 V
*Gene not expressed in this carrier.
Figure 12.9b Page 202
6,6 6,6
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 dont 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
Figure 12.10a
Page 204
Galactosemia
Caused by autosomal recessive allele
Gene specifies a mutant enzyme in the pathway that breaks down lactose
enzyme 1 enzyme 2 enzyme 3
lactose
galactose + glucose
galactose-1phosphate
galactose-1phosphate intermediate in glycolysis
In-text figure Page 204
Autosomal Dominant Inheritance
Trait typically appears in every generation
Figure 12.10b
Page 204
Huntington Disorder
Autosomal dominant allele
Causes involuntary movements, nervous system deterioration, death Symptoms dont 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
Figure 12.12a
Page 205
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
In-text figure Page 206
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 nonhomologous chromosome
nonreciprocal translocation In-text figure Page 206
In-text figure
Page 206
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+1
n+1
n-1
chromosome alignments at metaphase I
n-1 nondisjunction alignments at at anaphase I metaphase II anaphase II Figure 12.17 Page 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
Mothers Age
Incidence/1000births Age = 35
Bow with Downs 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)
Turners 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
