Chromosomes and Human Genetics
Oct 24, 2014
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
(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
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
X
X Y
X
XX
XY
XX
XY
X X
Y
X
x
x
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
ovary
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. “
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
recessive male
Gametes:
XX X Y
All F1 have red eyes
x
1/4
1/4
1/4
1/4
1/2
1/2 1/2
1/2
F2
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
x
AB ab
50% AB 50% ab
All AaBb
meiosis, gamete formation
Parents:
F1 offspring:
Equal ratios of two types of gametes:
AB
ab
AB
ab
ab
AB
Figure 12.8aPage 201
Incomplete Linkage
Parents:
F1 offspring:
Unequal ratios of four types of gametes:
All AaCc
x
meiosis, gamete formation
AC acA
C A
C
AC
a
c
ac
Ac
aC
a
c
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
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
Figure 12.9aPage 202
Pedigree for Polydactyly
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
Figure 12.9bPage 202
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
Figure 12.10aPage 204
Galactosemia
Caused by autosomal recessive allele Gene specifies a mutant enzyme in the
pathway that breaks down lactose
In-text figurePage 204
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
Figure 12.10bPage 204
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
Figure 12.12aPage 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 figurePage 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
In-text figurePage 206
Translocation
one chromosome
a nonhomologouschromosome
nonreciprocal translocation
In-text figurePage 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
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