Download I gene

Transmission (Classical, Mendelian)
Genetics Ch 11
• Gregor Mendel
– Experiments in Plant Hybridization, 1865
• Controlled experiments, mathematical
analysis
Pisum sativum, the garden pea
•
•
•
•
•
What makes this a good model organism?
easy to grow
hundreds of offspring per cross
short generation time
can self fertilize or cross
– Paint pollen (sperm) from one plant onto the
female parts of another (emasculated plant)
Mendel’s conclusions
1. Genes are physical units
– 2 alleles for each gene
– 1 allele inherited from each parent
Genes and alleles of Pisum sativum
Gene
• Pea color
• Flower color
• Pod shape
• Pea surface
• Stem height
Alleles
?
white, purple
constricted, inflated
?
tall, dwarf
2. Principle of Dominance
- One allele dominant, the other recessive
- The dominant allele is expressed in the
phenotype
Gene for flower color
P allele = purple
p allele = white
GENOTYPES
Homozygous dominant =
Heterozygous =
Homozygous recessive =
PHENOTYPE
3.
Random segregation of alleles into
gametes
– gamete receives ONE allele per gene
– random segregation of alleles 50/50
P generation
PP
pp
What is the phenotype of all offspring
in F1 generation?
Note that the P generation is true breeding
P
p
Genotype
Phenotype
p
P
How did Mendel do it?
The Monohybrid cross
YY yy
Which allele is dominant?
What is the genotype of the f1 generation?
Cross 2 f1 plants (or let one self-fertilize)
What is the ratio of phenotypes?
Results of Mendel’s monohybrid crosses
Parental Strains
F2 progeny
Ratio
Tall X dwarf
787 tall, 277 dwarf
Round seeds X wrinkled
5474 round, 1850 wrinkled
Yellow seeds X green
6022 yellow, 2001 green
Violet flowers X white 705 violet, 224 white
Inflated pods X constricted 882 inflated, 299 constricted
Green pods X yellow
428 green, 152 yellow
Axial flowers X terminal
651 axial, 207 terminal
gene = ?
alleles = ?
Test cross (one gene)
• A mouse has black fur, what are its 2
possible genotypes?
Test cross mouse to homozygous recessive
mouse
If black mouse is BB 
If black mouse is Bb 
A mouse was test crossed and 7 offspring
black, 2 white. What is mouse’s
genotype?
Pedigree Analysis Ch 11
Autosomal recessive inheritance (bb)
• unaffected parents can have
affected offspring
• May “skip” a generation
• Two affected parents cannot
have an unaffected child
• Not sex related
Autosomal recessive traits
•
•
•
•
Sickle cell disease
Albinism
Cystic fibrosis
O blood type
Phenylketonuria (Ch.4)
• PKU (1/12,000) Mutation in gene encoding
phenylalanine hydroxylase enzyme needed for
phe metabolism
Chromosome 12
12q24.1
All US babies tested at birth (Guthrie test)
missing
phenylalanine
hydroxylase
enzyme
If plasma phe level is too high, phe is converted
into a phenylpyruvate toxic to brain tissue
Why are these babies normal when born?
Pleiotropic effects
no tyrosine (little melanin)
slow growth
retardation
blue eyes
low adrenaline
Ch 4
1902 Archibald Garrod:
One gene: one enzyme
“Inborn errors of metabolism”
PKU
Albinism
Alkaptonuria
Tyrosinemia
Black
urine
arthritis
Fill in genotypes. If II,1 and II, 4 mate, what is the
chance of offspring having PKU?
How do we know
this is autosomal
recessive?
II, 1
X
II, 4
•p(aa AND a girl)?
p(aa)
If III-3 and II-1 mate p (normal child)
Product rule:
p (affected boy)?
All people have harmful recessive alleles, small
chance
That 2 people with same rare alleles will mate
Consanguinous marriage increases the chance
Bedoin intermarriage
Autosomal dominant disorders
Aa and AA =affected
aa =unaffected
•Tend to show up in every generation
•2 affected parents can have unaffected child
•2 unaffected parents cannot have an affected
child
Dominant pedigree
Achondroplasia -1/20,000 births
• Mutation in FGFR3 gene Chromosome 4
• Affects cartilage growth needed for bone
lengthening
• Most affected individuals Aa  why?
• Most cases spontaneous
(associated with increasing paternal age)
what is the genotype of parents in this case?
P(III, 3 and III, 5 have a child of normal height)
P ( II, 3 and III, 7 have a boy with
achondroplasia)
• Mutation in dog FGF4 gene
Dihybrid cross – 2 genes Ch. 11
Mendel’s Law of Independent assortment -
each allele for a trait is inherited independently of
other alleles
Seeds:
G = yellow allele
g = green allele
W = round
w = wrinkled allele
allele
gene?
gene?
Parents =
GGWW X
phenotype?
gametes?
F1 genotype
?
F1 phenotype
?
F1 Gametes?
ggww
Note that each gene gives the 3:1 ratio of a
monohybrid cross
Yellow/green ratio =
Round/ wrinkled =
Forked line method for phenotypes
GgWw X GgWw
Test cross
A pea is round and yellow. What is its genotype?
G-W-
X
ggww
Note the cross of the “unknown” to a homozygous recessive
If all yellow and round:
If all yellow and some wrinkled:
If all round and some green:
If 1:1:1:1:
Probability
Product rulethe probability that two outcomes occur simultaneously is
product of their individual probabilities
assumes independent assortment of genes
GgWw X GgWw
• What is the probability of a yellow AND wrinkled?
p(G-ww)
A female lilac tabby X A male black siamese genotype:
ww bb CC dd Aa X ww Bb CsCs Dd Aa
p( black tabby cat)
p (brown solid color cat)
W = white
B = black
C = solid (not siamese)
D = not dilute (full color)
A = striped (tabby)
Trihybrid cross
AaBbCc X AaBbCc
p(A-B-cc)
AabbCcDD X AaBbCcDd
p(triply recessive)
Modified Mendelian Ratios Ch. 13
1. Multiple alleles (more than 2 alleles for gene in
population)
Chromosome 9 I gene
• Example: Blood Groups
Karl Landsteiner 1900’s
ABO blood system = polymorphic I gene
Blood type
A
B
AB
O
genotype
IAIA or IAi
?
IAIB
ii
What is the mechanism of inheritance of A, B, AB, O?
Autosomal or sex chromosome?
Which two alleles are codominant?
Which allele is recessive?
Example
• A child has type O blood. The mother of the child
has Type B blood. What could the blood types of
the father?
2. Incomplete dominance
Example: snapdragons
Allelic symbols do not specify dominance
CR = red color
Cw = white color
CR CR
X Cw Cw
3. Codominance
Each allele encodes separate gene
product distinct in heterozygote
L gene for human blood cell surface protein
LM = M antigen LMLN x LMLN
LN = N antigen
1M
• A man with the M bloodtype has a child with a
woman of the MN bloodtype
• Expected ratio of offspring?
4. Lethal alleles
MM = normal spine
MM’ = manx cat (no tail)
M’M’ = lethal
Cross two manx, what is ratio of phenotypes in
offspring?
How do breeders obtain manx cats?
Lethal alleles in humans
• Tay Sach disease tt is fatal
• Huntington disease HH is fetal lethal
• Hh causes death ~ age 50.
Polydactyly, dominant
5. Penetrance
• % individuals that exhibit
phenotype corresponding to
genotype
Pp
5,5
pp
6, 5
6, 6
6. Expressivity (ex. Piebald spotting) =the
extent to which a trait is exhibited
Incomplete penetrance AND expressivity
• NF-1 = Neurofibromatosis1
– (1/4000, 17q11.2)
– (350 kb gene, 60 exons)
• Autosomal dominant trait NN and Nn with 50- 80%
penetrance
• Variable expressivity
Mild form
tumors on nerve CT coverings, skin, eyes, organs, face
speech, blood pressure, spine curvature, headaches
Gene expression also affected by:
•
•
•
•
Sex (baldness)
Temperature (melanin in Siamese cats)
Chemicals (PKU)
Diet (height, cancer)
7. Epistasis- gene product interactions
• A product of one gene influences, or masks,
the expression of another gene(s)
• Modification of dihybrid cross ratio
AaBb
X
AaBb
9:3:3:1
Epistasis in labrador retrievers
• B and E color genes (labs)
B black
E color
b brown
e no color (yellow)
ee is epistatic
Cross two double heterozygotes
Phenotypes of parents?
Phenotypes of offspring? ratio?
Epistasis in Cats
• W = white
w = not white
• B = black
b = brown
Mate 2 heterozygous cats
What is the expected ratio?
8. Polygenic traits
• Vary continuously
– Weight, height, IQ
Animal life cycle
• 1n haploid gametes have 1 set of
chromosomes
• 2n diploid zygote has 2 sets of chromosomes
Homologous chromosomes
1 pr sex chromosomes
22 prs. autosomes
KARYOTYPE
1. Obtain white blood cells from or fetal cells from
amniotic fluid
2. Proliferation via growth factor add colchicine at
metaphase to arrest spindle formation
3. add water to swell cell -> squash
4. stain ->photograph
Detects number of chromosomes,
sex, chromosomal abnormalities
57
Arrange in pairs according to:
• decreasing size
• centromere position
METACENT
RIC
SUBMETACEN
TRIC
• banding pattern
ACROCENT
RIC
58
metacentric (1) submetacentric (9)
p arm is the upper, shorter arm
59
Normal
male
46, XY
Which are
meta-,
submetaacrocentric?
60
Do more chromosomes mean more
intelligence?
Human
Chimpanzee
Dog
Cat
Alligator
Goldfish
Mosquito
Potato
Baker’s yeast
46
48
78
72
32
94
6
48
34
Chromosome Theory of Inheritance
• 1902 Sutton and Boveri
– A chromosome is a linkage group of Mendelian
factors (GENES)
– How many linkage groups in the human species?
• 1920s Morgan et al.
– Genes are in a linear sequence on the
chromosomes, they can be mapped
Sex chromosomes
1 pair sex chromosomes
XY heterogametic
XX homogametic
• Human Male hemizygous for X-linked traits
XHY
XhY
• Human Female = XX
– two alleles for each X-linked gene
– dominance
XHXH
XHXh
XhXh
X-linked genes
• Hemophilia (recessive) 1/5000 males
– Mutation in gene for clotting
factor
Xq28
•Mate IV 2 with homozygous normal female p(hemophilia)?
•Mate III 13 with III 1 Probability of offspring?
Criss cross inheritance of X linked traits
Fruit fly nomenclature
box 12.1
Red eyes is wildtype phenotype, brown is
mutant
bw+ = wildtype allele
bw = brown allele
genotype phenotype
red
brown
• Wingless is recessive mutant (wg allele)
• Genotype of wildtype, heterozygote, mutant?
w+ = wildtype allele w = white allele
X-linked recessive
A white-eyed female is crossed
with a red- eyed male. An F1
female from this cross is mated
with her father and an F1 male is
mated with his mother. What will
be the eye color of the offspring
of these two crosses?
The mutant fruit fly discovered by Thomas Hunt Morgan
Mammalian sex determination
= the Y system
A. Embryo is neither male nor
female
Week 7
How does embryo “know
to become male?
XY embryo sex chromosomes
• The Y determines sex
B. SRY gene encodes TDF
• SRY (sex determining region Y)
• p arm
• Gene TDF encode 20 aa transcription
factor
• Expression stimulates growth of
testes ->
• testosterone ---> sperm ducts, male
brain “sensitization”
• Sex of 45, XO?
(Turner syndrome)
• Sex of 47, XXY? (Klinefelter syndrome)
• Non-disjunction during meiosis
74
Clinical application
During sperm formation: SRY
crossed over to X chromosome
X containing sperm fertilized
egg
Child?
Clinical application
• 17 year old female presented with streak
ovaries, no uterus
• Karyotype is XY
3. Experiments with transgenic mice
XX males
Add SRY DNA to
female
mouse embryo
Pseudoautosomal region
of the X and Y
•~12 genes on X and Y
•regions allow X and Y
to pair during meiosis
•pseudoautosomal genes
are also transcribed from
the inactivated X!
•both males and females
have 2 active copies of
these genes
Dosage Compensation (mammals)
• Females have 2 Xs, males have 1 X. Do females
have an extra dose of X-linked genes/alleles?
X chromosome inactivation Lyon, 1961
• Dense “Barr body” at edge of nucleus in female cells
Male cell
female cell
cell with 2 Barr bodies
Number of X chromosomes?
Random X-inactivation
Epigenetic silencing of 1 X chromosome
Random
1000 cell embryo (16 day old in humans)
Female mosaics
• Females heterozygous for X-linked traits are
mosaics for those traits.
red/green colorblindness
phenotype = ?
XCXc
Anhydrotic ectodermal dysplasia
XAXa female
What happens to XaY?
Other sex determination systems
A. Drosophila
Ratio of X to sets of autosomes
The Y is not related to sex
X/A = 1 or >1 ------> female
X/A = 0.5 or <0.5 --------> male
X/A between 0.5 and 1 ---> intersex
Male
Sex of an XY fly with 2 sets of autosomes?
Sex of a fly with with 2 sets of autosomes, 1 X
chromosome
Sex of a triploid fly with 2 X chromosomes?
Female
ZW system - birds
• Females ZW (heterogametic)
• Males ZZ (homogametic)
Barred feathers is Z-linked and a dominant
allele
A male with non-barred feathers is crossed
to a female with barred feathers.
Allele key:
All female offspring?
Temperature sex determination (TSD)
• In some reptiles sex is not
determined genetically
Parthenogenesis – eggs
develop without sperm
(asexual)
Haplodiplod sex determination
Wasps
Haploid male
Diagnosis of disease Ch4
Fetal Chromosomal Analysis
Amniocentesis > week
14 needle into amniotic
sac
Fluid contains fetal cells
Karyotype, DNA test
Risk of miscarriage =
1/300
90
Chorionic villus sample (CVS) ~week 8
Biopsy of chorion
More risky
91
Ch. 16 Variations in chromosomes
• Chromosomal aberration
– Spontaneous
– Induced
Visible aberration in 6/1000 live births
Deletions (del)
•
•
•
•
Part of chromosome missing
observe large ones by karyotype
If centromere lost  chromosome lost
Cause
– Chemicals, radiation
– Unequal crossing over during meiosis
• If deletion homozygous  lethal
93
46,XX,del(7)(q21.12,q21.2)
Heterozygous del  pseudodominance
94
Cri du Chat
• 46, XY, 5p-
Microcephaly, myotonia,
“cry of cat”, brain
impairment
if individuals make it past
childhood, symptoms
lessen
Duplications
• segment of a chromosome doubles
• May be tandem or reverse
• problems during meiosis
96
dup(5)(qter->q33.1::p15.3->qter)
• Sample of cord blood from
stillborn male with anencephaly
97
• Inversions (inv)
– 180o turnaround of segment
• no loss of genetic material
• may change length ratio of p/q arms
– Position effect
• change in gene position with respect to
centromere may influence expression
98
Translocations
• segment moves to other chromosome interstitial or reciprocal exchange
• Individual has all genetic material, but what
about gametes?
99
t(11;13) (q21;q14.3)
• parent who has
translocation is
phenotypically normal
• The gametes are not 
multiple miscarriages
100
Translocation (cont.)
• Robertsonian fusion
– ends of 2 acro- or telocentric break/fuse
– 45 chromosomes but no, or little, loss of genetic
material
101
Aneuploidy: chromosome # changes
• Nullisomy
– Loss of homologous pair of chromosomes
– Not viable in animals
Monosomy (only 1 viable in humans!)
• 45 XO
– Turner Syndrome (1/2000 live births)
• Partial monosomy 46, 5p-
103
• Trisomy
• 47, 21+
(1/800 live births)
21 may be small, but contains 33,546,361 bp of DNA!
104
Trisomy 13 (Patau)
• Fatal< 1 year (usually)
• Deaf, blind, clyclopia, polydactly,
cleft palate
• 1/5000 live births
47, XY, 13+
105
47, XY, 18+ (Edward’s)
• < few months
1/5000 live
births
106
• Tetrasomy
– Extra chromosome pair
108
Polyploidy = extra SETS of chromosomes
109
• Many plants are
polyploid
• Some bees and wasps
are monoploid
110
Somatic mosaics
More than one genetically distinct population of
cells in individual
Ex: 46XX embryo, one cell loses an X
--- 46,XX/45X mosaic
– Symptoms less severe than the standard Turners
syndrome
111
• Somatic mosaics – chimeras in people and
animals
Note: there will be a small amount of additional
information from the lecture on Tuesday