Download Genes and alleles

Transmission (Classical, Mendelian)
Genetics Ch 11
• Gregor Mendel
– Experiments in Plant Hybridization, 1865
• Simple, controlled, data collection,
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)
• parental plants true breeding strains
Genes and alleles of Pisum sativum
Gene
• Pea color
• Flower color
• Pod shape
• Pea surface
• Stem height
Alleles
?
white, purple
constricted, inflated
?
tall, dwarf
I. Monohybrid cross
Mendel’s results from the
monohybrid cross
F2
787 long
277short
= PHENOTYPES
Ratio tall/dwarf =
4 Conclusions:
1. Genes discrete units passed on from parent to offspring
2. A dominant allele masks expression of recessive allele
3. “Unit factors in pairs”- each gene has 2 alleles
why?
Genotypes
Homozygous dominant =
Heterozygous =
Homozygous recessive =
4. Random segregation
– gamete receives ONE allele per gene
– random segregation of alleles 50/50
– Humans
Sperm + egg
23 + 23 chromosomes
1 set alleles + 1 set
haploid + haploid
fertilized egg
?
?
?
Summing it up
• Sperm and egg (gametes) are haploid.
– Each contains half the genes, or one allele for each gene
• When sperm and egg unite, organism formed is
diploid
– 2 alleles per gene
More results of Mendel’s
monohybrid crosses
Parental Strains
Tall X dwarf
Round seeds X wrinkled
Yellow seeds X green
Violet flowers X white
Inflated pods X constricted
Green pods X yellow
Axial flowers X terminal
gene = ?
alleles = ?
F2 progeny
Ratio
787 tall, 277 dwarf
5474 round, 1850 wrinkled
6022 yellow, 2001 green
705 violet, 224 white
882 inflated, 299 constricted
428 green, 152 yellow
651 axial, 207 terminal
II. Test cross (one gene)
• mouse “Z” has black fur, what are its 2
possible genotypes?
Test cross mouse “Z” to homozygous
recessive mouse
Z was test crossed and 6 offspring were
black 2 were white. What is Z’s
genotype?
Autosomal recessive inheritance (bb)
• unaffected parents can have
affected offspring
• affected progeny male, female
• May “skip” a generation
• Two affected parents cannot
have an unaffected child
Phenylketonuria pp (Ch. 4 pg 73)
• PKU (1/12,000) Mutation in gene encoding
phenylalanine hydroxylase enzyme needed for
phe metabolism
missing
phenylalanine
hydroxylase
enzyme
If plasma phe level is too high, phe is converted
into a phenylpyruvate toxic to brain tissue
Pleiotropic effects
no tyrosine (little melanin)
slow growth
retardation
blue eyes
low adrenaline
) No nutrasweet
low phe diet
($5K/yr
Page 68
1902 Archibald Garrod:
One gene: one enzyme
“Inborn errors of metabolism”
PKU
Albinism
Alkaptonuria
Tyrosinemia
Black urine
arthritis
One gene/one enzyme
• Garrod’s work on alkaptonuria
“Inborn Errors of Metabolism” 1902
Autosomal recessive metabolic disease
All people have harmful recessive alleles, small
chance
That 2 people with same rare alleles will mate
Consanguinous marriage increases the chance
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)
p (affected boy)?
Autosomal dominant disorders
Aa and AA are affected
aa is 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 one allele of FGFR3
gene Chromosome 4
• Affects cartilage growth needed for
bone lengthening
• Most affected individuals are Aa
why?
• Most cases are spontaneous aa X aa
Pg. 291
P(III, 3 and III, 5 have a child of normal
height)
P ( II, 3 and III, 7 have a boy with
achondroplasia)
Fruit fly nomenclature
pg 317 box 12.1
Red eyes is normal phenotype, brown is mutant
bw+ = wildtype allele
bw = brown allele
genotype phenotype
red
brown
• Try it:
• Wingless is recessive mutant (wg allele)
• Genotype of wildtype, heterozygote,
mutant?
Sex-linked genes
Ch 12 pg 314 – 317, 326 - 328
• Human Female = XX
– two alleles for each X-linked gene
– normal application of recessive and
dominance
X HX H
X HX h
X hXh
• Human Male XY
XHY
XhY
Sex-linked genes
• Most on X chromosome
• Hemophilia (recessive) 1/5000
males
– Mutation in gene for clotting
factor
•Mate III 13 with III 1 Probability of a hemophiliac son?
•Mate IV 2 with homozygous normal female p (hemophilia)?
*Criss cross inheritance of X linked traits
w+ = wildtype allele
w = white allele
X-linked recessive
The mutant fruit fly discovered by Thomas Hunt Morgan
• A white-eyed female is crossed with a redeyed 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?
Dihybrid cross – 2 genes
• 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 allele
w = wrinkled allele
gene?
gene?
Parents =
GGWW X
phenotype?
Gametes?
F1 genotype
?
F1 phenotype
?
F1 Gametes?
ggww
Forked line method for phenotypes
GgWw X GgWw
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)
¾ X ¼ = 3/16
Trihybrid cross
AaBbCc X AaBbCc
p(A-B-cc)
AabbCcDD X AaBbCcDd
p(triply recessive)
Modified Mendelian Ratios
1. INCOMPLETE DOMINANCE
R = red flower (snapdragon)
R’ = white flower
* allele symbols do not connote dominance
* phenotypic ratio = genotypic ratio = ?
P
CrCr
X
Cw Cw
F1
F2
Incomplete dominance
2. Codominance
Each allele encodes separate gene
product distinct in phenotype of heterozygote
L gene for human blood cell surface protein
LM = M antigen
LN = N antigen
• A man with the M bloodtype has a child
with a woman of the MN bloodtype
• Expected ratio of offspring?
3. Multiple alleles (more than 2 alleles for
gene in population)
• Example: Blood Groups
Karl Landsteiner 1900s
ABO blood system = polymorphic I gene
Blood type
A
B
AB
O
genotype
IAIA or IAi
IBIB or IBi
?
ii
What is the mechanism of inheritance of A, B, AB, O?
Autosomal or sex chromosome?
Example
• A child has type O blood. The mother of the child
has Type B blood. What could the blood types of the
father be?
4. Dominance series – C series/ rabbits
c+ = full color
cch = chinchilla (hypomorphic)
ch = himalayan (hypomorphic)
c = albino (apomorphic allele = nonfunctional)
Chinchill
a
Himalayan
Albino
Genotype
cch cch
cch ch
ch c
c+ cch
c+ = full color
cch = chinchilla (hypomorphic)
ch = himalayan (hypomorphic)
c = albino (apomorphic allele = nonfunctional)
phenotype?
5. 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?
6. Epistasis- gene product interactions. Table 13.4
page 355 (look at 4 phenotypic classes and fewer than 4)
• 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 Cats
• W = white
w = not white
• B = black
b = brown
Mate 2 heterozygous cats
What is the expected ratio?
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?
Polydactyly, dominant
7. Penetrance
• % individuals that exhibit
phenotype corresponding to
genotype
Pp
5,5
pp
6, 5
6, 6
8. Expressivity (ex. Piebald spotting) –
the extent to which a trait is exhibited
osteogenesis imperfecta pg. 359
Penetrance AND expressivity
• NF-1 = Neurofibromatosis1
– (1/4000, 17q11.2)
– (350 kb gene, 60 exons)
• Autosomal dominant trait N(in many it’s a spontaneous mutation)
• 50 – 80% penetrance
• Expressivity
– Pigmented skin to tumors on nerve CT coverings
(neurofibromas) on skin, eyes, organs, face
– Speech, blood pressure, spine curvature, headaches
9. Quantitative (multifactorial) traits
• Vary continuously
– Weight, height, IQ
Gene expression also affected by:
•
•
•
•
Sex (baldness)
Temperature (melanin in Siamese cats)
Chemicals (PKU)
Diet (height, cancer)
+ many other factors!
Chromosome Theory of
Inheritance
• 1902 Sutton and Boveri
– A chromosome is a linkage group of Mendelian
factors (GENES)
• 1920s Morgan et al.
– Genes are in a linear sequence on the
chromosomes, they can be mapped
Chromosomes in most animals
• pairs of autosomes
• 1 pair sex chromosomes
– XY heterogametic
– XX homogametic
Human karyotype ->
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
I. 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…. XY = male XX =
female
B. SRY gene encodes TDF (Testes
determining factor, 1990)
• SRY (sex determining region Y)
• TDF stimulates the growth of testes
-->
• testosterone ---> sperm ducts, male
brain “sensitization”
XX males: If SRY crosses over to the X
chromosome during meiosis (formation of
sperm)
Father during meiosis
X from father +
X from mother
3. Experiments with transgenic mice
XX males
Add SRY DNA to female
mouse embryo
• A 17 year old female presented with
“streak” ovaries, no uterus, no menstrual
cycle
• XY female
– Embryo has Y chromosome but does not
develop as male
• Mutation in SRY  ?
II. Other sex determination
systems
A. Drosophila
Ratio of X to sets of autosomes
– embryo “calculates” ratio
X/A = 1 or >1 ------> female
X/A = 0.5 or <0.5 --------> male
X/A between 0.5 and 1 ---> intersex
• What is the sex of an XY fly with 2 sets of autosomes?
• 1X/2A = 0.5 = male
• What is the sex of a fly with with 2 sets of autosomes but
1 X chromosome
• 1X/2A = 0.5 = male
• What is the sex of a triploid fly with 2 X chromosomes?
• 2X/3A = 0.66 = intersex
B. ZW system - birds
• Females are ZW
(heterogametic)
• Males are ZZ (homogametic)
C.Temperature sex determination (TSD)
• In some reptiles sex is not
determined genetically!
(Varies widely)
• majority of endangered reptiles
use TSD - sea turtles, Galapagos
tortoises, alligators, crocodiles
•
sex determined during mid-trimester of development by T of
incubation
IV. 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
• Observe dense “Barr body” at edge of nucleus
in female cells
– Heterochromatic (stains darker)
Male cell
female cell
cell with 2 Barr bodies
Number of X chromosomes?
Female mosaics
• All females heterozygous for X-linked traits
are mosaics for those traits.
red/green colorblindness
XCXc
phenotype = ?
Look at retina of heterozygous female
Anhydrotic ectodermal dysplasia
XAXa females
XaY males
Tooth + nail
abnormalities, life
threatening hyperthermia,
sparse hair
• Most genes on Y are for
development and fertility
Chromosomal Abnormalities
KARYOTYPE
Obtain white blood cells from or fetal cells from
amniotic fluid
Detects number of chromosomes,
sex, chromosomal abnormalities
76
Amniocentesis usually done week 14
Karyotype and analyze
fluid for enzyme
defects
77
Chorionic villus sample (CVS)
usually done week 8
More risk, but
earlier results
78
Arrange in pairs according to:
• decreasing size
• centromere position
METACENT
RIC
SUBMETACEN
TRIC
• banding pattern
ACROCEN
TRIC
79
metacentric (1) submetacentric (9)
p arm is the upper, shorter arm
80
Normal
male
46, XY
Which are
meta-,
submetaacrocentric?
81
Aneuploidy (versus euploidy)
• Trisomy (not triploid)
• 47, 21+
21 may be small, but contains 33,546,361 bp of DNA!
82
Down Syndrome (J. Langdon H. Down, 1866)
effects
– Developmental delays
– Possible heart defects,
hearing loss, hypotonia,
thyroid problems, obesity
– Epicanthic eye folds
– Wide tongues
– Greater risk of Alzheimer’s
83
Trisomy 13 (Patau)
• Fatal< 1 year (usually)
• Deaf, blind, clyclopia, polydactly,
cleft palate
• 1/5000 live births
47, XY, 13+
84
47, XY, 18+ (Edward’s)
• < few months
1/5000 live
births
85
Human trisomies of the sex
chromosomes (see pg 293)
• 47, XXY = Klinefelter’s
• 47, XXX
• 47, XYY
86
Monosomy (only 1 viable in
humans!)
• 45 X,
– Turner Syndrome (1/2000 live births)
• Partial monosomy 46, 5p– Cri du Chat
– Arises due to a deletion on the short arm
of chromosome 5
87
Cri du Chat 46, 5p• pseudodominance for
deleted region
• Microcephaly, myotonia,
“cry of cat”, retardation
88
Somatic mosaics
More than one genetically distinct population
of cells in an individual (like random X
inactivation)
Example: 46XX embryo, one cell loses an X
--- 46,XX/45X mosaic
– Symptoms less severe than the standard Turners
syndrome
89
Polyploidy = extra SETS of
chromosomes
• # in humans
• Triploid, tetraploid
• Octoploid etc..
90
• Many plants are
polyploid
• Some bees and wasps
are monoploid
91
Deletions (del)
•
•
•
•
can observe large ones by karyotype
If centromere is lost, then chromosome will be lost
Heat, chemicals, radiation
Unequal crossing over during meiosis
92
46,XX,del(7)(q21.12,q21.2)
Pseudodominance
 Lethal if both chromosomes

Leads to problems during meiosis
93
Duplications
• segment of a chromosome doubles
• May be tandem or reverse
• problems during meiosis
94
dup(5)(qter->q33.1::p15.3->qter)
• Sample of cord blood from
stillborn male with anencephaly
95
• 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
• being near heterochromatic region may
influence expression
96
Translocations - segment moves to other
chromosome - interstitial or reciprocal exchange
• t (13;14)
• Individual has all
genetic material, but
what about gametes?
97
t(11;13) (q21;q14.3)
• the parent who has the
translocation is
phenotypically normal as
all genetic info is present
• The gametes, however,
are not as evidence by
multiple miscarriages
98