Transmission (Classical, Mendelian) Genetics Ch 11blinderl/documents/1genegeneticsposted.pdf ·...
Transcript of Transmission (Classical, Mendelian) Genetics Ch 11blinderl/documents/1genegeneticsposted.pdf ·...
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)
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 Alleles
• Pea color ?
• Flower color white, purple
• Pod shape constricted, inflated
• Pea surface ?
• Stem height tall, dwarf
2. Principle of Dominance
- One allele is dominant the other is recessive
- The dominant allele is expressed in the
phenotype
Gene for flower color
P allele = purple
p allele = white
GENOTYPES PHENOTYPE
Homozygous dominant =
Heterozygous =
Homozygous recessive =
3. Random segregation of alleles into
gametes
– gamete receives ONE allele per gene
– random segregation of alleles 50/50
PP pp
What is the phenotype of all offspring
in F1 generation?
P generation
Test cross (one gene)
• A mouse has black fur, what are its 2
possible genotypes?
Test cross mouse to homozygous recessive
mouse
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
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
1902 Archibald Garrod:
One gene: one enzyme
“Inborn errors of metabolism”
PKU
Albinism
Alkaptonuria
Tyrosinemia
Black
urine
arthritis
Ch 4
Fill in genotypes. If II,1 and II, 4 mate, what is the
chance of offspring having PKU?
II, 1 X II, 4 p(aa)
•p(aa AND a girl)?
How do we know
this is autosomal
recessive?
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
Achondroplasia -1/20,000 births
• Mutation in one allele of 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)
Mendel’s Law of Independent assortment -each allele for a trait is inherited independently of other alleles
Seeds:G = yellow allele g = green allele gene?
W = round allele w = wrinkled allele gene?
Dihybrid cross – 2 genes Ch. 11
Parents = GGWW X ggww
phenotype?
gametes?
F1 genotype ?
F1 phenotype ?
F1 Gametes?
Forked line method for phenotypes
GgWw X GgWw
Product rule-the 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)
Probability
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)
1. Multiple alleles (more than 2 alleles for gene in
population)
• Example: Blood Groups
Karl Landsteiner 1900’s
Chromosome 9 I gene
Modified Mendelian Ratios Ch. 13
ABO blood system = polymorphic I gene
Blood type genotype
A IAIA or IAi
B ?
AB IAIB
O 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?
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.
5. Penetrance
• % individuals that exhibit
phenotype corresponding to
genotype
Polydactyly, dominant
Pp pp
5,5 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)
• 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
7. Epistasis- gene product interactions
Epistasis in labrador retrievers
• B and E color genes (labs)
B black b brown
E color 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. Quantitative (multifactorial) traits
• Vary continuously
– Weight, height, IQ
Ch. 12 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
45
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
46
Arrange in pairs according to:
• decreasing size
• centromere position
• banding pattern
ACROCENT
RIC
METACENT
RIC
SUBMETACEN
TRIC
47
metacentric (1) submetacentric (9)
p arm is the upper, shorter arm
Do more chromosomes mean more
intelligence?
Human 46
Chimpanzee 48
Dog 78
Cat 72
Alligator 32
Goldfish 94
Mosquito 6
Potato 48
Baker’s yeast 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
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?
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”
60
• Sex of 45, XO? (Turner syndrome)
• Sex of 47, XXY? (Klinefelter
syndrome)
• Non-disjunction during meiosis
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
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?
Female mosaics
• Females heterozygous for X-linked traits
are mosaics for those traits.
red/green colorblindness XCXc
phenotype = ?
Anhydrotic ectodermal dysplasia
XAXa female
What happens to XaY?
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
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?
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
• Turtles
• Crocodile
• Lizards
Parthenogenesis – eggs
develop without sperm
(asexual)
72
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
73
Chorionic villus sample (CVS) ~week 8
Biopsy of chorion
More risky
Ch. 16 Variations in
chromosomes
• Chromosomal aberration
– Spontaneous
– Induced
75
• 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
Deletions (del)
76
46,XX,del(7)(q21.12,q21.2)
Heterozygous del pseudodominance
Cri du Chat
• 46, XY, 5p- Microcephaly, myotonia,
“cry of cat”, brain
impairment
78
Duplications
• segment of a chromosome doubles
• May be tandem or reverse
• problems during meiosis
79
• 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
• Chromosome 5
• Human Chimp
81
Translocations
• segment moves to other chromosome -
interstitial or reciprocal exchange
• Individual has all genetic material, but what
about gametes?
Aneuploidy: chromosome # changes
• Nullisomy
– Loss of homologous pair of chromosomes
– Not viable in animals
83
Monosomy (only 1 viable in
humans!)
• 45 XO
– Turner Syndrome (1/2000 live births)
• Partial monosomy 46, 5p-
84
• Trisomy
• 47, 21+
85
Down Syndrome = trisomy 21
effects
– Developmental delays
– Possible heart defects, hearing loss, hypotonia, thyroid problems, obesity
– Epicanthic eye folds
– Wide tongues
– Greater risk of Alzheimer’s
86
Trisomy 13 (Patau)
• Fatal< 1 year (usually)
• Deaf, blind, clyclopia, polydactly,
cleft palate
• 1/5000 live births
47, XY, 13+
87
47, XY, 18+ (Edward’s)
• < few months
1/5000 live
births
• Tetrasomy
– Extra chromosome pair
89
90
Polyploidy = extra SETS of
chromosomes
91
• Many plants are
polyploid
• Some bees and wasps
are monoploid
92
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
93
Geep = mosaic combination of goat
and sheep embryo
• Courtesy of Dr. Gary Anderson, University of Califonia at Davis