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

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 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 = ?

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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