Lecture 8 - Genetics of Biologic Processes

Question 1

Developmental Process - General

Answer 1

-initially there is ecto/endo/meso-derm
-Conrad said -> developing embryo represented as an
EPIGENTIC LANDSCAPE
-a landscare as a series of valleys which cell may pass as it differentiates toward final tissue type (toti->pluri->monopotent)

Question 2

iPS

Answer 2

-Induced Pluripotent Stem Cells:

> > Somatic cells can be reprogrammed to take different path of differentiation

Question 3

Totipotent

Answer 3

• stem cell of the fertilized egg
• can give rise to any cell/entire organism
• lasts 4 days

Question 4

Pluripotent

Answer 4

• Stem cell that can give rise to any cell

- Cannot give rise to an entire organism

Question 5

Multipotent

Answer 5

-more differentiated stem cell that give to rise to progenitors of cell lines

Question 6

What is Naive Multipotent Cell and what are the types

Answer 6

Naive Multipotent cell –> Commited to it’s cell line

Specialized State:
-> reversible

Determined State:
-> Irreverisble

Question 7

Cell Differentiation is based on

Answer 7

1) INTRINSIC:
- Lineage

2) EXTRINSIC:
- Positional identity (influenced by -> morphagens/cell:cell interaction/Cell:Matrix Interaction)

Question 8

Morphagen

Answer 8

• soluble signalling molecule

- depending on their conc grad -> exert diff effect on their target cells

Question 9

Example of Morphagen Genes

Answer 9

1) Maternal Effect Genes: - expressed in other during oogeneis + acts on mature oocyte
2) Gap Genes/Pair Rule Genes: - acting on fertilized egg to cause segmentation
3) Homeotic Genes: - regulate segment identity

Question 10

Specific Example of a Morphagen

Answer 10

Morphogen Activin (TGF-B):

• mesoderm differentiation is affected
• 0.1ng/ml -> blood like cells
• 100ng/ml -> heart cells

Question 11

Sonic Hedgehog Gene

Answer 11

• produced Morphogen -> SHP

- expressed in Notochord + Central Cells of Ventral Neural Tube

Question 12

What does Sonic Hedgehog protein do

Answer 12

• Develop of CNS + MUSCLE + LIMBS
• lateralization process

small amt of SHP in Dorsal tube -> Sensory Neuron
-Lg amt of SHP in Ventral -> Motor Neuron

Question 13

Homeotic (HOX) genes

Answer 13

• all have similiar 60-codon long homeobox seq
• master regulator gene -> reg expression of other gene
• encode TF
• it’s expression affected by Morphagen

Question 14

What happens when HOX is mutated

Answer 14

-one part of body becomes phenotypically similar to another disimilar part

Question 15

SRY gene

Answer 15

• Sex Determining Region on Y-chromosome –> Determines maleness
• Architectural TF –> binds + bends DNA –> regulates expression of certain genes

Question 16

Sertolli + Leydig Cells

Answer 16

!!Sertoli cells!! –> Anti-mullerian hormone –> inhibits Female Diff

!!Leydig cells!! –> Test –> Male sex diff

Question 17

Mechanism of SRY

Answer 17

SRY –> incr SOX9 –> FGF9 –> amplifies SOX9

When SOX9 reches appreciable level –> bipotential cells begin to differ into Sertoli cells

Question 18

Female Sexual Differentiation

Answer 18

RSPO1 + Wnt4 –> act Synergetically

in absence of SRY -> act on bipotential cells –> female differentiation

Question 19

SEX REVERSION

Answer 19

-point mut or deletion of SRY –> creates phenotypic Females

Question 20

Factors causing Developmental Abnormality

Answer 20

1. Tetratogens
2. Chromosome Imbalance
3. Complex Inheritance
4. Single Gene Mutation

Question 21

Disorders of HOX gene

Answer 21

-mut in HOX gene can cause mild symptoms or life threatening

Question 22

HOXD mutation

Answer 22

-Syndactyly (fused digits) + Polydactyly (extra digits)

Question 23

HOXA mutation

Answer 23

-Hand-Foot-Genitals Syndrome

Question 24

Chromosome Imbalance examples

Answer 24

• Patau
• Turner
• Fetal Hydrops

Question 25

Classification of Tetratogens

Answer 25

1) Synteratogen - needs to combine with another for effect (lead, cadmium) 2) Proteratogen: - not effective until metabolised

Question 26

Effect dependence of Teratogens

Answer 26

-Dose -Sensitivity > genetic background > developmental period

Question 27

Examples of Teratogens

Answer 27

1) Drugs/Chemical: lead/cadmium/coke/mercury 2) Infect. Agens: TORCH 3) Ionizing Radiation 4) Maternal Metabolism Factors: DM/PKU/Starvation

Question 28

DES

Answer 28

-synthetic Estrogen --> used prophylactically to prevent Miscarriage + Abortion CAUSES: - > vaginal tumours in child - > ectopic preg - > T-shaped uterus

Question 29

Oncogenetics - General

Answer 29

- 40% chance of developing some form of cancer in our lifetime - tumours are only 10% affected by inheritance but genotype does affect our overall risk -oncogenics is stepwise --> accumulation of somatic mutations

Question 30

Most common Mutating genes in Oncogenetics

Answer 30

1. Oncogenic: - dominant mutations - gain of function mutation 2. TSG: - recessive mutation - loss of function mutation 3. Mutator Gene: - genes of DNA repair - rate of germline/somatic mut increase when theese affeted

Question 31

Inherited Oncogenes

Answer 31

Inherited mutation of RET Gene: - MEN2A - FMTC Inherited mutation of RAS Gene: - Myeloid Leukemia

Question 32

Mechanisms that oncogenes can be activated

Answer 32

1) Double Minute Chromosomes 2) Point Mutation 3) Translocation 4) Retrovirus Encoded Promotor/Enhancer 5) Oncogene Hypomethylation

Question 33

Double Minute Chromosome

Answer 33

- small fragments of circular extrachromosomal DNA | - manifest during abnormal gene amplification --> give tumour cells advantage to survive

Question 34

Point Mutation in Oncogenes

Answer 34

RAS (p21): - RAS codes for G protein - mut in H-RAS --> decr Hydrolysis of activated RAS --> cellular proliferation

Question 35

Translocation in Oncogenes

Answer 35

Philadephilia Chromosome

Question 36

Retrovirus Encoded Promotor/Exchanger

Answer 36

-infection carriers these enhancers to oncogene --> overexpression

Question 37

Oncogene Hypomethylation

Answer 37

IN LIVER TUMOURS: | -promotor of N-RAS is hypomethylated

Question 38

TSG Mechanism of Cancer

Answer 38

-loss of Hetereozygoity (2 hit hypothesis)

Question 39

Common TSF

Answer 39

-p53 + RB

Question 40

Epigenetics relation to TSG and cancer

Answer 40

-hypermethylation -> inhbits

Question 41

Most cancers are

Answer 41

MULTIFACTORIAL PROCESS

Question 42

Environmental factors and Cancer

Answer 42

-environmental factors may not cause mutation but still cause cancer HPV: proteins bind to RB + P53

Question 43

Somatic Gene Re-arrangement (VDJ)

Answer 43

- VJ = Light chain | - VDJ = Heavy chain