11L. Genetics of biological processes Flashcards
(34 cards)
Genetics of development: development potentials (totipotent, pluripotent, multipotent, unipotent), cell differentiation
- Totipotent: all the cell types in a body, plus the extraembryonic, or placental, cells (zygote - fertilized egg)
- Pluripotent: all of the cell types that make up the body (inner cell mass, epiblast, stem cells)
- Multipotent: can develop into more than one cell type, but are more limited (endo-, meso-, ectoderm)
- Unipotent: can develop into only one type of cell or tissue
Significance of stem cells
1) Tissues/cells for therapy
2) Drug development and toxicity tests
3) Experiments to study development and gene control
Role of morphogens and their concentration gradient (Sonic hedgehog)
Morphogens
- Soluble signalling molecules with concentration gradient in eggs or developing embryos
- Act differently on same target cell types depending on location and concentation
- Example: embryonic cranio-caudal axis or proximo-distal axis of lims are due to conc. grad. of morphogens
- Become different cells in response to different concentration of morphogens (e.g 1ng/ml activin -> muscle cells, while 10 ng/ml -> notochord cells)
Sonic Hedgehog
- Coding a morphogen (signalling molecule)
- Protein expressed in notocord and later in central cells of VENTRAL neural tube
- Involved in development of CNS, muscle, limbs and in lateralization and eye development (polyphemos)
*Small amount of SHH => sensory neuron
Medium/lots of SHH => motor neuron at different locations
**Mutants lacking SHH have no motor neurons=>die
Genetics of sex: sex determination
1) Genetic
- Sex chromosomes
- SRY and other genes
2) Environmental
- Temperature
- Body mass
Genetics of sex: male sex determination
SRY gene
- Binds to and bends DNA - regulates genes that control development of testis
- Affect Sertoli cells -> AMH (anti-Mullerian hormone) -> inhibit female differentiation
- Affect Leydig cells -> Testosterone -> induce male sexual differentiation
Genetics of sex: causes of maldevelopment
1) Sex reversion
- XX -> male: SRY has been transferred to X chr
- XY -> female: SRY has been lost from Y chr
* Cause: abnormal crossing-over during male gametogenesis (meiosis I)
Oncogenes
- Dominant mutations, usually somatic
- Gain-of-function mutation in proto-oncogene (only one allele must be mutated)
- Most common: RAS oncogene
Tumor suppressor genes, LOH
- Recessive mutation in cellular level, but they often result in a dominantly inherited predisposition
- Loss-of-function mutation (both alleles must be mutated, but still more common than gain-of-function mutation)
LOH: loss of heterozygosity
- Often found in cancers
*Most common: p53 tumor suppressor gene
Tumor mutator genes
- Play a role in DNA repair, germline and somatic mutations
- Dominantly inherited predisposistion - or - AR tumorigenic syndrome may be caused
Activation mechanisms of oncogenes
1) Amplification (too many gene copies)
- Double minute chromosomes (DMs)
- ecDNA (extrachromosomal DNA) is found in nearly half of cancers and contributes to intrantumoral heterogeneity (mostly driver oncogenes - e.g MYC)
* Genes in cancer can be amplified in chromosomes or in circular ecDNA including double minutes
2) Point mutations
- Ex: Gly12Val of H-Ras
3) Chromosome translocation results in chimeric protein
- Philadelphia chromosome (med: imatinib/Gleevec)
4) Insertion of a retrovirus derived promoter/enhancer into the proximity of an oncogene
5) Oncogene hypomethylation (epigenetic)
Immunogenetics: somatic gene rearrangement
Light chain
- V-JC: DNA splicing (lambda)
- V-J: DNA splicing (kappa)
- VJ-C intron excision (RNA splicing)
Heavy chain
- D-J: DNA splicing
- V-DJ: DNA splicing
- VDJ-C intron excision (RNA splicing)
- RNA splicing: from the 3rd membrane-bound C domain of IgM to 3rd soluble C domain
- Class switch: DNA splicing
Immunogenetics: role of epigenetics
Epigenetic disease: DNMT3B (de novo methyltransferase mutation)
Immunogenetics: genetic background of antibody diversity
Fra nett:
1) Germ line theory: each antibody-producing cell has genes coding for all possible antibody specificities, but expresses only the one stimulated by antigen;
2) Somatic mutation theory: antibody-producing cells contain only a few genes, which produce antibody diversity by mutation
3) Gene rearrangement theory: antibody diversity is generated by the rearrangement of variable region gene segments during the differentiation of the antibody-producing cells.
Cell reprogramming + future applications
Cell reprogramming is the process of reverting mature, specialised cells into induced pluripotent stem cells
- Induced pluripotent stem cells (iPS)
Future applications:
- Autologous cell therapies
- Allogenic cell therapies
- Disease modeling
- Drug screening
- Transplantation studies
- Maybe: self-fertilization, same-sex fertilization if epigenetic alterations are added
Major applications for iPS
1) Age-related macular degeneration (retinal pigment epithelium)
2) Parkinson’s disease (A9 dopaminergic neuron)
3) Spinal cord injury (oligodendrocyte progenitor)
4) Diabetes (β-cell progenitor)
5) Myocardial infarction (cardiomyocytes)
Maternal effect genes
Expressed in mother during oogenesis and acting on or within maturing oocytes
Gap genes -> pair-rule genes -> segment polarity genes
Segmentation genes expressed after fertilization.
Modify either the number or polarity of segments.
Act one-after-the-other and determine smaller and smaller regions of the embryo
Homeotic genes (HOX genes)
Master regulatory genes (most important)
- Regulate segment identity w/o influencing the number, polarity and size of segments
- Mutation: “kroppsdeler på feil sted” - e.g polydactylia
- All such genes contain a homeobox sequence (!)
- Code transcription factors that regulates expression of other genes
- Spatial co-linearity kept between species: the genes are expressed the same way along ant-post axis
Dorsal and ventral gradients needed for normal neuron differentiation
Ventral: SHH (sonic hedgehog)
Dorsal: TGF-β family
Apoptosis inducing and inhibiting factors
Inducing: BMP (bone morphogenetikus protein
Inhibiting: Gremlin
*Only in chicken/ducks?
Genes in male vs female differentiation
Female
- No SRY -> no inhibition of RSPO1
- RSPO1 inhibit SOX9 => no testis
- WNT4: promotes female and represses male
Male
- Have SRY -> inhibition of RSPO1
- SOX9 uninhibited => testis
- FGF9 also needed for male development (activated by SOX9 -> feedforward loop)
Disorders caused by HOX gene mutations
- Polydactylia
- Hand-foot-genitals syndrome
- Synpolydactylia
- Cleft palate
- Brain abnormalities
- Uterus abnormalities
- Retinoic acid acting on HOX genes causes developmental abnormalities
Teratorgens types + effect
1) Synteratogens: not effective alone, only in combination with another chemical
2) Proteratogens: only the metabolite is effective
Effect depends on:
1) Dose
2) Sensitivity
- Genetic background (SNPs)
- Developmental period (teratogenic window)
