11L. Genetics of biological processes Flashcards
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)
Abnormalities in female offspring due to maternal DES exposure
1) Vaginal or cervical cancer (adenocarcinoma)
2) Uterine/vaginal malformations
- Sterility/infertility
- Spontaneous abortions
- Premature birth
- Stillbirth
- Ectopic pregnancy
* DES also increase risk of breast cancer
Inheritance tumor risk
< 10% Mendelian inheritance
BUT genotype affect our overall cancer risk!
Heritable oncogene mutations
RET gene, cause
- MEN2A (multiple endocrine neoplasia)
- FMTC (familial medullary thyroid cancer)
K-RAS - germline activating mutations, cause
- Noonan syndrome -> increased risk for myeloid leukemia
Epigenetics in cancer
1) Hypermethylation of TSG or mutator genes
2) Chromatin remodeling
3) Telomerase activity (?)
4) Drugs, chemicals, hormones etc
Epigenetic profiling in diagnosis and prognosis
MGMT: brain biopsy, prediction of drug response
GSTP1: urine system biopsy, tumor detection
Loss of imprinting (LOI) in cancer
- IGF2 (normally paternal allele expressed)
- > colon cancer when maternal also expressed
Development of a colon cancer cell
I rekkefølge
1) APC (chr5) => increased cell growth
2) DNA loses methyl groups (epigenetic) => Polyp (low)
3) K-RAS mutation => Polyp (mid level)
4) Loss of MCC amd DCC (chr18) => Polyp (high level)
5) Loss of p53 (chr 17) => Malignant tumor
6) Other chromosome losses => metastases
Human papilloma virus
- Can increase cancer risk
- No oncogene in them! But the virus proteins alter the expression of their own genes
- Some proteins encoded by early viral genes bind p53 and RB TSGs and inhibit them
Transmissible cancer
1) DFTD: Devil facial tumor disease
- MHC I and II lack functional diversity - avoid immune system recognition
2) CTVT: Canine transmissible venereal tumor
- Progressive phase: no MHC, but TGF1
- Regressive phase: MHC I and II
Primary T cell immunodeficiencies
1) SCID-X1
2) JAK3 deficiency
3) Adenosine deaminase deficiency
