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GENETICS OF DEVELOPMENT
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Development represents:
The biochemical, morphological, physiological changes during all the life (from birth up to death),
which are under genetic control and realize in specific individual environment condition (maternal factors, personal internal factors, external factors).
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The main steps of ontogenesis
fertilization
prenatal development
postnatal development
ageing, death
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Errors during fertilization
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Control of development
Genetic program of zygote
Maternal factors
Environmental factors
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The sexual process is required for normal development
There is a differentiated contribution of genetic material inherited from mother and father genetic dosage;
The presence of both genomes is required for normal development (genomic imprinting, uniparental disomy)
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The chances of zygote to survive - 1:80.
50% of zygotes die before implantation.
50-60% of embryos carry a chromosomal
mutation and are eliminated.
0,5-0,7% of new-borns are carriers of a
chromosomal aberration.
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Maternal effect
Cytoplasmic inheritance mitochondrial DNA;
mRNA synthesized during oogenesis;
Asymmetric distribution of molecules in cytoplasm of egg cell - cytoplasmic determinism;
Metabolic substances that pass trough placenta.
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Environment effect
Teratogen factors: physical (irradiations)
chemical (drugs, alcohol ...)
biological (viruses, toxins ...)
May induce abnormalities: Congenital abnormalities;
Phenocopies.
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The effect of thalydomyde on
development
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The mechanisms of congenital abnormalities
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Normal genetic factors + favourableenvironmental conditions normaldevelopment.
Normal genetic factors + unfavourableenvironmental conditions abnormaldevelopment.
Abnormal genetic factors (mutations) +/-unfavourable environmental conditions abnormal development.
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Types of congenital anomalies
Malformations
Deformations
Disruptions
Abnormal histogenesis (displasia)
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Malformations
Morphologic defect of an organ as result of internal effect abnormal primordium embryo abnormality
Examples:
agenesis (kidney agenesis);
Partial development (cleft leap; syndactily); excessive development (polydactily).
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Deformation abnormal shape of a part of body determined by pressure or other mechanical forces. Its derived from normal primordium.
Ex: clubfoot deformity.
Factors:
Small uterus;
Olygohydroamnios;
Abnormalities of CNS
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Deformation
Dysplasia abnormal tissue development = dyshistogenesis.
Ex: abnormal cartilages.
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Disruption a morphological defect of a part of organism determined by breaks.
Abnormalities fetal abnormalities. Determined by teratogen factors.
Ex: amniotic bridges may cause amputations or other abnormalities
Causes of congenital abnormalities
Idiopathic (unknown factors) 60%
Multifactorial 20%
Monogenic 7,5%
Chromosomal 6%
Maternal factors 3%
Congenital infections 2%
Drugs, alcohol, radiations 1,5%
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Cell events during development
Cell proliferation
Cell differentiation
Cell-cell interactions
Cell migration
Apoptosis
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Cell differentiation
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Differential gene expression
Cell specialization
Irreversible
Cell-cell interactions
Interactions between equivalent cells;
Interactions between non-equivalentadjacent cells;
Interactions between non-equivalentnon-adjacent cells, through hormones,growth factors and respectivereceptors.
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Apoptosis
Assures the shape, volume and proportionsof organs;
Selection of mutant cells;
Regression of provisory organs;
Elimination of old cells;
Elimination of tumoral cells.
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Genetic control of development
Segmentation genes
Homeotic genes
Hox proteins
Transcription factors
Growth factors
Lethal mutations
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Homeotic genes
Control formation of an organ or a regionof body
Contain a highly conserved sequence ofDNA Homeo-box (180 bp) whichcorrespond to homeodomens in proteins
In humans there are 4 gene familiesHoxA, HoxB, HoxC, HoxD 38 genes
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Genetic mechanisms in human development
Genomic imprinting
Uniparental disomy
Cell mosaics
Cell selection during embriogenesis
X chromosome inactivation
Telomarase activity
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Genomic imprinting
Genomic imprinting control of geneticdosage through selective inactivation ofgenes inherited from mother or father :
DNA methilation
DNA heterochromatinisation
Effect of position.
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Uniparental disomy
Zygote contains two cromosomes inheritedfrom the same parent:
Disomy in a gamete followed by removingof an additional chromosome;
Robertsonian translocation.
Ex:
7, 14 and 15 from mother,
11, 14 and 15 from father
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Aneuploidy resque
Correction of abnormal number of chromosomes, through elimination of supernumerary chromosomes (trisomy) or achieving of absent chromosome (monosomy).
Non-disjunction
Anaphase lag
Endoreplication
Transverse cleavage
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Mosaics
In all tissues
In some embryonic tissues
In placenta
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The consequences of mosaics
Abnormal embryonic development;
Developmental retardations, miscarriages;
Perinatal death.
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