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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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