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Multifactorial, Multifactorial, polygenic polygenic traits and traits and disordersdisorders
RNDr. Z.PolívkováRNDr. Z.Polívková
Lecture No 424 – course: HeredityLecture No 424 – course: Heredity
PolygenicPolygenic = = numerous genes at numerous genes at different different loci with small additive effect loci with small additive effect
Multifactorial Multifactorial = = multiple genes are multiple genes are assumed to interact with assumed to interact with
environmental environmental factors (complex factors (complex inheritance)inheritance)
QuantitativeQuantitative = = quantitative quantitative differences in differences in traitstraits
Polygenic heredityPolygenic heredity
1.Normal traits with continuous variation –normal distribution – in population
Gaussian curve – x = average value
abnormal phenotypes
= extreme variants of normal range
traits: stature, intelligency, blood pressure
2. Isolated congenital malformations – multifactorial treshold traits
sharp distinction between normal and abnormal
phenotype s continuous variation in liability to the malformation treshold (in liability=sum of polygenes) divides population into unaffected and
affected
disorders: pyloric stenosis, neural tube defects : (anencephalus, spina bifida), congenital heart defects
cleft lip and cleft palate
3.Disorders of adult life – important role of nongenetic factors - role of prevention
coronary artery disease
obesity
diabetes mellitus
schizophrenia
manic-depressive psychosis
allergy
Role of environmental factors: Congenital malformations: prenatally (in organogenesis), teratogenic factors
Diseases of adult life: postnatal environmental factors
Characteristics of multifactorial heredity
1. The risk for first-degree relatives depends on population freguency (approx. the square root of the population risk)
2. The risk is sharply lower for second-degree relatives than for first-degree relatives and declines for more remote relatives
3. The recurrence risk is higher when more than one family member is affected (liability is high in such family, difference from mendelian traits)
4. The more severe malformation (disease), the grater reccurence risk (greater liability, more genetic factors)
5. If a multifactorial trait is more frequent in one sex than in the other, the risk is higher for relatives of patients of the less susceptible sex (higher liability)
6. Increased risk when the parents are consanquineous
♂♂ unilateral – less genetic factors, more environmental factors
better possibility of prevention
♀♀ bilateral – more genetic factors, less environmental factors
worse possibitity of prevention
Combination of sex and relevance of expression - cleft
Calculation of risk: Edwards formula or empiric
risks
r = √ population frequencyExample:
cleft palate: population frequency = 0.0016
Risk for 1st degree relatives (if 1 person/parent is
affected) = √0.0016 = 0.04 = 4%
Empiric risk (from population studies) = 4.2%
If both parents are affected - risk = 17%
For 2nd degree relatives - risk = 0.7%
For 3rd degree relatives - risk = 0.3%
Possibilities of prevention
Preconceptional care =
only prevention of polygenic disorders• gynecologic caregynecologic care• vitamin supplementation (vitamin supplementation (folic acid …)• adjustment of healthy stateadjustment of healthy state• adjustment of life styleadjustment of life style• protection against mutagens, protection against mutagens, teratogens …teratogens …
HERITABILITY= proportion of genetic variance to the total
phenotypic variance (result of interaction of genetic and nongenetic factors in population)variance=statistical measure of how much an individual value is likely to vary from the mean of group
Method of estimating of heritability from twins studies:monozygotic twins share 100% of their genesdizygotic twins share 50% of their genes
Concordance = both members exhibit a certain trait CMZ - CDZ
H = 100 - CDZ
H = 0 – 0.2 low genetic determination, great role of environmentH = 0.2 – 0.5 mean genetic determinationH = 0.5 – 1.0 determination is primarily genetic, less succesfull prevention Prevention: by preconceptional care:
till the risk 10% - is succesfull risk more then 10%: care after
conception - ultrasound examination
Genetic determination
Environmental factors
0
0H = 0Disorders caused by environmental factors only
100%
100%H = 1Monogenic disorders
Morphogenetic processes:
- proliferation- distribution and migration- integration- reduction
TeratogenesisTeratogenesis
Embryotoxic effect: death malformation growth retardation disturbance of function
Sensitivity to teratogenes depends on :
genotype of mother and embryo type and dose of teratogene ability of teratogene to go through placenta stage of pregnancy
Critical period:
period of development of morphogenetic system
Sensitive period of teratogene:
It is dependent on type and teratogen dose
In overlapping of critical and sensitive periods
→ origin of congenital malformation
Teratogenes:
- generally cytotoxic - effect on
proliferation
- specific – need receptors
Increased environmental pollution:
frequency of malformation is stable,
but spectrum of malformations is
changed
functional maturation
implantation
histogenesis
fertilisation
embryogenesis organogenesis birth
0 5- 6 25 60 29 weekdays
embryonal period fetal perinatal postnatal
all/nothing large malformations
abnormality of functions (carcinogenesis)
small malf.
TeratogenesPhysical: ionizing radiation, radioisotopes hypertermia (>39oC>2 days)Chemical: proved : vitamin A and its analogs in
abundance cytostatics warfarin possible : antiepileptics lithium (psychofarmacs) hormons salicylates drugs : alcohol, smoking
Biological:
1. viruses: rubella, small-pox, influenza, CMV
2. bacteria: Treponema pallidum – syphilis
3. parasites: Toxoplasma gondii (acute infection)
Maternal factors:
1.nutrition: iodine, calcium, vitamin D, follic acid, protein malnutrition
2.diseases: diabetes mellitus, fenylketonuria,
hypo(hyper)thyreosis, hypoxia