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

Scheme of multifactorial heredity

environmental factors

treshold

polygenic system

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

Cleft - dependance on the sex, expression

♂♂ 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

Thompson &Thompson: Genetics in medicine,5th ed.

Chapter 15: Genetics of disorders with multifactorial inheritance

Chapter 17: Genetic aspects of development-Teratogens

+ informations from presentation

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