Multifactorial, polygenic
traits and disorders
RNDr. Z.Polívková
Lecture No 424 – course: Heredity
Polygenic heredity
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Polygenic = numerous genes at different
loci with small additive effect
Multifactorial = multiple genes are
assumed to interact with environmental
factors (complex inheritance)
Quantitative = quantitative differences in
traits
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
Combination of sex and relevance of expression - cleft
♂
unilateral – less genetic factors, more environmental factors
better possibility of prevention
♀
bilateral – more genetic factors, less environmental factors
worse possibitity of prevention
Calculation of risk: Edwards formula or empiric risks
r = √ population frequency
Example:
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)
If both parents are affected - risk
For 2nd degree relatives - risk
For 3rd degree relatives - risk
= 4.2%
= 17%
= 0.7%
= 0.3%
Possibilities of prevention
Preconceptional care =
only prevention of polygenic disorders
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gynecologic care
vitamin supplementation (folic acid …)
adjustment of healthy state
adjustment of life style
protection against mutagens, 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 genes
dizygotic twins share 50% of their genes
Concordance = both members exhibit a certain trait
CMZ - CDZ
H=
100 - CDZ
H = 0 – 0.2
H = 0.2 – 0.5
H = 0.5 – 1.0
low genetic determination, great role of
environment
mean genetic determination
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
0
100%
Environmental
factors
Genetic
determination
100%
H=1
Monogenic
disorders
0
H=0
Disorders caused
by environmental
factors only
Teratogenesis
Morphogenetic processes:
-
proliferation
distribution and migration
integration
reduction
Embryotoxic effect:
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death
malformation
growth retardation
disturbance of function
Sensitivity to teratogenes depends on :
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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
histogenesis
implantation
fertilisation
embryogenesis
0 5- 6
days
organogenesis
25
embryonal period
all/nothing
large malformations
functional maturation
birth
60
29 week
fetal
perinatal postnatal
small malf.
abnormality of functions
(carcinogenesis)
Teratogenes
Physical: 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
http://dl1.cuni.cz/course/view.php?id=324