Polygenic
and
Multifactorial Inheritance
Doc. Ing. Helena Gbelcová, Ph. D.
TOPICS:
• basic terms
• normal traits with polygenic and multifactorial
inheritance
• pathological traits with polygenic and multifactorial
inheritance
• the way to decide if the trait is genetically governed
Multifactorial trait is result of a combination of
genetic factors and environmental factors.
genetic factors - a large number of minor genes
with additive effect
environmental factors – hormones, food, age,
gender...
Polygenic and Multifactorial Inheritance
Polygene trait (qualitative) is encoded by more than
one major gene (alleles pair).
Types of traits in regard to distribution in population
Distribution (appearance) of trait:
Discontinous = separated forms of trait
- qualitative traits (e.g. blood groups)
- single-gene inherited (one gene = 2 alleles)
- no effect of environment
Continous = transition of trait forms (normal variability)
- a) qualitative traits with threshold (effect)
- polygene inherited or multifactorial
- strong influence of environment
- b) quantitative traits (e.g. body height)
41,5
14,1
6,6
37,8
A B AB O
blood group
0
10
20
30
40
50
%%
Common is something what is convinient to your nature
or your approach to topic!
If something is out of this = it is unusual, extraordinary,
unbelievable e.t.c. !
Normal is expressed by formula: mean +/- 1 (2) SD !!!!
If something is out of this range of variability =
a) out of extremes
b) pathological form of trait behind a threshold.
-5 -4 -3 -2 -1 0 1 2 3 4 5
Normal distribution of quantitative trait
Standard
Deviation
Mean
Mean +/- 1SD = 66% of values; +/- 2SD = over 94% of values
(average -
center of
distribution)
Occurrence of quantitative trait is characterised by median (or
arithmetic average) and curve, that describes the variability of trait.
Normal (or common) is expressed like median +- 1(2) SD.
The interval between the two SD above and below the average
contains 94% of all observations in population.
Trait values in population that exceed out of 2 SD in the both
directions are out of extremes or pathological traits.
NORMAL TRAITS
• Determined by more than one gene
• Phenotypes are often distributed as a bell
curve
• Eye color
• Skin color
• Height
• Fingerprint patterns
Skin Color
• Assume 3 alleles pairs for skin color
• Each dominant allele makes the skin
darker
• At the borders, there are not shown
an albinism and black man. Just
extremes of Caucasian skin colour
• Bell curve distribution
A three-gene model for human Caucasian skin colour - it is just an
oversimplification of the highly variable trait, in reality, this trait is
encoded by many more than three genes.
Lewis: Human Genetics, Concepts and Applications, Fifth Edition, The McGraw-Hill Companies, 2003, pp 135.
Eye Color
• pure polygenic trait – one with no
enviromental input
• two genes specify greenish-blue pigments
called lipochromes
• two or more other genes encode the
brownish melanins
• genes intercact in a hierarchy-the brown
genes masking the green/blues, and
everything masking pure blue
Variations
in Eye ColorsA model of two genes, with two
alleles each, can explain the
existence of five eye colors in
humans.
The frequency distribution of
eye colors forms characteristic
bell-shaped curve for a
polygenic trait.
Lewis: Human Genetics, Concepts and Applications, Fifth Edition, The McGraw-Hill Companies, 2003, pp 134.
Eye Color Solution• AaBb are hypothetical genes for eye color
• Each dominant allele make the eyes
darker
• aabb = light blue
• One dominant allele = deep blue or green
• Two dominant alleles = light brown
• Three dominant alleles = medium brown
• Four dominant alleles = dark brown
Height • multifactorial trait
• Assume 4 genes control height
• aa bb cc dd = 152,4 cm male or
139,7 cm female
– Girls bones stop growing sooner than boys
– Boys generally grow 12 cm taller than girls with the same genotype
• AA BB CC DD = 193,0 cm male or
180,34 cm female
• Each dominant allele adds 5 cm height
Lewis: Human Genetics, Concepts and Applications, Fifth Edition, The McGraw-Hill Companies, 2003
Environment Affects Height
• Poor nutrition will result in shorter height
• Average American today is taller than the
average in 1900
– Better nutrition
Fingerprint patterns
• the number of ridges in a fingerprint is
largely determined by genes, but also
responds to the environment
Why the fingerprints of identical
twins , that share all genes, are
in some case not exactly alike?
• certain disorders (Down syndrome)
include unusual ridge patterns
During weeks 6 through 13 of prenatal
development, the ridge pattern can be altered
as the fetus touches the finger and toe pads to
the wall of the amniotic sac. This early
environmental effect explains why the
fingerprints of identical twins, that share all
genes, are in some case not exactly alike.
Pathological traits
Threshold model of disease
Polygenic/multifactorial inheritance that assumes a threshold beyond
which liability is so great that a malformation is manifested.
As more severe pathology is – as less often it is.
Threshold Traits
• Trait is either present or absent
(club foot, diabetes, cleft lip)
• Bell-shaped distribution in the
population with respect to
liability to a trait
• Only those individuals
exceeding the threshold on the
liability scale will express the
trait
genes +
environment
normal pathology
nu
mb
er o
f p
eop
le
qualititative trait
threshold
Pathological traits
Congenital malformations
• Cleft lip/palate
• Congenital hip dislocation
• Congenital heart defects
• Neural tube defects
• Pyloric stenosis
• Talipes (Pes equinovarus)
Adult onset disorders
Diabetes mellitus
Epilepsy
Glaucoma
Hypertension
Ischemic heart disease
Manic depression
Schizophrenia
Cleft lip with or without cleft palate
• One of the most common congenital malformations
• Originates as a failure of fusion of the frontal process with
the maxillary process at about day 35 of gestation
• 60-80% are males
• Asian>Caucasian>African>American
Cleft lip and palate(combinated or separated)
Can be :
• caused by mutations in major genes located on chromosomes
1, 2, 3, 4, 6, 11 and 13;
• a part of phenotype of more than 200 syndromes – e.g.
Apert, Marfan and Larsen;
• a part of pathological phenotypes of syndromes associated
with chromosomal aberrations – e.g. trisomy 13, 18 or 21
• one of the consequences of teratogens action
• a consequence of the interaction between genetic
predisposition and external factors (MULTIFACTORIAL
inheritance)
Genes involved in development of
orofacial clefts
• genes expressed in some parts of the embryo development – e.g.
TGF–α, TGF-β2, TGF-β3
• genes encoded products indirectly associated with development of
orofacial structures – e.g. receptor for RA, receptor for MTHFR,
receptor for FA
• homeiotic genes MSX-1 and MSX-2
• genes involved with metabolism of xenobiotics – e.g. cytochrome
system P-450
Neural tube defects(Failure of closure of the neural tube in early embryogenesis)
Cause:
- part of certain single-gene inherited
syndromes
- part of multifactorial inheritance
(e.g. Meckel syndrome)
- chromosomal aberration (trisomy 13, 18)
- associated with other CNS anomalies
Spina bifida
- developmental
defect in which the
spinous processes
and vertebrae arcs
do not develop
https://www.medindia.net/patientinfo/neural-tube-defects.htm, 20.1.2016
Neural tube defects(Failure of closure of the neural tube in early embryogenesis)
Anencephaly
- the absence of a large part
of the brain and the skull
- it happens when the upper
part of the neural tube fails
to close
Cause:• environmental toxins (lead, chromium, mercury, and nickel)
• lack of folic acid intake of the mother
• it can be also inherited (woman who has had one child with a neural tube defect such as
anencephaly has about a 3% risk of having another child with a neural tube defect)
• woman taking medications for epilepsy and women with insulin-dependent diabetes have also
a higher risk of having a child with a neural tube defect
https://omicspublishinggroup.wordpress.com/2013/06/12/anencephaly/, 20.01.2013
Pes equinovarus
Cause:
• just the result of the position of the baby while it is developing in
uterus
• combination of genetic and environmental factors that is not well
understood
• part of syndromes
• flexion of foot or hand
bones connection in the
joint capsule
https://www.physio-pedia.com/Introduction_to_Clubfoot, 20.01.2016
Congenital heart defects
• include short cut faults, when oxygenated blood mix with deoxygenated one
Cause:
• chromosomal abnormalities, especially trisomy 21
• maternal infections such as Rubella
• the use of drugs or an illness (diabetes)
• BMI over 30https://www.dreamstime.com/royalty-free-stock-photography-congenital-heart-defect-image12977867
Pyloric stenosis
• caused by an enlarged pylorus
• feedings are blocked from
emptying out of the stomach
• the retained feedings cause the
infant to vomit
• 5x more common in boys than girls
• pyloric stenosis occurs more
commonly in children of parents
who had pyloric stenosis themselves as infants
• 18x more common in sons of affected women than in sons of
affected man !!!!
https://eapsa.org/parents/learn-about-a-condition/f-o/hypertrophic-pyloric-stenosis/
Cardiovascular Diseases
• Plaques build up in the
coronary artery that feeds
the heart muscle
• Blood clot forms when a
plaque ruptures or greatly
reduces blood flow in the
artery
Heart Attack
• Blocked artery cuts off
blood supply to part of heart
muscle
• Part of the heart muscle dies
• Heart attack or myocardial
infarction
Heart Diseases are Multifactorial
Uncontrollable risk factors
– Age
– Male sex
– Genetics• Lipid metabolism
Controllable risk factors
• Fatty Diet
• Smoking
• Stress
• Lack of Exercise
• Obesity
• Hypertension
• Diabetes
Risk factors can be controlled by lifestyle changes and medication!
There are only two factors that cause any trait:
1. Genetics
2. Environment
Nature vs. Nature
Interaction of them is multifactorial
Genetic conselor
What happens when parents ask you the risk of
having a child with a complex (multifactorial)
disorder?
• cannot calculate an exact statistical
likelihood based on Mendel´s laws
• Instead give: - heritability estimates
- empiric risk
Is the trait governed genetically?
• Calculate Heritability
• Heritability (H2) = proportion of the trait that is
controlled by genetics
– H2 = 100% - trait is fully genetic
– H2 = 0% - trait is fully environment
• Multifactorial (complex) traits are somewhere in between
Heritability: Twins studies
Monozygotic twins
100% genes
100% home environment
Dizygotic twins
50% genes
100% home environment
Heritability – Expected:
Relationship Percent genes shared
Monozygotic twins 100%
Dizygotic twins 50%
Siblings 50%
Parent and child 50%
Aunt or uncle 25%
Grandparent 25%
First cousin 12,5%
Problems with Heritability?
What do you think is wrong, or lacking, with
H2 estimate from relative pairs?
1. Families share genetics AND environment
2. More shared genetics usually correlates to
more shared environment too:
Ex: twins usually share bedroom, siblings
raised in same house, unlike cousins
Separate GENES from ENVIRONMENT
1. Adopted children
• Compare birth parents to adopted parents
• Sharing environment only, not genes
2. Twins
• Compare MZ vs. DZ twins
• Differences in twins is only difference
between amount of genes shared,
environment is constant
Problem with concordance?
More shared genetics usually correlates to
more shared environment too
• MZ twins can be raised in more similar
environments than DZ twins
Ex: Tuberculosis was found more often in MZ twins
than DZ twins (TB caused by bacteria is not
genetic at all!!!!!)
What would be ideal?
• MZ twins, separated at birth, raised
completely apart
• Animal models, where one can separate the
genetics from the environment
EMPIRIC RISK
• The incidence of the trait differs among the
specific population:
a. Differs based on ethnic background
b. Depending on whether relative has trait
Empiric risk of cleft palate
Relationship
Recurrence
Risk
General population 0.1%
First cousin 0.3%
Niece or nephew 0.8%
Child 3.5%
Sibling 4.1%
Identical twin 40.0%
Conclusion: How evidence is gathered
for genetic factors in complex disease?
• Familial risks
• Twin studies
• Adoption studies
• Population and Migration studies
PROBLEM 1
For certain malformation, the recurrence riskin sibs and offspring of affected persons is 10percent, the risk in nieces and nephews is 5percent, and the risk in first cousins is 2.5percent.
1. Is this more likely to be an autosomal dominant trait with reduced penetrance or multifactorial trait? (Explain)
2. What other information might support your conclusion?
• Autosomal dominant with reduced penetrance.
• If it were truly multifactorial, the risk for more
distantly relatives would drop by more than 50
percent.
• In dominant disease, you would expect no increase
in risk after an affected person has had two affected
children, whereas in multifactorial inheritance, the
risk after two affected child because, with two
affected, there is a greater likelihood that the parents
are carrying a significant load of predisposing alleles
at multiple loci.
PROBLEM 2
A large sex differences in affected persons isoften a clue to X-linked inheritance.
How would you establish that pyloric stenosis is multifactorial rather than
X–linked?
Male-to-male transmission can disprove X linkage.
Pyloric stenosis
• caused by an enlarged pylorus
• feedings are blocked from
emptying out of the stomach
• the retained feedings cause the
infant to vomit
• 5x more common in boys than girls
• pyloric stenosis occurs more
commonly in children of parents
who had pyloric stenosis themselves as infants (18x more common
in sons of affected women than in sons of affected man !!!!)
PROBLEM 3
A series of children with a particular
congenital malformation includes both boys
and girls. In all cases, the parents are healthy.
How would you determine whether the
malformation is more likely to be
multifactorial than autosomal recessive?
For autosomal recessive but not for multifactorial
inheritance, there is almost no chance that a parent
will be affected.