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.