DWI ANITA SURYANDARIDepartemen Biologi Kedokteran FKUI

FAKTOR POLIGENI DAN MULTIFAKTORIALPewarisan genetik ada 3 macam/pola:

Single gene faktor = satu fenotip dipengaruhi oleh faktor gen tunggal

Poligeni = satu fenotip dipengaruhi oleh banyak gen

Multifaktorial = satu fenotip dipengaruhi oleh banyak gen yang berinteraksi dengan faktor lingkungan

Allele – for example, the gene for brown eyes would be one variant or one allele; the gene for blue eyes, another variant—allele.

KROMOSOM

AUTOSOM

RANGKAI SEKS

AUTOSOM DOMINAN

AUTOSOM RESESIF

RANGKAI SEKS-X DOMINANRESESIF

RANGKAI SEKS-Y

GENE PHENOTYPE

Environment

Other Genes

Single gene traitSingle gene trait

ABNORMAL

NORMAL= VARIASI

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Genetic Genetic Disorders of Disorders of InterestInterest

Autosomal Recessive Disorders

• In this pattern, the child is affected but neither parent is affected.

• Therefore, since the parents are heterozygous, they can be called carriers.

• Recessive disorders can by passed on by parents who are unaffected (ie. Albinism).– Tay-Sachs Disease.

• Allele located on chromosome 15.• Jewish of central, eastern European descent.• Lysosome build-up in brain, leads to progressive

neurological / psychomotor deterioration.

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Autosomal Recessive Pedigree Chart

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P1

F1/P2

F2/P3

F3/P4

Autosomal recessive inherited disease （ 3）

Autosomal Dominant Disorders• In this pattern, the child and at least one parent are

affected, due to a dominant allele on an autosomal chromosome.

• Dominant disorders are passed on by a parent who has, or will develop, the disorder (ie. Achondroplasia, brachydactyly, hyercholesterolemia, Marfan syndrome).– Neurofibromatosis (NF)

• Also known as von Recklinghausen disease.• Allele located on chromosome 17.

– Huntington Disease (HD).• Allele located on chromosome 4.

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Autosomal Dominant Pedigree Chart

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Beyond Simple Inheritance Patterns• Unfortunately, life is not so simple as simple

dominance problems would imply.• There are complicating factors, other patterns of

inheritance. . . . • Polygenic (Multifactorial) Inheritance.

– Polygenic - one trait is governed by two or more sets of alleles.

• Continuous variation of phenotypes.– Skin Color, height, weight, metabolic rate, behavior, intelligence.

– Multifactorial - a polygenic trait that is particularly influenced by the environment.

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Gene1

Gene 2

Gene 3

Gene 4

PHENOTYPE

Environment

Polygenic traitPolygenic trait

Polygenic (Multifactorial)

Inheritance

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Environmental Influences• The environment can influence the phenotype.• Human disorders include: cleft lip/palate, club-foot,

hypertension, diabetes, schizophrenia ……• For example: Siamese cats, Himalayan rabbits are

darker in color at the ears, nose, paws, and tail.• Why?• Homozygous for allele involved in melanin production

(ch) via produced enzyme that is active only at lower temperature………

• Therefore, black fur occurs at the extremities where body heat is lost to the environment!

• Polygenic traits seem to be particularly influenced by the environment.

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Beyond Simple Inheritance Patterns• Incomplete Dominance and Codominance.

– Codominance occurs when alleles are equally expressed in a heterozygote.

– Example: human blood type AB.– Incomplete Dominance is exhibited when the

heterozygote has an intermediate phenotype between that of either homozygote.• Familial hyper/cholesterol/emia (FH)• Sickle Cell Disease.

–HbA vs. HbS

–Heterozygotes protected from malaria.

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Multiple alleles of rabbit fur

c+ - allele for wild typecch - allele for chinchillach - allele for himalayanc - albino

dominancy rank : c+ cch ch c thus, cch c chinchilla ch c himalayan etc.

Wild type

chinchilla

himalayan

albino

MHC system – code for major histocompatibility complexantigens surface proteins determine for tissue incompatibilities.

Human MHC HLA system – code for human leukocyte antigens (transplantation antigens) :- determine tissue incompatibilities in humans- mediate distinction of self from nonself- mediate antigen recognition by T cell receptor (TCR)

HLA gene :

- situated in the locus 6p21-23- contain 3 main regions : HLA class I, HLA class II, HLA class III- HLA class I consist of 3 subregions : HLA-B; HLA-C; HLA-A- HLA class II consist of 3 subregions : HLA-DR; HLA-DQ; HLA-DP- each subregion has plenty of alleles generate large number of genotype variants among individuals.- each genotype express specific surface proteins which varies among individuals, though they are siblings of one generation.

HLA class IHLA class II

Diseases associate with HLA allotypes (HLA antigens)Disease HLA allotype

Ankylosing spondylitisReiter’s diseaseRheumatoid arthritisMultiple sclerosisMyasthenia gravisPsoriasisAddison’s diseaseGrave’s diseaseCoeliac diseaseHemochromatosisActive chronic hepatitis

B27B27DRw4A3, B7, Bw2, DRw2B8, DRw3A1, B13, Bw37, Cw6Dw3B8, Bw35, Dw3B8, Dw3A3B8, DRw3

Single gene diseases versus

polygenic diseases

Whereas the mutations causing single gene Whereas the mutations causing single gene diseases have a major impact on the function of diseases have a major impact on the function of

the gene product, and are therefore rare, the gene product, and are therefore rare, those causing polygenic disease have a more those causing polygenic disease have a more

moderate effect, and are therefore moderate effect, and are therefore relatively commonrelatively common

Polygenic trait characteristics• Common

– Unlike single gene traits

• Multi-gene involvement– Each gene has varying effects on trait occurrence and

development

• Often have major non-genetic influences– i.e. environmental factors

• Unclear transmittance patterns

DisorderDisorder Frequency (%)Frequency (%)

SchizophreniaSchizophrenia

AsthmaAsthma

Ankylosing spondylitisAnkylosing spondylitis

Hypertension (essential)Hypertension (essential)

OsteoarthritisOsteoarthritis

Type II diabetes (NIDDM)Type II diabetes (NIDDM)

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Frequency of several polygenic Frequency of several polygenic diseasesdiseases

Type II diabetes

• Hyperglycaemia, developing in the adult– Pancreas produces insulin but cells are resistant

• Polygenic disease with major environmental risk factors– High calorie intake and low exercise– Up to 10 times more prevalent in the obese

• Prevalence is increasing as populations become “westernized”

An osteoarthritic hipAn osteoarthritic hip

OA prevalence in the UKOA prevalence in the UK2 million adults2 million adultsMajority aged > 60 yearsMajority aged > 60 years

Over 1 million GP appointments Over 1 million GP appointments each yeareach year

Affected individual joining Affected individual joining the family, emphasizing the the family, emphasizing the

common nature of the disease common nature of the disease

Late-onset disease with Late-onset disease with few members of the few members of the

younger generation yet younger generation yet affectedaffected

An affected individual An affected individual with unaffected parentswith unaffected parents

An osteoarthritis pedigreeAn osteoarthritis pedigree

Overall - no clear inheritance patternOverall - no clear inheritance pattern

Risk factors for coronary artery disease

Uncontrollable (but identifiable)

Family history (genetics)AgeMale sex

Potentially controllable or treatable

Fatty dietHypertensionSmokingHigh serum cholesterolLow serum HDLHigh serum LDLStressInsufficient exerciseObesityDiabetes

Major effort to identify common disease susceptibility genes underway

How does one initially assess whether such a disease has a genetic component?

• Twin pair studies

• Relative risk studies

1/3 Monozygotic 2/3 Dizygotic

Twin-pair studiesTwin-pair studies1 in 89 deliveries

Do both twins show the same characteristic or trait? Comparing MZ/DZ twins can give evidence for genetic and/or

environmental influences

60%90%IQ

52%95%Height

DizygoticMonozygotic

Concordance rate

Trait

MZ twins share all their genes and environmentDZ twins share 50% genes and environment

MZ DZ

Cystic Fibrosis 100 25

Hypertension 30 10

Type I diabetes (IDDM) 36 5

Rheumatoid Arthritis

30 5

% Concordance rates% Concordance rates

Heritability• The proportion of the causation of a character

that is due to genetic causes

DisorderDisorder Frequency (%)Frequency (%) HeritabilityHeritability

SchizophreniaSchizophrenia

AsthmaAsthma

Ankylosing spondylitisAnkylosing spondylitis

Hypertension (essential)Hypertension (essential)

OsteoarthritisOsteoarthritis

Type II diabetes (NIDDM)Type II diabetes (NIDDM)

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8585

8080

7070

6262

5555

2626

20% 60%40% 80% 100%0%

Estimated heritability of osteoarthritis Estimated heritability of osteoarthritis at different sitesat different sites

Cervical SpineCervical Spine

Lumbar SpineLumbar Spine

HipHip

KneeKnee

HandHand

Spector & MacGregor, Osteoarthritis and Cartilage, 2003

Common diseases

• Congenital malformationsCleft lip/palateCongenital hip dislocation Congenital heart defectsNeural tube defectsPyloric stenosisTalipes

• Adult onset disorders Diabetes mellitus Epilepsy Glaucoma Hypertension Ischaemic heart disease Manic depression Schizophrenia

Multifactorial

Examples include some cases of cleft lip and palate; neural tube defects; diabetes and hypertension

Caused by a combination of genetic predisposition and environmental influences

Pattern – more affected people in family than expected from incidence in population but doesn’t fit dominant, recessive or X-linked inheritance patterns

Pleiotropy

• Most genes have multiple phenotypic effects. The ability of a gene to affect an organism in many ways is called pleiotropy.

Thanks you very much

&Be Successful