DWI ANITA SURYANDARI

Departemen Biologi Kedokteran FKUI

FAKTOR POLIGENI DAN MULTIFAKTORIAL

Pewarisan 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 variantallele.

AUTOSOM DOMINAN

AUTOSOM

AUTOSOM RESESIF

KROMOSOM
RANGKAI SEKSX DOMINAN RESESIF

RANGKAI SEKS

RANGKAI SEKS-Y

Single gene trait

Environment
NORMAL= VARIASI

GENE

PHENOTYPE

ABNORMAL

Other Genes

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Genetic Disorders of Interest

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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

P1 F1/P2 F2/P3

F3/P4

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Autosomal recessive inherited disease3

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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Polygenic trait
Environment
Gene1
Gene 2 Gene 3 Gene 4

PHENOTYPE

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+ cch ch c - allele for wild type - allele for chinchilla - allele for himalayan - albino

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

Wild type

himalayan

chinchilla

albino

MHC system code for major histocompatibility complex antigens 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 II

HLA class I

Diseases associate with HLA allotypes (HLA antigens) Disease HLA allotype
Ankylosing spondylitis Reiters disease Rheumatoid arthritis Multiple sclerosis Myasthenia gravis Psoriasis Addisons disease Graves disease Coeliac disease Hemochromatosis Active chronic hepatitis B27 B27 DRw4 A3, B7, Bw2, DRw2 B8, DRw3 A1, B13, Bw37, Cw6 Dw3 B8, Bw35, Dw3 B8, Dw3 A3 B8, DRw3

Single gene diseases versus polygenic diseases

Whereas the mutations causing single gene diseases have a major impact on the function of the gene product, and are therefore rare, those causing polygenic disease have a more moderate effect, and are therefore relatively 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

Frequency of several polygenic diseases

Disorder Schizophrenia Asthma Ankylosing spondylitis Hypertension (essential) Osteoarthritis Type II diabetes (NIDDM) Frequency (%) 1 4 0.2 5 5 6

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

OA prevalence in the UK 2 million adults Majority aged > 60 years

Over 1 million GP appointments each year

An osteoarthritic hip

An osteoarthritis pedigree

An affected individual with unaffected parents Affected individual joining the family, emphasizing the common nature of the disease

Late-onset disease with few members of the younger generation yet affected

Overall - no clear inheritance pattern

Major effort to identify common disease susceptibility genes underway

Risk factors for coronary artery disease

Uncontrollable (but identifiable) Family history (genetics) Age Male sex

Potentially controllable or treatable Fatty diet Hypertension Smoking High serum cholesterol Low serum HDL High serum LDL Stress Insufficient exercise Obesity Diabetes

How does one initially assess whether such a disease has a genetic component?
Twin pair studies Relative risk studies

Twin-pair studies
1 in 89 deliveries

1/3 Monozygotic

2/3 Dizygotic

Do both twins show the same characteristic or trait?

Comparing MZ/DZ twins can give evidence for genetic and/or environmental influences

Trait Height IQ

Concordance rate Monozygotic Dizygotic 95% 90% 52% 60%

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

% Concordance rates
MZ Cystic Fibrosis 100 DZ 25

Hypertension

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10
5

Rheumatoid 30 Arthritis Type I diabetes (IDDM) 36

Heritability
The proportion of the causation of a character that is due to genetic causes
Disorder Schizophrenia Asthma Ankylosing spondylitis Hypertension (essential) Osteoarthritis Type II diabetes (NIDDM) Frequency (%) 1 4 0.2 5 5 6 Heritability 85 80 70 62 55 26

Estimated heritability of osteoarthritis at different sites

Cervical Spine Lumbar Spine Hip Knee

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

Spector & MacGregor, Osteoarthritis and Cartilage, 2003

 Congenital malformations
Cleft lip/palate Congenital hip dislocation Congenital heart defects Neural tube defects Pyloric stenosis Talipes

Common diseases

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 doesnt fit dominant, recessive or Xlinked 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