poligen & multifaktor.ppt
DESCRIPTION
Penurunan sifat berdasarkan banyak faktor baik dari dalam (genetika) maupun luar (lingkungan)TRANSCRIPT
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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0.20.2
55
55
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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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44
0.20.2
55
55
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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.
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