Blok 2 2011 Genetika Kedokteran dr. Arfianti, M.Biomed, M.Sc.
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Transcript of Blok 2 2011 Genetika Kedokteran dr. Arfianti, M.Biomed, M.Sc.
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Blok 2 2011
Genetika Kedokteran
dr. Arfianti, M.Biomed, M.Sc
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Basic Concepts• Gene – basic unit of genetic
information. Genes determine the inherited characters.
• Genome – the collection of genetic information.
• Chromosomes – storage units of genes.
• DNA - is a nucleic acid that contains the genetic instructions specifying the biological development of all cellular forms of life
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Chromosome Structure
• Locus – location of a gene on the chromosome.
• Allele – one variant form of a gene at a particular locus.
Locus1Possible Alleles: AA,Aa, aa
Locus2Possible Alleles: BB,Bb,bb
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Human Genome
Most human cells contain 46 chromosomes:
• 2 sex chromosomes (X,Y):XY – in males.XX – in females.
• 22 pairs of chromosomes named autosomes.
KARIOTIPE
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KARIOTIPE
• gambaran lengkap kromosom yang telah disusun berdasarkan pasangan homolog dan jenisnya
• Tujuan mempermudah mempelajari kromosom
• Sampel limfosit, sumsum tulang, kulit, cairan amnion atau vili korion.
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TELOMER
• Telomer ujung kromosom sikuen tandem repeat (pada manusia adalah GGGTTA).
• Direplikasi oleh enzim telomerase
• Proses penuaan aktivitas telomerase akan semakin menurun panjang dari telomer akan semakin berkurang.
TELOMER
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BARR BODY
• Wanita salah satu kromatin X-nya mengalami inaktivasi kondensasi kromatin di inti sel pada saat interfase barr body atau kromatin X.
• Apus mukosa pipi (buccal smear) • Kromatin seks 1-10% sel neutrofil
wanita dalam bentuk drumstick.
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MITOSIS DAN MEIOSIS
• Mitosis seluruh sel tubuh dan berfungsi membentuk sel dengan jumlah kromosom yang sama
• Meiosis hanya terjadi pada organ kelamin dan berfungsi mereduksi jumlah kromosom menjadi separuhnya.
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MEIOSIS
• Proses gametogenesis spermatogenesis dan oogenesis sel gamet dengan jumlah kromosom separuh dari jumlah kromosom sel somatik.
• 2 tahap meiosis yaitu Meiosis I dan Meiosis II.
• Meiosis I diploid menjadi haploid. • Meiois II = mitosis. • Antara meiosis I dan meiosis II tidak terjadi
sintesis DNA.
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Genotypes↔Phenotypes
• At each locus (except for sex chromosomes) there are 2 genes genotype at the locus.
• The expression of a genotype phenotype. E.g: hair color, weight, or the presence or absence of a disease.
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Genotypes Phenotypes
• IA dan IB- dominant allele.• i- recessive allele.
genotypes
phenotypes
Genotypes Phenotypes
IAIA or IAi A
IBIB or IBi B
IAIB AB
ii O
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Dominant vs. Recessive
• A dominant allele is expressed even if it is paired with a recessive allele.
• A recessive allele is only visible when paired with another recessive allele.
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One Locus Inheritance
heterozygote homozygote
2 1A | A a | a
A | a 3 4 a | a
A | a 5 6 a | a
Male
Female
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Mendel’s 1st Law
Y / y y / y
½y/y
½Y/y
½y
½Y
all yGamete
production
Gamete production
The law of segregation: Allele pairs separate or segregate during gamete formation, and randomly unite at fertilization.
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Mendel’s 2nd LawThe law of independent assortment: during gamete formation the segregation of the alleles of one allelic pair is independent of the segregation of the alleles of another allelic pair
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Mendel 2nd law cont…
Female Gametes
GW Gw gW gw
MaleGametes
GWGGWW (Yellow,round)
GGWw (Yellow,round)
GgWW (Yellow,round)
GgWw (Yellow,round)
GwGGWw (Yellow,round)
GGww (Yellow,
wrinkled)
GgWw (Yellow,round)
Ggww (Yellow,
wrinkled)
gWGgWW (Yellow,round)
GgWw (Yellow,round)
ggWW (Green,round)
ggWw (Green,round)
gwGgWw (Yellow,round)
Ggww (Yellow,
wrinkled)
ggWw (Green,round)
ggww (Green,
wrinkled)
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Genetic Disorders
6 general patterns of inheritance are observed:
• Autosomal recessive• Autosomal dominant• X-linked recessive• X-linked dominant• Codominant • Mitochondrial
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Autosomal recessive
• Manifest only in homozygous state
• Both males and females affected equally
• Carriers (HTZ) unaffected• Consanguinity increases
risk of recessive disorder• e.g., cystic fibrosis: disease
affecting the mucus lining of the lungs, leading to breathing problems and other difficulties
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Autosomal dominant• Both males and females have
equal chance to inherit gene• Both can transmit disorder to both
sons and daughters• HMZ often more severely affected
than HTZ • Affected males and females
appear in each generation of the pedigree.
• Affected mothers and fathers transmit the phenotype to both sons and daughters.
• e.g., Huntington disease.
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Huntington disease
• Huntington's chorea is an inherited disorder characterized by abnormal body movements called chorea, and loss of memory.
• 5 to 8 per 100,000. • the New York physician George Huntington who first
described it precisely in 1872.
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X-linked recessive
• Expressed in males but not usually in females
• Carrier female– 50% risk of affected sons– 50% risk of carrier
daughter • Affected male
– all daughters carriers– all sons unaffected
• e.g., hemophilia: impair the body's ability to control bleeding
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X-linked dominant
• Males and females affected, females usually less severely affected than males
• 1 in 2 risk to children of affected female
• All daughters of affected male affected but no male to male transmission
• e.g. fragile X syndrome: a range of developmental problems:learning disabilities and mental retardation
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X-linked dominant inheritance
Males and females affected
• Vitamin D resistant rickets
• Fragile X syndrome
Lethal in males• Incontinentia
pigmenti• Rett syndrome• XL
chondrodysplasia punctata
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Codominant inheritance
• Two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein
• Both alleles influence the genetic trait or determine the characteristics of the genetic condition.
• E.g. ABO locus
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Mitochondrial inheritance
• Mitochondria are exclusively maternally inherited
• Genes in mitochondrial DNA
• Mitochondrial disorders can appear in every generation of a family and can affect both males and females E.g. Leber's hereditary optic neuropathy (LHON)
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Question #1
• PKU is a human hereditary disease resulting from inability of the body to process the chemical phenylalanine (contained in protein that we eat).
• It is caused by a recessive allele with simple Mendelian inheritance.
• Some couple wants to have children. The man has a sister with PKU and the woman has a brother with PKU. There are no other known cases in their families.
• What is the probability that their first child will have PKU ?
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Question #2-Solution Highlights
P/p P/p P/p P/p
p/p p/pP-/ P-/
P – the normal allelep – the mutant allele
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X-linked dominant disorders
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Question #3
1 2 3 4 5 6 7 8 9 10
a. What is the most likely mode of inheritance ?
• The disease is rare.
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a. Observations:– After the disease is introduced into the family
in generation #2, it appears in every generation dominant!
– Fathers do not transmit the phenotype to their sons X-linked!
Question #3-Solution Highlights
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Chromosomes
• Number: – Aneuploidy
• Trisomy• Monosomy
– Polyploidy• triploidy (69 chromosomes)
• Structure: deletion/insertion/ inversion/ring
translocation
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Trisomy
• Trisomy 21• Trisomy 18• Trisomy 13• No survivable autosomal monosomy• Sex chromosome aneuploidy:• 45X 47XXX 47 XXY 47XYY
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Trisomy 21: Down’s Syndrome
• 1 in 700 births - maternal age related
• Learning disability• Hypotonia• Nuchal thickening, short neck• Flat face, brachycephaly• Epicanthic folds, Brushfield
spots• Small mouth and ‘large’ tongue • Small ‘square’ ears• Transverse palmar creases,
sandal gap
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45,X
• Turner syndrome 1:1000 female births
• Cardiac defects especially coarctatio aorta
• Horseshoe kidney• Short stature• Streak gonads and
infertility• Webbed neck, ptosis• IQ in normal range, some
specific learning diffs
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47XXX
• Triple X syndrome• Tall stature in childhood• Normal appearance and fertility• Not associated with structural
abnormalities• Learning disability, speech delay, passive
personality
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47,XXY
• Klinefelter syndrome• Males• Tall stature, eunuchoid fat distribution• Small testes and low testosterone• Poor beard growth, gynaecomastia• IQ usually within normal range but < sibs• Some increase in behaviour problems• Increased risk diabetes, varicose veins, breast
cancer
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Chromosomal inheritance
• Pedigree doesn’t conform to mendelian pattern
• May be history of miscarriages• Affected children may have different
patterns of physical and developmental abnormality
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Genetic conselling
• Prenatal testing• “An education process that seeks to assist
affected (and/or ‘at risk’) individuals to understand the nature of the genetic disorder, the nature of its transmission and the options open to them in management and family planning.”
• Tests in pregnancy- – Villi chorialis– Cairan amnion