Download Genetika Kedokteran

Genetika Kedokteran
dr. Arfianti, M.Biomed, M.Sc
Blok 2 2011
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
Chromosome Structure
• Locus – location of a gene on the
chromosome.
• Allele – one variant form of a gene
at a particular locus.
Locus1
Possible Alleles: AA,Aa, aa
Locus2
Possible Alleles: BB,Bb,bb
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
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.
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
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.
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.
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.
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.
Genotypes
Phenotypes
Genotypes
Phenotypes
IAIA or IAi
A
IBIB or IBi
B
I AI B
AB
ii
O
• IA dan IB- dominant allele.
• i- recessive allele.
genotypes
phenotypes
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.
One Locus Inheritance
Female
A|A
Male
1
2
A|a
3
A| a
heterozygote
a|a
4
5
6
a|a
a|a
homozygote
Mendel’s 1st Law
The law of segregation: Allele pairs separate or
segregate during gamete formation, and
randomly unite at fertilization.
Y/y
y/y
all y
½ y/y
Gamete
production
½y
½ Y/y
½Y
Gamete
production
Mendel’s 2nd Law
The 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
Mendel 2nd law cont…
Female Gametes
GW
Gw
gW
gw
GW
GGWW
(Yellow,
round)
GGWw
(Yellow,
round)
GgWW
(Yellow,
round)
GgWw
(Yellow,
round)
Gw
GGWw
(Yellow,
round)
GGww
(Yellow,
wrinkled)
GgWw
(Yellow,
round)
Ggww
(Yellow,
wrinkled)
gW
GgWW
(Yellow,
round)
GgWw
(Yellow,
round)
ggWW
(Green,
round)
ggWw
(Green,round)
gw
GgWw
(Yellow,
round)
Ggww
(Yellow,
wrinkled)
ggWw
(Green,
round)
ggww
(Green,
wrinkled)
Male
Gametes
Genetic Disorders
6 general patterns of inheritance are observed:
•
•
•
•
•
Autosomal recessive
Autosomal dominant
X-linked recessive
X-linked dominant
Codominant
• Mitochondrial
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
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.
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.
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
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
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
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
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)
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 ?
Question #2-Solution Highlights
P/p
P/p
P/p
P/p
p/p
P/-
P/-
p/p
P – the normal allele
p – the mutant allele
X-linked dominant disorders
Question #3
• The disease is rare.
1
2
3
4
5
6
7
8
a. What is the most likely mode of inheritance ?
9
10
Question #3-Solution Highlights
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!
Chromosomes
• Number:
– Aneuploidy
• Trisomy
• Monosomy
– Polyploidy
• triploidy (69 chromosomes)
• Structure: deletion/insertion/ inversion/ring
translocation
Trisomy
•
•
•
•
•
•
Trisomy 21
Trisomy 18
Trisomy 13
No survivable autosomal monosomy
Sex chromosome aneuploidy:
45X
47XXX
47 XXY 47XYY
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
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
47XXX
•
•
•
•
Triple X syndrome
Tall stature in childhood
Normal appearance and fertility
Not associated with structural
abnormalities
• Learning disability, speech delay, passive
personality
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
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
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