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.

GenotypesPhenotypes
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
Genotypes

Phenotypes

IAIA or IAi

IBIB or IBi

IAIB

AB

ii

IA dan IB- dominant allele.

i- recessive allele.

Phenotypes
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

A| a

A| a
heterozygote

a|a
4

a|a

a|a
homozygote

Mendels 1 Law
st

The law of segregation: Allele pairs separate or

segregate during gamete formation, and
randomly unite at fertilization.
Y/y
Gamete
production

y
Y

y/y
all y
y/y
Y/y

Gamete
production

Mendels 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.

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: Downs 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 doesnt 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