Konsep Dasar Genetika Kedokteran

Suratno Lulut Ratnoglik, MD.,PhD.

 Textbook:
Genetics in Medicine, 7th edition. Nussbaum,
McInnes & Willard. W.B. Saunders Co. (2007).

Reference
Emerys Elements of Medical Genetics, 13th
edition, Turnpenny & Ellard. Churchill
Livingstone. (2007).
Glossary & Definitions

Genetics is concerned with variation and

heredity in all living organisms
Human genetics is the science of
variation and heredity in humans
Medical genetics deals with human
genetic variation of significance in
medical practice and research
Cytogenetics: the study of chromosomes
Glossary & Definitions
Genomics: the study of genome, its organization
and functions
Population genetics: genetic variation in human
populations and factors that affect allele
frequencies
Clinical genetics: application of genetics to
diagnosis and patient care
Genetic counseling: risk information,
psychological and educational support to patients
and/or their families
History of Genetics
People have known about inheritance for a long time :
Children resemble their parents
Domestication of animals and plants, selective breeding
for good characteristics
Bible and hemophilia
Mid 1800s Discoveries
Three major events in the mid-1800s led directly to the
development of modern genetics.
1859: Charles Darwin publishes The Origin of Species,
which describes the theory of evolution by natural
selection. This theory requires heredity to work.
1866: Gregor Mendel publishes Experiments in Plant
Hybridization, which lays out the basic theory of
genetics. It is widely ignored until 1900.
1871: Friedrich Miescher isolates nucleic acid from pus
cells.
Major Events in the 20th Century
1900: rediscovery of Mendels work by Robert Correns, Hugo de
Vries, and Erich von Tschermak .
1902: Archibald Garrod discovers that alkaptonuria, a human
disease, has a genetic basis.
1904: Gregory Bateson discovers linkage between genes. Also
coins the word genetics.
1910: Thomas Hunt Morgan proves that genes are located on the
chromosomes (using Drosophila).
More 20th Century Events
1926: Hermann J. Muller shows that X-rays induce mutations.
1944: Oswald Avery, Colin MacLeod and Maclyn McCarty show that DNA
can transform bacteria, demonstrating that DNA is the hereditary material.
1953: James Watson and Francis Crick determine the structure of the DNA
molecule, which leads directly to knowledge of how it replicates
1966: Marshall Nirenberg solves the genetic code, showing that 3 DNA
bases code for one amino acid.
1972: Stanley Cohen and Herbert Boyer combine DNA from two different
species in vitro, then transform it into bacterial cells: first DNA cloning.
2001: Sequence of the entire human genome is announced.
Timeline of Recent Changes
 James Watson and Francis Crick (1953)
Discovery of DNA Structure Double
Helix
APLIKASI GENETIKA MODERN
Penemuan obat-obatan dan vaksin (riset medis)
Identifikasi kelainan genetik
Deteksi kanker
Forensik
Obat-obatan dan vaksin(riset medis)
Rekayasa gen menghasilkan insulin manusia di dalam
bakteri humulin
o Keunggulan: non-allergenik (tdk bersifat allergen)
o Sedang ekstrak insulin sapi & babi bersifat allergen
Vaksin DNA
Terapi gen, etc.
Identifikasi Kelainan Genetik
Sebelum bayi lahir mencegah kerusakan permanen
Bayi baru lahir.

Amniocentesis
Deteksi Kanker
Deteksi kanker secara dini pengobatan tumor paling efektif
 The Family History
The Family History is a powerful tool for estimating genetic
risk

Obtain information on children, sibs, and parents

Age/date of birth
Health status
Age at death
Cause of death

This is the nuclear family

Expand as necessary to grandparents, uncles & aunts, etc.

Normal female

Normal male

Single bar indicates mating

Normal parents and normal offspring

Single parent means partner is not significant for the analysis

 Double bar indicates consanguineous mating

Fraternal twins (not identical)

Identical twins

2 6 Number of children

Affected

Heterozygote

Female X-linked carrier

Dead Aborted or stillborn

Major types of genetic
disease
Chromosomal disorders

Single gene disorders

Polygenic diseases
Chromosomal disorders
Addition or deletion of entire chromosomes or parts of
chromosomes. Rearrangement of chromosomal segments

Typically more than 1 gene involved

Classic example is trisomy 21 - Down syndrome

Down Syndrome
Single gene disorders
Single mutant gene has a large effect on the patient
Transmitted in a Mendelian fashion
Autosomal dominant, autosomal recessive, X-linked, Y-linked
Examples :
o Osteogenesis imperfecta - autosomal dominant
o Sickle cell anemia - autosomal recessive
o Haemophilia - X-linked
o Cystic fibrosis
o Sickle cell anemia
o Marfan syndrome
Autosomal dominant pedigree
Polygenic diseases
The most common yet still the least understood of human
genetic diseases
Result from an interaction of multiple genes, each with a
minor effect
The susceptibility alleles are common
Examples :
Prenatal development disorders :
Hirschprung disease
Cleft lip and palate
Congenital heart defect etc.
Adult disorders :
Alzheimer disease
Diabetes
Hypertension etc.
 Genetic Variation

Genetic Disease Genetic Susceptibility

Classic
Medical Genetics

~20% ~80%

Single gene Common Gene Variation

Chromosome Gene + Environment

Early onset Delayed onset

(usually pediatric) (usually adult)

Marfan Syndrome Coronary Heart Disease

PKU Hypertension
Cystic Fibrosis Diabetes
Neurofibromatosis Cancer
Down syndrome Vascular Disease
Polygenic disease pedigree
 Human Genome
e: 2900- 3200 Mb (megabases = million bp)
~ 3 X 109 bp

nes: 25,000- 30,000 (exact number not known)

er: Most of DNA sequence is non-coding

(Exons contain only <1.5% of DNA)

Gene distribution uneven

Non-coding regions may be important

Why should we be excited about the human genome?

We know the entire sequence of the genome
and can locate genes and variants quickly.
Accessing the sequence
Public databases

Freely available

Continuously modified and updated

Human Genome Project: Approach

Lander E, et al. Nature 409:860, 2001

25,790,861 TTTTTCTCCA TGAATCTTCG TTGTGCATAT ATGATAGTAA ATTATTTATA
25,790,811 GACTGTGTAT TTGAGTCTGA TCTTTTATAA GAAGCAGGAA TCTGGGCCTA
25,790,761 CCTTATGTTC ACGTCTTTTC ATTTTCAAGA CTTTTTTTTT AAATCTTGCA
25,790,711 TATATTTTCG GTTCTAAACT GATTCTCACC ACACATCCTT TCTTCTAGGC
25,790,661 ATTGGCACAT CTCCACTTAA TAGAATATGT TGGAGAACAA ACTGCTTTGC
25,790,611 TAATAAAGGT AAAATAAATG CTATAATAGA AGGCACTCCA GCCACTGTTC
25,790,561 TTTGATTTTG TGAAAAAAAT TAAAAAAAAA AAGCACTCTG GTAAGAACAG
25,790,511 GTCCCATTAA TTATGTAAAA AGGCACAGCA GGGAACCTGT TCTATCCTGT
25,790,461 GCAGCCCAGA GATGAAGGGA GACTTTTTCC GAAGAATATG TAATTACAGA
25,790,411 TGCCTGCTCT TTTGCTTTTA GCCTTTATTT AAAGCCTGTC TGAGAAGGAG
25,790,361 TGGGATTGAC ACCAGCCTCA GTAAATGAGT GCTGCAGGCG CCCCAGCCCC
25,790,311 AGGGGTCTGC CGGGCCATCA GGTCAATGTG ACCAGTGTGC GCAGCCACCA
25,790,261 CATGGGGATG AGGGGCAGGG TCACTCTGCC TCCCCATCCA GGGGGCTGGC
25,790,211 AGGTCTGGGC ATGGCTGGGC TTTGCTGGTA GAAACCCAGC AGAGGCTCCT
25,790,161 GGTGTGGGTG TGGCCCTGGC TTGCACACCT ATGTCTGCCT TGGTCTCGTG
25,790,111 ATGGGTAAGA GGAAGGACTA ACACCCTCGG GCCCCTCTGA GTCTCGCGGC
25,790,061 TGGTGGGTCT GACCCTAAGT GCATGCGATG GAACACTGCA GCTGCTATTG
25,790,011 TCCTCCTTCC AGATGGTCCC AGAGGAGCAG CGCCTCATAG CCGCCATTGT
25,789,961 CCTGGTGGTG TGGGTCTCAG CCCTGGCGTC GTCCCTGATT GACAACATCC
25,789,911 CGTTCACTGC TACCATGGTG AGTTGCACAT GTCCATGTCG ACGGCTCAAC
25,789,861 TTTAGCCTGG ACATAGCCTG GGGCTCACCC TCCCTTCCTA AGGCAGCAGA
25,789,811 GGATGAAGCC TGCCCCTCTG CTGCACTCAC AGGTGTAGAG GACGAAAGTG
25,789,761 AGCAGAGCCC AGGGCAGCTG GGTGGGGAGT GCCGAGAGCC CAGACTGCAG
25,789,711 GCTGGGAGCC GAGGCTCTGC AGCTGCCGTG GACAGCACGT CCTGGGGTGA
25,789,661 CTGGTGATCT CGAGGTCAGC CCCACTGAGA GCTGCCACCC CTCCCAGAAA
25,789,611 AGGCTGTGCT TGCTTGCTTG CTTTCTCTCT TTCTTTCTCT TTCTTTCTTT
25,789,561 CTCTCTCTCT TTCTTTCTTT CTTTCTTTCT TTTTCTTTCT TTCTTTCTTT
25,789,511 CCTTTCTGTC TTTCCTTCCC TCCCTCCCTC CCTCCCTTCC TTCCTTCTTT
25,789,461 CCTTCCTTCC TTCCTTCCTT CTTTCCTTCC TTCCTTCTTT CCTTCCTTCC
http://www.ncbi.nlm.nih.gov/
What does NCBI do?

Established in 1988 as a national resource for

molecular biology information, NCBI creates
public databases, conducts research in
computational biology, develops software tools
for analyzing genome data, and disseminates
biomedical information - all for the better
understanding of molecular processes affecting
human health and disease.
All Databases
NCBI Web Site
-------------
PubMed
Protein
Nucleotide
Structure
Genome
Books
CancerChromosome
s
Conserved Domains
3D Domains
Gene
Genome Project
GENSAT
GEO Profiles
GEO Datasets
HomoloGene
Journals
LocusLink
MeSH
OMIA
OMIM
PMC
PopSet
Probe
PubChem BioAssay
PubChem
Compound
PugChem Substance
SNP
Taxonomy
UniGene
 Important databases in NCBI

All Databases Everything

PubMed On-line catalogue of published papers

Abstracts
.pdf files

OMIM Information on genetic diseases

SNP Common variants

Gene Information on genes

Map Viewer
http://www.ncbi.nlm.nih.gov/
Everyone carries anywhere from five to fifty
significant genetic flaws, and that virtually all diseases
- even AIDS - have a genetic component
FrancisCollins
DirectoroftheNationalHumanGenomeResearchInstitute
NIH