Konsep Dasar Genetika Kedokteran

Suratno Lulut Ratnoglik, MD.,PhD.

• Textbook:• Genetics in Medicine, 7th edition. Nussbaum, McInnes &

Willard. W.B. Saunders Co. (2007).

• Reference• Emery’s 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 GeneticsPeople 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 1800’s DiscoveriesThree major events in the mid-1800’s 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 Mendel’s 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 humulinoKeunggulan: 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 KankerDeteksi kanker secara dini pengobatan tumor paling efektif

The Family History is a powerful tool for estimating genetic risk

Obtain information on children, sibs, and parentsAge/date of birthHealth statusAge at deathCause of death

This is the ‘nuclear’ family

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

The Family History

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

Number of children

Affected

Heterozygote

Female X-linked carrier

Dead Aborted or stillborn

62

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 :

oOsteogenesis imperfecta - autosomal dominanto Sickle cell anemia - autosomal recessiveoHaemophilia - X-linkedoCystic fibrosiso Sickle cell anemiaoMarfan 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.

~20%

ClassicMedical Genetics

Single geneChromosome

Early onset(usually pediatric)

Marfan SyndromePKU

Cystic FibrosisNeurofibromatosis

Down syndrome

Genetic Disease

Genetic Variation

~80%

Genetic Susceptibility

Common Gene VariationGene + Environment

Delayed onset(usually adult)

Coronary Heart DiseaseHypertension

DiabetesCancer

Vascular Disease

Polygenic disease pedigree

Human GenomeSize: 2900- 3200 Mb (megabases = million bp)

~ 3 X 109 bp

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

Other: 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

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

Human Genome Project: Approach

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 TCTTCTAGGC25,790,661 ATTGGCACAT CTCCACTTAA TAGAATATGT TGGAGAACAA ACTGCTTTGC 25,790,611 TAATAAAGGT AAAATAAATG CTATAATAGA AGGCACTCCA GCCACTGTTC25,790,561 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 DatabasesNCBI Web Site-------------PubMedProteinNucleotideStructureGenomeBooksCancerChromosomesConserved Domains3D DomainsGeneGenome ProjectGENSATGEO ProfilesGEO DatasetsHomoloGeneJournalsLocusLinkMeSHOMIAOMIMPMCPopSetProbePubChem BioAssayPubChem CompoundPugChem SubstanceSNPTaxonomyUniGeneUniSTS

Important databases in NCBI

All Databases Everything

PubMed On-line catalogue of published papersAbstracts.pdf files

OMIM Information on genetic diseases

SNP Common variants

Gene Information on genesMap 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”

Francis Collins Director of the National Human Genome Research InstituteNIH