This document provides an overview of fundamentals of genetics. It discusses that humans have 23 chromosome pairs, 30,000-40,000 genes, and over 3 billion base pairs. The human genome project was completed in 2000. Genetics is studied to understand chromosomal abnormalities in pregnancies that can cause fetal loss, birth defects, or genetic diseases. Inheritance patterns can be monogenic/Mendelian including autosomal dominant, autosomal recessive, and X-linked, or polygenic/multifactorial. Genetic testing is used for diagnosis, carrier detection, early intervention and prevention of disease.

1. Fundamentals of Genetics
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2. Numbers in Homo sapiens
 Chromosome pairs- 23
 Genes- 30-40,000
 Base pairs (AT/GC)- 3,000,000,000
 Human genome project- completed
year 2000

3. Basic process
 DNA (nucleus/mitochondria)
Transcription
 mRNA
Translation
 Protein

4. Why study genetics?
 10-25% of all pregnancies have chromosomal
abnormalities
 Cause-
• fetal loss
• birth defect/mental retardation
• inherited genetic diseases

5. Inheritance
 Monogenic/Mendelian
-Autosomal dominant
-Autosomal recessive
-X linked
 Polygenic/Multifactorial- DM, CAD, HT,
Epilepsy, Schizophrenia

6. Autosomal dominant
 Majority, nearly 65%
 Successive generations affected
 50% offspring affected
 Manifest in heterozygous state
 e.g. HOCM, MODY, ADPKD, Marfan’s,
Neurofibromatosis, Huntington’s chorea

7. Autosomal dominant

8. Autosomal recessive
 Nearly 25%
 Skip generations, parents clinically normal
 25% affected, 50% carrier
 Manifest in homozygous state
 e.g. Cystic fibrosis, Thalassemia, Sickle cell
disease, Friedreich’s ataxia, most enzyme
deficiencies

9. Autosomal recessive

10. X linked
 Nearly 5%
 No father to son transmission
 All daughters of affected male are
carriers
 e.g. Hemophilia, Duchenne, G-
6-PD deficiency, Colour blindness

11. X-linked dominant

12. X linked recessive

13. Mitochondrial
 Matrilineal
 (cardio)myopathies/encephalopathies
 MELAS-myopathy.encephalopathy.lactic acidosis.stroke
 MERRF- myoclonic epilepsy with ragged red fibres
 Leber’s optic atrophy
 Progressive external ophthalmoplegia
 Pearson syndrome- BM & pancreatic failure
 Kearns-Sayre syn.- c’myopahty.o’plegia.retinal pigmentation

14. Mitochondrial

15. DNA damage
 Endogenous, by reactive oxygen species
from normal metabolism
 Exogenous; by radiation, chemicals,
chemotherapy, viruses
 A cell with accumulated DNA damage can
enter one of three possible states:
 Senescence, an irreversible state of dormancy
 Apoptosis, programmed cell death
 Unregulated cell division leading to Cancer

16. DNA repair
 A continuous process involving enzymes
DNA glycosylase, endonuclease, polymerase
and ligase
 DNA repair defects cause:
 Xeroderma pigmentosum
 Ataxia-Telangiectasia
 Bloom syndrome
 Lynch syndrome/HNPCC
 Fanconi syndrome

17. Genetic counseling
 Family history of genetic disease
 Early onset of disease in family
 Consanguinity
 Advanced maternal/paternal age
 High-risk ethnic groups
 Bad obstetric history
 Abnormal prenatal test- US/mat. assay

18. Genetic testing- Why?
 Diagnosis
 Carrier detection
 Early intervention
 Prevention of disease
 Genetic counseling

19. Genetic testing- How?
 Chorionic villous sampling- 10-12
weeks
 Amniocentesis- 15-17 weeks
 Percutaneous cord blood sampling-
2nd
/3rd
trimester

20. Commonly detected
 Aneuploidy- Trisomy 21
 Point mutation- MODY, Thalassemia
 Deletions
 Translocation- CML (9;22),
PML (15;17), Burkitt’s (8;14)

21. Cancer genetics
 Cancer is an abnormal clonal disease
 5-10 cumulative mutations are required
for normal to malignant phenotype
 Oncogenes (Her2, ras, myc) and
tumour suppressor genes (Rb, p53,
APC) control cell-division and apoptosis
 Mutations promote cancer development

22. Who is at risk?
 Positive family history
 At least one <50 years of age
 3 members over 2 generations affected
 BRCA ½- breast and ovary
 APC- HNPCC and FAP

23. Genetic testing- Problems
 Polygenic/multifactorial inheritance
 Variable penetrance
 Variable expressivity
 False +ve/-ve
 What after diagnosis?

24. Gene therapy
For SCID/ADA deficiency
Rest experimental

25. Pharmacogenomics
Individualised drug treatment
e.g. anti-hypertensives

26. Debate
 Genetic privacy
 Discrimination- employment/insurance
 Regulation of tests/treatment
 Education
 Ethics- cloning/aging