Fundamentals of Genetics

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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

Basic process DNA (nucleus/mitochondria) Transcription

mRNA Translation Protein

Post-translational modification

Why study genetics? 10-25% of all pregnancies have chromosomal

abnormalities

Cause- • fetal loss• birth defect/mental retardation• inherited genetic diseases

Inheritance Monogenic/Mendelian -Autosomal dominant -Autosomal recessive -X linked

Polygenic/Multifactorial- DM, CAD, HT, Epilepsy, Schizophrenia

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

Autosomal dominant

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

Autosomal recessive

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

X-linked dominant

X linked recessive

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

Mitochondrial

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

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

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

Genetic testing- Why? Diagnosis

Carrier detection

Early intervention

Prevention of disease

Genetic counseling

Genetic testing- How? Chorionic villous sampling- 10-12

weeks

Amniocentesis- 15-17 weeks

Percutaneous cord blood sampling- 2nd/3rd trimester

Commonly detected Aneuploidy- Trisomy 21 Point mutation- MODY, Thalassemia Deletions Translocation- CML (9;22),

PML (15;17), Burkitt’s (8;14)

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

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

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

Gene therapy

For SCID/ADA deficiencyRest experimental

Pharmacogenomics

Individualised drug treatmente.g. anti-hypertensives

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