GENETIC DISORDERS (Introduction)

Dr. Shahab Riaz

Chromosome:

• Greek (chroma, color) and (soma, body) bcz strongly stained by particular dyes

• organized structure of DNA and protein, found in cells

• single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences

• In eukaryotes, nuclear chromosomes are packaged by proteins into a condensed structure called chromatin

• very long DNA molecules to fit into the cell nucleus

Gene:

• basic unit of heredity in a living organism

• information to build and maintain the cells and pass genetic traits to

offsprings

• In general terms, a gene is a segment of nucleic acid that, taken as a whole, specifies a trait

Gregor Mendel

History:• Gregor Mendel (1822–1884) a priest and scientist • In 1860s, studied inheritance in pea plants father of genetics for his

study of the inheritance of certain traits in pea plants

• hypothesized a factor that conveys traits from parent to offspring • over 10 years of his life on one experiment • showed that the inheritance of these traits follows particular laws • Mendel's work was not recognized until the turn of the 20th century • Didn’t use the term gene, explained results in terms of inherited

characteristics • dominant and recessive traits, the distinction between a heterozygote

and homozygote, genotype and phenotype

Deoxyribonucleic acid (DNA): • nucleic acid 

• genetic instructions & the long-term storage of information

• blueprints, or a code for development and functioning

• Construction of cellular proteins and RNA molecules

• DNA segments that carry this genetic information are called genes

DNA Structure:

• two long polymers of simple units called nucleotides

• backbones made of sugars and phosphate groups joined by ester bonds

• two strands are anti-parallel

• Attached to each sugar is one of four types of molecules called bases

• sequence of these four bases along the backbone that encodes

information

Messenger ribonucleic acid (mRNA):

• molecule of RNA encoding a chemical "blueprint" for a protein

 product • mRNA is transcribed from a DNA template • carries coding information to the sites of protein synthesis: the ”

ribosomes” on RER

• the nucleic acid polymer is translated into a polymer of amino acids: a “protein”

• In mRNA as in DNA, sequence of nucleotides arranged into codons consisting of three bases each

• Each codon encodes for a specific amino acid • stop codons terminate protein synthesis

Codon:• Base triplet in mRNA transcribed by DNA

• If the base triplet in the DNA sequence is GCT Then• corresponding codon on the mRNA strand will be CGA

Transfer RNA (tRNA):• mediates recognition of the codon • provides the corresponding amino acid

Ribosomal RNA (rRNA):• central component of the ribosome's protein manufacturing machinery

Anti-Codon:• sequence of three adjacent nucleotides in transfer RNA • binds to a corresponding codon in messenger RNA

• designates a specific amino acid during protein synthesis

• 20 Amino Acids In Human Protein:Table of DNA Base Triplets, RNA Codons & Anticodons

GENETICS:

• Ancient Greek genetikos, “genitive” and that from genesis, “origin”

• science of heredity and variation in living organisms

• living things inherit traits from their parents prehistoric times improve crop plants and animals through selective breeding

• Modern genetics basis by Gregor Mendel

Genome:• full set of chromosomes or genes in a gamete • So a regular somatic cell contains two full sets of genomes • In haploid organisms, including bacteria, viruses, and mitochondria, a cell

contains only a single set of the genome

Genomics:• study of the genomes of organisms • entire DNA sequence of organisms and fine-scale genetic mapping efforts • Research of single genes does not fall into the definition of genomics

Importance of Genetics

• Life time frequency 670/1000

• Classic genetic diseases + CVS diseases and cancer

• Some diseases have both environmental + genetic role (atherosclerosis / HTN)

• In medical practice Iceberg of Genetic diseases less severe

• 50% of spontaneous abortions gross chromosomal abnormalities

Importance of Genetics

• 100,000 previously thought but actually approx 30,000

• Different combinations > 100,000 proteins

• Fully formed proteins can be sliced/stitched > peptides than expected

• Avoiding intra-uterine diseases

• Thalassemia inter-marriages

• Treatments of cancer Genetic Level

Interesting Fact

• 99.9% of genomic DNA sequence of any two humans is the same

• 0.1% rest of the genome accounts for the differences in features approx. 3 million base pairs

Molecular Basis of Human Diseases• Two general strategies used to isolate involved genes

Functional Cloning or Classical Approach:• Abnormal gene product / protein known • Isolate normal gene and clone• Determine molecular changes causing the disorder

Positional Cloning or Candidate Gene Approach:• In some diseases, multiple genes involved or no clue of defective product• Ignores the phenotype or protein product• Instead mapping disease phenotype to specific chromosome location• Marker genes identified Close proximity to disease locus• Localized narrow limits clone DNA from relevant site in vitro • Identification of protein aberrant protein encoded by mutant genes

Genetic Engineering

• Production of human biologically active agents

• Recombinant DNA technology

• Improving crop technology

• manufacture of synthetic human insulin through the use of modified bacteria

• manufacture of erythropoietin in hamster ovary cells

• Growth hormone

• GM-CSF & G-CSF

Genetic Engineering

1. Isolation of the genes of interest

2. Insertion of the genes into a transfer vector

3. Transfer of the vector to the organism to be modified

4. Transformation of the cells of the organism

5. Selection of the genetically modified organism (GMO) from those that have not been successfully modified

Gene Therapy

• insertion of genes into an individual's cells and tissues to treat a disease

• hereditary disease in which a deleterious mutant allele is replaced with a functional one

• Although the technology is still in its infancy, it has been used with some success.

• Appropriate Vectors ???• Random Insertion in other Cells