The Cellular and Molecular Basis of Inheritance

The Cellular and Molecular Basis of Inheritance The Cell DNA: The hereditary Material Nucleic Acids • Ribonucleic acid (RNA) : contains the five carbon sugar ribose • Deoxyribonucleic acid (DNA): the hydroxyl group at the 2 position of the ribose sugar is replaced by a hydrogen DNA and RNA both contain the purine bases adenine and guanine and the pyrimidine cytosine, but thymine occurs only in DNA and uracil is found only in RNA DNA replication • DNA replication provides an answer to the question of how genetic information is transmitted from one generation to the next. • During nuclear division, the two strands of the DNA separate with DNA helicase. • each DNA strand directing the synthesis of a complementary DNA strand through specific base pairing, resulting in two daughter DNA duplexes that are identical to the original parent molecule. DNA replication: Semiconservative Leading/ lagging strands • The synthesis of both complementary antiparallel DNA strands occurs in the 5‘ to 3' direction. • leading strand, is synthesized as a continuous process. • lagging strand, is synthesized in pieces called Okazaki fragments, which are then joined together as a continuous strand by the enzyme DNA ligase. • Neighboring replication origins are approximately 50 to 300 kilobases (kb) apart and occur in clusters or replication units of 20 to 80 origins of replication. • DNA replication in individual replication units takes place at different times in the S phase of the cell cycle. Chromosome Structure • A chromosome is very much wider than the diameter of a DNA double helix. • The packaging of DNA involves several orders of DNA coiling and folding. • there is secondary coiling around spherical histone 'beads', forming what are called nucleosomes. • There is a tertiary coiling of the nucleosomes to form the chromatin fibers that form long loops on a scaffold of nonhistone acidic proteins, which are further wound in a tight coil to make up the chromosome as visualized under the light microscope. Packaging of DNA Types of DNA Sequence • single- or low-copy number DNA sequences. – (60% to 70%) • moderately or highly repetitive DNA – (30% to 40%) – mainly satellite DNA and interspersed DNA Types of DNA Sequence Nuclear Genes • estimated to be 25,000 and 30,000 • heterochromatic and centromeric regions are mostly non-coding, • the highest gene density observed in subtelomeric regions. • Chromosomes 19 and 22 are gene rich, whereas 4 and 18 are relatively gene poor. Unique Single-Copy Genes • Most human genes are unique single-copy genes coding for polypeptides that are involved in or carry out a variety of cellular functions. • These include enzymes, hormones, receptors, and structural and regulatory proteins. Multigene Families • Similar functions, having arisen through gene duplication events with subsequent evolutionary divergence making up – physically close together in clusters: the α &β on chr 16 and 11 – widely dispersed throughout the genome occurring on different chromosomes, HOX homeobox gene family Multigene families Classic Gene Families – high degree of sequence homology – numerous copies of genes coding for the various ribosomal RNAs, organized in short arms of the five acrocentric chromosomes – tRNA gene families, which are dispersed In numerous clusters throughout the human genome. • Gene Superfamilies – HLA genes on chromosome 6 – T-cell receptor genes, which have structural homology with the (Ig) genes – these are derived from duplication of a precursor gene, with subsequent evolutionary divergence forming the Ig superfamily. • Gene Structure Pseudogenes • Occurrence of genes that closely resemble known structural genes but are not functionally expressed. • These are thought to have arisen in two main ways: – genes undergoing duplication events that are rendered silent through the acquisition of mutations in coding or regulatory elements. – result of the insertion of complementary DNA sequences, produced by the enzyme reverse transcriptase on a naturally occurring on mRNA transcript, that lack the promoter sequences necessary for expression Repetitive DNA sequences • Tandemly Repeated DNA Sequences (tandem repeats of non-coding DNA ) – Satellite DNA – Minisatellite DNA – Telomeric DNA – Hypervariable minisatellite DNA. • Interspersed Repetitive DNA Sequences – SINE – LINE Satellite DNA • 10% to 15% of the repetitive DNA sequences • consists of very large series of simple or moderately complex, short, tandemly repeated DNA sequences that are transcriptionally inactive and are clustered around the centromeres of certain cchromosomes. Minisatellite DNA • two families of tandemly repeated short DNA sequences: – telomeric – hypervariable minisatellite DNA sequences that are transcriptionally inactive Telomeric DNA • telomeres of the chromosomes contains 10 to 15 kb of tandem repeats of a 6-base pair (bp) DNA sequence known as telomeric DNA. • The telomeric repeat sequences are necessary for chromosomal integrity in replication and are added to the chromosome by an enzyme known as telomerase. Hypervariable minisatellite DNA • highly polymorphic DNA sequences consisting of short tandem repeats of a common core sequence. • These sequences make the basis of the DNA fingerprinting technique developed by Professor Sir Alec Jeffreys in 1984. Microsatellite DNA • Consists of tandem single, di-, tri-, and tetranucleotide repeat base-pair sequences located throughout the genome • rarely occur within coding sequences but trinucleotide repeats in or near genes are associated with certain inherited disorders. • The origin : incorrect pairing of the tandem repeats of the two complementary DNA strands during DNA replication, or what is known as slipped strand mispairing. Highly Repeated Interspersed Repetitive DNA Sequences • Short Interspersed Nuclear Elements(SINE) – 5% of the human genome consists of some 750,000 copies of SINE – The most common are 300 bp that have sequence similarity to a signal recognition particle involved in protein synthesis (Alu repeats). • Long Interspersed Nuclear Elements(LINE) – 5% of the DNA of the human genome – The most common LINE, is LINE-l or an Ll element, consists of more than 100,000 copies of a DNA sequence of up to 6000 bp that encodes a reverse transcriptase. – The function is not clear – Alu repeats could promote unequal recombination, which could lead to pathogenic mutations or provide selective advantage in evolution by gene duplication. – Both Alu and LINE-l repeat elements have been implicated as a cause of mutation in inherited human disease. Mitochondrial DNA -16.6 kb circular DD little repetitive DNA, codes for 37 genes, two types of ribosomal RNA, 22 transfer RNAs 13 protein subunits for enzymes, such as cytochrome b and cytochrome oxidase, which are involved in the energy producing oxidative phosphorylation pathways Maternal inheritance Translation Translation is the transmission of the genetic information from mRNA to protein. Post- Translational Modification • Many proteins, before they attain their normal structure or functional activity, undergo posttranslational modification: – chemical modification of amino-acid side chains (e.g., hydroxylation, methylation) – the addition of carbohydrate – lipid moieties (e.g., glycosylation), – proteolytic cleavage of polypeptides (e.g., the conversion of pro insulin to insulin). The Genetic Code • • 20 different AA are found in proteins; DNA is composed of four different nitrogenous bases, a single base cannot specify one AA • If two bases were to specify one amino acid, there would only 16 possible combinations. • three bases specified one amino acid then the possible number of combinations of the four bases would be 64. Regulation of Gene Expression • Housekeeping genes: are common to all cells, for example ribosomal, chromosomal and cytoskeleton proteins • Some cells express large quantities of a specific protein in certain tissues or at specific times in development, such as hemoglobin in red blood This differential control of gene expression can occur at a variety of stages Control of Control of Transcription • The control of transcription: – environmental (e.g., hormones) – Genetic • Signaling molecules that bind to regulatory sequences in the DNA known as response elements • intracellular receptors known as hormone nuclear receptors • receptors for specific ligands on the cell surface involved in the process of signal transduction Mutations