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Human Genetics

Human Genetics. Translation of RNA into Protein. Replication. DNA. Transcription. RNA. Nucleus. Translation. Protein. Cytoplasm. Central Dogma. Human Genome. 3.2 million DNA base pairs 1.5% encode proteins < = > 98.5% not protein encoding

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Human Genetics

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  1. Human Genetics Translation of RNA into Protein

  2. Replication DNA Transcription RNA Nucleus Translation Protein . Cytoplasm Central Dogma

  3. Human Genome 3.2 million DNA base pairs 1.5% encode proteins < = > 98.5% not protein encoding ~ 31,000 genes encoding 100,000 - 200,000 proteins How are 100,000 to 200,000 proteins produced from 31,000 genes? What is the 98.5% of the human genome that does not encode proteins?

  4. Noncoding portion of the human genome

  5. RNA Usually single-stranded Has uracil as a base Ribose as the sugar Carries protein-encoding information Can be catalytic DNA Usually double-stranded Has thymine as a base Deoxyribose as the sugar Carries RNA-encoding information Not catalytic Two types of nucleic acids

  6. # of strands kind of sugar bases used

  7. RNA Structure Depends on Sequence • A can pair with U and the C with G via hydrogen bonding just as with DNA. • Secondary RNA structure is critical in how it performs its function. • RNA Structure and RNA Sequence enable an RNA to interact specifically with proteins.

  8. RNA Processing mRNA transcripts are modified before use as a template for translation: • - Addition of capping nucleotide at the 5’ end • - Addition of polyA tail to 3’ end • Important for moving transcript out of nucleus • And for regulating when translation occurs Splicing - the removing internal sequences - introns are sequences removed - exons are sequences remaining

  9. RNA Processing

  10. Protein Structure was solved before DNA was known to be genetic material Linus Pauling and Alpha Helix led to model building by Watson and Crick

  11. Proteins • most abundant type of molecules in cells • responsible for most biological functions • muscle contraction - myosin and actin • oxygen transport - hemoglobin • immune system -antibodies • connective tissue - cartilage • hair/skin - keratin • metabolism - enzymes

  12. Gene Expression changes in Proteins during Development

  13. Protein Basics • Proteins are polymers assembled from amino acids • 20 different amino acids are used • Bond between amino acids is called the "Peptide Bond". • Peptide Bond is formed between the carboxyl group of one amino acid and the Alpha amino group of another amino acid. • mRNAs have a 5' end and a 3' end - they have Polarity. • Proteins also have polarity.

  14. Protein Folding is Critical • How is protein folding directed within cells? • This is still an active area of research, but to a large degree, protein sequence determines protein folding.

  15. Misfolding of Protein Impairs Function

  16. Protein Polarity • The Amino acid at one end of a protein chain has a free Alpha amino group. • Called "Amino-Terminus" or "N-terminus" of the protein. • Amino acid at other end has a free Alpha carboxyl group. • Called "Carboxy-Terminus" or "C-terminus" of the protein. • Direction of Protein Synthesis is from N-terminus to C-terminus.

  17. The Genetic Code • There is a 3 to 1 correspondence between RNA nucleotides and amino acids. • The three nucleotides used to encode one amino acid are called a codon. • The genetic code refers to whichcodons encode which amino acids. • How do we know it is a 3 letter code?

  18. Codons of one nucleotide: A G C U Codons of two nucleotides: AA GA CA UA AG GG CG UG AC GC CC UC AU GU CU UU Can only encode 4 amino acids Can only encode 16 amino acids How Do the mRNA Nucleotides Direct Formation of the Amino Acids in a Protein? Proteins are formed from 20 amino acids in humans.

  19. Codons of three nucleotides: AAA AGA ACA AUA AAG AGG ACG AUG AAC AGC ACC AUC AAU AGU ACU AUU GAA GGA GCA GUA GAG GGG GCG GUG GAC GGC GCC GUC GAU GGU GCU GUU CAA CGA CCA CUA CAG CGG CCG CUG CAC CGC CCC CUC CAU CGU CCU CUU UAA UGA UCA UUA UAG UGG UCG UUG UAC UGC UCC UUC UAU UGU UCU UUU Allows for 64 potential codons => sufficient!

  20. Theoretical Codes

  21. The Genetic CodeThree Conceivable Kinds of Genetic Codes

  22. DNA template strand DNA C A G C A G T T T Transcription A A G U C A G U C Messenger RNA mRNA Codon Codon Codon Translation Polypeptide (amino acid sequence) Protein Lysine Serine Valine Translation • The process of reading the RNA sequence of an mRNA and creating the amino acid sequence of a protein is called translation.

  23. How do we know a 3 nucleotide codon determines amino acid choice?

  24. Prediction of Amino Acid Sequence from Synthetic RNA molecules

  25. The genetic code is non-overlapping

  26. Universal Code? • In some organisms, a few of the 64 possible "words" of the genetic code are different. • Do a few different words mean that the code is not universal? • Perhaps: if you're willing to say that the US and Britain don't share a common language because elevators in the UK are called "lifts" and they spell the word "color" with a "u.“

  27. The Genetic Code Is • Linear: uses mRNA which is complementary to DNA sequence. • Triplet: the unit of information is the codon, a series of three ribonucleotides. • Unambiguous: each codon specifies only one amino acid (AA). • Degenerate: more than one codon exists for most amino acids.

  28. The Genetic Code Is: • Punctuated: there are codons that indicate “start” and “stop.” • Commaless: there is no punctuation within a mRNA sequence. • Nonoverlapping: any one ribonucleotide is part of only one codon (some exceptions exist). • Universal: the same code is used by viruses, bacteria, archaea, and eukaryotes.

  29. Point Mutations • Single Base Change can alter protein product. • Misssense: results in one amino acid change. • Nonsense: results in stop codon. • Frame-shift: change "reading-frame" of genetic message. • Silent mutations: point mutations that DON’T alter the protein product because of the degenerate nature of the genetic code.

  30. Frame Shift • Within a gene, small deletions or insertions of a number of bases not divisible by 3 will result in a frame shift. For example, given the coding sequence: AGA UCG ACG UUA AGC • corresponding to the protein arginine - serine - threonine - leucine - serine

  31. Frame Shift • The insertion of a C-G base pair between bases 6 and 7 would result in the following new code, which would result in a non-functional protein. Every amino acid after the insertion will be wrong. AGA UCG CAC GUU AAG C Corresponding to the protein: arginine - serine - histidine - valine – lysine • The frame shift could generate a stop codon which would prematurely end the protein.

  32. How to Recognize Protein Information in DNA • Don't assume that a dsDNA molecule will be read from left to right on the top strand. • Every dsDNA sequence has six possible translations: • top / bottom strand each with a 1st / 2nd / 3rd reading frame • Not every AUG or "stop" sequence is a start or stop codon. • ORF is the Open Reading Frame- It has an ATG in frame with a Stop codon. It could encode a protein.

  33. Comma free and non-overlapping are correct. • The living cell does decodes the messenger RNAs by a kind of dead-reckoning. • Ribosomes march along the messenger RNA in strides of three bases, translating as they go. • Except for signals that mark where the ribosome is supposed to start, there is nothing in the code itself to enforce the correct reading frame. • Three codons serve as stop signs: UAA, UAG or UGA

  34. What reading frame should be used? • In any mRNA sequence, there are three ways triplet codons can be read. • Each way to read the codons is called a "Reading Frame". • It is very important for ribosome to find correct reading frame. • If the wrong reading frame is used, translation generates a protein with the wrong amino acid sequence which is not functional.

  35. At what codon in the mRNA does the ribosome begin translation? • Recall there is a 5’ untranslated region of the messenger RNA. • The solution is that the ribosome begins translation at a specific AUG codon within the mRNA template termed the "Start Codon". • This is a methionine codon, so the first amino acid in proteins is almost always methionine.

  36. Translation has Three Steps Initiation - translation begins at start codon (AUG=methionine) Elongation - the ribosome uses the tRNA anticodon to match codons to amino acids and adds those amino acids to the growing peptide chain Termination - translation ends at the stop codon UAA, UAG or UGA

  37. Translation Initiation

  38. Leader sequence Small ribosomal subunit 5’ 3’ U U C G U C A U G G G A U G U A A G C G A A mRNA mRNA U A C Met Initiator tRNA Translation Initiation Assembling to begin translation

  39. A U G G G A U G U A A G C G A 5’ 3’ mRNA U A C C C U tRNA Aminoacid Gly Met Largeribosomalsubunit Translation Initiation Ribosome

  40. A U G G G A U G U A A G C G A 5’ 3’ mRNA U A C C C U Gly Met A C A Cys Translation Elongation

  41. A U G G G A U G U A A G C G A A C A 5’ 3’ mRNA C C U Gly C Met A U Cys Translation Elongation

  42. A U G G G A U G U A A G C G A A C A U U C 5’ 3’ mRNA C C U Gly Met C A U Cys Lys Translation Elongation

  43. A U G G G A U G U A A G C G A A C A 5’ 3’ mRNA U C U Cys U C C Lys Gly Lengthening polypeptide (amino acid chain) Met Translation Elongation

  44. A U G G G A U G U A A G C G A A C A 5’ 3’ mRNA U C U U Cys G C C U C Lys Gly Arg Met Translation Elongation

  45. A U G G G A U G U A A G C G A A C A 5’ 3’ mRNA U C U U Cys G C C U C Lys Gly Arg Met Translation Elongation

  46. A U G G G A U G U A A G C G A Stop codon 5’ mRNA U A A G C U Cys A C A Arg U C U Lys Gly Met Translation Termination Release factor

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