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Human Genetics

Human Genetics. The Human Genome. Genome. The genome of an organism is the complete set of genes specifying how its phenotype will develop (under a certain set of environmental conditions).

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Human Genetics

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  1. Human Genetics The Human Genome

  2. Genome • The genome of an organism is the complete set of genes specifying how its phenotype will develop (under a certain set of environmental conditions). • Diploid organisms (like us) contain two genomes, one inherited from our mother, the other from our father. • The total DNA of an organism. • Nuclear genome refers to the total DNA in the nucleus, which is distinguished from organellar genomes of the mitochondria and chloroplast.

  3. Genome size variation

  4. Comparison of genome organization

  5. Eukaryotic Genomes are Variable in Size

  6. Why the big differences? • Do Marbled Lungfish differ from Pufferfish? • Are Lilies all that much different than Arabidopsis? • These differences exist because: • Genomes have duplicated (chromosome doubling) • Individual genes have duplicated. • DNA exists that has no coding function.

  7. Gene structure I. Gene definition II. Genome organization (eukaryotic) 1. Genes and their noncoding regulatory sequences 2. “Nonfunctional” DNA 3. Duplicated genes 4. Repetitive DNA III. Mobile DNA IV. Gene Regulation

  8. Some Terms • A duplicate of a gene may acquire mutations and emerge as a new gene. • Noncoding DNA: a sequence of DNA contained in eukaryotic genomes that does not encode any genetic information and often consists of repetitive sequences. • Expression: DNA transcribed into RNA and RNA turned into protein are expressed. The regulation of this process is called gene expression.

  9. Nomenclature on DNA quantity • bp = one base pair within a double-stranded DNA • kb = 1,000 base pairs of double-stranded DNA • mb = 1 million base pairs of double-stranded DNA • n = number of chromosomes in a haploid genome • 2n = number of chromosomes in a diploid genome

  10. Definition(s) of a Gene 1. A hereditary unit that is composed of a sequence of DNA and occupies a specific position or locus. 2. Broadly, any genetic determinant of a specific functional gene product. 3. Molecular definition: Entire nucleic acid sequence necessary for the synthesis of a functional polypeptide (protein chain) or functional RNA

  11. Genes and Their Products • The majority of genes are expressed as the proteins they encode. • The process occurs in two steps: • Transcription = DNA -> RNA • Translation = RNA -> protein • This is the “Central Dogma" of Biology: • DNA makes RNA makes protein.

  12. The Central Dogma of Molecular Biology • WHY? • The DNA can retain integrity • The RNA step allows amplification • Multiple steps allow multiple points of control Protein DNA Translation RNA Transcription

  13. Most Genes Encode Proteins • Original Concept of the Gene: • One gene = one enzyme • This concept does not hold for those proteins that consist of two or more different subunits. • Revised Concept: • One gene = one messenger RNA = one peptide.

  14. RNA Genes • Some RNAs (tRNA, rRNA, snRNA, mtRNA) don’t code for proteins that are translated. • However, these are still referred to as genes-they are specific functional gene products. • Other DNA sequences regulate the transcription of other genes and can act like genes in some ways.

  15. Genes are interspersed along DNA molecules, being separated by DNA sequence of unknown function (intergenic regions)

  16. Coding region Nucleotides (open reading frame) encoding the amino acid sequence of a protein The molecular definition of gene includes more than just the coding region.

  17. Noncoding regions • Regulatory regions • RNA polymerase binding site • Transcription factor binding sites • Introns • Polyadenylation [poly(A)] sites

  18. “Nonfunctional” DNA • Higher eukaryotes have a lot of noncoding DNA • Some has no known structural or regulatory function (no genes) 80 kb

  19. Duplicated genes • Encode closely related (homologous) proteins • Clustered together in genome • Formed by duplication of an ancestral gene followed by mutation Five functional genes and two pseudogenes

  20. Mobile DNA • Moves within genomes • Most of moderately repeated DNA sequences found throughout higher eukaryotic genomes • L1 LINE is ~5% of human DNA (~50,000 copies) • Alu is ~5% of human DNA (>500,000 copies) • Some encode enzymes that enable movement

  21. Transposition • Movement of mobile DNA • Involves copying of mobile DNA element and insertion into new site in genome

  22. Why? • Molecular parasite: “selfish DNA” • Probably have significant effect on evolution by facilitating gene duplication, which provides the fuel for evolution, and exon shuffling

  23. RNA or DNA intermediate • Transposon moves using DNA intermediate • Retrotransposon moves using RNA intermediate

  24. LTR (long terminal repeat) • Flank viral retrotransposons and retroviruses • Contain regulatory sequences Transcription start site and poly(A) site

  25. LINES and SINES • Nonviral retrotransposons • RNA intermediate • Lack LTR • LINES (long interspersed elements) • ~6000 to 7000 base pairs • L1 LINE (~5% of human DNA) • Encode enzymes that catalyze movement • SINES (short interspersed elements) • ~300 base pairs • Alu (~5% of human DNA)

  26. Human Disease and Mobile DNA • Movement (transposition) of LINES and SINES can cause mutations and genetic disease by insertion into essential genes • Hemophilia (blood clotting factor VIII gene) • Muscular dystrophy (DMD) • Colon cancer (APC)

  27. RNA Transcription • The process of releasing information contained in a DNA sequence, because DNA itself is used only for storage and transmission. • The sequence of bases in the DNA template is copied into an RNA sequence, which is either used directly or translated into a polypeptide.

  28. Noncoding DNA can be Part of Transcribed Genes • Regulatory regions (Promoters) • Introns • Poly A+ Addition sites • 5’ untranslated regions • 3’ untranslated regions.

  29. Basic Gene Structure -35 -10 Prokaryotes like E. coli GC CAAT TATA Humans and other Eukaryotes

  30. Bacterial Gene

  31. Human Genes • Most have introns • Produce monocistronic mRNA: only one encoded protein • Large ( 1000->1,000,000 base pairs)

  32. Gene Transcription and Regulation

  33. A Puzzle about Cells • Each Cell has a complete copy of all the DNA. And yet, cells are different. • This is the theoretical basis of organism cloning. • So cells are only using some of the DNA to make RNA to make proteins at any time. • How does the cell know which DNA to chose to transcribe? • External environment sends signals that are recognized, and transcription is turned on or off in response to the signals.

  34. Transcription • Transcription is the synthesis of RNA from a DNA template. • Main Types of RNA each have different roles in the cell: • mRNA= Messenger RNA • tRNA = Transfer RNA • rRNA = Ribosomal RNA • mtRNA = Mitochondrial RNA • snRNA = Small nuclear RNA

  35. rRNA and tRNA are Cogs in the Machinery • rRNA is a structural part of the ribosome • tRNA helps the protein machinery to read the mRNA • Neither of these types of RNAs actually carries any information

  36. Messenger RNA • Messenger RNA carries the information in the DNA to the protein translation machinery (ribosomes) • Serves as the template for protein synthesis • Which mRNAs are transcribed in a cell decide the fate of that cell since they dictate which information in the DNA is read by the protein translation machinery

  37. RNA molecules • Synthesized by RNA polymerases using DNA as a template. • Polymer of ribonucleotides, where each consists of a phosphate group (PO4), ribose sugar, and a base (adenine, guanine, cytosine, or uracil). • Following synthesis of an RNA strand, it remains single-stranded.

  38. Gene Regulation can occur at any of these steps • Initiation- highly regulated step • Elongation- the rate at which the mRNA is made can control how quickly its made • Termination- premature termination can mean that the whole mRNA never gets made and neither does what it codes for: • Like receiving only part of the instructions on how to put together your “easy to assemble” bookcase/desk/whatever

  39. Steps of RNA Transcription • Initiation • Elongation • Termination • All RNA transcription is performed by enzymes called RNA polymerases. • RNA transcription starts at a Promoter sequence (analogous to ORI for DNA replication).

  40. Transcription of mRNA in Humans • Steps involved are the same as in prokaryotes: • Initiation • Elongation • Termination • Mediated by RNA polymerase II: • Very complex enzyme with many subunits

  41. Protein Human Transcription • Has to be more control of how more complex genetic material is read to create more variety (multicellular) • RNA has to be transcribed in the nucleus and then transported to the protein translation machinery in the cytoplasm before it can be read. DNA Nucleus

  42. Human genes • Most have introns • Produce monocistronic mRNA: only one encoded protein • Large genes

  43. Initiation • Initiation occurs at promoters as in prokaryotes- eukaryotic promoters are not well-characterized but have some well conserved elements- including the TATA box and CAAT box (both have A=T pairs) • In addition to the promoters there are region in the DNA called enhancersto which transcription factors bind and regulate which DNA is read and encoded in mRNA

  44. TF TF TF Enhancer Promoter Gene TF mRNA TF TF Enhancer Promoter Gene TF TF= Transcription Factor Transcription Factor Function Pol

  45. Transcription Factors • Although transcription is performed by RNA Polymerase, it needs other proteins to produce the transcript. • These proteins are either associated directly with RNA Polymerase or help it bind to the DNA sequences upstream of the initiation of translation.. • These associated proteins are called transcription factors.

  46. RNA transcription begins by the assembly of the RNA polymerase on a promoter region.

  47. Orientation of promoter elements specifies the direction of transcription -35 -10 prokaryote GC CAAT TATA eukaryote

  48. Transfer of Information Gene mRNA exon | intron | exon | intron | exon Exon - portion of the gene that contains DNA sequences that will be translated into protein. Intron - portion of the gene that will be cut out before translation

  49. Transfer of Information

  50. Translating Protein Reading the Genes in the Genome Signal recognizing Transcribing Processing mRNA AAA

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