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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). 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. Genome size variation Comparison of genome organization Organism Genome Size (n) 3,000,000,000 # of Genes 35,000 Chromosomes (n) 23 linear D. melanogaster C. elegans 140,000,000 13,600 4 linear 97,000,000 19,000 6 linear A. thaliana 125,000,000 25,500 5 linear 13,000,000 5,800 16 linear 4,700,000 4,000 1 circular 17,000 37 1 circular Human S. cerevisiae E. coli Human mtDNA Eukaryotic Genomes are Variable in Size Marbled lungfish 139,000,000,000 Salamander 50,000,000,000 Homo sapiens 3,000,000,000 Pufferfish 400,000,000 Fruit Fly 165,000,000 Arabidopsis 100,000,000 Baker’s yeast 12,067,280 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. 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 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. 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 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 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. 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 Transcription RNA Translation 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. 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. Genes are interspersed along DNA molecules, being separated by DNA sequence of unknown function (intergenic regions) 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. Noncoding regions Regulatory regions RNA polymerase binding site Transcription factor binding sites Introns Polyadenylation [poly(A)] sites “Nonfunctional” DNA 80 kb Higher eukaryotes have a lot of noncoding DNA Some has no known structural or regulatory function (no genes) 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 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 Transposition Movement of mobile DNA Involves copying of mobile DNA element and insertion into new site in genome Why? Molecular parasite: “selfish DNA” Probably have significant effect on evolution by facilitating gene duplication, which provides the fuel for evolution, and exon shuffling RNA or DNA intermediate Transposon moves using DNA intermediate Retrotransposon moves using RNA intermediate LTR (long terminal repeat) Flank viral retrotransposons and retroviruses Contain regulatory sequences Transcription start site and poly(A) site 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) 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) 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. Noncoding DNA can be Part of Transcribed Genes Regulatory regions (Promoters) Introns Poly A+ Addition sites 5’ untranslated regions 3’ untranslated regions. Basic Gene Structure -35 -10 Prokaryotes like E. coli GC CAAT TATA Humans and other Eukaryotes Bacterial Gene Human Genes Most have introns Produce monocistronic mRNA: only one encoded protein Large ( 1000->1,000,000 base pairs) Gene Transcription and Regulation 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. 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 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 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 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. 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 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). 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 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. Protein DNA Nucleus Human genes Most have introns Produce monocistronic mRNA: only one encoded protein Large genes 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 enhancers to which transcription factors bind and regulate which DNA is read and encoded in mRNA Transcription Factor Function TF TF TF TF Enhancer TF TF TF Enhancer Pol Promoter Gene mRNA Promoter Gene TF= Transcription Factor 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. RNA transcription begins by the assembly of the RNA polymerase on a promoter region. Orientation of promoter elements specifies the direction of transcription -35 -10 prokaryote GC CAAT TATA eukaryote 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 Transfer of Information Reading the Genes in the Genome Signal recognizing Transcribing Processing AAA mRNA Translating Protein