Genomes Chapter 21 Genomes Sequencing of DNA Human
- Slides: 49
Genomes Chapter 21
Genomes • • • Sequencing of DNA Human Genome Project 1990 -2003 6 countries 20 research centers
Human Genome Project • 3 stages • Linkage (or genetic) mapping • Physical mapping • DNA sequencing
Linkage map • Location of genetic markers • Based on recombination frequencies
Fig. 21 -2 -2 Chromosome bands Cytogenetic map Genes located by FISH 1 Linkage mapping Genetic markers
Physical map • • • Distance between genetic markers Based on physical measure Number of base pairs along DNA Cut a DNA molecule into fragments Arranged in order by overlap areas
Fig. 21 -2 -4 Chromosome bands Cytogenetic map Genes located by FISH 1 Linkage mapping Genetic markers 2 Physical mapping Overlapping fragments 3 DNA sequencing
Genome • • J. Craig Venter in 1992 Whole-genome shotgun approach Skips linkage & physical mapping Sequences random DNA fragments directly
Fig. 21 -3 -3 1 Cut the DNA into overlapping fragments short enough for sequencing 2 Clone the fragments in plasmid or phage vectors. 3 Sequence each fragment. 4 Order the sequences into one overall sequence with computer software.
Genomes • • Complete genome sequences Human, chimpanzee, E. coli, brewer’s yeast Nematode, fruit fly, house mouse,
Genomes • Comparison • Evolutionary history of genes • Taxonomic groups
Fig. 21 -1
Genomes • Genomics: • Study of whole sets of genes & their interactions • Bioinformatics: • Application of computers • Storage & Analysis of biological data
Genome • • Phenotype to genotype Red eye fruit flies (w+w or w+w+) Computer analysis of genome Identifies sequences likely to encode proteins • Genotype to phenotype
Genomes
Genome • • • NCBI Genbank BLAST Compare DNA Sequences Compare predicted protein sequences Domains (known aa sequences)
Fig. 21 -4
tatggagaga ataaaagaac tgagagatct aatgtcgcag tcccgcactc gcgagatact 61 cactaagacc actgtggacc atatggccat aatcaaaaag tacacatcag gaaggcaaga 121 gaagaacccc gcactcagaa tgaagtggat gatggcaatg agatacccaa ttacagcaga 181 caagagaata atggacatga ttccagagag gaatgaacaa gggcaaaccc tctggagcaa 241 aacaaacgat gctggatcag accgagtgat ggtatcacct ctggccgtaa catggtggaa 301 taggaatggc ccaacaacaa gtacagttca ttaccctaag gtatataaaa cttatttcga 361 aaaggtcgaa aggttgaaat atggtacctt cggccctgtc cacttcagaa atcaagttaa 421 aataaggagg agagttgata caaaccctgg ccatgcagat ctcagtgcca aggaggcaca 481 ggatgtgatt atggaagttg ttttcccaaa tgaagtgggg gcaagaatac tgacatcaga 541 gtcacagctg gcaataacaa aagagaagaagagctc caggattgta aaattgctcc 601 cttgatggtg gcgtacatgc tagaaagaga attggtccgt aaaacaaggt ttctcccagt 661 agccggcgga acaggcagtg tttatattga agtgttgcac ttaacccaag ggacgtgctg 721 ggagcagatg tacactccag gaggagaagt gagaaatgat gatgttgacc aaagtttgat 781 tatcgctgct agaaacatag taagaagagc agcagtgtca gcagacccat tagcatctct 841 cttggaaatg tgccacagca cacagattgg aggagtaagg atggtggaca tccttagaca 901 gaatccaact gaggaacaag ccgtagacat atgcaaggca gcaatagggt tgaggattag 961 ctcatctttc agttttggtg ggttcacttt caaaaggaca agcggatcat cagtcaagaa
Genome • Proteomics: • Systematic study of all proteins encoded by a genome • Proteins carry out most of the cell’s activities
Application • Finding DNA sequence of organisms • Predict structure & function of new proteins & RNA sequences • Families of related proteins • Phylogenic trees evolutionary relationships
Application • The Cancer Genome Atlas project • Monitors 2, 000 genes in cancer cells for changes • Mutations & rearrangements • Lung, ovarian and glioblastoma • Compare to normal cells
Application • DNA sequencing • Highlight diseases • Specialize tx
Genome size • Bacteria range from 1 to 6 million base pairs (Mb) • Eukaryotes usually larger • Humans have 3, 200 Mb
Table 21 -1
Fig. 21 -UN 1 Bacteria Archaea Genome size Most are 1– 6 Mb Number of genes 1, 500– 7, 500 Gene density Introns Other noncoding DNA Higher than in eukaryotes None in Present in protein-coding some genes Very little Eukarya Most are 10– 4, 000 Mb, but a few are much larger 5, 000– 40, 000 Lower than in prokaryotes (Within eukaryotes, lower density is correlated with larger genomes. ) Unicellular eukaryotes: present, but prevalent only in some species Multicellular eukaryotes: present in most genes Can be large amounts; generally more repetitive noncoding DNA in multicellular eukaryotes
Genome • • • Gene density: Number of genes in a given length of DNA Humans & other mammals-lowest Multicellular eukaryotes have many introns “Junk DNA”
Genome • Genomes of humans, rats, & mice • 500 noncoding regions-are the same • 98. 5% of the genome does not code for proteins, r. RNAs, or t. RNAs • 24% regulatory sequences & introns
Fig. 21 -7 Exons (regions of genes coding for protein or giving rise to r. RNA or t. RNA) (1. 5%) Repetitive DNA that includes transposable elements and related sequences (44%) L 1 sequences (17%) Introns and regulatory sequences (24%) Unique noncoding DNA (15%) Repetitive DNA unrelated to transposable elements (15%) Alu elements (10%) Simple sequence Large-segment DNA (3%) duplications (5– 6%)
Genome • • Pseudogene: Former genes, mutated Repetitive genes: Sequences in multiple copies
Genome • Transposable elements: • DNA that move from one site to another • Prokaryotes & eukaryotes • Barbara Mc. Clintock
Fig. 21 -8
Genome • Eukaryotic transposable elements • 1. Transposons: • • Move within a genome DNA intermediate 2. Retrotransposons: Move - RNA intermediate
Fig. 21 -9 a Transposon DNA of genome Transposon is copied New copy of transposon Insertion Mobile transposon (a) Transposon movement (“copy-and-paste” mechanism)
Fig. 21 -9 b Retrotransposon New copy of retrotransposon RNA Insertion Reverse transcriptase (b) Retrotransposon movement
Genome • • • Alu elements 10% of genome Transposable elements 300 nucleotides Do not code for protein Code for RNA
Genome • • Line-1 or L 1 17% genome Retrotransposons 6500 nucleotides Low transposition Regulate gene expression Developing neurons
Genome • • • Repetitive DNA not transposons 15% 1. Long sequences of DNA 2. Simple sequence DNA Many copies of repeated short sequences • GTTACGTTACGTTAC
Genome • Short tandem repeat (STR) • Repeating units of 2 to 5 nucleotides • Vary among individuals • Centromeres • Telomeres
Genome • Multigene families: • Collections of identical or very similar genes on a haploid set of chromosomes • Example: • Code for r. RNA products • Single transcript makes all r. RNA molecules • Transcript sequence repeated many times
Fig. 21 -10 a DNA RNA transcripts Nontranscribed spacer Transcription unit DNA 18 S 5. 8 S 28 S r. RNA 28 S 5. 8 S 18 S (a) Part of the ribosomal RNA gene family
Genome • • • Nonidentical genes Hemoglobin Chromosome 16 -α globulin Chromosome 11 -ß globulin Code separately Animal development
Fig. 21 -10 b -Globin Heme Hemoglobin -Globin gene family Chromosome 16 Embryo 2 1 Fetus and adult Chromosome 11 Embryo G A Fetus (b) The human -globin and -globin gene families Adult
Evolution • • Human & chimpanzee genomes differ by 1. 2% More Alu elements in humans Several genes are evolving faster in humans Genes involved in defense against malaria and tuberculosis • Gene that regulations brain size • Genes that code for transcription factors
Fig. 21 -15 Bacteria Most recent common ancestor of all living things Eukarya Archaea 4 3 2 Billions of years ago 1 0 Chimpanzee Human Mouse 70 60 50 40 30 Millions of years ago 20 10 0
Evolution • FOXP 2 gene • Vocalization • Mutation causes speech impairment • 2 aa difference chimps and humans
Evolution • Humans 23 pairs of chromosomes • Chimpanzees 24 pairs • Humans & chimpanzees diverged from a common ancestor • 2 ancestral chromosomes fused in humans • Duplications & inversions result from mistakes during meiotic recombination
Evolution • Evo-devo • Evolutionary developmental biology • Developmental processes in multicellular organisms • Genomic information shows minor differences in gene sequence or regulation • Results in major differences in form
Evolution • • • Homeotic genes Body segments (fruit fly) 180 -nucleotide sequence Homeobox Related homeobox sequences have been found in regulatory genes of yeasts, plants, and even eukaryotes
Fig. 21 -17 Adult fruit fly Fruit fly embryo (10 hours) Fly chromosome Mouse chromosomes Mouse embryo (12 days) Adult mouse
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