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Genomes

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Title: Genomes


1
Genomes
2
Figure 17.7 Synthetic Cells
3
17 Genomes
  • 17.1 How Are Genomes Sequenced?
  • 17.2 What Have We Learned from Sequencing
    Prokaryotic Genomes?
  • 17.3 What Have We Learned from Sequencing
    Eukaryotic Genomes?
  • 17.4 What Are the Characteristics of the Human
    Genome?
  • 17.5 What Do the New Disciplines of Proteomics
    and Metabolomics Reveal?

4
17 Genomes
No other mammal shows as much phenotypic
variation as dogs. The Dog Genome Project
sequences entire genomes of different breeds and
identifies genes that control specific traits,
such as size.
Opening Question What does dog genome
sequencing reveal about other animals?
5
17.1 How Are Genomes Sequenced?
  • Genome sequencing determine the nucleotide base
    sequence of an entire genome.
  • The information is used to
  • Compare genomes of different species to trace
    evolutionary relationships
  • Compare individuals of the same species to
    identify mutations that affect phenotypes

6
17.1 How Are Genomes Sequenced?
  • Identify genes for particular traits, such as
    genes associated with diseases
  • The Human Genome Project was proposed in 1986 to
    determine the normal sequence of all human DNA.
  • Methods used were first developed to sequence
    prokaryotes and simple eukaryotes.

7
17.1 How Are Genomes Sequenced?
  • To sequence an entire genome, the DNA is first
    cut into millions of small, overlapping
    fragments.
  • Then many sequencing reactions are performed
    simultaneously.

8
17.1 How Are Genomes Sequenced?
  • High-throughput sequencing uses miniaturization
    techniques, principles of DNA replication, and
    polymerase chain reaction (PCR).
  • It is fully automated, rapid, and inexpensive.

9
Figure 17.1 DNA Sequencing
10
17.1 How Are Genomes Sequenced?
  1. DNA is cut into small fragments physically or
    using enzymes.
  2. The fragments are denatured using heat,
    separating the strands.
  3. Short, synthetic oligonucleotides are attached to
    each end of each fragment, and these are attached
    to a solid support.

11
17.1 How Are Genomes Sequenced?
  • Fragments are amplified by PCR.
  • Sequencing
  • Universal primers, DNA polymerase, and the 4
    nucleotides (dNTPs, tagged with fluorescent dyes)
    are added.
  • One nucleotide is added to the new DNA strand in
    each cycle, and the unincorporated dNTPs are
    removed.

12
17.1 How Are Genomes Sequenced?
  1. Fluorescence color of the new nucleotide at each
    location is detected with a camera.
  2. Fluorescent tag is removed and the cycle repeats.

13
17.1 How Are Genomes Sequenced?
  • Then the sequences must be put together.
  • The DNA sequence fragments, called reads, are
    overlapping, so they can be aligned.

14
17.1 How Are Genomes Sequenced?
  • Example Using a 10 bp fragment, cut three
    different ways
  • TG, ATG, and CCTAC
  • AT, GCC, and TACTG
  • CTG, CTA, and ATGC
  • The correct order is ATGCCTACTG.

15
Figure 17.2 Arranging DNA Fragments
16
17.1 How Are Genomes Sequenced?
  • The field of bioinformatics was developed to
    analyze DNA sequences using complex mathematics
    and computer programs.

17
Figure 17.3 The Genomic Book of Life
18
17.1 How Are Genomes Sequenced?
  • Genome sequence information is used in two
    research fields
  • Functional genomicssequence information is used
    to identify functions of various parts of
    genomes
  • Open reading framesgene coding regions

19
17.1 How Are Genomes Sequenced?
  • Amino acid sequences, deduced from sequences of
    open reading frames
  • Regulatory sequences, such as promoters and
    terminators.
  • RNA genes
  • Other noncoding sequences

20
17.1 How Are Genomes Sequenced?
  • Comparative genomics comparison of a newly
    sequenced genome with sequences from other
    organisms.
  • This provides more information about functions of
    sequences and can be used to trace evolutionary
    relationships.

21
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • The first life forms to be sequenced were the
    simplest viruses with small genomes.
  • The first complete genome sequence of a
    free-living cellular organism was for the
    bacterium Haemophilus influenzae in 1995.

22
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Bacterial and archaeal genomes are
  • Small, and usually organized into a single
    chromosome
  • Compact85 is coding sequences
  • Usually do not have introns
  • Have plasmids, which may be transferred between
    cells

23
Table 17.1
24
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Functional genomics
  • H. influenzae chromosome has 1,727 open reading
    frames.
  • When it was first sequenced, only 58 coded for
    proteins with known functions.
  • Since then, the roles of many other proteins have
    been identified.

25
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Highly infective strains of H. influenzae have
    genes for surface proteins that attach the
    bacterium to the human respiratory tract.
  • These surface proteins are now a focus of
    research on treatments for H. influenzae
    infections.

26
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Comparative genomics
  • M. genitalium lacks enzymes to synthesize amino
    acids, so it must obtain them from the
    environment.
  • E. coli has 55 genes that encode transcriptional
    activators, whereas M. genitalium has only 7a
    relative lack of control over gene expression.

27
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Genome sequencing provides insights into
    microorganisms that are important in agriculture
    and medicine.
  • Surprising relationships between organisms
    suggests that genes may be transferred between
    different species.

28
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Rhizobium bacteria form symbiotic relationships
    with plants. The bacteria fix N into forms
    useable by plants.
  • Sequencing has identified genes involved in
    successful symbiosis, and may broaden the range
    of plants that can form these relationships.

29
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • E. coli strain O157H7 causes illness in humans.
  • 1,387 genes are different from those in the
    harmless strains of this bacterium, but are also
    present in other pathogenic bacteria, such as
    Salmonella.
  • This suggests genetic exchange among species.

30
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Severe acute respiratory syndrome (SARS) was
    first detected in southern China in 2002 and
    rapidly spread in 2003.
  • Isolation and sequencing of the virus revealed
    novel proteins that are possible targets for
    antiviral drugs or vaccines.

31
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Genome sequencing of organisms involved in global
    ecological cycles
  • Some bacteria produce methane, a greenhouse gas,
    in cow stomachs.
  • Others remove methane from the air.
  • Understanding the genes involved in methane
    production and consumption may help us slow the
    progress of global warming.

32
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Traditionally, microorganisms have been
    identified by culturing them in the laboratory.
  • Now, PCR and DNA analysis allow microbes to be
    studied without culturing.

33
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • DNA can also be analyzed directly from
    environmental samples.
  • Metagenomicsgenetic diversity is explored
    without isolating intact microorganisms.
  • Sequencing is used to detect presence of known
    microbes and previously unidentified organisms.

34
Figure 17.4 Metagenomics
35
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • It is estimated that 90 of the microbial world
    has been invisible to biologists and is only
    now being revealed by metagenomics.
  • The increased knowledge of the microbial world
    will improve our understanding of ecological
    processes and better ways to manage environmental
    problems.

36
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Transposable elements (transposons) are DNA
    segments that can move from place to place in the
    genome or to a plasmid.
  • If a transposable element is inserted into the
    middle of a gene, it will be transcribed, and
    result in abnormal proteins.

37
Figure 17.5 DNA Sequences That Move (A)
38
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Composite transposons transposable elements
    located near one another will transpose together
    and carry the intervening DNA sequence with them.
  • Genes for antibiotic resistance can be multiplied
    and transferred between bacteria in this way, via
    plasmids.

39
Figure 17.5 DNA Sequences That Move (B)
40
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Certain genes are present in all organisms
    (universal genes) and some universal gene
    segments are present in many organisms.
  • This suggests that a minimal set of DNA sequences
    is common to all cells.

41
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • Efforts to define a minimal genome involve
    computer analysis of genomes, the study of the
    smallest known genome (M. genitalium), and using
    transposons as mutagens.
  • Transposons can insert into genes at random the
    mutated bacteria are tested for growth and
    survival, and DNA is sequenced.

42
Figure 17.6 Using Transposon Mutagenesis to
Determine the Minimal Genome
43
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • M. genitalium can survive in the laboratory with
    only 382 functional genes.
  • One goal of the research is to design new life
    forms for specific purposes, such as cleaning up
    oil spills.

44
17.2 What Have We Learned from Sequencing
Prokaryotic Genomes?
  • An artificial genome has been created and
    inserted into bacterial cells.
  • The entire genome of Mycoplasma mycoides was
    synthesized, then transplanted into empty cells
    of Mycoplasma capricolum.
  • The new cells genome had extra sequences, so it
    was a new organism Mycoplasma mycoides
    JCV1-syn.1.0.

45
Figure 17.7 Synthetic Cells
46
Working with Data 17.1 Using Transposon
Mutagenesis to Determine the Minimal Genome
  • In the experiment to create a synthetic genome
    and determine the minimum set of genes necessary
    for survival, transposon mutagenesis was used
    with Mycoplasma genitalium, which had the
    smallest known genome.

47
Working with Data 17.1 Using Transposon
Mutagenesis to Determine the Minimal Genome
  • Growth of M. genitalium strains with gene
    insertions (intragenic) was compared with strains
    with insertions in noncoding regions (intergenic).

48
Working with Data 17.1 Using Transposon
Mutagenesis to Determine the Minimal Genome
  • Question 1
  • Explain these data in terms of genes essential
    for growth and survival.
  • Are all of the genes in M. genitalium essential
    for growth?
  • If not, how many are essential?
  • Why did some of the insertions in intergenic
    regions prevent growth?

49
Working with Data 17.1 Using Transposon
Mutagenesis to Determine the Minimal Genome
  • Question 2
  • If a transposon inserts into the following
    regions of a gene, there might be no effect on
    the phenotype.
  • Explain in each case
  • a. near the 3' end of a coding region
  • b. within a gene coding for rRNA
  • How does this affect your answer to Question 1?

50
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • There are major differences between eukaryotic
    and prokaryotic genomes
  • Eukaryotic genomes are larger and have more
    protein-coding genes.
  • Eukaryotic genomes have more regulatory
    sequences. Greater complexity requires more
    regulation.

51
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • Much of eukaryotic DNA is noncoding, including
    introns, gene control sequences, and repeated
    sequences.
  • Eukaryotes have multiple chromosomes each must
    have an origin of replication, a centromere, and
    a telomeric sequence at each end.

52
Table 17.2
53
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • Several model organisms have been studied
    extensively.
  • Model organisms are easy to grow and study in a
    laboratory, their genetics are well studied, and
    they have characteristics that represent a larger
    group of organisms.

54
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • The yeast, Saccharomyces cerevisiae
  • Yeasts are single-celled eukaryotes.
  • Yeasts and E. coli appear to use about the same
    number of genes to perform basic functions.
  • Compartmentalization of the eukaryotic yeast cell
    requires it to have many more genes.

55
Table 17.3
56
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • The nematode, Caenorhabditis elegans
  • A millimeter-long soil roundworm.
  • The transparent body is made up of about 1,000
    cells, yet has complex organ systems.
  • It has about 3.3 times as many protein-coding
    genes as do yeasts.

57
Table 17.4
58
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • The fruit fly, Drosophila melanogaster
  • Studies of fruit flies led to formulation of many
    basic principles of genetics. More than 2,500
    mutations have been described.
  • It has 10 times more cells and a larger genome
    than C. elegans, but fewer coding genes.

59
Figure 17.8 Functions of the Eukaryotic Genome
60
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • The thale cress, Arabidopsis thaliana
  • A small plant with a small genome.
  • Many of the genes found in animals have homologs
    in plants, suggesting a common ancestor.
  • But many genes are also unique to plants.

61
Table 17.5
62
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • Rice (Oryza sativa) and a poplar tree (Populus
    trichocarpa) have also been sequenced.
  • Comparison of the genomes shows many genes in
    common, comprising the basic minimal plant genome.

63
Figure 17.9 Plant Genomes
64
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • Eukaryotes have closely related genes called gene
    families.
  • These arose over evolutionary time when different
    copies of genes underwent separate mutations.
  • Example Genes encoding the globin proteins all
    arose from a single common ancestral gene.

65
Figure 17.10 The Globin Gene Family
66
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • During development, different members of the
    globin gene family are expressed at different
    times in different tissues.
  • Example Hemoglobin of the human fetus contains
    ?-globin, which binds O2 more tightly than adult
    hemoglobin.

67
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • Many gene families include nonfunctional
    pseudogenes (?), resulting from mutations that
    cause a loss of function.
  • A pseudogene may simply lack a promoter, and thus
    fail to be transcribed, or a recognition site
    needed for the removal of an intron.

68
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • Eukaryotic genomes have repetitive DNA sequences
  • Highly repetitive sequencesshort sequences (lt
    100 bp) repeated thousands of times in tandem
    not transcribed.
  • Short tandem repeats (STRs) of 15 bp can be used
    in DNA fingerprinting.

69
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • Moderately repetitive sequences are repeated
    101,000 times.
  • Includes genes for tRNAs and rRNAs
  • Single copies of the tRNA and rRNA genes would
    be inadequate to supply the large amounts of
    these molecules needed by cells.

70
Figure 17.11 A Moderately Repetitive Sequence
Codes for rRNA (Part 1)
71
Figure 17.11 A Moderately Repetitive Sequence
Codes for rRNA (Part 2)
72
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • Transposons (transposable elements) are
    moderately repetitive sequences.
  • Three types are retrotransposons
  • SINEs (short interspersed elements)
  • LINEs (long interspersed elements)
  • LTRs (long terminal repeats)

73
Table 17.6
74
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • Retrotransposons are transcribed into RNA, which
    is a template for new DNA. The new DNA becomes
    inserted at a new location, resulting in two
    copies of the transposon.
  • DNA transposons are excised from the original
    location and become inserted at a new location
    without being replicated.

75
17.3 What Have We Learned from Sequencing
Eukaryotic Genomes?
  • Insertion of a transposon at a new location can
    have important consequences, such as mutations
    and gene duplications.
  • They can result in shuffling the genetic material
    and creating new genes.
  • Transposons may have played a role in
    endosymbiosis.

76
17.4 What Are the Characteristics of the Human
Genome?
  • Sequencing of the human genome revealed many
    interesting facts
  • Protein-coding regions make up about 1.2, or
    21,000 genes.
  • The average gene must code for several different
    proteins, and posttranscriptional mechanisms
    result in different proteins.

77
17.4 What Are the Characteristics of the Human
Genome?
  • An average gene has 27,000 base pairs.
  • All human genes have many introns.
  • About half of the genome is transposons and other
    repetitive sequences.

78
17.4 What Are the Characteristics of the Human
Genome?
  • 99.5 of the genome is the same in all people.
  • Variation among individuals is due to single
    nucleotide polymorphisms (SNPs), and differences
    in sequence copy number from chromosomal
    deletions, duplications, or translocations.

79
17.4 What Are the Characteristics of the Human
Genome?
  • Genes are not evenly distributed over the genome.
  • The Y chromosome has the fewest genes (231)
    chromosome 1 has the most (2,968).

80
17.4 What Are the Characteristics of the Human
Genome?
  • Comparisons of prokaryote and eukaryote genomes
    have revealed evolutionary relationships between
    genes.

81
Figure 17.12 Evolution of the Genome
82
17.4 What Are the Characteristics of the Human
Genome?
  • The genomes of many primates have been sequenced,
    and biologists are interested in which genes make
    humans unique.
  • Chimpanzees are our closest living relative they
    share almost 99 of our DNA sequences.

83
17.4 What Are the Characteristics of the Human
Genome?
  • DNA from the bones of Neanderthals, who lived in
    Europe up to 50,000 years ago, has also been
    sequenced.
  • It is 99 identical to human DNA, justifying
    classification of Neanderthals as part of the
    same genus, Homo.

84
17.4 What Are the Characteristics of the Human
Genome?
  • Comparisons of human and Neanderthal genes
  • A mutation in MC1R in Neanderthals causes lower
    activity of MC1R, known to result in fair skin
    and red hair.
  • FOXP2, involved in vocalization, is identical in
    humans and Neanderthals, suggesting that
    Neanderthals were capable of speech.

85
Figure 17.13 A Neanderthal Child
86
17.4 What Are the Characteristics of the Human
Genome?
  • There are some distinctive human DNA sequences
    and also distinctive Neanderthal sequences.
  • There is some mixture of the two, indicating
    that humans and Neanderthals interbred.

87
17.4 What Are the Characteristics of the Human
Genome?
  • Rapid genotyping technologies are being used to
    understand the genetic basis of diseases such as
    diabetes, heart disease, and Alzheimers disease.
  • Haplotype maps are used to identify SNPs that
    are linked to genes involved in disease.

88
17.4 What Are the Characteristics of the Human
Genome?
  • A haplotype is a piece of chromosome with a set
    of SNPs that are usually inherited as a unit.
  • By comparing the haplotypes of individuals with
    and without a particular genetic disease, the
    loci associated with the disease can be
    identified.

89
Figure 17.14 SNP Genotyping and Disease
90
17.4 What Are the Characteristics of the Human
Genome?
  • New technologies analyze thousands or millions of
    SNPs to determine which ones are associated with
    specific diseases.
  • As the cost of sequencing entire genomes
    decreases, SNP testing may be superseded.

91
Table 17.7
92
17.4 What Are the Characteristics of the Human
Genome?
  • Pharmacogenomics is the study of how an
    individuals genome affects response to drugs or
    other outside agents.
  • SNPs that are associated with specific drug
    responses can be identified to personalize drug
    treatments and determine if a patient will
    respond to a drug.

93
Figure 17.15 Pharmacogenomics
94
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • Many genes encode more than one protein.
  • Alternative splicing and posttranslational
    modifications increase the number of proteins
    that can be derived from one gene.
  • But many proteins are produced only by certain
    cells under specific conditions.

95
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • Proteome sum total of proteins produced by an
    organism it is more complex than the genome.
  • Proteomics seeks to identify and characterize all
    the expressed proteins in an organism.

96
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • Two techniques are used to analyze the proteome
  • Two-dimensional gel electrophoresis separates
    proteins based on size and electric charges.
  • Mass spectrometry identifies proteins by their
    atomic masses.

97
Figure 17.16 Proteomics
98
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • Comparisons of eukaryotic proteomes has revealed
    a common set of about 1,300 proteins that provide
    the basic metabolic functions.

99
Figure 17.17 Proteins of the Eukaryotic Proteome
100
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • Proteins have different functional regions or
    domains.
  • Proteins that are unique to a particular organism
    are often just unique combinations of domains
    that exist in other organisms.
  • This reshuffling of the genetic deck is a key to
    evolution.

101
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • Gene and protein function are both affected by
    the internal and external environments of the
    cell.
  • Enzyme activities affect concentrations of their
    substrates and products, called metabolites.
  • As the proteome changes, so will the abundances
    of metabolites.

102
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • Metabolome quantitative description of all of
    the small molecules in a cell or organism.
  • Primary metabolitesinvolved in normal processes
    such as pathways like glycolysis. Also includes
    hormones and other signaling molecules.

103
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • Secondary metabolitesoften unique to particular
    organisms or groups.
  • Examples include antibiotics made by microbes and
    chemicals made by plants for defense.

104
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • Measuring metabolites involves gas chromatography
    and high-performance liquid chromatography, which
    separate molecules.
  • Mass spectrometry and nuclear magnetic resonance
    spectroscopy are used to identify them.

105
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • A human metabolome database has been established
    and contains 6,500 metabolites.
  • The challenge now is to relate levels of these
    substances to physiology.

106
17.5 What Do the New Disciplines Proteomics and
Metabolomics Reveal?
  • Plant metabolomics has been studied for many
    years.
  • Tens of thousands of secondary metabolites have
    been identified.
  • The metabolome of the model organism Arabidopsis
    thaliana is now being described.

107
17 Answer to Opening Question
  • Myostatin is a protein that inhibits muscle
    growth.
  • In dog breeds with highly developed leg muscles,
    the gene for myostatin has a mutation that makes
    the protein inactive.
  • In humans it may be possible to manipulate
    myostatin to treat muscle-wasting diseases such
    as muscular dystrophy.
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