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Title: Genome and proteom


1
Genome and proteom
2
  • 3 broad areas
  • Genomes, transcriptomes, proteomes
  • Applications of the human genome project
  • (C) Genome evolution

3
A) Genomes, transcriptomes, proteomes
  • Genome projects
  • - Human Genome Project (HGP) a history
  • - Other genome projects why do it
  • - Genome organisation
  • insights from HGP
  • Repeat elements
  • Transposable elements
  • Mitochondrial genomes
  • Y chromosome
  • Post-genomics
  • -transcriptomes
  • - proteomes

4
(A) Genomes, transcriptomes and proteomes
genome
Entire DNA complement of any organism which
include organelle DNA
transcriptome
All RNA transcribed from genome of a cell or
tissue
proteome
all proteins expressed by a genome, cell or tissue
5
Why study the genome?
  • 3 main reasons
  • description of sequence of every gene valuable.
    Includes regulatory regions which help in
    understanding not only the molecular activities
    of the cell but also ways in which they are
    controlled.
  • identify characterise important inheritable
    disease genes or bacterial genes (for industrial
    use)
  • Role of intergenic sequences e.g. satellites,
    intronic regions etc

6
HGP
  • Goal Obtain the entire DNA sequence of human
    genome
  • Players
  • International Human Genome Sequence Consortium
    (IHGSC)
  • - public funding, free access to all, started
    earlier
  • - used mapping overlapping clones method
  • (B) Celera Genomics
  • private funding, pay to view
  • - started in 1998
  • - used whole genome shotgun strategy

7
Whose genome is it anyway?
  • International Human Genome Sequence Consortium
    (IHGSC)
  • - composite from several different people
    generated from 10-20 primary samples taken from
    numerous anonymous donors across racial and
    ethnic groups
  • (B) Celera Genomics
  • 5 different donors (one of whom was J Craig
    Venter himself !!!)

8
Strategies for sequencing the human genome
9
Figure 12.2 Arranging DNA Sequences
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Strategies for sequencing the human genome
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Whole-genome shotgun sequencing
Private company Celera used to sequence whole
human genome
  • Whole genome randomly sheared three times
  • Plasmid library constructed with 2kb inserts
  • Plasmid library with 10 kb inserts
  • BAC library with 200 kb inserts
  • Computer program assembles sequences into
    chromosomes
  • No physical map construction
  • Only one BAC library
  • Overcomes problems of repeat sequences
  • Whole genome randomly sheared three times
  • Plasmid library constructed with 2kb inserts
  • Plasmid library with 10 kb inserts
  • BAC library with 200 kb inserts
  • Computer program assembles sequences into
    chromosomes
  • No physical map construction
  • Only one BAC library
  • Overcomes problems of repeat sequences

Fig. 10.13 Genetics by Hartwell
Fig. 10.13
12
sequencing larger genomes
Mapping phase
Genomes - Dr. MV Hejmad
Sequencing phase
http//www.DNAi.org
13
Other genomes sequenced
1997 4,200 genes
2002 36,000 genes
1998 19,099 genes
Sept 2003 18,473 human orthologs
2002 38,000 genes
Science (26 Sep 2003)Vol301(5641)pp1854-1855
14
Genomics World's smallest genome
  • the smallest genome known is the DNA of a
    'nucleomorph' of Bigelowiella natans, a
    single-celled algae of the group known as
    chlorarachniophytes.
  • 373,000 base pairs and a mere 331 genes
  • The nucleomorph is an evolutionary vestige that
    was originally the nucleus of a eukaryotic cell.
    The eukaryotic cell swallowed a cyanobacterium to
    acquire a photosynthetic 'plastid' organelle, and
    that cell was in turn engulfed by another cell to
    produce B. natans as we know it. Now, most of the
    nucleomorph's genome is concerned with its own
    maintenance, and just 17 of its genes still exert
    any control over the plastid. Its small size
    suggests it is heading for evolutionary oblivion.

Proc. Natl Acad. Sci. USA 103, 95669571 (2006)
by G McFadden, University of Melbourne, Australia
15
Organisation of human genome
  • Mitochondrial genome
  • Nuclear genome (3.2 Gbp)
  • 24 types of chromosomes
  • Y- 51Mb and chr1 -279Mbp

http//www.ncbi.nlm.nih.gov/Genomes/
16
Nuclear genome organisation (human)
Genomes 2 by TA Brown pg 23
17
Nuclear genome organisation (human)
  • 1) Gene and gene related sequences
  • Coding regions Exons (5)
  • Non-coding regions
  • RNA genes
  • Introns
  • Pseudogenes
  • Gene fragments

18
  • Basic structure of a gene

Fig. 21.11
19
Polypeptide-coding regions
20
Non polypeptidecoding RNA encoding
21
Nuclear genome organisation (human)
RNA genes -
Major classes of RNA involved in gene expression
  • rRNA
  • tRNA
  • snRNA
  • snoRNA
  • 16S, 23S, 28S, 18S etc
  • 22 types of mitochondrial 49 cytoplasmic
  • U1,U2.U4,U5,U6 etc
  • gt 100 types
  • Other RNA classes
  • microRNA
  • XIST RNA
  • Imprinting associated RNA
  • Nervous system specific
  • Antisense RNA
  • Others

22
introns
Non-coding regions..
23
Pseudogenes (?)
Non-coding regions..
  • A non functional copy of most or all of a gene
  • Inactivated by mutations that may cause either
  • inhibition of signal for initiation or
    transcription
  • prevent splicing at exon-intron boundary
  • premature termination of translation

Human Mol Gen 3 by Strachan Read pgs 262-264
24
Pseudogenes (?)
Non-coding regions..
  • Different classes include
  • Non-processed
  • contain non functional copies of genomic DNA
    sequence incl exons and introns
  • arise from gene duplication events
  • E.g. rabbit pseudogene ?b2

25
rabbit pseudogene ?b2
Non-coding regions..
  • Related to b1
  • Usual exon and intron organisation

b1
?b2
26
Pseudogenes - processed
Non-coding regions
27
Nuclear genome organisation (human)
28
Nuclear genome organisation (human)
  • 2) Extragenic (intergenic) DNA
  • (62 of genome)
  • A) Unique or low copy number sequences
  • B) Repetitive sequences ( 53)

29
A) Unique or low copy number sequences
  • Non coding, non repetitive and single copy
    sequences of no known function or significance

30
B) Repetitive sequences
  • Significance
  • Evolutionary signposts
  • Passive markers for mutation assays
  • Actively reorganise gene organisation by
    creating, shuffling or modifying existing genes
  • Chromosome structure and dynamics
  • Provide tools for medical, forensic, genetic
    analysis

31
  • 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 are
    scattered around the genome and can be used in
    DNA fingerprinting.

32
  • Moderately repetitive sequences are repeated
    101,000 times.
  • Includes the genes for tRNAs and rRNAs
  • Single copies of the tRNA and rRNA genes are
    inadequate to supply large amounts of these
    molecules needed by cells, so genome has multiple
    copies in clusters
  • Most moderately repeated sequences are
    transposons.

33
  • Transposons are of two main types in eukaryotes
  • Retrotransposons (Class I) make RNA copies of
    themselves, which are copied into DNA and
    inserted in the genome.
  • LTR retrotransposons have long terminal repeats
    of DNA sequences
  • Non-LTR retrotransposons do not have LTR
    sequencesSINEs and LINEs are types of non-LTR
    retrotransposons

34
  • Transposons (or transposable elements) are DNA
    segments that can move from place to place in the
    genome.
  • They can move from one piece of DNA (such as a
    chromosome), to another (such as a plasmid).
  • If a transposon is inserted into the middle of a
    gene, it will be transcribed and result in
    abnormal proteins.

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DNA Sequences That Move (Part 2)
37
  • DNA transposons (Class II) do not use RNA
    intermediates.
  • They are excised from the original location and
    inserted at a new location without being
    replicated.

38
Table 12.3 Types of Sequences in Eukaryotic
Genomes
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Concept 12.4 The Human Genome Sequence Has Many
Applications
  • By 2010 the complete haploid genome sequence was
    completed for more than ten individuals.
  • Soon, a human genome will be sequenced for less
    than 1,000.

44
Concept 12.4 The Human Genome Sequence Has Many
Applications
  • Some interesting facts about the human genome
  • Protein-coding genes make up about 24,000 genes,
    less than 2 percent of the 3.2 billion base pair
    human genome.
  • Each gene must code for several proteins, and
    posttranscriptional mechanisms (e.g., alternative
    splicing) must account for the observed number of
    proteins in humans.

45
Concept 12.4 The Human Genome Sequence Has Many
Applications
  • Over 50 percent of the genome is transposons and
    other repetitive sequences.
  • Most of the genome (97 percent) is the same in
    all people.
  • Chimpanzees share 95 percent of the human genome.

46
Concept 12.4 The Human Genome Sequence Has Many
Applications
  • Rapid genotyping technologies are being used to
    understand the complex genetic basis of diseases
    such as diabetes, heart disease, and Alzheimers
    disease.
  • Haplotype maps are based on single nucleotide
    polymorphisms (SNPs)DNA sequence variations that
    involve single nucleotides.
  • SNPs are point mutations in a DNA sequence.

47
Concept 12.4 The Human Genome Sequence Has Many
Applications
  • SNPs that differ are not all inherited as
    independent alleles.
  • A set of SNPs that are close together on a
    chromosome are inherited as a linked unit.
  • A piece of chromosome with a set of linked SNPs
    is called a haplotype.
  • Analyses of human haplotypes have shown that
    there are, at most, 500,000 common variations.
  • .

48
Concept 12.4 The Human Genome Sequence Has Many
Applications
  • Technologies to analyze SNPs in an individual
    genome include next-generation sequencing
    methods and DNA microarrays.
  • A DNA microarray detects DNA or RNA sequences
    that are complementary to and hybridize with an
    oligonucleotide probe.
  • The aim is to find out which SNPs are associated
    with specific diseases and identify alleles that
    contribute to disease.

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Figure 12.13 SNP Genotyping and Disease
52
Concept 12.4 The Human Genome Sequence Has Many
Applications
  • Genetic variation can affect an individuals
    response to a particular drug.
  • A variation could make an drug more or less
    active in an individual.
  • Pharmacogenomics studies how the genome affects
    the response to drugs.
  • This makes it possible to predict whether a drug
    will be effective, with the objective of
    personalizing drug treatments.

53
Figure 12.14 Pharmacogenomics
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https//genographic.nationalgeographic.com/
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