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Part 1
The Structure of
Genes and Genomes
[ Chapter 2 in Griffiths et al. ]
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What’s on the Menu
What is the structure of DNA?
What is the organization of a gene?
What are chromosomes? What is chromatin?
What’s in a genome?
How are genes organized in the genome?
How are genomes different among living organisms?
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1. The Structure of DNA
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Nature of DNA
• Transformation (uptake of foreign DNA) in prokaryotes and eukaryotes has repeatedly
shown that DNA is the hereditary material.
• DNA is accurately replicated prior to each
cell division.
• DNA encodes proteins needed by the cell
and the organism.
• DNA is capable of mutation, providing raw
material for evolutionary change.
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The Griffith and Avery experiments (1928-1944)A
C
E
DNA is the hereditary material.
Negative controlexperiment: degrade DNA
with DNase -> virulence
not transmitted anymore
F
D
B
?
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The nucleotide
• Building block of DNA (and RNA)• Deoxyribose (pentose sugar), with 3’ –OH
• Phosphate (on 5’ carbon)
• Nitrogenous base – purine
• Adenine: A
• Guanine: G
– pyrimidine
• Thymine: T
• Cytosine: C
P CO
N
N
base
sugar
5’
3’OH
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The structure of DNA:
The Double Helix
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WATSON, J.D. & CRICK, F.H.C. A Structure for
Deoxyribose Nucleic Acid. Nature 171, 737-738 (1953)
“We wish to suggest a structure for the salt of deoxyribose
nucleic acid (D.N.A.). This structure has novel features which areof considerable biological interest.”
James Watson, Francis Crick and Maurice Wilkins, Nobel Prize 1962
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The double helix
• DNA normally consists of twoantiparallel polynucleotide chains
– sugar–phosphate backbone
• phosphodiester bonds
• 5’ to 3’ connection
– complementary base pairs
• A – T
• G – C
• hydrogen bonds
– 2 per A – T
– 3 per G – C
• 5’→ 3’ chain polarity
• Major and minor grooves (see
model)
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5’ 3’
3’ 5’
5’-AATTGGCCGATC-3’
3’-TTAACCGGCTAG-5’
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Figure 1.9 Genomes 3 (© Garland Science 2007)
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WATSON, J.D. & CRICK, F.H.C. A Structure for
Deoxyribose Nucleic Acid. Nature 171, 737-738 (1953)
“We wish to suggest a structure for the salt of deoxyribose
nucleic acid (D.N.A.). This structure has novel features which areof considerable biological interest.”
James Watson, Francis Crick and Maurice Wilkins, Nobel Prize 1962
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Blah, blah, blah...
???...
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Rosalind Franklin“The Dark Lady of DNA”
1920-1958
"The instant I saw the picture my mouth fell open and my pulse began
to race.... the black cross of reflections which dominated the picture
could arise only from a helical structure... mere inspection of the X-ray
picture gave several of the vital helical parameters.” -JD Watson
Franklin R & Goslind RG. Evidence for a 2-chain Helix in
the Crystalline Structure of Sodium Deoxyribonucleate.
Nature 172: 156 (1953)
X-ray diffraction photograph of DNA
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Rosalind Franklin
Franklin and Wilkins X-ray diffraction studies
revealed that DNA was helical and had two
distinctive regularities of 0.34 nm and 3.4 nm along
the axis of the molecule. In addition, it was shown
that DNA had a uniform thickness of 2 nm.
Maurice Wilkins
The DNA double helix is 2 nm wide.
A stack of 10 base pairs (= one turn of the
helix) have a linear length of 3.4 nm.
2 nm
3.4 nm
10 bp
2 nm
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Erwin Chargaff’s rules:
(early 1950’s)
1. The composition of DNA may
vary from one species to
another in the relative amount
of A, T, C, G
2: But for any DNA:
% A = % T
% C = % G
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Chargaff’s rules
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WATSON, J.D. & CRICK, F.H.C. A Structure for
Deoxyribose Nucleic Acid. Nature 171, 737-738 (1953)
The model fitted:
(1) The X-ray diffraction data produced by Franklin(2) Chargaff’s rules
The structure also fulfilled the requirements for a
hereditary molecule:
(1) The ability to store information (coding capacity)(2) The ability to self-replicate (strand separation and
specificity of base pairing)
(3) The ability to change over time, ie. to mutate
(base substitution)
The double helix model of Watson & Crick: conclusions
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James Watson, Francis Crick and Maurice Wilkins, Nobel Prize 1962
YIPEEE!
Blah, blah, blah...
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DNA: summary
• Units of measurement – base pair (bp)
– kilobase (kb)
– megabase (Mb)
• Replication: each strand serves as templatefor synthesis of complement, using rules of
base pairing
• Information: specified by sequence of
nucleotides; may be copied into RNA
• Mutation: replacement, insertion, deletionof nucleotide results in altered sequence
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2. The Structure of Genes
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Structure of genes
• Gene = transcriptional unit
• Gene may encode coding RNA (mRNA) OR
non-coding RNA (tRNA, rRNA, miRNA...)
• Gene is a functional element of the chromosome and is transcribed intoRNA at the correct time and place in development or cell cycle
• To some researchers, gene actually includes its adjacent regulatory
region(s) such as the promoter (remember, definition of gene may
vary)
DNA encoding functional RNApromoter
RNA primary transcript
gene
TSS=Transcription
start site
TTS=Transcription
termination site
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Eukaryotic genes: introns and exons
• Intron: noncoding region of gene, excised from
primary RNA transcript (=intron splicing)• zero to many intron per eukaryotic gene
• variable length, may represent most of gene length
• Function of introns poorly understood (no general function
known, but they often contain functional regulatory sequences)
• Exon: coding region of gene (sequence is
included in mature transcript)
E1 E2I1 I2 E3 I3 E4
E1 E2 E3 E4
Primarytranscript
Mature transcript
nuclear processing steps,
including splicing
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Introns are only present in eukaryotic genes(but they may be absent in some eukaryotic genes)
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Because of the abundance and large size of introns,
some eukaryotic genes can attain huge sizes
An extreme example: human dystrophin gene, 2.5 Mb long
(1.5% of entire chr. X), 78 introns !
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3. The Structure of
Genomes
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The nature of genomes
Genomics: study of structure and function of genomes
• Nuclear Genome (very variable size, especially in
eukaryotes)
• Organellar genomes
– chloroplast, mitochondrion – derived by endosymbiosis from bacterial ancestors
• Plasmids
– symbiotic DNA molecules, not essential but often useful to
the organism (antibiotic resistance) – mostly circular in prokaryotes
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The Prokaryotic genome
• Usually circular DNA, often a singlemolecule per cell (= 1 single chromosome)
• Gene-dense: genes are close together with
little intergenic spacer
• Genes are often organized in operon
– tandem cluster of coordinately regulated genes
– Several genes transcribed as single mRNA
• No spliceosomal introns
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The Lactose Operon
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A ‘simple’ genome:
the bacterial genome§ Unicellular organism
§ Single, circular
chromosome
§ Compact genome, gene
dense, 90% coding DNA
§ ~500 to ~5,000 genes,
depending on species
E. coli
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Mycoplasma: one of the smallest gen
- Extremely streamlined: 580 kb
- ~500 genes
- Gene-dense: 90% is coding DNA
- Very short intergenic regions
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Viral genomes• Virus=Replicating, infectious but nonliving particle, can only
replicate within a host cell (and can move from cell to cell) – Genome=nucleic acid
– Encodes multiple proteins
Many viruses cause infectious diseases
• Viral Genome = DNA or RNA
– single-stranded or double-stranded
– linear or circular
• Generally compact genomes with little spacer DNA, containingfrom a few to many genes (note: some viral genes contain introns, likeeukaryotic genes. Recently giant ‘mimivirus’ discovered, 1.1 Mb long)
• Unknown origin of viruses, but some appear to have evolvedfrom mobile genetic elements. The latter are normally containedwithin the host genome but they can acquire infectious capacityallowing them to escape the cell (e.g. retroviruses originate fromretrotransposons)
Note: In prokaryotes,
viruses are referred
to as bacteriophages.
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1918 Influenza pandemics caused 20-30 million deaths
The flu virus, influenza: a single-stranded RNA virus
Hemaglutinin
Neuraminidase
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The swine flu virus, H1N1 (ssRNA virus)
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Conceptual structure of HIV, a ssRNA
virus using reverse-transcription
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The replicative
cycle of HIV-1
retrovirus
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Restricted tovertebrates
Example: HIV-1
Widespread in eukaryotes
Example: Ty1 element in yeast,
By acquisition of envelope gene, a
retrotransposon can gain infectious
capacity, it becomes a retrovirus
(example of an intermediate: gypsy in
fruit flies)
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Eukaryotic genome: 2 or 3 genomes per cell
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The Mitochondrial Genome
- Circular - Resembles a reduced
prokaryotic genome in
terms of organization and
gene numbers- Encodes genes mostly
involved in the production
of energy (oxydative
phosphorylation) and in
translation (tRNAs, rRNA)
- Maternally inherited
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Human(mammal)
16.5 kb
Yeast
(fungus)
75 kb
Marchantia(moss)
186 kb
Mitochondrial genomes can vary in
size between species
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The Chloroplast Genome (plants)
- Circular
- Resembles a reduced
prokaryotic genome in
terms of organization and
gene numbers
- Encodes genes mostlyinvolved in photosynthesis
and electron transport
- ‘Maternally’ inherited
(transmitted through theseed)
- Do not vary much in sizeMarchantia (moss)
CpDNA 121 kb
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4. The structure of
eukaryotic chromosomes
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Eukaryotic nuclear genome: chromosomes (1)
• Linear structure
• Chromosome number is conserved within species but greatlyvaries between species
• Ploidy refers to number of complete sets of chromosomes – haploid (1n): one complete set of chromosomes (e.g. yeast)
– diploid (2n): two sets of chromosomes (e.g. most animals)
– polyploid (≥3n): more than two sets (e.g. many plants, a few animals)
• In diploids, chromosomes come in homologous pairs(homologs) – structurally similar (i.e size and position of centromere)
– same assortment of genes (homologous genes)
– may contain different alleles for each gene: each gene exist either ashomozygote state (same two alleles) or heterozygote state (two differentalleles)
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In humans, somatic cells have 2n = 46 chromosomes
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Remy’skaryotype
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Human chromosomes 11 and 17
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• Cytogenetics: microscopic study of chromosomes
• Variable centromere position
– telocentric: centromere at end
– acrocentric: centromere close to end
– metacentric: centromere in middle – For human chromosomes: p arm is shortest, q arm is
longest
• Telomere: end of chromosome
• Nucleolar organizer region (NOR): The chromosomal regionaround which the nucleolus forms (contains rRNA genetandem array)
• Chromomere (or knob): small bead-like region of condensedchromatin visible during meiosis and mitosis
Eukaryotic nuclear genome:
chromosomes (2)
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Maize chromosomes (2n = 20)
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• Considerable difference in size and in the
number of genes carried on chromosomes, both
between and within species
• Genes may occupy only a minor fraction of a
chromosome (extreme case is human Y)
Eukaryotic nuclear genome:
chromosomes (3)
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0
50
100
150
200
250
300
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y
Chromosome size (Mb)
Gene density (per 10 Mb)
1 2 3 4 5 6 7 8 9 10 1112 13 141516 17 18 19 20 21 22 X Y
Human chromosomes: size and gene density
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• Heterochromatin – densely stained regions of highly condensed
DNA
– mostly made of non-coding repetitive DNA, low
gene density and transcription activity• Euchromatin:
– poorly stained, less compact chromatin
– contains most transcribed genes
Note: Polytene chromosomes
– replicated, unseparated chromosomes
– present in certain tissues of dipteran insects (salivary glands)
Eukaryotic nuclear genome:
chromosomes (4)
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The chromosomes of maize (corn)
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Microscopic view of atomato chromosome
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Organization of Nuclear DNA
• Highly organized, various degrees of coiling
• Nucleosome – fundamental unit of chromatin
– 146 bp of DNA wrapped twice around histone core(histone octamer)
• histones are highly conserved proteins
• H2A, H2B, H3, H4
• Chemical modification of histones underlie
changes in chromatin compaction
– Nucleosome forms a 10 nm fiber
– 6 nucleosomes coil to form Solenoid, 30 nm fiber
• Higher order coiling – solenoid loops attach to scaffold (SAR, MAR)
– form larger diameter fibers
Chromatin is a highly dynamic structure
A haploid set of
humanchromosomes
consists of about
3 feet of DNA !
ll i f A d d hi f i l
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Illustration of DNA wrapped around histones, forming a nucleosome
Ill i f DNA d d hi f i l
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Illustration of DNA wrapped around histones, forming a nucleosome
H2A
H3
H2B
H4
H1
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Solenoid
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Electron micrograph of chromosome
shows long DNA loops emanating
from the protein scaffold (at the
bottom of the pic) . Note that there are
only loops -no ends- at the top of the
pic.
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5. Genome landscapes and
Comparative Genomics
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Prokaryotes and eukaryotes have very
different genome landscapes
• In prokaryotes, genes are compactly
arranged, with little or no spacer sequences
in between (short intergenic regions) = most
of the genome is coding DNA• In eukaryotes, there is considerable spacer
DNA between genes (large intergenic
regions) and within genes (introns) = most
of the genome is ‘non-coding’ DNA
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E k t
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– Where is non-coding DNA? In introns, intergenicregions, centromeric regions, telomeric regions
– the majority of non-coding DNA is repetitive DNA
= identical or nearly identical repeated units
- two types of repetitive DNA:
• Tandem repeats (e.g. DNA at centromeres andtelomeres)
• Interspersed repeats
– Most interspersed repeats are derived frommobile genetic elements (aka transposable elements)
Eukaryote genomes:
A whole lotta non-coding DNA
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Genome Size
• In eukaryotes, most of the cell DNA isfrom the nuclear genome
• Genome size is measured in pg or Mb(1pg ~ 1000 Mb) human genome is ~3.2 pg
• Nuclear genome size is extremelyvariable among eukaryote species
• ‘C-value paradox’ : no obvious
correlation between genome size andorganism complexity
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The ‘C-value paradox’
Genome size does NOT correlate with
organismal complexity
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Extensive variation in genome size (= C-value)
within and among the main groups of life
Gregory 2005
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C-value of eukaryotic nuclei varies ~200,000-fold, but
there is only ~20 fold variation in the number of protein-coding genes
Encephalitozoon cuniculi : 2.8 Mb, 2,000 genes
Navicola pelliculosa (diatom): >690,000 Mb (probably less than 40,000 genes)
-> Variation in gene numbers cannot explain
variation in genome size among eukaryotes
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• Most of variation in genome size is due tovariation in the amount of repetitive DNA (mostly
derived from TEs)• TEs accumulate in intergenic and intronic regions
Transposable Elements and
genome size
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The amount of TE correlate positively with
genome size
P l a s m
o d i u m
S l i m
e m o l d
B u d d i n
g y e a s t
F i s s i o
n y e a s t
N e u r
o s p o r
a
A r a b i d
o p s i s
B r a s s i c a R i c e M
a i z e
N e m
a t o d e
D r o s o p h i l a
M o s q u
i t o
S e a s
q u i r t
Z e b r
a f i s h F u g u
M o u s e
H u m
a n
0
500
1000
1500
2000
2500
3000 Genomic DNA
TE DNA
Protein-coding
DNA
Mb
Feschotte & Pritham 2006
Th ti f t i di d ith
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TEs
Protein-coding
genes
The proportion of protein-coding genes decreases with genome
size, while the proportion of TEs increases with genome size
Gregory, Nat Rev Genet 2005
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• Variation in gene numbers cannot explainvariation in genome size among eukaryotes
• Most of variation in genome size is due tovariation in the amount of non-coding, repetitiveDNA (mostly transposable elements, TEs)
• TEs accumulate in intergenic and intronic
regions
Repetitive DNA and genome size
Contrasted Genome Landscapes
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Transposable Element
Contrasted Genome Landscapes
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What have we learned
from the humangenome sequence?
2001: first
draft of the
human
genome
sequence
Most of the Human Genome does not code
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Coding
Non-coding
1.5%
Most of the Human Genome does not code
for proteins
Half of the Human Genome is derived from
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Coding
Non-coding
1.5%
TE-derived
DNA
48.5%
Half of the Human Genome is derived from
Transposable Elements (TEs)
The human Genome Browser at UCSC
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A snapshot of the Human Genome
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A snapshot of the Human Genome
TEs
Genes
Conservation in other species
TEs are the most rapidly changing components of the
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TEs
Genes
Human-
specific TE
Ape-
specific TE
Primate-specific
TE
Cons-
erved
Exon
TEs are the most rapidly changing components of the
genome
Rapid changes in genome size in the grasses
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430 Mb 750 Mb2500 Mb
Genome size:
4800 Mb
Rapid changes in genome size in the grasses
~50 myr
~10 myr
Figure adapted from Sue Wessler
The maize genome: tiny gene islands floating on
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RIPRIP RIP RIP
gene A gene B genes C & D
The maize genome: tiny gene islands floating on
an ocean of repetitive DNA
Cluster of Repetitive DNACluster of Repetitive DNA
A typical maize chromosome
Nested LTR retrotransposons
Expansion of intergenic regions in maize by
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San Miguel et al. (1996) Nested Retrotransposons in the Intergenic Regions of the
Maize Genome. Science 274: 765-768
(+ other studies from Bennetzen lab)
Expansion of intergenic regions in maize by
accumulation of LTR-retrotransposons
Retrotransposon amplification has resulted in the
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San Miguel et al. (1998) The paleontology of intergene
retrotransposons of maize, Nature Genet. 20:43-45
Retrotransposon amplification has resulted in the
doubling of the maize genome in the last ~6 myr
Variation in TE activity triggers rapid changes
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430 Mb 750 Mb 2500 MbGenome size:
4800 Mb
in genome size in grasses
Genes
TEs
~50 myr
~10 myr
Comparati e genomics
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Comparative genomics
• Study of similarities and differences among
genomes
• Many genes are shared among all living things or
between related groups
• Study of genes in model organisms provides usefulinformation regarding genes in other organisms
• Large genome projects produce considerable
amount of information
– Requires computer analysis and development of newsoftware to analyze the avalanche of data (bioinformatics)
2001 fi
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What have we learned
from the humangenome sequence?
2001: first
draft of the
human
genome
sequence
1996: S. cerevisiae 1998: C. elegans 2000: D. melanogaster 2000: A. thaliana 2001: H. sapiens
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2002: S. pombe 2002: P. falciparum 2002: A. gambiae2002: F. rubripes
2002: M. musculus
2004: R. norvegicus
2002: O. sativa
2002: C. intestinalis
2004: T.pseudonana
2004: T.nigroviridis
2004: B. mori
2003: N. crassa2003: C. familiaris
2005: E. histolytica 2005: P. troglodytes
Genome sequences can be aligned and compared
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Genome sequences can be aligned and compared
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Human-Mouse
genome
comparison
A snapshot of the human genome browser at UCSC
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p g
Genes
THIS WEEK’S MENU
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What is the structure of DNA?
What is the organization of a gene?
What are chromosomes? What is chromatin?
How is DNA organized at the chromosome and chromatin level?
How are genes organized in the genome?
What makes the genome of a prokaryote and a eukaryote different?
What’s in a genome?
How are genomes different among eukaryotes?
Overview
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Overview• Each species has a uniquely fundamental set of
genetic information, its genome.
• The genome is composed of one or more DNAmolecules, each organized as a chromosome.
• The prokaryotic genome is generally compact andmade of a single circular chromosome.
• The eukaryotic genome consists of one or two setsof linear chromosomes confined to the nucleus.
• A gene is a segment of DNA that is transcribedinto a ‘functional’ RNA molecule.
• Introns interrupt many eukaryotic genes.
• Eukaryotic genomes are littered with repetitiveDNA (mostly derived from transposable elements)