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Comparative Genomics: The study of genome conservation
and variation among organisms
Chromosome numberChromosome morphology
Gene numberGenome sizeGene order
Measures of Genome Size
C value : amount of DNA in the haploid genome, generally measured in picograms or in base pairs (Kb or Mb)
Range of C Values in Prokaryotes
Taxon Genome Size (Kb) Ratio
Bacteria 580 - 13,200 23 Mollicutes 580 - 2,200 4 Gram negatives 650 - 9,500 15 Gram positives 1,600 - 11,600 7 Cyanobacteria 3,100 - 13,200 4Archaea 1,600 - 4,100 3
~ 20 fold range in genome size
Genome Size (x 106 bp)
1000
2000
3000
4000
5000
GeneNumber
Gene Number and Genome Size in 12 CompletelySequenced Bacterial Species
C value : So, what about eukaryotes?
• In general, more DNA• Much greater variation in genome size
• 80,000 fold range across eukaryotes• Largest range observed among unicellular protists (20,000 fold)• 3,000 fold range in animals• No relationship between c value and organismal complexity:
the c value paradox
Species C value (Kb)Saccharomyces cerevisiae 12,000Caenorhabditi elegans 80,000Drosophila melanogaster 180,000Strongylocentrotus purpuratus 870,000Gallus domesticus 1,200,000Canis familiaris 2,900,000Rattus norvegicus 2,900,000Xenopus laevis 3,100,000Homo sapiens 3,600,000Nicotiana tabacum 3,800,000Ambystoma tigrinum 32,000,000Pinus resinosa 68,000,000Lepidosiren paradoxa 120,000,000Ophioglossum petiolatum 160,000,000Amoeba dubia 690,000,000
C values from eukaryotic organisms ranked by genome size
What explainsthe C value paradox?
Polyploidization: complete genome duplication
Role of Regional Duplications in Genome Evolution
Genome size and amount of heterochromatin
98% of variance explained
Genic Fraction vs Genome Size
Synteny : Occurence of two or more genes on a chromosome.
Conserved Synteny : Synteny of orthologous genes between species.
Terms for Comparing Gene Order
A B C D E F
I H G J K L M
D E F G H I J K L M
translocation
A B C
A B C D E F G
G H I J K L M
inversion
Speciation
Ancestral Condition
1 2 3 4 5 6 a b 7 8 9
6 5 4 c d e 9 8 7 1 2 3
1 2 3 4 5 6 7 8 9
6 5 4 9 8 7 1 2 3
Delete
(a,b) & (c,d,e)
Reconstructing the Evolution of Gene Order
1 2 3 4 5 6 7 8 9
6 5 4 9 8 7 1 2 3
1 4 72 5 83 6 9
6 9 15 8 24 7 3
Bundle1, 2 & 34, 5 & 67, 8 & 9
Invert
(1 2 3) & (4 5 6)
6 3 75 2 84 1 9
6 9 15 8 24 7 3
1 2 3 4 5
3 5 2 4 1
1 2 3 4 5
3 2 5 4 1
Invert
2 & 5
Invert
(541)
1 2 3 4 5
3 2 1 4 5
Invert
(321)
1 2 3 4 5
3 2 1 4 5
E = D + R
Evolutionary EditDistance
= Minimal #Deletions +
Minimal #Rearrangements
OTUsb Hs Gg Sp Ap Po Dy As
Hs(human) 1 18 16 19 13 25
Gg(chick) 0 19 17 17 12 26
Sp(urchin) 0 0 2 1 26 27
Ap(starfish) 4 4 4 1 22 24
Po(starfish) 1 1 1 5 23 24
Dy(fruitfly) 0 0 0 4 1 28
As(roundworm) 1 1 1 5 1 1
Deletion Distance
Rearrangement Distance
Data from mitochondrial genomes
300
65
100
(0.1)(1.1)(0.2)
Chicken Mouse Human
Rate of Chromosome Rearrangement(per million years)
Ehrlich et al (1997) : Gene rearrangements occur with amazing rapidity among mammals; rate of synteny disruption 25 times higher in mouse lineage; interchromosomal rearrangements are common.
Chicken 128 72
Mouse 152 171
Human 96 195
Chicken Mouse Human
Total number of autosomalconserved syntenies
Total number of rearrangements
Chromosomal Distribution of Orthologous Genes
Human MouseCount 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Count 1 2 3 4 5 6 7 8 9 10 11 12 13 14chr1 1 1 6 11 0 6 3 0 3 12 5 1 2 0 chr1 2 1 2 1 2 0 0 1 1 5 3 1 1 0chr2 0 1 6 0 5 1 0 2 1 0 0 0 2 0 chr2 5 0 7 1 2 1 3 1 2 0 0 1 1 0chr3 0 0 15 1 1 0 2 5 1 0 1 1 0 0 chr3 3 1 3 7 0 0 0 2 3 6 2 0 0 0chr4 0 3 1 0 0 0 0 0 0 0 0 0 0 0 chr4 0 4 0 1 1 6 3 1 0 2 1 0 0 0chr5 7 5 0 0 0 1 0 0 0 0 0 0 0 0 chr5 2 1 5 0 2 0 0 3 0 0 0 0 0 0chr6 0 3 2 1 0 2 0 0 3 0 1 1 2 0 chr6 4 2 11 1 1 0 0 2 11 0 1 0 0 1chr7 1 0 9 0 3 0 0 2 7 0 2 0 0 1 chr7 5 0 9 8 0 0 0 0 0 0 1 0 0 0chr8 1 3 1 0 0 1 0 2 0 0 0 0 0 0 chr8 3 3 2 4 0 0 0 1 0 2 0 0 0 0chr9 0 7 0 2 0 1 3 0 0 0 0 0 0 0 chr9 5 1 3 0 0 6 2 1 1 1 1 0 1 0chr10 1 0 6 0 0 0 4 3 0 0 0 0 0 0 chr10 3 1 1 4 3 0 3 1 5 0 0 0 1 0chr11 1 0 11 2 0 0 0 1 2 0 1 0 1 0 chr11 12 1 11 3 3 0 0 6 2 0 13 0 2 0chr12 11 1 2 1 1 0 0 4 11 0 1 0 0 0 chr12 2 1 5 1 0 0 0 0 1 0 1 0 0 7chr13 0 0 0 0 0 0 0 0 1 0 0 1 0 0 chr13 0 3 4 3 0 0 0 0 2 0 0 0 1 0chr14 0 0 6 2 0 0 0 0 0 0 1 0 0 6 chr14 2 0 6 1 0 0 2 2 0 0 1 1 0 0chr15 1 1 2 1 0 8 0 0 1 1 0 0 0 0 chr15 7 4 4 0 0 2 0 0 3 0 1 0 0 0chr16 4 0 6 3 0 0 0 0 0 2 1 0 0 0 chr16 1 0 0 0 1 0 0 2 1 0 0 1 0 0chr17 7 1 7 3 2 0 0 2 0 0 12 0 0 0 chr17 2 1 5 2 0 1 0 0 1 0 1 1 1 0chr18 0 5 0 0 0 0 0 0 0 0 1 0 0 0 chr18 0 2 0 0 0 0 0 0 0 0 1 1 0 0chr19 8 0 3 15 1 0 0 1 0 0 0 0 0 0 chr19 0 3 12 2 0 1 0 0 0 0 0 0 0 0chr20 7 1 2 1 0 0 0 1 0 0 0 1 1 0 chrX 0 2 3 0 0 0 0 1 0 0 0 3 1 0chr21 0 0 0 1 3 0 0 0 0 0 0 0 0 0chr22 1 0 2 0 0 0 0 0 4 0 0 0 0 0chrX 0 2 3 0 0 0 0 1 0 0 0 3 1 0chrY 0 0 0 0 0 0 0 0 0 0 0 1 0 0
Chicken RatCount 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Count 1 2 3 4 5 6 7 8 9 10 11 12 13 14chr1 5 2 9 1 0 2 0 2 7 0 2 3 1 0 chr1 5 4 18 8 0 0 0 1 0 0 0 0 2 0chr2 1 8 8 2 0 0 1 1 0 0 3 0 0 0 chr2 2 5 0 4 0 1 0 1 1 5 0 0 0 0chr3 4 0 4 1 0 2 0 0 1 0 0 0 5 0 chr3 3 1 3 0 1 1 2 2 0 0 2 0 1 0chr4 0 4 1 0 0 1 2 0 0 0 0 0 0 0 chr4 4 0 8 1 1 0 1 1 5 0 3 0 0 0chr5 1 0 4 4 0 0 0 1 1 0 0 0 0 6 chr5 2 2 1 0 2 3 1 1 0 1 0 0 0 0chr6 0 0 1 0 0 0 3 1 0 0 1 0 0 0 chr6 2 1 4 0 1 0 0 1 0 0 1 0 1 2chr7 0 0 1 0 7 0 0 0 2 0 0 1 0 0 chr7 3 0 4 4 0 0 0 2 6 0 2 0 0 0chr8 1 1 0 0 0 0 0 0 0 11 0 0 0 0 chr8 4 0 2 3 0 5 1 1 2 1 0 0 0 0chr9 0 0 0 2 4 0 0 3 0 0 0 0 0 0 chr9 0 1 0 0 2 0 0 0 0 0 0 0 0 0chr10 1 0 0 3 0 6 0 0 1 1 0 0 0 0 chr10 10 2 8 2 0 0 0 2 1 0 7 0 0 0chr11 0 1 0 3 0 0 1 0 0 1 0 0 0 0 chr11 2 0 0 1 1 1 0 1 0 0 1 1 0 0chr12 0 0 7 0 0 0 0 0 2 0 1 0 0 0 chr12 0 1 5 0 2 1 0 1 0 1 2 0 0 0chr13 5 0 0 0 0 0 0 1 0 0 0 0 0 0 chr13 1 1 0 0 0 0 0 0 0 3 0 0 0 0chr14 1 0 9 0 0 0 0 0 1 0 0 0 0 1 chr14 0 1 0 0 0 0 0 1 1 0 0 0 0 0chr15 0 0 0 0 0 1 0 1 2 0 0 0 0 0 chr15 2 0 5 1 0 0 1 0 0 0 0 0 0 0chr16 1 0 0 0 0 0 0 0 0 0 0 0 0 0 chr16 2 0 3 1 0 0 1 2 1 0 0 0 0 0chr17 1 0 0 0 0 0 4 0 0 0 0 0 0 0 chr17 2 0 1 1 0 0 0 0 2 0 0 0 0 0chr18 6 1 4 0 0 0 0 0 0 0 0 0 0 0 chr18 2 3 1 1 1 0 0 0 0 0 1 1 0 0chr19 2 0 0 0 4 0 0 3 0 0 0 0 0 0 chr19 0 1 2 1 0 0 0 1 0 1 0 0 0 0chr20 5 1 0 1 0 0 0 0 0 0 1 0 0 0 chr20 0 0 0 0 0 0 0 0 1 0 1 0 1 0chr21 2 0 0 0 0 0 2 0 0 0 0 0 0 0 chrX 0 1 3 0 0 0 0 1 0 0 0 0 1 0chr22 0 0 0 0 0 0 0 1 0 0 0 0 0 0chr23 0 0 0 0 0 4 0 0 0 0 0 0 0 0chr24 1 0 0 1 0 0 0 0 2 0 0 0 0 0chr26 0 0 1 0 0 0 0 0 1 0 2 0 0 0chr27 0 1 0 0 0 0 0 0 0 0 5 0 0 0chr28 1 0 3 3 0 0 0 0 0 0 0 0 0 0chrZ 1 7 0 1 0 1 0 0 0 0 0 0 0 0
HUMAN
CHICKEN
MOUSE
RAT
Salamander Salamander
N = 402Refseq database size = 21,098
N = 338Refseq database size = 16,800
N = 338Refseq database size = 11,348
N = 236Refseq database size = 12,427
Number of Conserved Syntenies
Comparison #a #b
Human 69 28Mouse 82 24Chicken 52 17Rat 58 14
#a based on 2 or more orthologues
#b based on 4 or more orthologues
Spatial Distribution of Orthologous Loci :
Segmental Homology
Lg1 Lg2 Lg3 Lg14
Salamander Genome
HUMAN
GENOME(1-23)
white met melanoid
Lg1 Lg2 Lg3 Lg14
Salamander Genome
CHICKEN
GENOME(1-23)
Conserved Synteny based upon 3 or more genes
white met melanoid
Candidate Genes
met
white
sex
melanoid
Cross-Referencing
Chromosomal Sex Determination
Birds Mammals
300-350 mya
ZZ - ZWMale Female
XY - XXMale Female
Sry Locus:testes determining
factor
?
Ohno’s Hypothesis
Bird and Mammalian Sex Chromosomes were derivedfrom the same ancestral autosomal pair
ZW Birds
X
Y
Mammals
A
A XX
ZZ
Ohno’s Hypothesis Predicts:
The same orthologous loci will be identifiedbetween the sex chromosomes of
birds and mammals (i.e. conserved synteny)
CHD-WATPA1-W
p
q20 cM
ATPA1-Z
GHR
OTC
CHD-ZCHRNB3
ALDOB
GGTB2 IREB1
Chick W Chick Z Human Mouse
18q
5p
Xp
5q8p
9q
9p9
18
15
17
4
44
Fridolfsson et al 1998
Chick Z Human 9
p
q
IFN1/IFNA1IFN2.IFNB1
DMRT1
VLDLRBRM/SMARCA2
NTRK2GGTB2/B4GALT1
ACO1TMOD
ALDOBPTCH
AMBPABL1AK1
RPL7ACD39L1
Comparative Locations of Orthologous Loci
p
q
Chick microchromosome(linkage group E41W17)
Nanda et al (1999)
Conclusion
Bird and Mammalian Sex Chromosomes Evolved Independently from Different
Autosomal Precursors