경암 바이오유스캠프 강의 2014
유전자와 게놈의 진화
성재영려대학 의과대학고려대학교 의과대학
인간 염색체와 유전자 수
http://en.wikipedia.org/wiki/Chromosome
생명체는 어떻게 유전자 수를 늘려왔는가?
influenza 12 유전자 수
E.coli
63 9
4497
fly
yeast
15771
6349
takifugu 20308
human
chicken
29399
21211
rice
human
30534
http://www.ncbi.nlm.nih.gov/genome/genomes/ 2014.06.24 update
HOX 유전자들
인간염색체 7번에 있는 HOX-A 유전자
인간염색체 2번에 있는 HOX-D 유전자
A C
인간 염색체에 존재하는 HOX 유전자
인간염색체HOXA1HOXB1HOXD1
HOXA9HOXC9
HOXD9
A C
HOXD9HOXB9HOXA10HOXC10HOXD10HOXA11
HOXC11HOXC11HOXD11
HOXD12HOXC12HOXA13HOXB13HOXC13B
-HOXD1 -HOXA1
-HOXA2
-HOXB1
-HOXB2
Chr #2 Chr #7 Chr #12 Chr #17
HOXC13HOXD13
HOXA2HOXB2
HOXA6HOXB6HOXC6
-HOXD3
-HOXD4
HOXD8
HOXA2
-HOXA3
-HOXA4
-HOXA5
-HOXA6
-HOXA7
-HOXC4
-HOXC5
-HOXC6
HOXC8
HOXB2
-HOXB3
-HOXB5
-HOXB6
-HOXB7
HOXB8
유전자소실
-HOXB4
HOXA7HOXB7HOXB8
HOXC8HOXD8
HOXB3-HOXD8
-HOXD9
-HOXD10
-HOXD11
-HOXD12
-HOXD13
-HOXA9
-HOXA10-HOXA11
-HOXA13
-HOXC8
-HOXC9
-HOXC10
-HOXC11
-HOXC12
-HOXC13
-HOXB8
-HOXB9
-HOXB13
HOXA3HOXD3HOXA4HOXB4HOXC4
HOXD4HOXA5
HOXB5HOXC5
A C
HOX 유전자의 복제 및 진화
인간염색체HOXA1HOXB1HOXD1
HOXA9HOXC9
HOXD9
A C
HOXD9HOXB9HOXA10HOXC10HOXD10HOXA11
HOXC11HOXC11HOXD11
HOXD12HOXC12HOXA13HOXB13HOXC13B
-HOXD1 -HOXA1
-HOXA2
-HOXB1
-HOXB2
-HOX -HOX1
-HOX2
Chr #2 Chr #7 Chr #12 Chr #17
조상 유전자
조상염색체
조상염색체
HOXC13HOXD13
HOXA2HOXB2
HOXA6HOXB6HOXC6
-HOXD3
-HOXD4
HOXD8
HOXA2
-HOXA3
-HOXA4
-HOXA5
-HOXA6
-HOXA7
-HOXC4
-HOXC5
-HOXC6
HOXC8
HOXB2
-HOXB3
-HOXB5
-HOXB6
-HOXB7
HOXB8
HOX2
-HOX3
-HOX4
-HOX5
-HOX6
-HOX7
HOX8
유전자복제
염색체복제 (x2)
유전자소실
-HOXB4
HOXA7HOXB7HOXB8
HOXC8HOXD8
HOXB3-HOXD8
-HOXD9
-HOXD10
-HOXD11
-HOXD12
-HOXD13
-HOXA9
-HOXA10-HOXA11
-HOXA13
-HOXC8
-HOXC9
-HOXC10
-HOXC11
-HOXC12
-HOXC13
-HOXB8
-HOXB9
-HOXB13
-HOX9
-HOX10-HOX11
-HOX13
-HOX8
-HOX12
HOXA3HOXD3HOXA4HOXB4HOXC4
HOXD4HOXA5
HOXB5HOXC5
척추동물에서 HOX 유전자의 복제
Ravi et al., PNAS, USA 2009
동물계에서 HOX 유전자의 복제
Garcia-Fernàndez J (2005) The genesis and evolution of homeobox gene clusters. Nature Reviews Genetics 6:881-892.
유전자 복제와 유전자 가족
Gene Organism
Replicator (복제자) Vehicle (운반자)Replicator (복제자) Vehicle (운반자)
Program (Software) Robot (Hardware)
복제/생식
다양성/특이성/특이성/소멸
체계/위계질서/독자성
유전자 복제 기전
Replication SlippageEctopic Recombination
12
A B C D E
A B C D EDNA Replication
34
A B C D E
A B C D E
A B C D E
DNA Repair Mechanisms
12
3
A B C D E
A B D E
A B C C D E
4A B C D E
Retrotransposition Aneuploidy
Expanded
Retrotransposition
DNA Copy
Reverse Transcription
Aneuploidy
Transcription
RNA Copy
Nondisjunction
Trisomy
G E N E GENEDNA
Intron
j
Monosomy
Whole Genome Duplication (WGD)
Susumu Ohno was born to Japanese parents in Seoul, Korea but spent most of his life in the US.
His work concerned the role of chromosomal exchange, and particularly on the sex chromosomeparticularly on the sex chromosome
Major Contribution: Barr Body & Concept of Junk DNA
Oh ’ H h i P l l l id (WGDOhno’s Hypothesis: Paleopolyploidy (WGD in the distant Past) has contributed to f j i i di ifast jumps in genetic diversity.
Springer-Verlag; 1St Edition edition (1970)
진핵 생물계에서 다배체화 (Polyploidy)
Polyploidy
복제된 유전자의 운명
Dysfunctionalization of a copy
유전자 복제
조상 유전자기능상실기능유지
Neofunctionalization of a copy유전자 복제
돌연변이 vs.
진화적 선택압력
신기능획득기능유지
Neofunctionalization of a copy
진화적 선택압력
부분기능상실 부분기능상실
Subfunctionalization of copies4가지 기능을가지는 유전자
유전자기능의 복잡성 유전자다양성 획득
기능의 복잡성생명체 다양성
POST-GENOME ERA (무엇을 어떻게 할 것인가?)
• 인간유전자 명명위원회 (HUGO nomenclature Committee)가 밝힌 유전자 수:2003년: ~25,0002003년: 25,000 2014년: ~30,000
• 기능이 밝혀지지 않은 유전자 수:3,000~5,000, ,
무엇을 할 것인가?
1) 새로운 유전자의 발굴2) 새로운 유전자의 기능 규명) 새로운 유전자의 기능 규명
어떻게 할 것인가?
1) 생물정보학 (tools)) 생물정 학 ( )2) 유전자의 진화 메커니즘 규명 (Rules)3) 유전자 기능 유추 (Prediction)
G-단백질 연결 수용체 (G protein coupled receptors)
Small Molecules
Ca++
Odorantspheromones
Small Molecules- amino acids, amines- nucleotides, lipids- peptides
Light Proteins- TSH- LH- FSH …
Effector
G
- Enzyme- Channel- ….
DP
GPCR
G-단백질 연결 수용체의 진화
Perez et al., Mol Pharmacol 2005, 67:1383
CXCR3
인간 GPCR 계통수와 고아 GPCR Red : peptide receptorsBlue : amine receptorsGreen : lipid receptorsOrange : Nucleotide receptorsGray : other receptorsBlack : orphan receptors
GPR120
GPR22
GNRHR GPR150MTNR1A
MTNR1B
TACR2
TACR1
TACR3
PRLHR
NPY2R
PROKR1
PROKR2
AVPR2
OXTRCXCR4
CCR10
CXCR3CXCR5
IL8RBIL8RA
CCBP2
XCR1
CCR4
CCRL2
CCR3CCR1
CCR5
CCR2
CX3CR1CC
979
1000
980882
943
995
802
940334
1000
482
360
392
330
812492
997
911
481927
846
1000
997
569
715
483Black : orphan receptorsGPR161
NPFFR2NPFFR1HCRTR2HCRTR1
NPY5R
PPYR1
NPY1R
GPR83
CCKARCCKBR
NPSR1
CCR8
APLNR AGTR2
AGTR1
GPR15GPR25
BDKRB2BDKRB1
OPRD1OPRM1
SSTR2
NPBWR2
NPBWR1
1000
1000
966613
688
908
990
242
385
1000
603
1000
447
304
995
995
902
917
355
999
795
989820
471 971
756
737
974
1000999
987
987
856
186 985
783
350751
60
940574
868
720
361
60
245
245
228
1000
545
999 604
249
58
71
158
134
201
229
SecretinSecretin likelike
GALR2GALR3
NPFFR2
KISS1RGALR1
NPBWR1SSTR5
SSTR3RXFP4RXFP3
VIPR1
ADCYAP1R1
GLP2R
GIPR
GLP1R
GCGR
438
780
487
524
938
821
998
998
9739451000128
270 134
495 996
126 997
471
998737856
152
126
100245
SecretinSecretin--likelike
S1PR1
S1PR3
MC1R
MC4R
MC3R
MC5R
MC2R
GPR17 GPR183 CYSLTR2
CYSLTR1
PTAFRGPR34
GPR171
P2RY14GPR87
P2RY12
P2RY10GPR174
GPR31OXER1
GPR81GPR132
GHRHRVIPR2
SCTR
885 504 504998 1000
846
995
894
990
660
231
258
363249
384989
966
773 1000
999230
492
662
988958
565
462
950445
45
121
232
237
109 56
19257
GPR176ADRA2A
HTR4
DRD1DRD5
GPR21GPR52
GPR139GPR142
S1PR4
S1PR5
S1PR2
S1PR1P2RY13
GPR81
NIACR1NIACR2
GPR132GPR65
GPR4GPR68
GPR20
GPR27
GPR85GPR173
FFAR1
1000
9991000
439366
439
1000
999 556 131 330
442
952
792
540998
962454
995 998
269 980
1000
738
948998
451
1000
204
738
1000990
1000
662
1000
949
153
386
848
262
153
62
880`153
192
625579
482455
343
400738
847
757
385
952
41
939957
998
757 1000
828994
60988
1000
131
45
385
OPN4OPN3
OPN5
HRH2
TAAR1
TAAR5HTR6HTR2B
HTR1A
DRD3
DRD2
ADRA2B
ADRA2C GPR78
GPR26
C3AR1
757
998816
868
272
272
998
964
1000
238
818
999
1000
955
501
406
262
361
262
1000 154
408
174
981996
923
989
366524
330408
999998
301
882
262
309961
398
414272
874
371
958985
510
TAAR9
HTR6
ADRB3HRH4
HRH3
CHRM3
CHRM1CHRM5
CHRM2
CHRM4
HTR2BHTR2C
DRD4HRH1
GPR101
GPR32
FPR1
FPR2FPR3948
1000
1000
999
997868106
946 997 962
765
GPCR에 작용하는 펩타이드 유전자
1. PACAP, VIP, Secretin, GHRH2. Adrenomodulin1, ADM2
Short Peptides (79 genes/~100 peptides) 28. Neuropeptide B29. Neuropeptide W30. Neurotensin (Neuromedin N, NTS)29. PTH, PTH2, PTHLH30. Dynorphin, Enkephalin, Nociceptin
3. AGRP, ASIP4. Anaphylatoxin C3, CA4, C55. Angiotensin6. Apelin7. AVP, OT
30. Dynorphin, Enkephalin, Nociceptin31. POMC (ACTH, MSH, -endorphin)32. Prolactin releasing peptide, QRFP33. Melanin stimulating hormone34. Prokineticin1, 235 Somatostatin cortistan Urotensin2 2D,
8. Bradykinin9. CALCA (calcitonin, CGRP-1), CALCB, IAPP10. CARTPT11. CRH, Urocortin, Urocortin 2, Urocortin 312 Cholestokinin Gastrin
35. Somatostatin, cortistan, Urotensin2, 2D36. TAC1 (substance P), 3 (NKB), 4 (endokin)37. TRH
Glycoprotein hormones (9 genes 5 peptides)12. Cholestokinin, Gastrin13. Endothelin 1, 2, 314. Galanin, GALP (GALP, Alarin)15. Gastrin releasing peptide16. Ghrelin (Ghrelin, obestatin), Mortilin17 GCG (Gl GLP 1 GLP 2) GIP
Glycoprotein hormones (9 genes, 5 peptides)
1. Beta- LH, cG (3 copies), FSH, TSH, Thyrostimulin 2. Alpha-1 (common), Alpha-2 (TSH)
LH = LH17. GCG (Glucagon, GLP-1, GLP-2), GIP18. GnRH1, GnRH219. Kisspeptin20. Orexin (Orexin1, 2)21. Insulin-like peptide 3, 4, 5, 6, Relaxin1, 2, 3
LHcGFSHTSH
+ subunit LH
= cG= FSH= TSH
TSH2 + 2 subunit = Thyrostimulinp p , , , , , ,22. Neuromedin B23. Neuromedin S, U24. Neuromedin U25. NPFF, NPVF26 Neuropeptide S
Chemokines (44 genes)
1. CC chemokine (24)2. CXC chemokine (17)
y
26. Neuropeptide S27. NPY, PPY, PYY
( )3. XC chemokine (2)4. CX3C chemokine (2)
생물정보학/비교유전체학을 이용한 신규 분비성 펩타이드의 발굴
■■ 인간유전체인간유전체 해독해독 이후이후 새로운새로운 유전자의유전자의 대량대량 발굴발굴
■■ 신규신규 유전자유전자 중중 분비성분비성 신경조절신경조절 펩타이드펩타이드 유전자가유전자가 다수다수 있을있을 것으로것으로 예상예상■■ 신규신규 유전자유전자 중중 분비성분비성 신경 절신경 절 펩타이펩타이 유전자가유전자가 다수다수 있을있을 것것 예상예상
⇒ ⇒ 고아수용체고아수용체 다수다수 발굴발굴
인간유전자표기위원회
기능을 모르는 신규 유전자: ~5,000 고아수용체: 74■ 분비성분비성 신경조절신경조절 펩타이드펩타이드 유전자유전자 발굴의발굴의 용이성용이성
30,00030,000
개수
25 000
5,000 74분비성 신경조절펩타이드 유전자
25,000
인간
유전
자 25,000341
연도2003 2011 인간유전자 수
분비성 펩타이드수용체 유전자 수● 분비를 위해 NN말단말단 시그날시그날 펩타이드펩타이드 서열서열 존재
● 번역 후 공정 과정의 특이성: 변형 및 절단 부위의 보존
● 성숙된 펩타이드 서열의 진화적 보존: 비교유전체학적비교유전체학적 접근의접근의 유용성유용성
신규펩타이드 유전자 발굴을 위한 생물정보학
Download Genes From ENSEMBLSecretome6 250 ORF
Neuropeptides
RF
~50,000 ORF
Gene with Signal Peptide
6,250 ORF
(223 ORF)
# o
f O
R
1009080
KNOWN(5,842 ORF)
Uncharacterized(408 ORF)
Signal P probability0 20 40 60 80 100
Candidate Peptide ligands: genes
Genome synteny &Sequence alignment
Dibasic a.a &Peptide length
Candidate Peptide ligands: genes
Spexin , C5orf46,INSL6, C7orf34, C12orf73, C21orf62, CARTPT, FAM150A ScRG 1 C1orf54 FAM19A5
Putative peptidome95 ORF
FAM150A, ScRG-1, C1orf54,FAM19A5, C17orf67, FAM19A5, RPLK9433, C4orf48, C6orf120, C11orf38,PYY-like,C20orf108, C20orf106, PSP9 ..
Spexin
새로운 신경펩타이드 Spexin의 발굴Spexin
R R NWT P QAM L Y L KG T QGR RR R NWT P QAM L Y L KG T QGR R
Zf_SPX1To SPX1
R R NWT P QAM L Y L KGAQGR RHu_SPX1
R R NWT P QAM L Y L KG T QGR RR R NWT P QAM L Y L KGAQGR RR R NWT P QAM L Y L KGAQGR R
To_SPX1An_SPX1Ch_SPX1
Coel_SPX1 R R NWT P QAM L Y L KGAQGR RMd_SPX1 R R NWT P QA I L Y L KGAQGH RSt_SPX1 R R NWS P QAM L Y L KG T QGR R
SPX1
R NWG P Q SM L Y L KGR Y GR RAn_SPX2R NWG P Q SM L Y L KGR Y GR -R NWG P Q S I L Y L KGR Y GR RK NWG P Q SM L Y L KGK HGR R
Coel_SPX2Ch_SPX2Zf SPX2
SPX2K NWG P Q SM L Y L KGK HGR RR NWG P Q SMMY L KGR HGR R
HWG P Q SMMY L KGK Y GK R
Zf_SPX2Xe_SPX2Md_SPX2
Spexin, KiSS, GAL 신경펩타이드의 진화적 관련성
TE
AD
4
KIS
S2
SY
T10
1212
PLE
KH
A5
12
SP
X1
12
GO
LT1B
12
Human
333 19 2121
PLE
KH
A7
PIK
3C2A
KC
NC
1
SY
T9
11 1111 1111
PP
P6R
3
GA
L
SU
V42
0H1
111111
SP
X2
TE
AD
1
EK
HA
6
3C2B
S1
FIA
4
T6
AD
3
LT1A
121617 177 686768
Human
PLE
PIK
3
KIS
S
PP
F
SY
T
11 111
204 204 204202114
TE
A
6
35
GO
L
1
204
Human
H2
R NWG P Q S I L Y L KGR Y GR RK NWG P Q SM L Y L KGK HGR R
Ch_SPX2Zf SPX2
R R NWT P QAM L Y L KGAQGR RCh_SPX1R R NWT P QAM L Y L KGAQGR RHu_SPX1
SPX2
SPX1
KIS
S3
KC
NC
3
PP
FIA
3
191919
PP
P6R
1
GA
LP
SU
V42
0 H
191919
TE
AD
2
Human
K NWG P Q SM L Y L KGK HGR RZf_SPX2
K RGWT L N S AG Y L L G P HAVGNHRSFSDKNGLTSKRHu_GALCoel_GALHu_GALP
Coel_GALP
H KiSS1
K RGWT L N S AG Y L L G P R RRGGWT L N S AG Y L L G P VLHLPQMGDQDGKR….K RGWT L N S AG Y L L G P HAHTLSDKRGLSGKR….
Y NW N S F G L R F GK R
GAL
GALPHAPA
P K E
KIS
S
GA
L
SP
X
VAC
5049 555556 49 Hu_KiSS1Xe_KiSS1
Coel_KiSS1Xe_KiSS2
Coel_KiSS2
Y NW N S F G L R F GK RY NW N S F G L R Y GK RY NW N T F G L R Y GK R
R S K F N F N P F G L R F GK RR S K F N F N P F G L R F GK R
KiSS1
Xe KiSS3 Y N V N S F G L R F GK R
KiSS2
- -- -- -- -- -- -
Coel_KiSS3 F NW N S F G L R F GK KXe_KiSS3 Y N V N S F G L R F GK R
KiSS3- -
CXCR3
인간 GPCR의 계통수 분석Red : peptide receptorsBlue : amine receptorsGreen : lipid receptorsOrange : Nucleotide receptorsGray : other receptorsBlack : orphan receptors
GPR120
GPR22
GNRHR GPR150MTNR1A
MTNR1B
TACR2
TACR1
TACR3
PRLHR
NPY2R
PROKR1
PROKR2
AVPR2
OXTRCXCR4
CCR10
CXCR3CXCR5
IL8RBIL8RA
CCBP2
XCR1
CCR4
CCRL2
CCR3CCR1
CCR5
CCR2
CX3CR1CC
979
1000
980882
943
995
802
940334
1000
482
360
392
330
812492
997
911
481927
846
1000
997
569
715
483Black : orphan receptorsGPR161
NPFFR2NPFFR1HCRTR2HCRTR1
NPY5R
PPYR1
NPY1R
GPR83
CCKARCCKBR
NPSR1
CCR8
APLNR AGTR2
AGTR1
GPR15GPR25
BDKRB2BDKRB1
OPRD1OPRM1
SSTR2
NPBWR2
NPBWR1
1000
1000
966613
688
908
990
242
385
1000
603
1000
447
304
995
995
902
917
355
999
795
989820
471 971
756
737
974
1000999
987
987
856
186 985
783
350751
60
940574
868
720
361
60
245
245
228
1000
545
999 604
249
58
71
158
134
201
229
SecretinSecretin likelike
GALR2GALR3
NPFFR2
KISS1RGALR1
NPBWR1SSTR5
SSTR3RXFP4RXFP3
VIPR1
ADCYAP1R1
GLP2R
GIPR
GLP1R
GCGR
438
780
487
524
938
821
998
998
9739451000128
270 134
495 996
126 997
471
998737856
152
126
100245
SecretinSecretin--likelike
S1PR1
S1PR3
MC1R
MC4R
MC3R
MC5R
MC2R
GPR17 GPR183 CYSLTR2
CYSLTR1
PTAFRGPR34
GPR171
P2RY14GPR87
P2RY12
P2RY10GPR174
GPR31OXER1
GPR81GPR132
GHRHRVIPR2
SCTR
885 504 504998 1000
846
995
894
990
660
231
258
363249
384989
966
773 1000
999230
492
662
988958
565
462
950445
45
121
232
237
109 56
19257
GPR176ADRA2A
HTR4
DRD1DRD5
GPR21GPR52
GPR139GPR142
S1PR4
S1PR5
S1PR2
S1PR1P2RY13
GPR81
NIACR1NIACR2
GPR132GPR65
GPR4GPR68
GPR20
GPR27
GPR85GPR173
FFAR1
1000
9991000
439366
439
1000
999 556 131 330
442
952
792
540998
962454
995 998
269 980
1000
738
948998
451
1000
204
738
1000990
1000
662
1000
949
153
386
848
262
153
62
880`153
192
625579
482455
343
400738
847
757
385
952
41
939957
998
757 1000
828994
60988
1000
131
45
385
OPN4OPN3
OPN5
HRH2
TAAR1
TAAR5HTR6HTR2B
HTR1A
DRD3
DRD2
ADRA2B
ADRA2C GPR78
GPR26
C3AR1
757
998816
868
272
272
998
964
1000
238
818
999
1000
955
501
406
262
361
262
1000 154
408
174
981996
923
989
366524
330408
999998
301
882
262
309961
398
414272
874
371
958985
510
TAAR9
HTR6
ADRB3HRH4
HRH3
CHRM3
CHRM1CHRM5
CHRM2
CHRM4
HTR2BHTR2C
DRD4HRH1
GPR101
GPR32
FPR1
FPR2FPR3948
1000
1000
999
997868106
946 997 962
765
Spexin은 GAL 수용체 2, 3형과 결합함(Kim et al., Endocrinology 2014)( gy )
Nothing Comes from Nothing
BC 540 515
ParmenidesEleatic Philosophy
Nothing comes from nothing (Latin: ex nihilo nihil fit) is a philosophical expression
BC 540-515
of a thesis first argued by Parmenides, an ancient Greek philosopher born in Elea
The Roman poet and philosopher Lucretiusd thi i i l i hi fi t b k f D
Lucretiusexpressed this principle in his first book of De Rerum Natura (eng. title On the Nature of Things) Hellenistic
philosophy
But only Nature's aspect and her law,Which, teaching us, hath this exordium:
BC 99-55
Nothing from nothing ever yet was born.
From Wikipedia