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