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1 Outline CS4HS 생물정보학 생물정보학및암정보의학 맟춤의학과생물정보학 김선 서울대학교컴퓨터공학부생물정보연구소생물정보학협동과정 유전체학, 후생유전체학을이용한암연구와맟춤의학 1 2 Central Dogma in Biology PART1. 생물정보학 How do we measure DNA, RNA, and proteins? 가장중요한질문은 DNA, RNA, and Proteins 을전체세포에서우리가측정할수있느냐하는것

2 DNA Sequencing The 1 st Whole enome Sequencing 5 6 Human enome Sequencing (2001) Bioinformatics Whole genome sequencing은많은양의데이터를만들었으며, 짧은 DNA 단편을연결할수있도록하는정교한알고리즘을필요로하게됨. whole genome sequencing 이시작되면서 Bioinformatics 라는용어를만들어짐. 생물정보는게놈프로젝트의 설계 단계에서필요에의해시작된학문. ( 이전에도수학, 컴퓨터를이용한생물연구는많이되어있었다 (computational or mathematical biology). 이에대한차이는나중에논의함 )

DNA to RNA We have sequences of genomes. Now what? http://en.wikipedia.

3 DNA to RNA We have sequences of genomes. Now what? RNA are from DNA but they are cell, condition speci fic. Can we measure RNA? 9 10 Need for Very High Throughput Sequencing Technology Revolution Again 다양한조건에서 RNA 측정하기위해서는여러번 sequencing 을해야함. 많은사람 ( 유전체집단 ) 의서열을필요로함. 인간게놈프로젝트는과학사에서 2 번째로많은비용이들어간프로젝트임. 이렇게많은비용이들어가는 sequencing 을여러번할수있을까?

4 Bioinformatics vs. Computational Biology NS can measure genome wide genetic and epigenetic data. Computational Biology 1960 s DATA! DATA! Bioinformatics 1990 s Bioinformatics & Computational Biology 2010 s Availability of Data and Bioinformatics 차세대또는 3세대시퀀싱기술은세포내부의메커니즘데이터를측정할수있음. 20년이상개발되어온여러 computational bioinformatics 방법들은세포내부의데이터를분석하는데사용될수있음. 맟춤의학

enetic and Epigenetic Elements Transcription

islands Coding genes Histone modifications Long

5 enetic and Epigenetic Elements Transcription factors DNA methylation mrna Micro RNAs Cp islands Coding genes Histone modifications Long nc RNAs Data Measurement from Cell Surface to DNA Data Can be Measured! Is a gene there? enome sequencing Is the gene disease susceptible? SNP, WAS Is the gene active? Epigenomics Are proteins made? Proteomics Are proteins functional (or mal functional)? PTMs: glycomics and glycoproteomics Mass Spectrometry 19 High throughput sequencing technology lycan microarray 20 5

Medical images, etc enome Sequence Phenotype Susceptibilty, Static Year 1 Year 2 Year 3.

6 What Is Happening? Comparing Patients to DB Before treatment Human enome Sequencing Physical observation 혈압, Cholesterol, Medical images, etc enome Sequence Phenotype Susceptibilty, Static Year 1 Year 2 Year 3... enomics, Epigenomics Proteomics, lycomics Treatment Day1, Week 1, Month, etc Susceptibilty, 유전체학, Dynamics Beyond Human 후생유전체학 enome Sequencing 단백질체학, lycomics 21 Year k 22 생물정보학협동과정 서울대생물정보연구소

7 유전학 (genomics) 개요 Central Dogma in Biology Central dogma Cell Computer DNA base Code bit RNA transcription translation Compiling How do we measure DNA, RNA, and proteins? Protein Executive program

8 Chromosome( 염색체 ) DNA 들의집합체 A C C A C A C A C C A 29 ENE ( 유전자 ) 특정 Protein 이나 RNA 를 encoding 하는염색체상의서열집합 ene Chromosome 30 enome 개체를대표하는 chromosome 들의합 enome Variation enetic variations (SNP, single nucleotide polymorphism) ene fusion Alternative splicing enome re arrangement Copy number variations

VARIATIONS ENOME VARIATIONS 단일염기다형성 (single nucleotide polymorphisms SNPs) DNA 염기서열에서하나의염기서열 (A,T,,C)

9 enetic Variations enetic Variation( 유전자변이 ) 유전자변이는사람의 46개염색체각각에서나타날수있지만, 모든염색체에서고르게나타나는것은아님. 유전자변이는돌연변이와다형성 (polymorphisms ) 을포함 Human genome variation 의 90% 가단일염기다형성 (SNPs) 의형태로나타남 ENOME VARIATIONS ENOME VARIATIONS 단일염기다형성 (single nucleotide polymorphisms SNPs) DNA 염기서열에서하나의염기서열 (A,T,,C) 의차이를보이는유전적변이 대략 1,000개의염기마다 1개꼴로나타남 전체 DNA의 0.1% SNP는질병과관련된유전자연구, 의약관련연구 ( 개인맞춤의약 ) 의매우중요한도구 암, 심장병, 정신병등다양한질병과관련 특정약물에대한개개의반응성파악및최적의약물개발등

ENOME VARIATIONS dbsnp dbsnp 는생명체에서연구되어진단일염기다형성과관련된모든자료를저장, 관리하는데이터베이스 dbsnp 는임상적으로의미있는인간의변이뿐만아니라양성 polymorphisms도포함하며, 연구자들로부터받은자료들을모아저장하기도함. 다형성의종류와대립유전자의정보제공 http://www.ncbi.nlm.nih.

10 ENOME VARIATIONS dbsnp dbsnp 는생명체에서연구되어진단일염기다형성과관련된모든자료를저장, 관리하는데이터베이스 dbsnp 는임상적으로의미있는인간의변이뿐만아니라양성 polymorphisms도포함하며, 연구자들로부터받은자료들을모아저장하기도함. 다형성의종류와대립유전자의정보제공 Build 135: in 1000 genomes, submitted SNP= 57,911,353 reference SNP (unique SNP) =39,484, enome Rearrangement genome rearrangements 의 3 가지유형 enome re arrangement pdf

Massive enomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development 2%~3% 의암은특정유전체영역에서 10 100s 의재배열을보임.

Cell, Volume 144, Issue 1, 27 40, 7 January 2011 ene Fusion 41 42 ene Fusion ene Fusion and Cancer 서로다른두개의유전자가결합한것 Translocation, interstitial deletion 또는 chromosomal inversion

11 Massive enomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development 2%~3% 의암은특정유전체영역에서 s 의재배열을보임. 모든종양에서발견됨 특히, bone cancers( 최대 25%) 암을유발할수있는 genomic lesions 을만들기도함. Cell, Volume 144, Issue 1, 27 40, 7 January 2011 ene Fusion ene Fusion ene Fusion and Cancer 서로다른두개의유전자가결합한것 Translocation, interstitial deletion 또는 chromosomal inversion 등에의해발생할수있음. Fusion gene은 oncogenes이기도함. 대부분의 fusion genes은혈액암, 육종 (sarcomas), 전립선암에서발견됨. Oncogenic fusion genes은원래의유전자와다른혹은새로운기능을갖는유전자를만들기도함 RAF gene fusion breakpoints in pediatric brain tumors are characterized by significant enrichment of sequence microhomology enome Res :

Eukaryotic ene Alternative splicing Adapted in part from http://online.itp.ucsb.

하나의유전자로부터다양한단백질이만들어질수있음 Alternative splicing event의약80% 이상이단백질수준에서의변화 진화적인관점에서보면 Alternative

12 Eukaryotic ene Alternative splicing Adapted in part from Alternative splicing Alternative splicing of gene Alternative splicing 의역할 하나의유전자로부터다양한단백질이만들어질수있음 Alternative splicing event의약80% 이상이단백질수준에서의변화 진화적인관점에서보면 Alternative splicing이진핵생물체의표현형적다양성에관여 많은인간질병이 Alternative splicing에의해유발 Pre mrna 는서로다른 splice 결합을통해두개이상의 mrna molecules 을만듦. 사람의경우 multi exon gene 의 95% 에서 alternatively splice 가일어남

Alternative Splicing http://www.cs.uni.edu/~fienup/cs188s05/lectures/lec25_4 19 05.

유전자복제수변이 (Copy Number Variations) Reference 유전체와비교하여 copy number의차이를보이는 1kb의 DNA 조각 유전자의삭제

CNVs는수백bp~ 약 1Mb에이르는염기서열이결실되거나증폭되는변이로, 이로인해특정유전자의숫자가사람마다달라지게됨. 각각다른사람의 genome은대략0.

13 Alternative Splicing htm Copy number variations ( 유전자복제수변이 ) Copy Number Variations Copy Number Variations 유전자복제수변이 (Copy Number Variations) Reference 유전체와비교하여 copy number의차이를보이는 1kb의 DNA 조각 유전자의삭제 (deletions), 중복 (duplications), 역위 (inversions) 그리고전좌 (translocations) 와같은유전체의구조적재배열에의해일어날수있음. CNVs는수백bp~ 약 1Mb에이르는염기서열이결실되거나증폭되는변이로, 이로인해특정유전자의숫자가사람마다달라지게됨. 각각다른사람의 genome은대략0.4% 의 copy number가다를것으로예상됨. CNVs는질병에대한직접적인원인혹은감수성 (susceptibility) 인자로작용 알츠하이머병, 크론병, 파킨슨병, 자폐증등 CNVs는암세포와관련

14 enomics and Disease Epigenomics ( 후성유전체학 ) Epigenomics Epi (epi on; upon) + genomics Yes, it is a control mechanism for genomic elements (e.g., genes). DNA methylation Histone modification microrna, long non coding RNA

What is Epigenomics? enomics : Hardware Epi genomics : Software NOVA Science http://www.

org/asset/biot09_vi d_epigenetics/ A group of modifications at genetic level Epigenome tells

15 What is Epigenomics? enomics : Hardware Epi genomics : Software NOVA Science d_epigenetics/ A group of modifications at genetic level Epigenome tells body how to work and when to work DNA Methylation DNA methylation 고등동물의정상적인기관의발달과세포분화에있어서중요한부분 DNA methylation

DNA Methylation and ene Silencing in Cancer Cells DNA

2 3 4 M C M C M C M C C C C Cancer 1 2 3 4 X Bio & Health

National cancer center institute 62 Histone modification

바느질할때실패의실을풀어서사용하는것처럼 30 억 bp DNA( 실 ) 는실패 ( 히스톤 ) 에감겨져있음.

Chromatin regulation Histone modifications은유전자발현및세포사멸조절,

16 DNA Methylation and ene Silencing in Cancer Cells DNA Methylation and Cancer Cp island CC C C C M C M C Normal M C M C M C M C C C C Cancer X Bio & Health Informatics Lab, SNU C: cytosine m C: methylcytosine 61 National cancer center institute 62 Histone modification Histone and DNA 핵내DNA와결합하고있는염기성단백질 실을실패에감싸서실이엉키지않도록보관하고, 바느질할때실패의실을풀어서사용하는것처럼 30 억 bp DNA( 실 ) 는실패 ( 히스톤 ) 에감겨져있음. 2m길이의 DNA를눈에보이지않을만큼작은세포속에저장가능. 응축된후에는 5000배가까이짧아짐. Chromatin regulation Histone modifications은유전자발현및세포사멸조절, DNA 복제및수선, 체세포분열등과같은생물학적기작에관여

Histone modifications: Histone Code microrna Nature

v.s. protein coding gene Roles of MicroRNA in Cancer

suppressors( 종양억제 ) MicroRNAs as modulators of tumor

deregulation of micrornas in cancer http://www.

17 Histone modifications: Histone Code microrna Nature Reviews enetics 8, (April 2007) microrna.v.s. protein coding gene Roles of MicroRNA in Cancer MicroRNAs as oncogenes( 발암유전자 ) MicroRNAs as tumor suppressors( 종양억제 ) MicroRNAs as modulators of tumor progression and metastasis( 종양진행및전이조절자 ) lobal deregulation of micrornas in cancer Ventura and Jacks, Cell Feb 20;136(4):

18 Cancer epigenetics reaches mainstream oncology Acknowledgement 장현숙, 유정현 서울대학교생물정보연구소 Nature Medicine (2011)

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Can032.hwp Chromosomal Alterations in Hepatocellular Carcinoma Cell Lines Detected by Comparative Genomic Hybridization Sang Jin Park 1, Mahn Joon Ha, Ph.D. 1, Hugh Chul Kim, M.D. 2 and Hyon Ju Kim, M.D. 1 1 Laboratory