年輔仁大學 年輔仁大學轉譯醫學人才培育計畫 轉譯醫學人才培育計畫

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2011/ 8/

2011/ 8/

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100 100 年輔仁大學 年輔仁大學 轉譯醫學人才培育計畫 轉譯醫學人才培育計畫

 Genomics is “the study of functions and interactions Genomics is “the study of functions and interactions of all the genes in the genome, including their

of all the genes in the genome, including their interactions with environmental factors.”

interactions with environmental factors.”

(Source: Collins, Francis, and Alan Guttmacher. “Genomic Medicine—A Primer,” NEJM, Vol. 347:1512-1520.)(Source: Collins, Francis, and Alan Guttmacher. “Genomic Medicine—A Primer,” NEJM, Vol. 347:1512-1520.)

 A genome is “all the DNA contained in an organism or A genome is “all the DNA contained in an organism or a cell, which includes both the chromosomes within a cell, which includes both the chromosomes within

the nucleus and the DNA in mitochondria… all our the nucleus and the DNA in mitochondria… all our

genes together.”

genes together.”

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The genome is our Genetic Blueprint The genome is our Genetic Blueprint

Brief review of genomics- regarding to HGP Brief review of genomics- regarding to HGP

U.S. Department of Energy Human Genome Project ~ www.ornl.gov/hgmis

• Collection of Collection of DNA molecules DNA molecules that carries the “ that carries the “ book of life book of life ” of ” of each organism.

each organism.

• In single-cell organisms the genome is one In single-cell organisms the genome is one circular circular DNA molecule. DNA molecule.

• In multi-cell organisms the genome is packaged in several In multi-cell organisms the genome is packaged in several chromosomes

chromosomes and every cell has a complete genome. and every cell has a complete genome.

大英百科全書

Human Genome

26 英文字母 四種核甘酸

23 卷 23 對染色體

200,000 篇文章 35,000 基因

兩億個字元 30 億鹼基對

8.5”×12×20,000 頁 長 ~2 m× 直徑 100 Å

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CACACTTGCATGTGAGAGCTTCTAATATCTAAATTAATGTTGAATCATTATTCAGAAACAGAGAGCTAACTGTTATCCCATCCTGACTTTATTCTTTATG AGAAAAATACAGTGATTCC AAGTTACCAAGTTAGTGCTGCTTGCTTTATAAATGAAGTAATATTTTAAAAGTTGTGCATAAGTTAAAATTCAGAAATAAAACTTCATCCTAAAACTCTGTGTGTTGCTTTAAATAATC AGAGCATCTGC TACTTAATTTTTTGTGTGTGGGTGCACAATAGATGTTTAATGAGATCCTGTCATCTGTCTGCTTTTTTATTGTAAAACAGGAGGGGTTTTAATACTGGAGGAACAA CTGATGTACCTCTGAAAAGAGA AGAGATTAGTTATTAATTGAATTGAGGGTTGTCTTGTCTTAGTAGCTTTTATTCTCTAGGTACTATTTGATTATGATTGTGAAAATAGAATTTATCC CTCATTAAATGTAAAATCAACAGGAGAATAGCAAAAACTTATGAGATAGATGAACGTTGTGTGAGTGGCATGGTTTAATTTGTTTGGAAGAAGCACTTGCCCCAGAAGATACACAAT GAAATTCATGTTATTGAGTAGAGTAGTAATACAGTGTGTTCCCTTGTGAAGTTCATAACCAAGAATTTTAGTAGTGGATAGGTAGGCTGAATAACTGACTTCCTATC ATTTTCAGGTT CTGCGTTTGATTTTTTTTACATATTAATTTCTTTGATCCACATTAAGCTCAGTTATGTATTTCCATTTTATAAATGAAAAAAAATAGGCACTTGCAAATGTCAGATCACTTGCCTGTGGT CATTCGGGTAGAGATTTGTGGAGCTAAGTTGGTCTTAATCAAATGTCAAGCTTTTTTTTTTCTTATAAAATATAGGTTTTAATATGAGTTTTAAAATAAAATTAATTAGAAAAAGGCAA ATTACTCAATATATATAAGGTATTGCATTTGTAATAGGTAGGTATTTCATTTTCTAGTTATGGTGGGATATTATTCAGACTATAATTCCCAATGAAAAAACTTTAAAAAATGCTAGTGA TTGCACACTTAAAACACCTTTTAAAAAGCATTGAGAGCTTATAAAATTTTAATGAGTGATAAAACCAAATTTGAAGAGAAAAGAAGAACCCAGAGAGGTAAGGATATAACCTTACC AGTTGCAATTTGCCGATCTCTACAAATATTAATATTTATTTTGACAGTTTCAGGGTGAATGAGAAAGAAACCAAAACCCAAGACTAGCATATGTTGTCTTCTTAAGGAGCCCTCCCCT AAAAGATTGAGATGACCAAATCTTATACTCTCAGCATAAGGTGAACCAGACAGACCTAAAGCAGTGGTAGCTTGGATCCACTACTTGGGTTTGTGTGTGGCGTGACTCAGGTAATCT CAAGAATTGAACATTTTTTTAAGGTGGTCCTACTCATACACTGCCCAGGTATTAGGGAGAAGCAAATCTGAATGCTTTATAAAAATACCCTAAAGCTAAATCTTACAATATTCTCAAG AACACAGTGAA ACAAGGCAAAATAAGTTAAAATCAACAAAAACAACATGAAACATAATTAGACACACAAAGACTTCAAACATTGGAAAATACCAGAGAAAGATAATAAATAT TTTACTCTTTAAAAATTTAGTTAAAAGCTTAAACTAATTGTAGAGAAAA AACTATGTTAGTATTATATTGTAGATGAAATAAGCAAAACATTTAAAATACAAATGTGATTACTTAAAT TAAATATAATAGATAATTTACCACCAGATTAGATACCATTGAAGGAATAATTAATATACTGAAATACAGGTCAGTAGAATTTTTTTCAATTCAGCATGGAGATGTAAAAAATGAAAA TTAATGCAAAAAATAAGGGCACAAAAAGAAATGAGTAATTTTGATCAGAAATGTATTAAAATTAATAAACTGGAAATTTGACATTTAAAAAAAGCATTGTCATCCAAGTAGATGTG TCTATTAAATAGTTGTTCTCATATCCAGTAATGTAATTATTATTCCCTCTCATGCAGTTCAGATTCTGGGGTAATCTTTAGACATCAGTTTTGTCTTTTATATTATTTATTCTGTTTACTAC ATTTTATTTTGCTAATGATATTTTTAATTTCTGACATTCTGGAGTATTGCTTGTAAAAGGTATTTTTAAAAATACTTTATGGTTATTTTTGTGATTCCTATTCCTCTATGGACACCAAGGCT ATTGACATTTTCTTTGGTTTCTTCTGTTACTTCTATTTTCTTAGTGTTTATATCATTTCATAGATAGGATATTCTTTATTTTTTATTTTTATTTAAATATTTGGTGATTCTTGGTTTTCTCAGCC ATCTATTGTCAAGTGTTCTTATTAAGCATTATTATTAAATAAAGATTATTTCCTCTAATCACATGAGAATCTTTATTTCCCCCAAGTAATTGAAAATTGCAATGCCATGCTGCCATGTGG TACAGCATGGGTTTGGGCTTGCTTTCTTCTTTTTTTTTTAACTTTTATTTTAGGTTTGGGAGTACCTGTGAAAGTTTGTTATATAGGTAAACTCGTGTCACCAGGGTTTGTTGTACAGATCA TTTTGTCACCTAGGTACCAAGTACTCAACAATTATTTTTCCTGCTCCTCTGTCTCCTGTCACCCTCCACTCTCAAGTAGACTCCGGTGTCTGCTGTTCCATTCTTTGTGTCCATGTGTTCTC ATAATTTAGTTCCCCACTTGTAAGTGAGAACATGCAGTATTTTCTAGTATTTGGTTTTTTGTTCCTGTGTTAATTTGCCCAGTATAATAGCCTCCAGCTCCATCCATGTTACTGCAAAGAA CATGATCTCATTCTTTTTTATAGCTCCATGGTGTCTATATACCACATTTTCTTTATCTAAACTCTTATTGATGAGCATTGAGGTGGATTCTATGTCTTTGCTATTGTGCATATTGCTGCAAG AACATTTGTGTGCATGTGTCTTTATGGTAGAATGATATATTTTCTTCTGGGTATATATGCAGTAATGCGATTGCTGGTTGGAATGGTAGTTCTGCTTTTATCTCTTTGAGGAATTGCCATG CTGCTTTCCACAATAGTTGAACTAACTTACACTCCCACTAACAGTGTGTAAGTGTTTCCTTTTCTCCACAACCTGCCAGCATCTGTTATTTTTTGACATTTTAATAGTAGCCATTTTAACT GGTATGAAATTATATTTCATTGTGGTTTTAATTTGCATTTCTCTAATGATCAGTGATATTGAGTTTGTTTTTTTTCACATGCTTGTTGGCTGCATGTATGTCTTCTTTTAAAAAGTGTCTGTT CATGTACTTTGCCCACATTTTAATGGGGTTGTTTTTCTCTTGTAAATTTGTTTAAATTCCTTATAGGTGCTGGATTTTAGACATTTGTCAGACGCATAGTTTGCAAATAGTTTCTCCCATTC TGTAGGTTGTCTGTTTATTTTGTTAATAGTTTCTTTTGCTATGCAGAAGCTCTTAATAAGTTTAATGAGATCCTGATATGTTAGGCTTTGTGTCCCCACCCAAATCTCATCTTGAATTATA TCTCCATAATCACCACATGGAGAGACCAGGTGGAGGTAATTGAATCTGGGGGTGGTTTCACCCATGCTGTTCTTGTGATAGTGAATGAGTTCTCACGAGATCTAATGGTTTTATGAGG GGCTCTTCCCAGCTTTGCCTGGTACTTCTCCTTCCTGCCGCTTTGTGAAAAAGGTGCATTGCGTCCCTTTCACCTTCTTCTATAATTGTAAGTTTCCTGAGGCCTTCCCAGCCATGCTGAA CTTCAAGTCAATTAAACCTTTTTCTTTATAAATTACTCAGTCTCTGGTGGTTCTTTATAGCAGTGTGAAAATGGACTAATGAAGTTCCCATTTATGAATTTTTGCTTTTGTTGCAATTGCTT TTGACATCTTAGTCATGAAATCCTTGCCTGTTCTAAGTACAGGACGGTATTGCCTAGGTTGTCTTCCAGGGTTTTTCTAATTTTGTGTTTTGCATTTAAGTGTTTAATCCATCTTGAGTTGA TTTTTGTATATTGTGTAAGGAAGGGGTCCAGTTTCAATCTTTTGCATATGGCTAGTTAGTTATCCCAGTACCATTTATTGAAAAGACAGTCTTTTCCCCATCGCTCGTTTTTGTCAGTTTT ATTGATGATCAGATAATCATAGCTGTGTGGCTTTATTTCTGGGTTCTTTATTCTGTTCTATTGGTTTATGTCCCTGTTTTTGTGCCAGTACCATGCTGTTTTGGTTAACATAGCCCTGTAGT ATAGTTTGAGGTCAGATAGCCTGATGCTTCCAGCTTTGTTCTTTTTCTTAAGATTGCCTTGGCTATTTGGCCTCTTTTTTGGTTCCACATGAATTTTAAAACAGTTGTTTCTAGTTTTTGAA GAATGTCATTGGTAGTTTGATAGAAATAGCATTTAATCTGTAAATTGATTTGTGCAGTATGGCCTTTTAATGATATTGATTCTTCCTATCCATGAGCATGATATGTTTTCCATTTTGTTTG TATCCTCTCTGATTTCTTTGTGCAGTGTTTTGTAATTCTCAT TGTAGAGATTTTTCACCTCCCTGGTTAGTTGTATTTTACCCTAGATATTT TATTCTTTTTGTGAAAATTGTGAATGGGAT TGCCTTCCTGATTTGACTGC CAGCTTGGTTACTGTTGGTTTATAGAAATGCTAGTGATTTTTGTACATTG ATTTTCTTTCTAAAACTTTGCTGAAGTTTTTTTTATTAGCAGAAGGAGCT TTGGGGCTGAGACTATGGGGTTTTCTAGATATAGAATCATGTCAGCTTCAAATAGGGATAATTTTACTTCCTCTCTTCCTATTTGGATGCCCTTTATTTCTTTCTCTTGCCTGATTACTCTG

5000 bases per page 5000 bases per page

Brief review of genomics- regarding to HGP Brief review of genomics- regarding to HGP

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Fully understanding the genome of us will improve to Fully understanding the genome of us will improve to

identify and investigate the unknown genes, which identify and investigate the unknown genes, which

may benefit the research of human health.

may benefit the research of human health.

* Genome sequencing projects!

* Genome sequencing projects!

1. 1. Genomic mapping. Genomic mapping.

2. 2. Genetic mapping. Genetic mapping.

3. 3. Physical mapping. Physical mapping.

4. 4. Nucleotide or Nucleotide or

Genome sequencing.

Genome sequencing.

How?

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Genomic mapping Genomic mapping

The chromosome content of an organism (its

karyotype

karyotype ) )

can be visualized using a microscope.

~ Different chromosomes are usually different

~ Different chromosomes are usually different sizes

sizes (ranging in the human from 279x10 (ranging in the human from 279x10

bp for bp for chromosome 1 to 45x10

chromosome 1 to 45x10

bp for chromosome 21). bp for chromosome 21).

~ distinct chromosome banding patterns.

~ distinct chromosome banding patterns.

(Giemsa stain) (Giemsa stain) shorter arm

shorter arm

longer arm longer arm

Cytological map

Cytological map (low resolution) (low resolution)

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Some chromosome abnormalities that cause inherited Some chromosome abnormalities that cause inherited

genetic diseases can be observed by karyotype analysis.

genetic diseases can be observed by karyotype analysis.

e.g. Down’s Sydrome (trisomy 21) e.g. Down’s Sydrome (trisomy 21)

Klinefelter’s syndrome (47XXY) Klinefelter’s syndrome (47XXY)

* Cystic fibrosis

* Cystic fibrosis   chromosome 7q31; CFRT chromosome 7q31; CFRT

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The different types of cytological, genetic and The different types of cytological, genetic and

physical map of a chromosome.

physical map of a chromosome.

cM: centiMorgan

cM: centiMorgan Mbp: Megabase pairs Mbp: Megabase pairs

曼哈頓計劃導致了核武器

曼哈頓計劃導致了核武器

若要探索生命的奧秘，就必須解讀出人體的 若要探索生命的奧秘，就必須解讀出人體的 DNA DNA 密碼。而解開人類 密碼。而解開人類 所有 所有 DNA DNA 序列的構想，最早是由科學家 序列的構想，最早是由科學家 Renato Dulbecco Renato Dulbecco 在 在 1985 1985 年時提 年時提 出，而美國政府隨後在

出，而美國政府隨後在 1990 1990 年正式地推行，預計耗資 年正式地推行，預計耗資 30 30 億美元，透過國 億美元，透過國 際實驗室的合作，用

際實驗室的合作，用 15 15 年時間，描繪出人類基因體的遺傳圖和物理圖，並 年時間，描繪出人類基因體的遺傳圖和物理圖，並 且定出人類

且定出人類 DNA DNA 的全部核苷酸序列，，並對其它的生物進行類似的研究。 的全部核苷酸序列，，並對其它的生物進行類似的研究。

　　在各國的通力合作下，提前在

　　在各國的通力合作下，提前在 2000 2000 年完成 年完成 了人類基因的定序草圖，並將基因資訊公開在美 了人類基因的定序草圖，並將基因資訊公開在美 國國家生物資訊中心（

國國家生物資訊中心（ NCBI NCBI ）的基因資料庫裡 ）的基因資料庫裡

，提供所有科學家查詢的服務。

，提供所有科學家查詢的服務。人類基因體計畫 人類基因體計畫 (Human Genome Project)

(Human Genome Project) 、 、 曼哈頓計畫 曼哈頓計畫 與阿波 與 阿波 羅登月計畫

羅登月計畫並稱為人類科學史上的三大工程 並稱為人類科學史上的三大工程，表 ，表

示其具有重大科學意義以及社會效益。此外，基

示其具有重大科學意義以及社會效益。此外，基

因體計畫的實施，也有助於促進一系列生命科學

因體計畫的實施，也有助於促進一系列生命科學

的發展，對於生命的起源、演化、細胞發育、分

的發展，對於生命的起源、演化、細胞發育、分

化及疾病發生等研究，提供了很好的參考資料 。

化及疾病發生等研究，提供了很好的參考資料 。

11 ¹¹¹¹ James D. Watson

Brief review of genomics- regarding to HGP Brief review of genomics- regarding to HGP

 A public-private collaborative, supported by A public-private collaborative, supported by the National Institutes of Health and the U.S.

the National Institutes of Health and the U.S.

Department of Energy, that is mapping all Department of Energy, that is mapping all

human genes.

human genes. (3x10 (3x10

bp) bp)

 The final draft of the genome The final draft of the genome

was published in April 2003. was published in April 2003.

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How to sequence the genome?

How to sequence the genome?

How to reconstruct the original genome sequence How to reconstruct the original genome sequence

based on the small fragments that are cloned based on the small fragments that are cloned

into individual vectors?

into individual vectors?

Strategies Strategies

  Whole genome shotgun Whole genome shotgun

  Hierarchical shotgun Hierarchical shotgun

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Whole genome shotgun (WGS) Whole genome shotgun (WGS)

~ the fragments of the

~ the fragments of the genome, which have been genome, which have been randomly generated

randomly generated , are , are

cloned into a vector and each cloned into a vector and each insert is sequenced.

insert is sequenced.

  the sequence is then the sequence is then

examined for overlaps and the examined for overlaps and the genome is reconstructed by genome is reconstructed by assembling the overlapping assembling the overlapping sequences together.

sequences together.

- was first used to sequence the genome of the bacterium

- was first used to sequence the genome of the bacterium

Haemophilus influenzae. Haemophilus influenzae.

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* Contig:

* Contig:

~ ~ contiguous sequence of DNA contiguous sequence of DNA created by assembling created by assembling

overlapping sequenced fragments of a chromosome. overlapping sequenced fragments of a chromosome.

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Hierarchical shotgun Hierarchical shotgun

-- --

preferred by the Human Genome Project

In this approach, genomic DNA In this approach, genomic DNA is cut into pieces of about

is cut into pieces of about 150 150 Mb Mb and and inserted into BAC inserted into BAC

vectors

vectors , transformed into , transformed into E. E.

coli coli where they are replicated where they are replicated and stored.

and stored.

Each BAC fragment is Each BAC fragment is

fragmented randomly into fragmented randomly into

smaller pieces and each piece is smaller pieces and each piece is cloned into a plasmid and

cloned into a plasmid and sequenced on both strands.

sequenced on both strands.

These sequences are aligned so These sequences are aligned so that identical sequences are that identical sequences are overlapping.

overlapping.

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Two general strategies for sequencing a complete genome.

Two general strategies for sequencing a complete genome.

1980-1990 1990-2005 > 2005

Radio - gel Fluorescent - capillary Next generation Thousand bp/day Million bp/day Billion bp/day

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DNA sequencing: Sanger’s method DNA sequencing: Sanger’s method

~ dideoxynucleotide

~ dideoxynucleotide

~ based upon the faithful replication of

~ based upon the faithful replication of DNA using a DNA DNA using a DNA

polymerase. polymerase.

Chain termination by ddNTP.

Chain termination by ddNTP.

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Pyrosequencing Pyrosequencing

The sequencing reaction The sequencing reaction contains template, primer, contains template, primer, DNA polymerase, sulfurylase, DNA polymerase, sulfurylase, luciferase and other co-

luciferase and other co- factors, but no dNTPs.

factors, but no dNTPs.

A four-base “

A four-base “ tag tag ” is added ” is added to all DNA fragment,

to all DNA fragment, which which is read first and is used to is read first and is used to

calibrate the sequencing calibrate the sequencing

reaction, i.e.

reaction, i.e. to determine to determine the level of light emission the level of light emission

due to incorporation of one due to incorporation of one

nucleotide

nucleotide . .

From a public health perspective, genomics is the From a public health perspective, genomics is the

study of the gene-environment-host interaction study of the gene-environment-host interaction that leads to disease — or disease prevention — that leads to disease — or disease prevention —

in populations.

in populations.

 Rare diseases

 Single gene disorders

 Public health activities

 Newborn screening

 Reproductive health

 Genetic services

 Common diseases Common diseases

 Multiple genes Multiple genes

 Gene/environment interactions Gene/environment interactions

 Public health activities Public health activities /implications

/implications

 Chronic diseases Chronic diseases

 Infectious diseases Infectious diseases

 Environmental health Environmental health

 Epidemiology Epidemiology

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 Genetic mutations have been identified that Genetic mutations have been identified that play a role in:

play a role in:

 Chronic diseases Chronic diseases

 Cancer Cancer

 Cardiovascular disease Cardiovascular disease

 Occupational diseases Occupational diseases

 Bladder cancer Bladder cancer

 Infectious diseases Infectious diseases

 HIV/AIDS HIV/AIDS

 Genetic testing Genetic testing

 To detect mutations To detect mutations

 For disease diagnosis and prognosis For disease diagnosis and prognosis

 For the prediction of disease risk in individuals or For the prediction of disease risk in individuals or families

families

 Several hundred genetic tests are in use. Several hundred genetic tests are in use.

 Rare genetic disorders (muscular Rare genetic disorders (muscular

dystrophies, cystic fibrosis, Huntington’s dystrophies, cystic fibrosis, Huntington’s

disease) disease)

 Complex conditions (breast, ovarian, Complex conditions (breast, ovarian, and colon cancers)

and colon cancers)

 Pharmacogenomics Pharmacogenomics

 The development of drugs tailored to specific The development of drugs tailored to specific subpopulations based on genes

subpopulations based on genes

 Pharmacogenomics has the potential to: Pharmacogenomics has the potential to:

 Decrease side effects of drugs Decrease side effects of drugs

 Increase drug effectiveness Increase drug effectiveness

 Make drug development faster and less costly Make drug development faster and less costly

 Recent research in genomics includes: Recent research in genomics includes:

 Learning more about the genetic Learning more about the genetic underpinnings of chronic diseases underpinnings of chronic diseases

 Developing mouse models of human genes Developing mouse models of human genes

 Developing genetic fingerprinting Developing genetic fingerprinting for childhood cancer

for childhood cancer

 Conducting stem cell research Conducting stem cell research

 Identifying tumor suppressor genes Identifying tumor suppressor genes

 Policy developments related to Policy developments related to genomics include:

genomics include:

 Activities related to anti-discrimination and Activities related to anti-discrimination and ethics

ethics

 Expanded newborn screening Expanded newborn screening

 New funding for research on rare diseases New funding for research on rare diseases

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The Human Genome Project Timeline contains major The Human Genome Project Timeline contains major

milestones in genomics from 1865 to 2003.

milestones in genomics from 1865 to 2003.

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- - Expression Arrays Expression Arrays - Protein microarrays

- Protein microarrays (Proteomics) (Proteomics) - Resequencing arrays

- Resequencing arrays - CGH arrays-

- CGH arrays- Comparative genomic hybridization Comparative genomic hybridization - SNP Arrays

- SNP Arrays

- Antibody Arrays - Antibody Arrays

- Exon arrays-Alternative splice variant - Exon arrays-Alternative splice variant detection detection

- Tissue Arrays - Tissue Arrays

Array-based methods: Microarray

Alteration in DNA Copy Number:

Alteration in DNA Copy Number:

amplification and deletion amplification and deletion

 Abnormal quantity of appearance of a genomic Abnormal quantity of appearance of a genomic region in the genome.

region in the genome.

 Size: single gene - whole chromosome Size: single gene - whole chromosome

 Abnormality: deletion – amplification Abnormality: deletion – amplification

 Some variations among normal individuals Some variations among normal individuals

 Can cause defects in human development Can cause defects in human development

 Contributors to cancer Contributors to cancer

 Can effect function and gene expression Can effect function and gene expression

Molecular Biology of the Cell, Alberts et. al. (4th eddition, figure 23-33 (

Molecular Biology of the Cell, Alberts et. al. (4th

eddition, figure 23-28 (

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35

36 from T. Ried, NEJM, 2004

Comparative Genomic Hybridization

chromosomal in situ suppression (CISS) hybridization to normal metaphase chromosome

spreads

Loss Gain Gain

R at io o f F IT C /T R IT C

Copy Number Change

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 Ideally, the signal intensity Ideally, the signal intensity is proportional to copy

is proportional to copy number

number

 Several genomes can be Several genomes can be compared simultaneously compared simultaneously

 Goal: Goal: to detect copy number alterations using a to detect copy number alterations using a gene chip

gene chip