The Human Genome Project-SEPCHE_NO_FIGS-1

8/2/2019 The Human Genome Project-SEPCHE_NO_FIGS-1

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The Human GenomeProject:The Holy Grail of Biology

Sherry Fuller-Espie, 2002


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What is the Human Genome?

The entire geneticmakeup of the humancell nucleus.

Genes carry theinformation for makingall of the proteinsrequired by the body forgrowth and

maintenance.

The genome alsoencodes rRNA andtRNA which are

involved in proteinsynthesis.


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Made up of ~35,000-50,000 genes

which code for functional proteins inthe body.

Includes non-coding sequences

located between genes, whichmakes up the vast majority of theDNA in the genome (~95%).


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The particular order of nucleotidebases (As, Gs, Cs, and Ts)determines the amino acidcomposition of proteins.

Information about DNA variations

(polymorphisms) among individualscan lend insight into newtechnologies for diagnosing, treating,and preventing diseases that afflicthumankind.


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What Goals Were Established

for the Human Genome Project

When it Began in 1990?

Identify all of the genes in human DNA.

Determine the sequence of the 3 billion

chemical nucleotide bases that make uphuman DNA.

Store this information in data bases.

Develop faster, more efficient sequencing

technologies. Develop tools for data analysis.

Address the ethical, legal, and socialissues (ELSI) that ay arise form the project.


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Two Different Groups Worked to

Obtain the DNA Sequence of the

Human Genome

The HGP is a multinational consortiumestablished by government researchagencies and funded publicly.

Celera Genomics is a private companywhose former CEO, J. Craig Venter, ran anindependent sequencing project.

Differences arose regarding who shouldreceive the credit for this scientificmilestone.

June 6, 2000, the HGP and CeleraGenomics held a joint press conference toannounce that TOGETHER they had

completed ~97% of the human genome.


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Published

The International Human GenomeSequencing Consortium publishedtheir results in Nature, 409 (6822):860-921, 2001.

Initial Sequencing and Analysis of theHuman Genome

Celera Genomics published theirresults in Science, Vol 291(5507):1304-1351, 2001. The Sequence of the Human Genome


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Which Branches of Biology

will Benefit from thisKnowledge?


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Medicine

Improvements in diagnostic and

therapeutic applicationsImplementation of preventative

measures.

Increases in gene therapyapplications.


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Biotechnology

Production of useful protein products foruse in medicine, agriculture,

bioremediation and pharmaceuticalindustries. Antibiotics

Protein replacement (factor VIII, TPA,streptokinase, insulin, interferon)

BT insecticide toxin (from Bacillusthuringiensis)

Herbicide resistance (glyphosate resistance)

Bioengineered foods [e.g. Flavr Savr tomato(antisensepolygalacturonase) to delayrotting]

Pharm animals


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Bioinformatics

The newest, fastest growing specialty inthe life sciences that integrates

biotechnology and computer science.Involved in DNA sequence assembly and

analysis using computer-basedtechniques to determine gene function,regulation and control.

Unknown gene sequences can becompared to databases of known genesto enable similarities to lead todetermination of an unknown genes

function.


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Proteomics

Investigates patterns and levels of

gene expression in diseased cellsthat can be analyzed to build

databases of expression profiles.


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Microarray Technology


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Microarray Results


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DNA Chip Technology


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Pharmacogenomics

Investigates DNA mutations

associated with diseasesusceptibility and drug

sensitivities.


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Developmental Biology

Regulation of embryonic

development.Regulation of the aging process.


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Evolutionary and

Comparative Biologists

Because DNA mutates at a

constant rate, comparisons of DNAbetween different organisms can

provide evolutionary histories.


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Mapping the Human Genome

Low Resolution Mapping

The Gene Linkage Map

Identifies position of genes by locatingmarker base sequences associated

with restriction fragment length

polymorphisms (RFLPs)


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Based on how close together twogenes are.

The closer together two genes are, theless likely they are to separate duringmeiotic recombination in germ cells.

The frequency of recombination betweentwo genes can help to decipher thedistance between them on a gene linkagemap.

Genes separated by more that 50cM arenot considered linked. (~50 million basepairs)


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Studies of families affected by genetic

disease have proven useful for geneticlinkage analyses (e.g. Huntingtons

disease, neurofibramatosis, cystic

fibrosis, Duchennes muscular

dystrophy).


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The Cytogenetic Map

Characteristic

banding patternsobserved on

metaphase-

arrested

chromosomes

after stainingwith dyes.


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Dyes bind only to transcriptionally activeregions of chromosomes.

Can increase sensitivity of a gene linkage

map by identifying expressed regions of a

chromosome.


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Mapping the Human Genome

High Resolution Mapping

The Physical MapProvides the actual distances in base

pairs between genes on a given

chromosome.Prepared by aligning the sequences of

adjacent DNA fragments from smalloverlapping clones to form a continuousmap called a contiguous map, or contigmap.

Sequence tag sites (STSs) mark sites onchromosomes and help to locateadjacent segments of DNA. (If two DNA

fragments share an STS, they overlap and arecontiguous.)


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1992 - Milestone

Combining STSs with megaYACs yieldshigh resolution maps of two humanchromosomes making up 2% of the total

human genome.

Daniel Cohen and coworkers publish a high-resolution physical map for human chromosome21.

David Page and coworkers publish a high-resolution physical map for the human Ychromosome (the chromosome found only inmales).


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How is the DNASequence Determined?


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The Sanger Dideoxy Chain-

Termination Method

Nucleotide analogs (calleddideoxynucleotides or ddNTP) areincorporated into DNA during its

synthesis together with normalnucleotides (called deoxynucleotidesor dNTP).

When a ddNTP is inserted, thereaction stops = chain termination.


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Radioactively Labeled

ddNTPs

Four differentreactions areperformed.

Each reactioncontains eitherddA, ddG, ddC, orddT.

Autoradiography

enable analysis ofdifferent fragmentlengths whichcorrespond todifferenttermination points.


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Fluorescently Labeled

ddNTPs

One reaction is carriedout.

All four ddNTPs are

incorporated in thesame reaction.

Each ddNTP is labeledwith a differentfluorescent dye (red,

green, yellow or blue). Automated DNA

sequencers interfacedwith computersdetermine the order ofthe dyes, and hence

the DNA sequence.


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Chromosome Walking

Analysis of DNA sequences ofchromosomes by extending thesequenced region a little bit further

each time until the tips of thechromosomes are reached.

The next round of sequencing isbased on the results of the previousround by synthesizing appropriateDNA primers to extend further.


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Other CompletedGenomes


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Completed Microbial

Genomes

Haemophilus

influenzae


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Completed Microbial

Genomes

Escherichia coli


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Completed Microbial

Genomes

Bacillus subtilus


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Completed Microbial

Genomes

Helicobacter

pylori


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Completed Microbial

Genomes

Borrelia

burgdorferi


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Completed Microbial

Genomes

Streptococcus

pneumoniae


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Completed Microbial

Genomes

Saccharomyces

cerevisiae

C l t d Mi bi l


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Completed Microbial

Genomes

Caenorhabditis

elegans

C l t d Mi bi l


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Others include:Archaeglobus fulgidus

Methanobacterium thermoautotrophicum

Methanococcus jannaschii

Mycoplasma pneumoniae

Mycoplasm genitaliu

Rickettsia prowazekii

Mycobacterium tuberculosis

Treponema pallidum

Staphylococcus aureus

And more!

Completed Microbial

Genomes

C l t d Pl t


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Completed Plant

Genomes

Arabidopsis

thaliana

C l t d I t


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Completed Insect

Genomes

Drosophila

melanogaster

C l t d R d t


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Completed Rodent

Genomes

Mus musculus


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Ethical, Legal and SocialIssues (ELSI)


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Examples of ELSI

Privacy legislation

Gene testing

Patenting

Forensics

Behavioral Genetics

Genetics in the Courtroom


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Societal Concerns

F i i th U f


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Fairness in the Use of

Genetic Information

Who should have access to thisinformation?

EmployersInsurers

Schools

Courts

Adoption agencies

Military


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Philosophical Implications

Human responsibility

Free will versus geneticdeterminism

Wh O d C t l


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Who Owns and Controls

Genetic Information?

How is privacy and confidentiality

managed?

Ps chological Impact


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Psychological Impact

and Stigmatization

Affects on the individual

Affects on societys perceptionsand expectations of the individual


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Clinical Issues

Growing demand to educate health careworkers to accurately evaluate genetic

tests.Public needs to gain scientific literacy

and understand the capabilities,limitations and risks.

Standards need to be establishedincluding quality controls to ensureaccuracy and reliability.

Federal regulation?


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Genetic Counseling

Informed consent for complexprocedures

Counseling about the risks,limitations and reliability ofgenetic screening techniques

Reproductive decision makingbased on genetic information

Reproductive rights

M ltif t i l Di d


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Multifactorial Diseases and

Environmental Factors

Genetic predispositions do not mandate

disease development

Caution must be exercised when

correlating genetic tests with

predictions


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Commercialization

Who owns genes and DNA sequences?

The person (or company) who discovered it, or

the person whose body it came from?

Should genetic information be the property of

humanity?

Is it ethical to charge someone for access to a

database of genetic information?


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Patents

Is it time to raise the bar?Will patent protection slow the advance

of research and be detrimental to societyas a whole in the long run?

This is a land grab of historic proportions. Its

as if somebody just discovered English andallowed the alphabet to be patented.(Michael S. Watson, American College ofMedical Genetics)


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Summary

The significance of the completion of thehuman genome project cannot beoverstated.

With the dictionary of the genomeavailable, the molecular mechanisms ofhuman health and disease will be resolved.

Armed with this knowledge atransformation in medical diagnostics and

therapy is underway and will continue intothe next few decades.

The application of this knowledge needs tobe regulated and restricted to practicesdeemed ethically sound

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