醫(yī)學(xué)教學(xué)課件：Chapter 2 Human Genomics II

1、Human Genomics II-Application1Human Genomics has changed medicine: (1) Biochips2vStamp-sizedvOne spot per DNA fragmentvThousands of spots/chipSamples may be from different tissues of patients and healthy people, or virus, pathogens, and so onDNA-based biochipsvTwo types:Detection of mutations in spe

2、cific genes as diagnostic markers of the onset of a particular diseasevBasis: SNPsDetection of the differences in gene expression levels between patients and the healthyvBasis: mRNA level3SNP-based ExamplesvAffymetrix GeneChip base on the mutation (SNPs):p53 GeneChipHIV GeneChipP450 GeneChipBreast c

3、ancer gene, BRCA1Bacterial pathogens4Expression-based examples vAs a diagnostic toolvFor drug designUnique targets that are present only in diseased cells. For example, during the process of cancer transformation oncogenes and proto-oncogenes are activated, which never occurs in healthy cells. 5vBio

4、chip can allow rapid screening of any type of cancer in principle, just look and see what SNP is present in the cancer patient.Example: In two forms of leukemia each gene changes from normal, but importantly, the changes were different in each case. Each had their own characteristic SNP.6Biochip exa

5、mpleto screen for cancer7vDisease possible SNPsvGWAS: Genome-wide association study to compile a database of thousands of SNPs8Facts and ApplicationvMore than 85% of SNPs identified to be associated with disease in genome-wide studies (GWAS) occur within non-coding regionsvThus, examining the role o

6、f these regions of the genome will be important for understanding and potentially treating diseasevApplication: screen the associated genes9Go to doctor:“First check my genome, doctor”10Debate about GWASvA good-natured debate about whether GWAS will eventually help unravel the genetic basis of human

7、 hypertension entertained many at the recent American Society of Hypertension 2010 Scientific Meeting. vArguing that such studies have cost millions of dollars but failed to live up to expectations in the field of hypertension, Dr Theodore W Kurtz (University of California, San Francisco) said that

8、it was time to put a stop to further GWAS: They have taught us little about the genetics, pathophysiology, or treatment of hypertension. vDr Anna Dominiczak (University of Glasgow, Scotland), taking the opposing position, said that although it is true that GWAS have so far yielded only a few genetic

9、 variants, which explain a very small proportion of the total variation in blood pressure, the best is yet to come.11Biochip raise critical issue of personal privacy12SCARINGvyou, your health, your behavior, your future potentialPhilosophy:vMany scientists and physicians think that many medical bene

10、fits could flow from knowing the location and sequences of all the genesvSuch knowledge would facilitate locating genes that are associated with diseases or disease susceptibilityHuman Genomics has changed medicine: (2) Gene therapy13What is “Gene Therapy”?vTo introduce a normal gene, via geneticall

11、y engineered cell, into individuals who do not possess a functional copy of this gene, for therapeutic purposes.14Gene Therapy for SCIDSvGene therapy has been successfully used to treat severe combined immune deficiency syndrome (SCIDS)Fatal disease in which a child is born without a functional immu

12、ne systemUnable to fight infectionsThese children die from the slight infection unless they are lived in total isolation: Boy/girl in a bubble treatmentEnzyme that control SCIDS:vAdenosine deaminase (ADA)vADA locates on chromosome 2015SCIDvDeficiency of ADA will cause SCID, while gene therapy can tr

13、ansfer gene for ADA into immune cells of patients, in which there is dysfunction of both B and T lymphocytes with impaired cellular immunity and decreased production of immunoglobulins.16Adeno-associated virus (AVV)AVVCloning17AssemblyAVV particleTreatment1819202122(3)- New drugs23242526272829Design

14、 the drugsBeyond the Human GenomevThe DNA sequence tells only a small fraction of the story about what a specific cell is doingvWith all the DNA that codes for a human in hand, researchers begin a more challenging task: Proteomics3031Gene protein Disease2-D gel323334353637Beyond the HGP: Whats Next?

15、HapMapSystems BiologyExploring Microbial Genomes for Energy and the EnvironmentChart genetic variation within the human genome38Beyond the HGP . . .Whats next? - contNext project for DOE: GTL (Genomes to Life)Builds on data and resources from the Human Genome Project, the Microbi

16、al Genome Program, and systems biology Goal is to accelerate understanding of dynamic living systems for energy and environmental applications.Specific uses in energy production, waste cleanup, and climate change mitigation39Environmental Genome Project （EGP）vEGP is a multi-disciplinary, collaborati

17、ve effort focused on examining the relationships between environmental exposures, inter-individual sequence variation in human genes and disease risk in U.S. populations. vTo target the systematic identification and genome-wide genotyping of SNPs40Phase 1 - Candidate Gene Resequencing (completed)vTo

18、 target typically all promotor, intronic and exonic regions of 647 candidate genes involved in apoptosis, cell cycle control, DNA repair, drug metabolism, oxidative stress and many other medically and biologically important.41Phase 2 - Exome Sequencing (in progress)vTo greatly expand the set of vari

19、ant data within candidate genes and across the entire gene coding region, second-generation DNA sequencing technology is being used.42HapMap (Haplotype map)43 A sequence of consecutive alleles on a particular To find genetic variants affecting health, disease and responses to drugs and environmental factors.