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42 Cards in this Set
- Front
- Back
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Introduction
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A. No need to cover this until 2000 when human genome project was completed
B.Goal was to sequence the whole genome of man C.The race to sequence the human genome was started in 1990 by DOE & originally slated to finish about 2005 (i).chromosomes sections were assigned to many labs around the world: USA, Great Britain, China, France, Germany, Russia, etc (ii).used technologies that gave very accurate sequence but was laborious and slow (iii). used genomes of several anonymous donors |
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Introduction continued
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D.Race was joined by Celera Genomic in 1995 using robotic DNA sequencers
1.they fragmented the genome&sequenced the pieces 2.then used computers to overlap the pieces to generate a map 3.much quicker, but possibly less accurate 4.genome used was the president of the company: Craig Venter 5.the pieces were patented, even though Celera didnt know the functions (if any) of the indicial pieces E.Celera won the race by publishing the draft sequence in 2000 (official announcement was that it was a tie) F.Final publication of a highly accurate human genome by Celera was in Sept. 2003 |
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Introduction continued
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G.Now Celera & many other Univ. & private labs around the world are bust with:
1.sequence annotation & discovery of new products 2.new tech. that involved methods for mining the huge amounts of data generated by the projects 3.sequencing other model or pathogenic organisms |
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Introduction continued
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H. Implications are enormous: Genomic has power to make molecular biology "smart". Used to be that when you need to find a gene or other sequence (e.g. Gene for Rubisco) you hunted for it by:
1.making DNA library of the organism of choice 2.screen library with a DNA probe i.probe: short sequence of DNA that is "unique" to that gene or other DNA segment ii.sometimes you have a good probe or not so good (very specific or not) iii.done by Southwern analysis of the clones in a DNA library 3.Could take up to 2 yrs of full-time work if unlucky |
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Introduction continued
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I. The power of having genemic into in a rapidly searchable database is enormous and it has changed molecular bio. profoundly and forever
1.it will change the world profoundly and molecualr bio dind in the 1980's 2.with the power of computers & databases, what once took years, now takes minutes 3.It will help in finding therapies to genetically based diseases more rapidly 4.It will help in finding cures for diseases that have a genetically determined host susceptibility profile 5.Potential for abuse is enormous |
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How is Genomics/Protoemic Done?
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Researchers now use a computer to do a search of a higd database of genome info called Genbank with a search engine
1.A popular search engine is run by the NIH & is calles eNtrez 2.Genbank is a searchable database of i. genomes ii.chromosomes iii.cloned pieces of DNA iv.viruses v.plasmids vi. tRNA's, rRNA's, mRNA's vii. cDNA's (DNA copies for mRNA's) viii. EST's (expresed sequence tags) viiii.proteins |
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How is Genomics/Protoemic Done?
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3. Includes links to other databases to protein sequences
(a). including 3D structures & interactions between molecules (b).with abilities to match & compare multiple sequence at will |
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Information from the HGP can be classified in 3 basic categories: Comparative Genomic
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A. Comparative genomic: compares the genomes of many different organisms, looking for the similarities and differences to find information on evolution
(a). requires the sequencing of the human genome & genomes of many other organisms (191 genomes done os of 3/2006, most recent is pif as 10/09) (b). mostly confirms what we know about living things (c) huge computer databases are required to: store the sequence info., search the sequence info., compare the sequence infor. in a variety of ways (d) the tree of life is completely generated computer generated from genomic info. |
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Information from the HGP can be classified in 3 basic categories: Structural Genomics
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Determine 3D structures of proteins (this info. is also computer generated and manipulated
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Information from the HGP can be classified in 3 basic categories: Pharmacogenomics
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Analy identify targets for therapeutic drugs
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How densely packed are the genes on chromosomes?
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1) Answer: it varies with the organism
2) In general, the simpler the organism, the genes are more densely packed on the chromosomes |
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Are genes with similar functions grouped?
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Answer: Sometimes, often depends of whether the genes has the same evolutionary origins or not
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Have we been able to map human chromosomes?
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Answer: Yes, but not yet finished
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Are genes that are used in the same metabolic pathway or developmental pathway grouped?
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Answer: Commonly but not always, for the same reasons as that we find genes are often linked
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Are genes that are used in a metabolic pathway or developmental pathway coordinately controlled?
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Answer: Many are (organized as a gene family) as this makes regulation more efficient
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Can genes on different chromosomes be coordinately controlled?
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Answer: yes
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Have Biologists been able to assign functions to all the genes in the human genome?
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Answer: As of December 2008 this has more or less been completed. However, it has now been realizes that knowing the function of an individual gene will not tell you the whole story of life.
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Are all genomes similar?
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(a). In terms of size ? the answer is no
(look at the table) (b). in terms of organization? answer: organisms that are closely related tend to have genomes that are organized similarly. Organisms that are not closerly related have genomes that are organized differently |
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How conserved are the genomes?
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Answer: in general, the more closely related, the more conserved (e.g. the genomes of chimp & man are between 98 and 99.5% the same)
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Do the more complex organisms have more complex genomes that the simplre organisms?
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Answer: yes
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How convserved are individual genes from organism to organism?
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Take the example of Cytochrome C, a housekeeping gene in ETS
(a). is the cytochrome C the same in ape and man? answer is yes (b). how about the cytochrome c in E.Coli and man? answer is yes (c). other non-housekeeping genes are not as tightly conserved. (d). are the non-coding areas as tightly conserved as coding areas? answer: in general, no. but there are exceptions |
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How different at the DNa level must and organism be to be a different species?
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Answer: it varies a lot
(a).up to a 25% difference in organisms called E.coli (b).difference between man & chimp is ~0.5 to 2% (c).has to do with a non-uniform definition of species between kingdoms |
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Will there kinds of comparison tell us something about evolution?
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Answer: yes, cladistics is based on it
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What does this tell us about man's origins in particular?
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Answer: plenty
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Genome Organizations at DNA level: Repetitive DNA
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DNA sequence that are repeated over & over at a locus in a chromosomes is called Repetitive DNA
(a). sequences that are usually exact copies are called: tendem repeats, satellite DNA or simple sequence DNA (b).often found at telomeres or centromeres (c).indicates that tandem repeats have some function 2.DNA sequences that are repeated over&over at several loci in a chromosomes are called interspersed repetitive DNA |
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Genome Organizations at DNA level: Repetitive DNA Continued
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3.Do repetitive DNA sequences map to anything significant?
a. not all of it, but tandem repeats do. (1).tandem repeats are found at telomeres of chromosomes (ends of chromosomes) and has a normal function in chromosomes replication (2).during each division some of the tandem repeats are lost (3).when almost of the repeats are lost, that seems to be a signal for apoptosis (4). old, mistake-laden cells are eliminated this way |
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Notes on Repetitive DNA
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(a)cloning of tandem repeats/satellite DNA has allowed the construction of artificial chromosomes that function similarly to natural chromosomes
(b)Huntington disease is a triple repeat disease with many extra CAG's.This leads to extra glutamines being added to a neurological proten which causes a nervous dysfunction and is 100% fatal (c)Some Alu sequences (which are tandem repeats) are expressed even though their function, if any, is unknown. |
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Comparison of Genomes: A side note
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(1).Humans have about 22k genes, so does the worm C. elegans, which has only about 500 cells total
(2).How is it possible that this 1mm long worm, of litthle structural complexity, have the same numver of genes as man, an organism of extreme structural compelxity? (3).Possible answer: Man has a much larger "interactone" (4). The "interctome" is the sume of all the proteins that interact (5). it is also likely that man has many more translational variants of common proteins than the worm |
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Human Genome Project: What is all that non-coding DNA doing?
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1). size: 3.2 billion base pairs
2).~1.5% coding, i.e. exons:~22,000 genes 3). 25% introns,regulatory sequences 4).25-45% interspersed repeats, transpoons & retrovirus footprints i.sometimes referred to as "selfish DNA" because it doesnt seem to do anything but is retained & has expanded itself ii. there seems to be no burden of carrying extra DNA in man & therefore no selection against it 5)10-15% tandem repeats, large segment repeats 6)~15% unique sequence but non-coding DNA |
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Human Genome Project: Summary
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~75% of human genome is what used to be called "Junk DNA"
(a).many pseudogenes: were obviously at one time functional, probably part of the 15% unique non-coding DNA (b).many footprints of transpoons (very possibly the tandem repeats are these) (c). lots of footprints of non-functional retroviruses (great way to follow evolution) (d). segment duplications (e).genes for siRNA & miRNA codes & other regulatory RNA's |
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"Junk" DNA continued
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(f). recent research is pointing to miRNA and siRNA coding DNA probably accounts for much of DNA tat doesn't code for protein in the human denome
(g).aside: reseaerches have hypothesized that the 22,000 genes of the human genome would not be able to account for the complexity of the human CNS.They have further hypothesized that the difference between man & other primates is not in the genes but in fine tuning of regulation of the same genes by siRNA and miRNA's, variable splicing of exons during RNA processing and translation variants |
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Pseudogenes
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(a). Pseudogenes extra copies of genes but are non-functional or marginally functional
(b). Pseudogenes are probably generated by gene amplification or transpoons (c). Pesudoentes are probably advantageous & retained through natural selection |
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Pesudogenes advantageous to retain in Euks.
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(1). Presense may allow for the incremental mutation of functional or non-functional genes into new genes
(2). They could act as back up genes that could take the place of a mutated primary gene (3). With backup genes, safer and therefore more rapid evolution can occur |
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Transponson
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"Jumping" genes
(a). genetic elements that copy themselves & insert themselves into "random" places in the genome (b). insertions can add a functionally or destroy a functionally (insertional inactivation) (c).Sectoring: an example of transposons making a phenotypic change by adding a functionally (d).dicovered by Barbara McClintock (nobel prize 80) |
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Retrovirus Footprints
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(a). retrovirus have RNA genomes that undergo reverse transcription to DNa
(b). the DNA then inserts into the genome (c). sometimes the retrovirus becomes mutated and is no longer functional = retrovirus footprint |
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Plant Genomes
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1.)Still much to be done
a).1st plant genome sequenced was in 2000:Arabidopsis thaliana b). Rice in 2002,several more including wheat,corn, tomato and Pinot noir grape recently 2). Plant genomes seems to be very plastic a). aneuploidy is common (e.g. 2n+1) b). polyploid is common (e.g. 6n) c). genome size varies immensely due to polyploidy (from fewer that 4 chromosomes to over 1000 chromosomes in some ferns, leading to a huge genome) |
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Plant Genomes Continued
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3). Transposons make up to 90% of some plant genomes
(a). this may be how some plant genomes expanded in size 4). many of the chloroplast genes have been transferred to the nuclear genome (a).therefore many of the chloroplast proteins that are made in the cytoplasm must be moved to chloroplast (b). similar story with mitochondria & most eukary. |
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How have plant and other genomes expanded?
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a). expanding the genome through transpons ,retrovirus, polyploid, aneuploidy we have already heard about
b). expansion of human globin genes probably occurred through replication mistakes that lead to replication (a). this type of event is called gene amplification (b).is this the origin of multigene families? (c). globin genes in mammals are likely expanded from a single ancestral gene by gene amplification |
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All of these mechanisms can lead to genome expansion and probably all have a role in expansion
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(1). old view in the '50, '60, '70, '80 was that genome was relatively static; that view has changed
(2). now know that these mechanisms for genome change occur commonly (3). They can drastically change a genome over a period of evolutionary time |
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Ultimate goal of Plant Molecular Biologists
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(1). plant molecular biologists are studying all aspects of plant biolody: PS, ion transport, development, metabolism and drug discovery
(2)ultimate goal is make a new virtual plant proccess (a). discover the function of all genes in Arabidposis (b).discover when&where these genes are expressed in the plant (c).with this info, the understanding of plant development at genetic level (d).next, write a computer programm to make a "virtual" plant (e). scientists be able to experiment on this virtual plant without having to do the lab work |
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Ethics in bioinformatics, genomics and biology
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1) all of this should amaze you & scare you
2) can this info be abused? Yes it can (a) insurance/employment discrimination (b) unauthorized experimentation: use of someone else's data, human info, use of someone else's cells to develop therapies 3) you detect an incurable genetic disease in a patient. Do you tell them they gave the gene? |
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Ethics in bioinformatics, genomics and biology Continued
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4) Just because somthing can be done, should it? (e.g. BST milk, human genetic engineering, human stem cells)
5) Abortion of a fetus with how many genetic defects? 6) How much money/hospital facilities/ hospital personnel do you use on treating one person, just because they have the money? a) would the money be better spent on low tech cures that will save many lives? b)e.g. cheap antibiotics in the 3rd world to fight diarrheal & respiratory diseases that kill ~10% children before age of 5 |
