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Unit 3 – Genetics and Molecular BiologyAfter reading through the text book and attending class lectures you should be able to answer these questions:

Chapter 12 – Mitosis Objectives:

1) What loses heat faster – an elephant or a mouse? Why?2) Why do cells divide?3) What is Mitosis? When do cells undergo mitosis?4) What are somatic cells? How many chomosomes do they contain? Do they undergo

mitosis?5) What are gametes? How many chomosomes do they contain? Do they undergo mitosis?6) What are chromosomes – why are they important for mitosis?7) What are genes? What is the genome?8) Describe the ultrastructure of the chromosome (include definitions for chromatin,

chromosome, beads on a string, histone and nonhistones). Make a quick sketch of how DNA is folded to make chromosomes.

9) What are sister chromatids? Draw them. What structure connects the two sister chromatids?

10) What is DNA Replication and how does it relate to sister chromatids?11) Why should DNA or chromosome replicate/duplicate itself? When does this happen

during the cell cycle?12) What is cytokinesis – when does it occur?13) What are the cell cycle phases? Use this cell cycle website to review it.

http://mama.uchsc.edu/vc/cancer/cellcycle/p1.cfm14) Using the above cell cycle website and the Sci. Am article – ‘How Cancer Arises’ write

an essay detailing how regulation of the cell cycle occurs and the consequences of the failure in the checkpoints of the cell cycle.

15) How long does a cell spend in the Mitosis Phase? How long does it spend in Interphase? 16) What are the three phases of Interphase? Describe what happens during each one.17) How many chromosomes do we have in each of our cells ? Why do we have 2 sets of

each chromosome even in G1 phase, before replication of DNA? So, how many chomosomes will we have then after S phase?

18) Describe what happens during the different phases of Mitosis. (Website - http://www.loci.wisc.edu/outreach/bioclips/CDBio.html)19) Compare plant and animal cell mitosis.20) Describe how the mitotic spindle is formed and used to pull the chromosomes apart.

Lab:AP Lab: MitosisReading:How Cancer Arises – Sci Am Article (Sept.1996)

Chapter 13 – Meiosis Cell Division Objectives:

1) Define heredity and variation.

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2) What is a karyotype?3) Where did you get your 23 pairs of chromosomes from?4) How many chromosomes does your gamete/germ cell contain?5) Why is sexual reproduction a price to pay compared to asexual reproduction? What are

the returns/benefits of going SEXUAL?6) Explain the terms – haploid and diploid.7) What are homologous chromosomes? Are they the same as sister chromatids? Why or

why not?8) How many sets of homologous chromosomes do you have?9) What happens to the homologous chromosomes during meiosis?10) Review question - What happened to the sister chromatids during mitosis? Will this

happen in meiosis at some point? When?11) What is reduction division – why is meiosis considered as such? In comparison, what is

mitosis also referred to as?12) Will the organism change from dipoid to haploid after meiosis? Why or why not?13) Describe how Prophase I of meiosis causes the genes from the homologous chromosome

pairs to get mixed up. What is this called? (Define tetrad, chiasmata, synapsis)14) Compare Metaphase I with Metaphase Ii. Do the same for the remaining phases of

Meiosis.15) How do crossing over, independent asortment and random fertilization contribute to the

diversity and variation among the offspring produced?16) Do the G1, S, and G2 phase occur before meiosis?

Lab:AP Lab: MeiosisGood website for animation- http://www.sumanasinc.com/webcontent/anisamples/majorsbiology/meiosis.htmlhttp://www.sumanasinc.com/webcontent/anisamples/majorsbiology/independentassortment.html

Chapter 14 – Mendelian Genetics and beyond - Objectives:

1) What are traits?2) Define the following:a) Phenotypeb) Genotypec) Allelesd) Homozygouse) Heterozygousf) Dominantg) Recessiveh) True breeding3) Draw Punnett squares and illustrate the follwing crosses:

a) Monohybrid Crossb) Dihybrid Crossc) Test or Back Cross

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4) State and prove Mendel’s Law of Segregation using an example.5) State and prove Mendel’s Law of Independent Assortment using an example.6) Illustrate rule of multiplication and rule of addition with examples.7) Explain the follwing exceptions to Mendelian rules with examples:

a) Incomplete Dominanceb) Codominancec) Pleiotropyd) Epistasise) Quantitative charactersf) Environmental effects on phenotype

8) How does a genotype determine the phenotype?9) What does DOMINANCE mean in the above context?10) How are human blood groups inherited? Do they follow Mendelian rules?11) What is a pedigree? How is it used?12) What are some methods of genetic screeing to determine abnormalities in the unborn

fetus?

Activity:Start at http://www.dnai.org/c/index.htmlLook up a genetic disease and make a triple fold brochure that details the genetic changes, mode of inheritance, anatomical (structural), and physiological (functional) changes, as well as treatment options available for the patients.

Genetics Problem Sets: Monohyrid, Test, Dihybrid Crosses and more…1) In certain trees, smooth bark is dominant over wrinkled. Cross two trees that are

heterozygous for smooth bark. If there are 160 offspring produced, how many will have wrinkled bark?

2) The ability to taste the chemical PTC is determined by a single gene in humans with the ability to taste given by the dominant allele T and inability to taste by the recessive allele t.  Suppose two heterozygous tasters (Tt) have a large family. 

a) Predict the proportion of their children who will be tasters and nontasters.  Use a Punnett square to illustrate how you make these predictions.

b) What is the likelihood that their first child will be a taster?  What is the likelihood that their fourth child will be a taster?

c) What is the likelihood that the first three children of this couple will be nontasters?

d) If 12 children are born to these parents, how many of them will be tasters?

3) In dogs, wire hair (S) is dominant to smooth (s). a) In a cross of a homozygous wire-haired dog with a smooth-haired dog, what will

be the phenotype of the F1 generation? b) If two of the dogs from the F1 generation above (the puppies) are mated, show

the Punnett square and calculate the genotype and phenotype ratios.

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c) If there are 24 puppies that are born from crossing the F1 parents, how many will be wire haired and how many will be smooth haired.

4) In dogs, there is an hereditary deafness caused by a recessive gene, “d.” A kennel owner has a male dog that she wants to use for breeding purposes if possible. The dog can hear, so the owner knows his genotype is either DD or Dd. If the dog’s genotype is Dd, the owner does not wish to use him for breeding so that the deafness gene will not be passed on.

a) How can the owner find out what the genotype of her dog is? b) Draw the Punnett squares to illustrate these possible crosses. In each case, what

percentage/how many of the offspring would be expected to be hearing? deaf? How could you tell the genotype of the owner’s male dog?

c) Also, using Punnett square(s), show how two hearing dogs could produce deaf offspring.

5) Go to the following website and complete the problem sets:a)http://www.biology.arizona.edu/mendelian_genetics/problem_sets/dihybrid_cross/dihybrid_cross.htmlb)http://www.biology.arizona.edu/mendelian_genetics/problem_sets/monohybrid_cross/monohybrid_cross.html

Chapter 15 Chromosomes and Heredity – Objectives

1) How do segregation, crossing over, and independent assortment lead to different genes ending up in different combinations in the offspring?

2) How did Thomas Hunt Morgan show that genes are carried on chromosomes using Drosophia? Show the Punnett squares for the F and F2 generations. (website 1)

3) What else did Morgan’s fruit fly experiment suggest other than the fact that chromosomes carry genes?

4) What are some common characteristics of X linked traits?5) What are linked genes? How are they inherited? (website 2)6) What are recombinants? How do they arise? (website 3)7) Show the parental and recombinant phenotypes in a comparison of meiosis end products

from linked and unlinked genes (website 2- last image).8) If there is a <50% frequency of reombinant offspring in a test cross involving one

heterozygote, then the genes are said to be - 9) What is recombination frequency – how can it be calculated? What is used to predict?10) What are linkage maps? What is one map unit? Are they a true indication of actual map

distances?11) What is the human genome project?12) How is sex (gender) determined in Drosophila and in humans?13) What is the SRY region?14) What are Barr bodies – where do they come from? 15) What are chromosomal aberrations?

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16) What is nondisjunction? Draw a sketch of how a Down’s syndrome offspring ends up with 3 copies of Chromosome 21 (trisomy). Show the egg and sperm meiosis process in the parents. (website 4)

17) What happens to most of the disorders in chromosome numbers at an early stage of fetus development?

18) What happens in Turner’s Syndrome and Klinefelter’s Syndrome – explain what aneuploidy means.

19) Explain what polyploidy means and what organisms are often polyploids?20) Descibe what happens during translocation, duplication, and inversion of chromosomes?

Good animations:1) Thomas Hunt Morgan's expriment with fruit flies 2) Linked Genes and Crossover Comparison between Unlinked Genes 3) Shows Crossing over In Regular and XY chromosomes 4) Down's Syndrome Nondisjunction Powerpoint and Animation

Chapter 16 DNA and its Replication – Objectives

1) How did the following scientists show that DNA and NOT protein is the genetic material of the cell: a) Griffith b) Avery c) Hershey and Chase

2) What is transformation? 3) What is a bacteriophage?4) What was known to scientists before Watson and Crick worked on their model for DNA

structure? Also, what was unknown?5) What did Chargaff observe and why was it critical to the discovery of DNA’s structure?6) What did Rosalind Franklin observe and why was it critical to the discovery of DNA’s

structure?7) Describe the Watson and Crick DNA model and draw a sketch of it. (- how are the sugar

and phosphates connected, where are the bases, how do they connect, what is the 3D structure that DNA assumes … ). Use this website and click on Animation for an excellent review of DNA structure discovery. (http://www.dnaftb.org/dnaftb/19/concept/index.html)

8) How does DNA replicate – conservatively, semiconservatively, or in a dispersive fashion? Draw quick sketch to illustrate your answer.

9) How did Meselson and Stahl prove the above using heavy isotope of Nitrogen? (http://www.sumanasinc.com/webcontent/anisamples/majorsbiology/meselson.html)

10) Use the following animation and desribe how DNA replication occurs on the leading and lagging strand in bullett form using our own words. (http://www3.interscience.wiley.com:8100/legacy/college/boyer/0471661791/animations/replication/replication.swf) Include the roles of helicase, primase, DNA polymerase, DNA ligase, leading and lagging strands, continuous and discontinuous replication, Okazaki fragments, replication fork, and ori sites.

11) How does DNA proofreading and repair occur when a mistake has been made in the replication process?

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12) What are telomeres and why could they represent the fountain of youth or be a cause for cancer? (http://www.wiley.com/legacy/college/boyer/0470003790/cutting_edge/telomeres/telomeres.htm)

Chapter 17 Protein Synthesis Objectives

1) Where did the early clues for ‘what a gene does in your cells’ come from?2) How does possessing the gene for dwarfism/achondroplasia lead to stunted skeletal

growth?3) What did Beadle and Tatum show with Neurospora/bread mould?

(http://www.dnaftb.org/dnaftb/16/animation/index.html)4) Why did the one gene one enzyme hypothesis change to one gene one polypeptide

hypothesis? Is the recent research in agreement with the one gene one polypeptide hypothesis?

5) What is gene therapy? Why can it work as a cure for certain diseases? Does it work for all diseases?

6) Outline the sequence of steps starting at the nucleus for a gene to make protein. What step are often referred to as the CENTRAL DOGMA?

7) Why do you think DNA does not directly make protein and instead goes through RNA?8) What is RNA and how is it different from DNA?9) What is transcription? Name the 3 stages of transcription.10) What happens during Initiation, Elongation, and Termination stages of transcription?11) Where can you find the Promotor sequence and what is its significance?12) What does an enzyme that has the tag “Polymerase” do? What Polymerase is involved

in transcription?13) What are transcription factors and what is their significance?14) What does the product of transcription look like before and after RNA

processing/splicing?15) What happens to the mRNA transcript in prokaryotes – how is it different in

eukaryotes?16) What is translation?What is the final product of translation? (WebSite 1)17) What is the Genetic Code? How was it discovered to be a triplet code (as oppossed to

double/quadruplet…)? (Website 3)18) Why is genetic code referred to as – degenerate, redundant, and unambiguous?19) How many nucleotides will it take to code for a polypeptide that is 100 amino acids

long?20) What is the “reading frame”, where is it, and why is it really critical during translation?21) What is a tRNA? What is its role in translation?22) How many nucleotides will each tRNA use in its ANTICODON? Why? (Website 2)23) How many different tRNA molecules will be needed? Why?24) What is a peptide bond – draw the bond. How is it formed? (Website 6)25) Describe how the translation occurs in sequence upto the pepide bond formation and

release of the polypeptide. 26) What happens to the polypeptide after it has been synthesized?27) What are point mutations? Can they be significant? (Website 4)

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28) What are substitute mutations – what are the 2 kinds of substitute mutations?29) What are insertions and deletions? What are frameshift mutations? (Website 5)30) How do DNA mutations occur- how frequently do they occur?Good websites for animations: Chapter 171) Good site - overall protein synthesis, spliceosome and mRNA processing, prokaryote vs

eukaryote protein synthesis2) Translation in Eukaryotes 3) DNA Learning Center - Khorana and Nienberg Experiment 4) Mutations and changes in amino acids 5) Frameshift Mutations 6) Peptide bond formation

Reading:The Cellular Chamber of Doom – Sci Am Article Jan 2001

Chapter 18 – Viruses and Bacteria Objectives:

1) What are viruses?2) How do they survive if they are not able to reproduce on their own?3) Describe the structure of a virus.4) Where is the viral envelope in some viruses derived from?5) What is the genetic material in viruses? Do viruses make proteins like eukaryotes using

their genetic material? (Wesite 1)6) How do viruses find their specific host?7) What are bacteriophages?8) How small are viruses and bacteria?9) Describe the lytic cycle and differentiate it from the lysogenic cycle. (website 2)10) What are RNA viruses and what is their popular name? Give some exmples of such

viruses.11) Describe how the AIDS (RNA/retro) virus replicates?12) What is a vaccine – how is it made?13) Can viruses cause cancer? How?14) Are viruses alive?15) What are prions – give an example.16) How is the genetic material of the bacteria organised? Are bacteria considered living?

Why/Why not?17) Does protein synthesis take place in the bacteria – if so, where does it occur?18) How does a bacteria reproduce by fission? (website 7)19) How can you get variation in bcteria from generation to generation (5 ways) if they

reproduce by fission? Are there any other mechanisms that allow this variation to occur –if so, what are they? Which mechanism produces the MOST variation in bacteria? Is this true in eukaryotes – why/why not?

20) Explain how variation in bacteria arises by bacterial transformation? (website 4)21) Explain how variation in bacteria arises by bacterial transduction? (website 5)22) Explain how variation in bacteria arises by bacterial conjugation? (website 6)23) What are plasmids and what is their function in bacteria?

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24) What are transposons – where were they discovered and why are they important?25) What do genes make? Why is it important to regulate genes?26) What are the two ways in which genes can be regulated?27) What is the OPERON – in which organism can it be found?28) What are the three elements that make up an OPERON?29) How does the OPERON help regulate gene expresion – explain using the lac Opeon.

(website 8)30) Why is the lac operon termed “inducible” type of gene regulation?31) What type of regulation is shown in the lac operon (negative or positive)? Why?32) Is there any other manner in which bacterial genes can be regulated?

Good animations:1) Viral Coat Derivation and life cycle of virus2) Lytic Cycle and Lysogenic Cycle - Reproduction In Viruses3) HIV Infection- Retrovirus replication4) Bacteria transformation and Homologous Recombination5) Bacterial Transduction - Generalized6) Bacterial Conjugation7) Rolling model for Binary Fission8) Lac Operon in bacteria

Reading:Are Viruses Alive Sci Am 2004 Article

Chapter 19 – Eukaryotic Genes and their Regulation Objectives:

1) How many genes do we carry in our genome? How many do bacteria carry?2) What percent of our genome has genes in them?3) Is the rest of it really “junk” – why/why not?4) Do bacteria have junk/noncoding DNA?5) What are the 3 broad types of noncoding DNA in eukaryotes?6) What are the two types of Repetitive DNA? What are some important functions of this

repetitive DNA? What percent of our genome has repetitive DNA?7) What future lab will we use microsatellites in?8) CAGCAGCAGCAGCAG – identify the name given to this noncoding DNA sequence.9) Epigenetics is very important in determining the fate of each cell (what it becomes in the

body) during embryonic development – why is this so?10) What is a multigene family? How did multigene families evolve – name the 2 important

processes that contributed to their evolution. What are pseudogenes? 11) How does your genome change in your lifetime (4 ways)?12) Explain how gene rearrangement allows you to combat a virus/bacteria.13) What is epigenetics?14) What are the different ways by which eukaryotic genes are regulated? Do eukaryotes

have operons like prokaryotes? 15) What is chromatin? How is DNA packaged in eukaryotes?

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16) How can DNA be physically changed in its packaging/chemically to alter gene expression?

17) How can you alter/control transcription in eukaryotes? Compare this with prokaryotes – use the website 1 below to view the processes. (Skip Intro to launch animation)

18) What is post-transcriptional control – how is it carried out (3 ways)?19) What is post-translational control – how is it carried out? (website 2)20) What are proto-oncogenes and why should we become worried if they become turned

on? (website 3)21) What are tumor suppressor genes – should we have these genes turned on/off?22) What is p53? Why is called the ‘angel’ gene?23) When oncogenes are turned on or tumor suppressor genes are turned off what processes

in the cell cycle are they influencing and how?

Good Animations:1) Link to lac operon vs eukaryotic gene regulation at transcription 2) Link to preteasome and ubiquitin protein breakdown 3) Link to proto-oncogenes and p53

Chapter 20 – Biotechnology Objectives

1) What is Biotechnology?2) What is Recombinant DNA technology?3) What is genetic engineering?4) What is insulin? What happens in patients with Diabetes Type I?5) How can a gene product – namely a protein that is lacking in the body be provided to

patients?6) What are Restriction Enzymes? What can they do to DNA? Where are they derived

from? (websites 1,2)7) What are plasmids? Why are they useful in Biotechnology? (websites 1,2)8) How are Restriction Enzymes used to combine a gene of interest (like firefly glowing

gene) to plasmids and make recombinant DNA? (websites 1,2)9) How can you clone the recombinant DNA to make milions of copies? (websites 1,2)10) How do you select the CLONE/colony of bacteria that has the recombinant DNA as

opposed to nonrecombinant/randomn DNA growing in the agar plate? (websites 1,2)11) What are the four important DNA regions in a recombinant plasmid? (websites 1,2)12) Can human insulin DNA be introduced in exactly the same wayinto Bacteria to make

millions of copies of the gene? Why or why not?13) What are the problems with creating human/eukaryotic gene recombinant DNA?14) What are the solutions to the above problems with eukaryotic recombinants?15) What is nucleic acid hybridization? When is it used? (website 3)16) Explain how a DNA library can be made of all the human genes in bacteria. How is this

useful? (website 4)17) How is a cDNA library different than the DNA library?18) What is the Shotgun Method and why did it not work without using the public DNA

sequence database? (website 5)19) What is the Human Genome Project? (website 6)

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20) What is PCR – explain its purpose, materials needed, where Taq polymerase is derived from, process in detail (website 7).

21) What is RFLP? How is it used in a crime scene to identify the criminal?22) How is Southern Blotting used in accomplishing one of the goals of biotechnology –

extraction of a gene of interest?23) How is a transgenic animal/plant made?24) What are microarrays?Good Animations:1) Making Recombinant DNA Using Plasmid as Vectors 2) Simpler Make Recombinant DNA Site 3) Nuceic Acid Hybridization 4) DNA Library 5) Shotgun Method to Sequence DNA Used by Celera/Craig Venter 6) Human Genome Project - the whole picture 7) PCR or Polymerase Chain Reaction

Chapter 21 –Developmental Genetics Objectives

1) How are cells in various locations of the body different - is the variation in their genome or in the proteins they express? Related to this, what is genomic equivalence?

2) What are undifferentiated cells and differentiated cells?3) What are the stages of development? Which of these stages have undifferentiated cells?4) What are the differences between totipotent and pluripotent stem cells – at what stages of

development are they found in a) human b) plant (hmmm)?5) What are adult stem cells – why is this name a misnomer? Where are they found?6) What is different in the nucleus of a differentiated cell vs. stem cell?7) Can differentiated cells be coaxed to retrace their steps and become de-differentiated?

How?8) What is SCNT? Describe how the process of producing stem cells could lead to cloning.9) What are the 2 types of cloning? What is the end result in each type?10) Why is the ‘stem cell ethical debate’ something that could be a thing of the past?11) What is morphogenesis?12) How do plants and animals differ in their differentiation and morphogenesis

(development of body plan)? Are all plant cells totipotent? How about animal cells?13) When you are a single stem cell – a fertilized egg, what cues do the egg already contain

that could determine certain developmental features? Explain this using the bicoid protein as an example.

14) When you are a ball of stem cells, what cues do nearby cells convey that could determine more developmental features? Explain this concept of induction using the sonic hedgehog rotein/vulva development in the nematode as an example.

15) What is pattern formation – what determines it?16) What are homeotic genes?17) How does a master gene control the developmental genes listed above like the homeotic

genes– (make sure you know what transcription factors are and how they fit into this answer)?

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18) Are there similarities in the development of pattern formation and genes of various species? How? What does this mean in terms of evolution? See below for animations:

Good Animations1) Scroll over videos and animations and open windows related to stem cells (it has all the

stem cell and cytoplasmic determinants videos)2) Your textbook activity site has some really good animations on development

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Ms. Sastry AP BiologyLeigh High School

Review Table: Protein Synthesis Players and their Roles: Chp 17 – 19 Players/Process Prokaryote/

EukaryoteLocation of player/process and Structure

Function How can this player/process be blocked from doing its function?

What will happen if this player fails/is blocked?

1) DNA - gene

2) TRANSCRIPTION

a) Promotor

b) RNA Polymerase

c) Transcription Factorsd) mRNA

3) RNA PROCESSING

a) 5’cap and polyA tail

b) Intron

c) Exon

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d) Spliceosome

e) Alternate Splicing

4) TRANSLATION

a) Ribosomes

b) Codon

c) tRNA

d) Anticodon

e) tRNA synthetase

f) Peptide bond formation

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The Secret of LifeMonday, Jul. 14, 1958 Time Magazine

A few sprouted hopefully but did not grow. These were the interesting spores. They acted as if they were trying to grow, but needed something that they could not get from the agar or produce for themselves. So when a microscope showed such a spore, it was tenderly fed with vitamins, amino acids and other growth-fostering chemicals in hope of making it perk up and grow normally.

At the start of the experiment, Beadle and Tatum resolved to make at least 1,000 tries before giving up. Such perseverence was not necessary. On the 299th try they found an ailing spore that needed only vitamin B-6 (pyridoxine) to make it grow lustily. When it had mated with a normal mold, it transmitted its need for vitamin B-6 to its descendants in the proper Mendelian manner for a single mutated gene.

This was what Beadle had been hoping for. His explanation is that the gene damaged by X-ray violence was originally responsible for producing an enzyme (organic catalyst) needed in the mold's process of making vitamin B-6 out of simpler nutrients. With the gene out of action, the process stopped, and the mold could not grow without help. It was like a human diabetic who needs an external source of the insulin that his body cannot make.

New Attitude. When Beadle and Tatum reported their success in 1941, they had quite a collection of defective molds, each needing some extra nutrient or having some other gene-controlled chemical ailment. In a few years their imitators filled their own laboratories with molds as unnatural as the most monstrous fruit flies. The coral fluffs of normal Neurospora are rare in the test tubes and Petri dishes. In their place are blackish warts, lichenlike incrustations, or sick-looking globules. One horrible kind of mold grown in a moving liquid floats in bunches with limp limbs like soft, dead crabs.

An immediate, practical result of Neurospora genetics was the application of mold irradiation to wartime penicillin production. Much more important were the long-range scientific results. The success with Neurospora yielded new techniques for using molds and other small organisms as genetic tools. Out of its use flowed a new attitude toward genetics. No longer were genes considered abstract units of heredity. They became actual things, not entirely understood but known to be concerned with definite chemical actions. Professor Joshua Lederberg, 33, of the University of Wisconsin, probably the world's leading young geneticist, says that the Neurospora work at Stanford clinched the whole idea that genes control enzymes, and enzymes control the chemistry of life.

In 1946 Caltech needed a new head for its now famous Division of Biology. Professor Morgan had retired. Beadle was tapped for the job and accepted, knowing well that he would have to curtail, perhaps abandon, his personal research. Some of his friends felt that a great scientist was being wasted on a routine administrative job, and there was a precedent for their fears in the history of genetics. Mendel himself did nothing of note after he was made abbot.

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Sci Am NewsJune 13, 2007The 1 Percent Genome Solution

The first results from a massive project to exhaustively catalogue all the functions of the human genome reveal a hotbed of activity in the gaps between genes. An international consortium of researchers sifted through 1 percent of the genome looking for pieces of DNA that are copied by the cell or help to control gene activity. The results indicate that most DNA is copied into molecules of RNA, including the long stretches between genes, and that genes overlap and interact with each other much more than researchers previously believed.

"We all suspected there was interesting stuff going on in these regions [between genes], and sure enough there is," says bioinformatician Ewan Birney of the European Bioinformatics Institute near Cambridge, England, a member of the project's computer analysis team.

Although researchers do not yet know the biological significance of these discoveries, they say that fully cataloguing the genome may help them understand how genetic variations affect the risk of contracting diseases such as cancer as well as how humans grow from a single-celled embryo into an adult. The next phase of the project, set to begin later this year, will attempt to inventory the full genome.

A genome consists of only four different nucleotide bases, or DNA subunits, arranged in a particular sequence. The publication of the human genome in 2001 revealed its sequence—the significance of which remains a mystery. In particular, genes account for only 1.2 percent of the genome's three billion bases. Once dismissed as "junk DNA," researchers have found that some of these so-called noncoding regions are shared among mammals, suggesting they play an important function.

To help uncover those functions and identify other important sequences, 35 research groups joined forces in 2003 to create the encyclopedia of DNA elements (ENCODE) project. This consortium selected 44 separate sections of the genome that included regions of high to low gene density and high to low similarity between mouse and human.

Like treasure hunters combing a vast beach with metal detectors, ENCODE researchers sifted through their patch of the genome in multiple ways that are described, along with the results, in a Nature paper published online today and in a special issue of Genome Research.

A major part of the project was identifying sequences that cells copy, or transcribe, into RNA molecules. Cells make proteins from RNA they copy from genes, but some RNAs play roles by themselves. In addition, some studies have found evidence that species from flies and worms to humans copy large amounts of RNA from noncoding DNA, with no apparent purpose. Nevertheless, "before ENCODE, I think a lot of people were skeptical of how real intergenic activity was," says bioinformatician and consortium member Mark Gerstein of Yale University.

Although genes make up only 3 percent of the ENCODE sequence, the consortium found that 93 percent of the sequence is transcribed. Some of the transcripts hail from noncoding DNA, the

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researchers report, but those that do match up with the 399 ENCODE genes overlap with each other extensively.

Transcripts from 65 percent of the genes incorporate pieces of DNA from relatively far outside of the genes or even from one or two other genes, says molecular biologist and consortium member Tom Gingeras of Affymetrix, a genome technology company in Santa Clara, Calif. Researchers know that cells chop single genes into shorter pieces called exons, which they mix and match into one transcript for creating a protein. Gingeras says the ENCODE findings confirm recent reports that humans and flies sometimes combine exons from two different genes.

Based on the transcript sequences, the researchers identified 1,437 new promoters—short DNA sequences where transcription begins—in or between genes, on top of the 1,730 promoters they knew of. That is nearly ten promoters per gene, Birney says. He adds that the abundance of transcripts that overlap each gene suggests that the very term "gene" should mean something different inside the cell nucleus, where transcription takes place, than outside of it, where finished proteins go.

Project members also catalogued sequences that mark areas where DNA unwinds from the round histone proteins that maintain the shape of chromosomes, allowing the cell's transcription machinery to activate genes in those areas. They discovered some potentially unwound areas that are far from promoters and may therefore play some other role, Birney says.

The consortium found that 5 percent of the studied sequence has been conserved among 23 mammals, suggesting that it plays an important enough role for evolution to preserve while species have evolved. But of all the new ENCODE sequences identified as potentially important, only half fall into the conserved group.

These unconserved sequences may be "bystanders," Birney says—consequences of the genome's other functions—that neither help nor hurt cells and may have provided fodder for past evolution.

They could also simply maintain a useful DNA structure or spacing between pieces of DNA regardless of their particular sequence, says genomics researcher T. Ryan Gregory of the University of Guelph in Ontario, who was not part of the consortium.

"The biological insights are mainly incremental at this point," says genome biologist George Weinstock of the Baylor College of Medicine in Houston, which he says is to be expected of such a pilot study. "This is a 'community resource' project, like a genome project, that makes lots of new data available to the community, who then dig into it and mine it for discoveries."

Gregory says the results, although still cryptic, do hint at new functions and a more complicated genome. "This study shows us how far we are from a comprehensive understanding of the human genome."