Biology 210
GENETICS
13 March, 1998
 

•  Introduction
• A list of genomes that have been sequenced
• The genome of Escherichia coli
• The human genome project

Introduction

Note: On the last exam, there were several people who seemed to confuse a single "gene" (which often codes for a single protein) with a "genome" (which is an organisms entire set of genes).  A chromosome contains perhaps several thousand genes.

Remember, human genes can be quite large - especially when compared to bacterial genes, which are usually around 1000 bp or less.

What is "genomics"?

Genomics is simply the study of complete genomes.  More recently, genomics has meant the analysis of the complete DNA sequence of an organism's genome.  This field wasn't really possible until the publication of the genome of Haemophilus influenzae in 1995.

A few words about the SIZE of genomes....

On Wednesday, we talked about bacteriophages.  Bacteriophage l has a genome of about 50,000 bp.  If you were to print the entire sequence out, with roughly 25,000 bp per page, it would take about 2 pages.  (The sequence would be in a very small font, and you could barely read it!)

The yeast Saccharomyces cerevisiae was the first (and only so far) eukaryote to be sequenced.  The yeast genome would occupy a thin volume of about 500 pages, or roughly twice the thickness of the E.coli volume.  I should mention that recent genetic analysis of the complete yeast genome has found that it likely has arisen from a duplication event - that is, yeast came from a more primitive organism which contained only half the number of chromosomes (see page 401 in your text).

The first "animal" to be sequenced is likely to be the nematode C.elegans, which is about 100,000 bp long. The plant Arabidopsis thaliana is also being sequenced, and it is about the same size.  Both of these genomes are likely to be completed within the next year or so.

FINALLY, the human genome, by comparison, is quite large.  Using the same analogy as above, the human genome would fill 80 volumes!

 
 
There seems to be a general trend here: the simple bacteriophage viruses have the smallest genomes, then bacteria, then simple eukaryotes (yeast), then simple animals & plants, then humans...

HOWEVER, in fact there is not such a nice correlation between an organism's complexity and the size of its genome.

Database Of Genome Sizes

DOGS abbreviated genome size table
-----------------------------------------------------------
Organism                                        Genome size
-----------------------------------------------------------
Protopterus aethiopicus                     139,000,000,000
Fritillaria assyriaca                       124,900,000,000
Lilium longiflorum                           90,000,000,000
Necturus maculosus                           50,000,000,000
Triturus cristatus                           18,600,000,000
Zea mays                                      5,000,000,000

Xenopus laevis                                3,000,000,000
Rattus norvegicus                             3,000,000,000
Oryctolagus cuniculus                         3,000,000,000
Mus musculus                                  3,000,000,000
Homo sapiens                                  3,000,000,000
Bos taurus                                    3,000,000,000
Sus scrofa                                    2,700,000,000
Gallus gallus                                 1,200,000,000

Oryza sativa                                    400,000,000
Fugu rubripes                                   400,000,000
Schistosoma mansoni                             270,000,000
Sarcocystis cruzi                               201,000,000
Drosophila melanogaster                         165,000,000
Caenorhabditis elegans                          100,000,000
Brugia malayi                                   100,000,000
Arabidopsis thaliana                            100,000,000
Toxoplasma gondii                                89,000,000
Eimeria tenella                                  70,000,000
Eimeria acervulina                               70,000,000
Plasmodium falciparum                            25,000,000
Plasmodium berghei                               25,000,000

Schizosaccharomyces pombe                        14,000,000
Saccharomyces cerevisiae                         12,067,280

Escherichia coli                                  4,639,221
Mycobacterium tuberculosis                        4,397,000
Bacillus subtilis                                 4,170,000
Synechocystis sp. strain PCC6803                  3,573,470
Mycobacterium leprae                              2,800,000
Haemophilus influenzae                            1,830,137
Helicobacter pylori                               1,667,867
Methanococcus jannaschii                          1,664,974
Borrelia garinii                                    953,000
Borrelia afzelii                                    948,000
Borrelia burgdorferi                                946,000
Mycoplasma pneumoniae                               816,394
Mycoplasma genitalium                               580,000
Human immunodeficiency virus type 1                   9,750
-----------------------------------------------------------
this list was last updated: Thu Sep 18 10:58:50 MDT 1997

For an updated version of this list, visit the DOGS site, at the CBS in Denmark

 

 A List of Genomes that have been Completely Sequenced:
(so far, as of 11 March, 1998) 
 
 

note: the organisms on the above chart were classified according to the "three-kingdom" type of scheme:

 

This is based in part from data from The Institute for Genomic Research.  For more information click on the TIGR logo.

There are presently more than  100  organisms (including humans), whose genomes are in the process of being sequenced....
 

Genome Sequencing Projects

Archaea

Eubacteria

Eukaryotae

some trivial numbers:

        4,639,221 bp total

               4288 protein coding genes:
                  30% "well characterised"
                 ~30% "no known function"

Average distance between genes: 118 bp;
  (only 70 regions >600 bp)

Protein coding genes account for ~88% of total.
                                       ~1% stable RNAs
                                       ~1% repeats
                                      ~10% "regulatory"
 

Leading & Lagging strands of DNA are subject to differential mutational rates....

Open Reading Frames  (ORFs):

        Average size - 317 aa (951 bp DNA)

                        (1500-1700 aa) -  4 proteins
                        (1000-1500 aa) - 51 proteins
                             (<100 aa)  - 381 proteins

        ~40% of ORFs are "uncharacterized"

        cp. : 43% ORFs "unchar." in Haemophilus
               45% ORFs "unchar." in Synechocystis
               32% ORFs "unchar." in Mycoplasma
 

 

very roughly (remember, ~40% unknown):

            
E.coli is most similar to Haemophilus (out of 5 genomes compared):
 
 

Only 16 proteins are conserved in all six organisms (!!?)  these are mainly translation associated proteins, including 7 rRNA proteins.

Nearly 60% of the proteins from E.coli have no match in the other organisms (or GenBank).

Largest family of proteins in E.coli is ABC transporters... 54 characterised by Monica Riley, + 26 new members - now 80 total proteins.
 

Operons - 2584 predicted & known operons, most (68%) have one promoter, and roughly 90% are thought to be regulated by only one protein.

    With the significance of the work firmly established, the genesis of the human genome project is described.  Apparently the idea of sequencing the entire DNA sequence for a "single" human being was first realistically proposed in 1985 by three different groups, who worked independently of each other.  These groups all realized that the technology was quickly becoming available to achieve such a daunting task.

  To give you an idea of the difficulty of the task - imagine that you were to start reading the human genome, at one base every second.  The genetic information coding for you (and all other animals and plants) is written down in a simple "text", just like this article.  In the language of DNA, there are only four "letters" - G, A, T, and C.   To read the DNA sequence of a human being would take about 140 years - if you were to read one base a second, 24 hours a day, non-stop.  The (frustrating) fact is that you really would not know anything about the person when you were done, except that they most likely had died (and had to pay taxes!) several years before their DNA sequence had been read.  Obviously, one needs computers to handle this kind of information.  The best place for computers was at the National Laboratories in the U.S. Southwest - mainly Lawrence Livermore & Los Alamos National Laboratories.  I had always thought that this was why the national labs had got involved in the genome project.  To be honest, I had often wondered how the Department of Energy wound up financing the project.  I was surprised to learn that, in fact, one of the first groups to propose sequencing the human genome was from Los Alamos.  This was perhaps a "from nuclear bombs to plowshares" type of philosophy.  But in fact, there was a bit more of a sinister twist to this plot.  The U.S. military was trying to study the effects of the atomic blasts on the Japanese survivors from World War II.  Furthermore, I know (from personal conversations with scientists at Los Alamos during this time) that the U.S. military was seriously operating under Ronald Reagan's philosophy of fighting and surviving (?) a nuclear war.  The result of all of this was that the human genome project was funded initially by the Department of Energy; basically it was a military project to ensure jobs for unemployed bomb makers (according to some of the critics at the time).

    The first "gene wars" aspect of this has to do with the politics of government funding.  Really, the most logical place to fund this research would be the National Institute of Health (NIH), but many people were still feeling the pinch of less money for basic research at the time, and were quite afraid that the human genome project would steal money from basic grants.  Furthermore, many scientists observed that, since roughly 98% of the human was "junk" (that is, it doesn't code for proteins), it would be a huge waste of money.  Indeed, to try and use present or "old technology" to sequence the human genome WOULD be stupid - but the genome project was all about heavily investing in technology to improve speed of sequencing.  In the 1960's, it was a very significant achievement to sequence 23 nucleotides (the equivalent of being able to read maybe 3 words in a sentence).  In 1977, Fred Sanger (funded by the MRC in England) developed a sequencing technology that made it possible to read the entire sequence of a bacterial virus (about 5400 nucleotides long, or roughly the same as being able to read a short paragraph).  This was significant enough to merit a Nobel Prize, shared with two Harvard scientists who had developed a different (slower) method for sequencing.  By 1985, Sanger's technique had begun to be automated, such that a MACHINE could read the DNA sequence automatically - it now was possible to routinely sequence more than 10,000 nucleotides (this would be like being able to read a full page - with enough work it wouldn't be too difficult to put together an entire chapter).  However, in 1985 the human genome project still was a pretty daunting task - at the present (1985) rate of sequencing, Jim Watson estimated that it would take about a thousand years to sequence the entire human genome!! (I should point out that if Fred Sanger had tried to sequence the human genome with his methodology from 1979, it would take close to a MILLION years to finish!  So a "mere" thousand years is quite an improvement, but still not good enough.)

   So the human genome project was set up to invest heavily in technology. In fact, when the program finally was officially launched in October of 1990, it was a 20 year project, with the first 10 years invested mostly into improved methods of sequencing, with most of the actual sequencing of the genome being done in the last few years.  In addition, the genomes of smaller organisms were set up as intermediary goal posts along the road.  In the past two years, we have already seen the realization of the early goals; the complete sequence for the genomes of more than a dozen bacteria are now available for research and comparison, and the genome of the first "animal" (simple yeast) was published earlier this year (1997).   Soon to come will be the first worm (nematode), first plant, and first insect.  It will probably be another 4 or 5 years before the first mammalian genomes become available.

     The human genome project was initially set up to run from 1990 through the year 2010.  The annual budget is roughly $200,000,000 per year (!) - of which about $120,000,000 is allotted to the NIH, and about $80,000,000 allotted to the DOE.  At the suggestion of the first Director of the Human Genome project (Jim Watson), about 5% of the budget is invested into "ethical considerations of the human genome sequencing project".  As Cook-Deegan points out, there are many ethical considerations to consider.  There are the problems in dealing with knowledge about the future of someone's life (for example, it is likely that this person will die of lung cancer at the age of 20).  There are also all the abortion related problems, since now that we know how to screen for many diseases, pre-natal screening now is much more predictive.  Finally, there are many financial problems, having to do with insurance, for example, as well as all the considerations of patent rights.

   In fact, a large part of the reason Jim Watson resigned as director was related to his strong objections to the U.S. government policy of trying to patent DNA sequences.  Although Cook-Deegan takes a more "middle of the road" approach, and tries to explain why the government wants to regain money invested in research (which I think this SOUNDS fair enough...) I really tend to agree with Watson.  Imagine.  You are living a thousand years in the future, and no one speaks English anymore - in fact, through years of neglect, it is almost a forgotten language.  Now you learn to read, and find one of Shakespeare's books.  Suppose you are the first person to read through part (not all, even) of one of his plays.  Does this mean that YOU have to right to charge anyone else royalties who wants to read this or use it in the future?  This is in fact what was at issue at the "bioearth" summit in Brazil in 1992.  The U.S. did not want to sign an agreement forbidding the patenting of DNA sequences, despite the agreement amongst all the other countries in the world.  I personally have no problems with patents - I think they are wonderful, provided they are for something that you have created.  But I do have serious problems with patenting DNA sequences, because this is just merely reading a text that someone else (God? Nature?) has already written.
 

 

    In summary, this book is a good history of the beginning of the Human Genome project.  For me, it was fun to see much fruit of this project in my own research.  I think this is an essential reading for anyone who wants to understand what the human genome project is all about, in terms not only of the science, but also the development of government policies and the personalities of the scientists involved.

 

A list of books on the human genome project:
 

1990

Understanding Our Genetic Inheritance, The U.S. Human Genome Project , The First Five Years: Fiscal Years 1991-1995 (U.S. Government printing office, 1990)  - click on this link (the web site is:)
http://www.nhgri.nih.gov/HGP/HGP_goals/5yrplan.html
 
 

"Mapping the Code : The Human Genome Project and the Choices of Modern Science", Joel Davis, (John Wiley & Sons, New York, 1990).
 
 

"Genome : The Story of the Most Astonishing Scientific Adventure of Our Time - The Attempt to Map All the Genes in the Human Body", Jerry E. Bishop, Michael Waldholz, (Simon & Schuster, New York, 1990).

1991

"The New Genetics : The Human Genome Project & Its Impact" (Grand Rounds Pr Ser.), Leon Jaroff (Whittle Communication, 1991).
 

"The Human Genome Project : Cracking the Genetic Code of Life", Thomas F. Lee, (Plenum Press, 1991).
 

"The Human Blueprint : The Race to Unlock the Secrets of Our Genetic Script", Robert Shapiro, (St Martins Press (Trade), 1991).
 

"Exons, Introns, and Talking Genes : The Science Behind the Human Genome Project", Christopher Wills, (Basic Books, 1991).
 

"Mapping Our Genes : The Genome Project and the Future of Medicine", Lois Wingerson, (Rei Edition, Plume publishing company, 1991).
 

 

1992

"Gene Mapping : Using Law and Ethics As Guides", George J. Annas, Sherman Elias (Editors), (Oxford Univ Press, 1992).
 

"The Code of Codes : Scientific and Social Issues in the Human Genome Project",  Daniel J. Kevles, Leroy Hood (Editors), (Harvard Univ Press, 1992).
 

"Human Genome Project", McCun, (Gem Publications; Publication date: June 1992, ISBN: 0865961344).
 

1993

"The Human Genome Project", Marianne Postiglione (Editor), (Itest Faith Science Press; Publication date: March 1993, ISBN: 0962543160).
 

"Guide to the Human Genome Project : Technologies, People, and Institutions" (Chemical Heritage Foundation Publication, No. 11), Susan L. Speaker, M. Susan Lindee, Elizabeth Hanson, Chemical Heritage Foundation; Publication date: February 1993, ISBN: 0941901106).
 

Human Genome Diversity Project : hearing before the Committee on Governmental Affairs, United States Senate, One Hundred Third Congress, first session, April 26, 1993 (Published by U.S. G.P.O. : For sale by the U.S. G.P.O., Supt. of Docs., Congressional Sales Office; ISBN: 0160433347)
 
 

1994

"Are Genes Us? : The Social Consequences of the New Genetics", Carl F. Cranor (Editor), (Rutgers University Press, 1994).
 

"The Human Genome Project : Deciphering the Blueprint of Heredity",  Necia Grant Cooper (Editor), (Univ Science Books, 1994).
 

"On the New Frontiers of Genetics and Religion",  J. Robert Nelson, (Wm. B. Eerdmans Publlishing Company, 1994).
 

"Justice and the Human Genome Project", Timothy F. Murphy, Marc A. Lappe (Editors), (University of California Press, 1994).
 

"Genes and Human Self-Knowledge : Historical and Philosophical Reflections on Modern Genetics",  Robert F. Weir (Editor), Susan C. Lawrence, Evan Fales (Editor), ro Weir, (Univ of Iowa Press, 1994).
 

"Perilous Knowledge : The Human Genome Project and Its Implications", Tom Wilkie, (University of California Press, 1994).
 
Department of Energy's human genome project issues arising from research : hearing before the Subcommittee on Energy of the Committee on Science, Space, and Technology, House of Representatives, One Hundred Third Congress, second session, October 4, 1994 (Published by U.S. G.P.O. : For sale by the U.S. G.P.O., Supt. of Docs., Congressional Sales Office; ISBN: 0160470382)
 

1995

"The Global Human Genome Program by the OECD Forum Megascience", (Published by O E C D; Publication date: October 1995, ISBN: 9264145753).
 

" The Book of Man : The Human Genome Project and the Quest to Discover Our Genetic Heritage", Walter Bodmer, Robin McKie (Scribner, 1995 - this first edition is hard to find - see 2nd edition, published in 1997).

1996

"The Gene Wars : Science, Politics, and the Human Genome", Robert Cook-Deegan, (W W Norton & Company, 1994).
 

"Morality and the New Genetics : A Guide for Students and Health Care Providers" (Jones and Bartlett Series in Philosophy),  Bernard Gert, (Jones & Bartlett Publishers, 1996).
 

"The Human Genome Project and the Future of Health Care" (Medical Ethics Series), Thomas H. Murray (Editor), Mark A. Rothstein (Editor),and Robert F. Murray, ( Indiana Univ Press, 1996).
 

The Human Genome Project : Cracking the Code Within Us" (Impact-Science),  Elizabeth L. Marshall,  (Franklin Watts, Incorporated, 1996).
 

"The New Genetics : Challenges for Science, Faith, and Politics", Roger Lincoln Shinn, (Moyer Bell Ltd., publisher, 1996).
 
 

"The Lives to Come : The Genetic Revolution and Human Possibilities",  Philip Kitcher (Touchstone Books, 1997).
 

"The Book of Man : The Quest to Discover Our Genetic Heritage", Robin McKie, Walter Bodmer, (Oxford Univ Press, 1997, 2nd edition (first edition was published in Jan. 1995, and is now hard to get.).
 

 

books in press: (As of 14 November, 1997)

"Controlling Our Destinies : The Human Genome Project from Historical, Philosophical, Social, & Ethical Perspectives" (Studies in Science & the humanities), Phillip R. Sloan (Editor), Brian H. Smith, (Univ of Notre Dame Pr; Publication date: December 1997, ISBN: 0268008183)

"Access to the Genome : The Challenge to Equality", Maxwell J. Mehlman, Jeffrey R. Botkin, (Georgetown Univ Pr; Publication date: April 1998, ISBN: 0878406778).
 

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Last modified on: 4 February, 2000 by Dave Ussery