And now begins the squabbling (Haseltine: "missed half the genes"; Venter: "Gene patents irrelevant"):
Sunday February 11, 9:12 am Eastern Time
Analysis shows it's proteins not genes that count
By Maggie Fox, Health and Science Correspondent
WASHINGTON, Feb 11 (Reuters) - Our future may not lie in our genes, after all.
Two separate teams of researchers will report on Monday that they have taken the first in-depth look at the human genetic code and found about half what they expected to find. Instead of 60,000 to 80,000 genes, we have only 30,000 to 40,000.
Both teams agree this means that, in humans anyway, it is proteins that matter -- much more so than genes.
``Those who are looking for forgiveness of responsibility for their own lives in the genetic code will be very disappointed,'' Craig Venter, president and chief scientific officer of Celera Genomics Inc. (NYSE:CRA - news), the private company that did one of the studies, said in a telephone interview.
The human body, it seems, is set up to adapt to its environment, by cutting up and recombining the protein ``products'' of genes to make a protein suitable for the circumstance.
Each gene makes one protein -- this is the basic function of any cell. Researchers had known that proteins often have to be sliced in a certain way, a process known as cleaving, before they do anything useful.
``Most of biology happens at the protein level, not the DNA level,'' Venter said.
What had not been known was the degree to which this is true. The implications could be profound for medical science, which had hoped to find easy genetic answers to disease and to how people will respond to drugs.
GENE PATENTS ``IRRELEVANT''
``This shows how irrelevant human gene patents are,'' Venter said. ``The drug industry has been saying 'one gene, one patent, one drug'. But the uses for this approach can be counted on fingers.''
Both teams, who publish their findings in the rival scientific journals Nature and Science, are fairly certain.
``Given all the tools that we threw at this problem, we cannot imagine that there are many more genes,'' Mark Adams, vice president at Celera, told a briefing for journalists.
``We only have twice as many genes as a fruit fly. But we are more complex. We can think more thoughts. Our bodies can do more things.''
Humans have 3.1 billion base pairs of genetic code. A base pair is a joining of two nucleotides -- known by the letters A,C,T and G. These repeat over and over in various combinations to make amino acids, which in turn combine to make proteins.
``The size of the genome, the number of base pairs, is irrelevant to biology,'' Venter said.
``Corn has the same number of genes as humans. The lily plant has 91 billion pairs of genetic code.''
Each protein equals a gene, but there are long stretches of base pairs that do not code for proteins, areas once known as junk DNA. These areas may help control genes.
Only just over one percent of the genome is accounted for by protein-expressing genes. Venter says all this means genes, per se, are just a small part of the story.
``Genes don't determine whether you get colon cancer,'' he said. ``They determine whether you have an increased risk for colon cancer. We get a set of probabilities from our genetic code, a sort of range of parameters that we can work within.''
KIND OF HUMBLING
``It's kind of humbling, isn't it?'' Ari Patrinos of the U.S. Department of Energy, which funded much of the public effort, said in a telephone interview.
``There are very, very few few traits or diseases that are monogenic (caused by a single gene). It's been an emerging consciousness over the past five years, and the recognition that ... our genes don't control everything.''
It also means the so-called ``junk DNA'' may be more important than at first thought.
``We just don't know. We don't call it junk,'' Venter said.
Eric Lander, who heads the genome lab at Massachusetts Institute of Technology's Whitehead Institute, said the ``alleged junk'' provides a history.
``The junk is amazing. Every piece of junk in the genome represents a transposable element,'' he said.
In other words, it is genetic material that people got from elsewhere, such as from bacteria the readily lend their DNA out, retroviruses that inject their genetic information into cells, or by a cut-and-paste process done by genetic elements known as transposons. If it stayed there through generations, it might do something useful.
Lander thinks some of the ``junk'' may help regulate genes -- a role that is more important the fewer genes there are.
And some of the genes are borrowed, too. Lander said his team found that the gene for monoamine oxidase, an enzyme implicated in depression and targeted by drugs called MAO inhibitors, came from bacteria.
NOT EVERYONE AGREES
Not everyone agrees with all the conclusions.
``We know that they have missed very, very many genes that we know exist,'' William Haseltine, head of Rockville, Maryland-based Human Genome Sciences Inc. (NasdaqNM:HGSI - news), said in a telephone interview.
``They have missed at least half the genes, maybe more,'' added Haseltine, whose company holds more than 100 gene patents. ``They have no medical discovery and they only found a third of the genes. That's a bore.''
Haseltine, whose company looks for ``expressed'' genes -- those that actually make a protein -- by using bits of DNA called expressed sequence tags (ESTs), says he believes there are 120,000 human genes.
Another company that says it has explored the genome, Palo Alto, California-based Incyte Pharmaceuticals Inc.(NasdaqNM:INCY - news), maintains there are 140,000.
-----------------------
Here are two abstracts on variant splicing, which may account for some of the difference in the number of genes:
Genome Res 1999 Dec;9(12):1288-93
Frequent alternative splicing of human genes.
Mironov AA, Fickett JW, Gelfand MS
State Center of Biotechnology NIIGenetika, Moscow, 113545, Russia.
Alternative splicing can produce variant proteins and expression patterns as different as the products of different genes, yet the prevalence of alternative splicing has not been quantified. Here the spliced alignment algorithm was used to make a first inventory of exon-intron structures of known human genes using EST contigs from the TIGR Human Gene Index. The results on any one gene may be incomplete and will require verification, yet the overall trends are significant. Evidence of alternative splicing was shown in 35% of genes and the majority of splicing events occurred in 5' untranslated regions, suggesting wide occurrence of alternative regulation. Most of the alternative splices of coding regions generated additional protein domains rather than alternating domains.
---------------
FEBS Lett 2000 May 26;474(1):83-6 Related Articles, Books, LinkOut
EST comparison indicates 38% of human mRNAs contain possible alternative splice forms.
Brett D, Hanke J, Lehmann G, Haase S, Delbruck S, Krueger S, Reich J, Borka P
Max-Delbruck-Centre for Molecular Medicine, Robert-Rossle-Strasse 10, Berlin-Buch 13125, Germany. dbrett@mdc-berlin.de
Expressed sequence tag (EST) databases represent a large volume of information on expressed genes including tissue type, expression profile and exon structure. In this study we create an extensive data set of human alternative splicing. We report the analysis of 7867 non-redundant mRNAs, 3011 of which contained alternative splice forms (38% of all mRNAs analysed). From a total of 12572 ESTs 4560 different possible alternative splice forms were detected. Interestingly, 70% of the alternative splice forms correspond to exon deletion events with only 30% exonic insertions. We experimentally verified 19 different splice forms from 16 genes in a total subset of 20 studied; all of the respective genes are of medical relevance.
Peter |
