modified by W. Barnes
Clarion University of
Pennyslvbania
May 13, 2002
One of the most unfortunate legacies of Mendelian genetics is the
lumping together of gene defects and genes. People with various genetic
defects may or may not manifest a disease phenotype. As both Horace
Freeland Judson and Sydney Brenner point out in the articles cited below
classical genetics was so firmly based on gene defects that only recently
have we begun to determine what "normal" or wild- type genes really
are. And careful reading and/or listening will often reveal that people
use the word gene and a number of related words and phrases (mutations
and other variants) very loosely and interchangeably.
How past history leads to present confusion
Horace Freeland Judson, writing in the Feb. 2001 human genome issue of Nature notes problems with terminology. "The phrases current in genetics that most plainly do violence to understanding begin "the gene for": the gene for breast cancer, the gene for hypercholesterolaemia, the gene for schizophrenia, the gene for homosexuality, and so on. We know of course that there are no single genes for such things. We need to revive and put into public use the term "allele". Thus, "the gene for breast cancer" is rather the allele, the gene defect - one of several - that increases the odds that a woman will get breast cancer. "The gene for" does, of course, have a real meaning: the enzyme or control element that the unmutated gene, the wild- type allele, specifies. But often, as yet, we do not know what the normal gene is for. ... Pleiotropy. Polygeny. Perhaps these terms will not easily become common parlance; but the critical point never to omit is that genes act in concert with one another - collectively with the environment. Again, all this has long been understood by biologists, when they break free of habitual careless words. We will not abandon the reductionist Mendelian programme for a hand- wringing holism: we cannot abandon the term gene and its allies. On the contrary, for ourselves, for the general public, what we require is to get more fully and precisely into the proper language of genetics." [Horace Freeland Judson "Talking about the genome" Nature 409: 769, 15 Feb. 2001]
Sydney Brenner, writing in the special Drosophila genome issue
of Science made a similar observation "Old geneticists knew what they were
talking about when they used the term "gene", but it seems to have become
corrupted by modern genomics to mean any piece of expressed sequence, just
as the term algorithm has become corrupted in much the same way
to mean any piece of a computer program. I suggest that we now use the
term "genetic locus" to mean the stretch of DNA that is characterized
either by mapped mutations as in the old genetics or by finding a complete
open
reading frame as in the new genomics. In higher organisms, we often
find closely related genes that subserve closely related, but subtly different,
functions." [Sydney Brenner "The End of the beginning" Science 287 (5451):
2173, Mar. 24, 2000]
Does defining "gene" only get harder? Or are we making progress by recognizing how complicated it really is?
This is not a new problem. The report of the Invitational DOE Workshop on Genome Informatics (26-27 April 1993, Baltimore MD) pointed out "The concept of "gene" is perhaps even more resistant to unambiguous definition now than before the advent of molecular biology. http://www.ornl.gov/hgmis/publicat/miscpubs/bioinfo/inf_rep2.html
A tutorial "Ontologies for Molecular Biology Workshop: Semantic Foundations
for Molecular Biologies" at the Intelligent Systems for Molecular Biology
Conference ( June 27-28, 1998) in Montreal, Canada noted "Molecular biology
has a communication problem. Many researchers and databases use (at
least partially) idiosyncratic terms and concepts for representing biological
information. Often, terms and definitions differ between groups, with different
groups not infrequently using identical terms with different meanings.
The concept 'gene', for example, is used with different semantics
by the major international genomic databases. http://www-lbit.iro.umontreal.ca/ISMB98/anglais/ontology.html
Definitions of gene
Gene is a good example of a word in the process of evolving from classical genetics meanings (fairly abstract concepts, rooted in the Mendelian model of monogenic diseases with high penetrance). The concept of "gene" has been changing so fast that most print resources (and some online) are out of date. The best source I've found is at http://www.ergito.com/ a project of Benjamin Lewin and colleagues (requires free registration) Molecular Biology: The best- selling textbook GENES online (which also has an extensive glossary).
The definition of gene is evolving (and lengthening) as we tease apart the incredible complexity of biological and molecular processes and discover that "junk DNA" has important regulatory functions. Gene identification in prokaryotes is almost trivial as their genomes consist almost entirely of exons. However human genes are only about 2 % of total human DNA. Human exons are widely separated by immense stretches of introns.
The concept of "gene" didn't come along until 1909, three years after the term genetics in 1906 (Evelyn Fox Keller, The century of the gene, Harvard University Press, 2000). For some time it remained a quite abstract term. With advances in molecular biology the definition is less and less abstract - but far from settled. Is a monolithic gene concept still valid?
Bioinformatics expert Nat Goodman writing in the April 2001 issue of
Genome Technology states that gene "is a highly nuanced noun like "truth".
Ten
years ago, it commonly meant "genetic locus" - a region of the genome
linked to a disease or other phenotype. Over time biologists became
more comfortable thinking of a gene as a transcribed region of the genome
that results in functional molecular product.
Gene definitions
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