Article: Rethinking Genetic Determinism

Rethinking Genetic Determinism With only 30,000 genes, what
is it that makes humans human? By Paul H. Silverman

For more than 50 years scientists have operated under a set
of seemingly incontrovertible assumptions about genes, gene
expression, and the consequences thereof. Their mantra: One
gene yields one protein; genes beget messenger RNA, which in
turn begets protein; and most critically, the gene is
deterministic in gene expression and can therefore predict
disease propensities.

Yet during the last five years, data have revealed
inadequacies in this theory. Unsettling results from the
Human Genome Project (HGP) in particular have thrown the
deficiencies into sharp relief. Some genes encode more than
one protein; others don't encode proteins at all. These
findings help refine evolutionary theory by explaining an
explosion of diversity from relatively little starting
material. We therefore need to rethink our long-held
beliefs: A reevaluation of the genetic determinism
doctrine, coupled with a new systems biology mentality,
could help consolidate and clarify genome-scale data,
enabling us finally to reap the rewards of the genome
sequencing projects.

UNEXPECTED RESULTS In the mid- and late 1980s, our testimony
before the congressional committees controlling HGP purse
strings relied upon our old assumptions.1 In describing the
genome's potential medical value, we elevated the status of
the gene in human development and by extension, human
health. At the same time, the deterministic nature of the
gene entered the social consciousness with talk of
"designer" babies and DNA police that could detect future
criminals.

Armed with DNA determinism, scientific entrepreneurs
convinced venture capitalists and the lay public to invest
in multi-billion-dollar enterprises whose aim was to
identify the anticipated 100,000-plus genes in the human
genome, patent the nucleotide sequences, and then lease or
sell that information to pharmaceutical companies for use in
drug discovery. Prominent among these were two Rockville,
Md.-based companies, Celera, under the leadership of J.
Craig Venter, and Human Genome Sciences, led by William
Haseltine.

But when the first draft of the human genome sequence was
published in the spring of 2001, the unexpectedly low gene
count (less than 30,000) elicited a hasty reevaluation of
this business model. On a genetic level, humans, it seems,
are not all that different from flies and worms.

Or maybe they are, if we can assume that genes are not
strictly deterministic. As Venter et al. reported in
their genome manuscript: "A single gene may give rise to
multiple transcripts, and thus multiple distinct
proteins with multiple functions by means of alternative
splicing and alternative transcription initiation and
termination sites."2

The industry shakeup was predictable. Celera, Human Genome
Sciences, and most of the other genomic sequencing firms
refocused their business plans and downsized. Venter
resigned as president of Celera, and Haseltine has indicated
his intention to do the same.

Read the rest at The Scientist http://www.the-
scientist.com/yr2004/may/research3_040524.html

Posted by Robert Karl Stonjek.

On Sat, 22 May 2004 22:44:34 +0000 (UTC),
Robert Karl Stonjek <rstonjek@bigpond.net.au> wrote:

> Rethinking Genetic Determinism With only 30,000 genes,
> what is it that makes humans human? By Paul H. Silverman
>
> For more than 50 years scientists have operated under a
> set of seemingly incontrovertible assumptions about genes,
> gene expression, and the consequences thereof. Their
> mantra: One gene yields one protein; genes beget messenger
> RNA, which in turn begets protein; and most critically,
> the gene is deterministic in gene expression and can
> therefore predict disease propensities.

This is total nonsense. I've been teaching about genes that
don't make mRNA or proteins for 25 years and I learned about
them long before that.

> Yet during the last five years, data have revealed
> inadequacies in this theory. Unsettling results from the
> Human Genome Project (HGP) in particular have thrown the
> deficiencies into sharp relief. Some genes encode more
> than one protein; others don't encode proteins at all.

I've also been teaching students about genes that encode
more than one protein for 25 years.

> These findings help refine evolutionary theory by
> explaining an explosion of diversity from relatively
> little starting material.

Really?

> We therefore need to rethink our long-held beliefs: A
> reevaluation of the genetic determinism doctrine, coupled
> with a new systems biology mentality, could help
> consolidate and clarify genome-scale data, enabling us
> finally to reap the rewards of the genome sequencing
> projects.

This soounds a lot like new-age doublespeak. Who is this
guy?

> UNEXPECTED RESULTS In the mid- and late 1980s, our
> testimony before the congressional committees controlling
> HGP purse strings relied upon our old assumptions.1 In
> describing the genome's potential medical value, we
> elevated the status of the gene in human development and
> by extension, human health. At the same time, the
> deterministic nature of the gene entered the social
> consciousness with talk of "designer" babies and DNA
> police that could detect future criminals.

Whatever ...

> Armed with DNA determinism, scientific entrepreneurs
> convinced venture capitalists and the lay public to invest
> in multi-billion-dollar enterprises whose aim was to
> identify the anticipated 100,000-plus genes in the human
> genome, patent the nucleotide sequences, and then lease or
> sell that information to pharmaceutical companies for use
> in drug discovery.

Most experts thought there would be fewer than 50,000 genes.
They turned out to be right.

> Prominent among these were two Rockville, Md.-based
> companies, Celera, under the leadership of J. Craig
> Venter, and Human Genome Sciences, led by William
> Haseltine.
>
> But when the first draft of the human genome sequence was
> published in the spring of 2001, the unexpectedly low gene
> count (less than 30,000) elicited a hasty reevaluation of
> this business model. On a genetic level, humans, it seems,
> are not all that different from flies and worms.

No experts were surprised at this result.

> Or maybe they are, if we can assume that genes are not
> strictly deterministic. As Venter et al. reported in their
> genome manuscript: "A single gene may give rise to
> multiple transcripts, and thus multiple distinct proteins
> with multiple functions by means of alternative splicing
> and alternative transcription initiation and termination
> sites."2
>
> The industry shakeup was predictable. Celera, Human Genome
> Sciences, and most of the other genomic sequencing firms
> refocused their business plans and downsized. Venter
> resigned as president of Celera, and Haseltine has
> indicated his intention to do the same.

I think Venter and Haseltine were probably kidnapped by
aliens or maybe they've been murdered by the Masons. It's
certain that there has to be some kind of world-wide
conspiracy in order to explain all these strange happenings.

> Read the rest at The Scientist http://www.the-
> scientist.com/yr2004/may/research3_040524.html

The Scientist is not a credible magazine.

Larry Moran

In article <c8ol4i$2ur2$1@darwin.ediacara.org>,
Robert Karl Stonjek <rstonjek@bigpond.net.au> wrote:
>Rethinking Genetic Determinism With only 30,000 genes, what
>is it that makes humans human? By Paul H. Silverman
...
>Armed with DNA determinism, scientific entrepreneurs
>convinced venture capitalists and the lay public to invest
>in multi-billion-dollar enterprises whose aim was to
>identify the anticipated 100,000-plus genes in the human
>genome, patent the nucleotide sequences, and then lease or
>sell that information to pharmaceutical companies for use
>in drug discovery. Prominent among these were two
>Rockville, Md.-based companies, Celera, under the
>leadership of J. Craig Venter, and Human Genome Sciences,
>led by William Haseltine.
>
>But when the first draft of the human genome sequence was
>published in the spring of 2001, the unexpectedly low gene
>count (less than 30,000) elicited a hasty reevaluation of
>this business model. On a genetic level, humans, it seems,
>are not all that different from flies and worms.
...
>The industry shakeup was predictable. Celera, Human Genome
>Sciences, and most of the other genomic sequencing firms
>refocused their business plans and downsized. Venter
>resigned as president of Celera, and Haseltine has
>indicated his intention to do the same.

As Larry Moran has also indicated, this is complete
nonsense. Venter's resignation and the shakeout at Celera
had nothing to do with the number of genes found. As I
understand it (admittedly from a distance) it had a lot to
do with the failure of Celera to find a way to make money
from its investiment in sequencing of the human genome. This
would be an issue whether there turned out to be 10,000
genes in the human genome or 100,000.

If the rest of the article makes as much sense as this part,
one can safely ignore its grand prouncements.

--
Joe Felsenstein joe@removethispart.gs.washington.edu
Department of Genome Sciences and Department of
Biology, University of Washington, Box 357730, Seattle,
WA 98195-7730 USA

>RJK:- Armed with DNA determinism, scientific entrepreneurs
>convinced venture capitalists and the lay public to invest
>in multi-billion-dollar
enterprises
>whose aim was to identify the anticipated 100,000-plus
>genes in the human genome, patent the nucleotide sequences,
>and then lease or sell that information to pharmaceutical
>companies for use in drug discovery.
Prominent
>among these were two Rockville, Md.-based companies,
>Celera, under the leadership of J. Craig Venter, and Human
>Genome Sciences, led by William Haseltine.
>
>But when the first draft of the human genome sequence was
>published in the spring of 2001, the unexpectedly low gene
>count (less than 30,000) elicited a hasty reevaluation of
>this business model. On a genetic level, humans, it seems,
>are not all that different from flies and worms.
...
>The industry shakeup was predictable. Celera, Human Genome
>Sciences, and most of the other genomic sequencing firms
>refocused their business plans and downsized. Venter
>resigned as president of Celera, and Haseltine has
>indicated his intention to do the same.

JF:- As Larry Moran has also indicated, this is complete
nonsense. Venter's resignation and the shakeout at Celera
had nothing to do with the number of genes found. As I
understand it (admittedly from a distance) it had a lot to
do with the failure of Celera to find a way to make money
from its investiment in sequencing of the human genome. This
would be an issue whether there turned out to be 10,000
genes in the human genome or 100,000. If the rest of the
article makes as much sense as this part, one can safely
ignore its grand prouncements.

JE:- Prof. Felsenstein does know of Haldane's dilemma. He
must know that the dilemma was the direct result of the
human genome being required to be much larger that it was
and the dilemma was only "solved" when the genome was found
to be small. However nobody has revised basic population
genetics assumptions to be able to explain how such a tiny
genome could code for all the heritable human phenotypes.
Prof. Felsenstein cannot ignore the simple logic that
without a heritable system of genetic epistasis 30-40,000
genes cannot code for all the heritable phenotypes unless a
2nd layer of genetic code that is not DNA/RNA based exists
above the DNA/RNA level.

Regards,

John Edser Independent Researcher (posting from Bonn
Germany)

P Box 266 Church Pt NSW 2105 Australia

edser@tpg.com.au

> RJS:- Rethinking Genetic Determinism With only 30,000
> genes, what is it that makes humans human? By Paul H.
> Silverman For more than 50 years scientists have operated
> under a set of seemingly incontrovertible assumptions
> about genes, gene expression, and the consequences
> thereof. Their mantra: One gene yields one protein; genes
> beget messenger RNA, which in turn begets protein; and
> most critically, the gene is deterministic in gene
> expression and can therefore predict disease propensities.

LM:- This is total nonsense. I've been teaching about genes
that don't make mRNA or proteins for 25 years and I
learned about them long before that.

RJS:- One gene can only yield one polypeptide, but these
polypeptides can be woven into more than just the one
protein. Many proteins commonly constitute one selectable
phenotype, e.g. haemoglobin the red pigment found in the
blood which carries both oxygen and carbon dioxide. Thus
most protein phenotypes are coded for by more than one gene.
Since selection is only possible at the _phenotypic_ level,
mostly, groups of genes are _dependently_ selected (selected
using the same phenotype). Thus, for the overwhelming
majority of genomic genes being "selfish" cannot pay unless
that gene's selfishness is mutual to at least all the other
genes that code for the one phenotype being selected.

> RJK:- Yet during the last five years, data have revealed
> inadequacies in this theory. Unsettling results from the
> Human Genome Project (HGP) in particular have thrown the
> deficiencies into sharp relief. Some genes encode more
> than one protein; others don't encode proteins at all.

LN:- I've also been teaching students about genes that
encode more than one protein for 25 years.

JE:- Incorrect. One gene codes for one polypeptide. As Dr
Moran well knows, a protein is not the same biological
entity as a polypeptide. More than one polypeptide normally
constitutes a protein and mostly, more than one protein
constitutes one selectable phenotype. Gene centric Neo
Darwinists prefer to oversimplify this situation in their
attempt to delete epistasis which is defined as _non_
additive. This just means all the genes that _must_ be
selected _together_ because they code for the one selectable
phenotype. Apparently, these should not be confused with
separate somatic phenotypes which are regarded as
selectively independent, i.e."additive",
L.O. polygenes for human height. Thus the genes that code
for the proteins that constitute the protein
haemoglobin are _dependently_ selected at that
phenotype but the proteins that form the walls of the
artery are supposed to constitute an _independent_
somatic phenotype. Clearly this is the case re: body
phenotypes but is not the case re: gene fitness because
haemoglobin and the proteins that form an artery wall
are FITNESS DEPENDENT on each other. A good haemoglobin
protein in a blocked artery is selected against because
that artery may reduce the _total_ number of _fertile_
forms reproduced into _one_ population by the
unfortunate Darwinian selectee who has the faulty
artery. A clean artery is selected against by sickle
cell anemia for a similar reason. In fact ALL then
proteins that form one Darwinian selectee (one fertile
form) are FITNESS DEPENDENT. This is clearly seen when
two phenotypes incorporate the same gene that coded for
just the one polypeptide. Here, just that one gene
would be independently selected at TWO separate
phenotypes as well as being dependently selected at two
phenotypes if more than one gene was requited to code
for each independent phenotype.

Since the human genome only has 30,000 or so genes but has
millions of heritable and thus selectable phenotypes, the
same genes must be dependently selected at more than just
one phenotype, i.e. genetic epistasis must dominate
entirely, human genetics. Yet, non epistasis is still
regarded as "inherited" but "not heritable" and thus, "non
selectable".

Like it or not, genomic genes form _dependent_ selective
_webs_ and not just independent selective chains. The Neo
Darwinistic model of independently selectable genomic genes
is not real. Not a single independently selectable genomic
gene has ever been documented within nature. The Neo
Darwinian model of independently selectable genes gave birth
to the model that just random events that change gene freq.
of such genes can now be regarded as "evolution", e.g.
genetic drift. They cannot. Such changes can only be validly
regarded as temporal variation. To do so is to _grossly_
misuse an oversimplified model. A model is not a theory, it
is always, a simplification/over simplification of an
existing theory. Such a model can never be validly used to
contest and win against the theory it was simplified from.
To do so is to turn science into a Mad Hatter's Tea Party.

> RKS:- These findings help refine evolutionary theory by
> explaining an explosion of diversity from relatively
> little starting material.

LP:- Really?

JE:- The argument is that genetic epistasis must provide
the basis for genetic fitness. The gene centric Neo
Darwinistic view that fitness epistasis is "inherited" but
"not heritable" must be discarded. Redefining ftness
epistasis as additive simply deletes all fitness epistasis
and is yet another Mad Hatter solution because not a single
independent in fitness genomic gene has ever been
documented within nature.

> RKS:- We therefore need to rethink our long-held beliefs:
> A reevaluation of the genetic determinism doctrine,
> coupled with a new systems biology mentality, could help
> consolidate and clarify genome-scale data, enabling us
> finally to reap the rewards of the genome sequencing
> projects.

LQ:- This soounds a lot like new-age doublespeak. Who
is this guy?

JE:- It is Dr Moran who employs "new-age doublespeak",
L.R. who employs post modern epistemology because he regards
just a random process as being testably causative to
something when it remains impossible to test for such
causation. At all times, random patterns can validly be
supposed to be caused by _either_ random or non random
processes. Thus the observation of just a random
pattern such as a random genetic drift is NEVER
definitive to just a random process.

>snip<

> RJK:- Armed with DNA determinism, scientific entrepreneurs
> convinced venture capitalists and the lay public to invest
> in multi-billion-dollar enterprises whose aim was to
> identify the anticipated 100,000-plus genes in the human
> genome, patent the nucleotide sequences, and then lease or
> sell that information to pharmaceutical companies for use
> in drug discovery.

LS:- Most experts thought there would be fewer than 50,000
genes. They turned out to be right.

JE:- Starting from Haldane's Dilemma and moving on, most
_required_ 100,000's of genes because genetic epistasis was
not allowed as heritable and thus selectable, information.

If we restrict all known heritable human phenotypes to just
1 million then each gene codes for, on average,
33.3 phenotypes. How is it possible to delete genetic
epistasis from such a situation? Clearly nature is not
just using one polypeptide within one selectable
phenotype she is being much more efficient. If such
events remain regarded as "inherited" but "not heritable"
and thus "selectable", how can the system work with just
30,000 or so genes?

> RJK:- Prominent among these were two Rockville, Md.-based
> companies, Celera, under the leadership of J. Craig
> Venter, and Human Genome Sciences, led by William
> Haseltine. But when the first draft of the human genome
> sequence was published in the spring of 2001, the
> unexpectedly low gene count (less than 30,000)
elicited
> a hasty reevaluation of this business model. On a genetic
> level, humans, it seems, are not all that different from
> flies and worms.

LT:- No experts were surprised at this result.

JE:- Dr Moran's comment is simply not credible. Haldane's
dilemma was only finally solved, after the human genome
project demonstrated that gene centric calculations based on
Fisher and Haldane's assumptions: only additive gene
associations are heritable and thus selectable (requiring an
enormous genome to be able to code for all the heritable
differences between man and chimp), was discovered to be
redundant. A tiny genome more efficiently used, i.e. that
allowed more than one gene that codes for one polypeptide to
be used within more than just one selected phenotype is the
only possible solution if DNA/RNA is alone considered to
provide genetic code. Of course it has been known for over
40 years that more than just DNA/RNA systems provides a
genetic code. Sonniborn demonstrated that the cell cortex
can provide heritable information that was not based on
DNA/RNA. He rearranged a patch cilia in single celled forms
to be cut out and reversed so the cell swam in circles. This
was passed on over countless generations. Prions form a
"prima face" case for proteins coding for protein folding
information. If a 2nd layer of heritable material exists
above the DNA/RNA level then the two systems acting
_together_ would provide a _levered_ system of inheritance,
i.e. a system where tiny changes provide many different
codes only requiring a tiny DNA/RNA base.

The blinkered view of gene centric Neo Darwinists that
bean bag population genetics can provide all the answers
is not credible. Such models are useful but have been
painfully misused.

> RJS:- Or maybe they are, if we can assume that genes are
> not strictly deterministic. As Venter et al. reported in
> their genome manuscript: "A single gene may give rise to
> multiple transcripts, and thus multiple distinct proteins
> with multiple functions by means of alternative splicing
> and alternative transcription initiation and termination
> sites."2 The industry shakeup was predictable. Celera,
> Human Genome Sciences, and most of the other genomic
> sequencing firms refocused their business plans and
> downsized. Venter resigned as president of Celera, and
> Haseltine has indicated his intention to do the same.

LU:- I think Venter and Haseltine were probably kidnapped by
aliens or maybe they've been murdered by the Masons. It's
certain that there has to be some kind of world-wide
conspiracy in order to explain all these strange
happenings.

JE:- No, just gene centric Neo Darwinistic intransigence. Dr
Moran refuses to take a non biased view and allows non
testable theory as science to maitain his position.

> RJS:- Read the rest at The Scientist http://www.the-
> scientist.com/yr2004/may/research3_040524.html

LV:- The Scientist is not a credible magazine.

JE:- Yes, only the non testable dictates of Dr Moran et al
are allowed as credible.

Respectfully,

John Edser Independent Researcher

PO Box 266 Church Pt NSW 2105 Australia

edser@tpg.com.au

RJS:- Rethinking Genetic Determinism With only 30,000 genes,
what is it that makes humans human? By Paul H. Silverman For
more than 50 years scientists have operated under a set of
seemingly incontrovertible assumptions about genes, gene
expression, and the consequences thereof. Their mantra: One
gene yields one protein; genes beget messenger RNA, which in
turn begets protein; and most critically, the gene is
deterministic in gene expression and can therefore predict
disease propensities.

LM:- This is total nonsense. I've been teaching about genes
that don't make mRNA or proteins for 25 years and I
learned about them long before that.

RJS:- One gene can only yield one polypeptide, but these
polypeptides can be woven into more than just the one
protein. Many proteins commonly constitute one selectable
phenotype, e.g. haemoglobin the red pigment found in the
blood which carries both oxygen and carbon dioxide. Thus
most protein phenotypes are coded for by more than one gene.
Since selection is only possible at the _phenotypic_ level,
mostly, groups of genes are _dependently_ selected (selected
using the same phenotype). Thus, for the overwhelming
majority of genomic genes being "selfish" cannot pay unless
that gene's selfishness is mutual to at least all the other
genes that code for the one phenotype being selected.

RJK:- Yet during the last five years, data have revealed
inadequacies in this theory. Unsettling results from the
Human Genome Project (HGP) in particular have thrown the
deficiencies into sharp relief. Some genes encode more than
one protein; others don't encode proteins at all.

LN:- I've also been teaching students about genes that
encode more than one protein for 25 years. JE:-
Incorrect. One gene codes for one polypeptide. As Dr
Moran well knows, a protein is not the same biological
entity as a polypeptide. More than one polypeptide
normally constitutes a protein and mostly, more than one
protein constitutes one selectable phenotype.

RAGLAND: The article states, "One gene can only yield one
polypeptide, but these polypeptides can be woven into more
than just the one protein." Is this true? Is the question
one gene can only yield one polypeptide framed incorrectly
in light of genetic epistasis? If genes are not the
causative factor in selecting phenotype then how can we
possibly be able to unravel the secrets of our DNA? Isn't it
likely at least with some genetic diseases the "gene-
centric" model will prove itself? Perhaps some traits are
more epistatic than others. For example, traits such as
aggression and intelligence are arguably epistatic based.
Certainly, it can be argued science will come up with
genetic engineering which will eliminate certain genetic
diseases before we can genetically engineer certain aspects
of intelligence and aggression.

JE: Gene centric Neo Darwinists prefer to oversimplify this
situation in their attempt to delete epistasis which is
defined as _non_ additive. This just means all the genes
that _must_ be selected _together_ because they code for the
one selectable phenotype. Apparently, these should not be
confused with separate somatic phenotypes which are regarded
as selectively independent, i.e."additive", e.g. polygenes
for human height. Thus the genes that code for the proteins
that constitute the protein haemoglobin are _dependently_
selected at that phenotype but the proteins that form the
walls of the artery are supposed to constitute an
_independent_ somatic phenotype. Clearly this is the case
re: body phenotypes but is not the case re: gene fitness
because haemoglobin and the proteins that form an artery
wall are FITNESS DEPENDENT on each other. A good haemoglobin
protein in a blocked artery is selected against because that
artery may reduce the _total_ number of _fertile_ forms
reproduced into _one_ population by the unfortunate
Darwinian selectee who has the faulty artery. A clean artery
is selected against by sickle cell anemia for a similar
reason. In fact ALL then proteins that form one Darwinian
selectee (one fertile form) are FITNESS DEPENDENT. This is
clearly seen when two phenotypes incorporate the same gene
that coded for just the one polypeptide. Here, just that one
gene would be independently selected at TWO separate
phenotypes as well as being dependently selected at two
phenotypes if more than one gene was requited to code for
each independent phenotype. Since the human genome only has
30,000 or so genes but has millions of heritable and thus
selectable phenotypes, the same genes must be dependently
selected at more than just one phenotype, i.e. genetic
epistasis must dominate entirely, human genetics. Yet, non
epistasis is still regarded as "inherited" but "not
heritable" and thus, "non selectable".

RAGLAND: You write, "Yet non-epistasis is still regarded as
"inherited" but not "heritable" and thus "non-selectable".
Don't you mean epistasis is still regarded as inherited but
not heritable and thus non-selectable? What is the
difference between inherited and heritable? Isn't this
splitting hairs?

JE: Like it or not, genomic genes form _dependent_ selective
_webs_ and not just independent selective chains. The Neo
Darwinistic model of independently selectable genomic genes
is not real. Not a single independently selectable genomic
gene has ever been documented within nature.

RAGLAND: What about the gene for sickle cell anemia?

JE: The Neo Darwinian model of independently selectable
genes gave birth to the model that just random events that
change gene freq. of such genes can now be regarded as
"evolution", e.g. genetic drift. They cannot. Such changes
can only be validly regarded as temporal variation.

RAGLAND: What is the difference between random genetic drift
and temporal variation?

JE: To do so is to _grossly_ misuse an oversimplified model.
A model is not a theory, it is always, a simplification/over
simplification of an existing theory. Such a model can never
be validly used to contest and win against the theory it was
simplified from. To do so is to turn science into a Mad
Hatter's Tea Party.

RKS:- These findings help refine evolutionary theory by
explaining an explosion of diversity from relatively little
starting material.

LO:- Really?

JE:- The argument is that genetic epistasis must provide
the basis for genetic fitness. The gene centric Neo
Darwinistic view that fitness epistasis is "inherited" but
"not heritable" must be discarded. Redefining ftness
epistasis as additive simply deletes all fitness epistasis
and is yet another Mad Hatter solution because not a single
independent in fitness genomic gene has ever been
documented within nature.

RAGLAND" I think sickle cell anemia is an exception. It
conferred protection against malaria. I tend to agree with
what your saying but the reply is "So what"? Science is
currently not advanced enough to understand genetic
epistasis and to be able to influence it. It's much like my
writing about aggression. We know hardly nothing about its
biological underpinnings. Perhaps you are writing to
attempt to create a shift in attitude away from the neo-
Darwinian gene-centric view but I would argue that will
only come when enough scientific discoveries have been made
it discredit it.

RKS:- We therefore need to rethink our long-held beliefs: A
reevaluation of the genetic determinism doctrine, coupled
with a new systems biology mentality, could help consolidate
and clarify genome-scale data, enabling us finally to reap
the rewards of the genome sequencing projects.

LP:- This soounds a lot like new-age doublespeak. Who
is this guy?

JE:- It is Dr Moran who employs "new-age doublespeak", i.e.
who employs post modern epistemology because he regards just
a random process as being testably causative to something
when it remains impossible to test for such causation.

RAGLAND: What are Dr. Moran's views on genetic epistasis
versus neo-Darwinian gene-centrism. Does he take sides or
does he accomodate both views. Can both views be reconciled
with each other?

JE: At all times, random patterns can validly be supposed to
be caused by _either_ random or non random processes. Thus
the observation of just a random pattern such as a random
genetic drift is NEVER definitive to just a random process.

RAGLAND: I think Dr. Moran understands natural selection and
random drift are not necessarily mutually exclusive
processes.

snip< RJK:- Armed with DNA determinism, scientific
entrepreneurs convinced venture capitalists and the lay
public to invest in multi-billion-dollar enterprises whose
aim was to identify the anticipated 100,000-plus genes in
the human genome, patent the nucleotide sequences, and then
lease or sell that information to pharmaceutical companies
for use in drug discovery.

LQ:- Most experts thought there would be fewer than 50,000
genes. They turned out to be right.

JE:- Starting from Haldane's Dilemma and moving on, most
_required_ 100,000's of genes because genetic epistasis was
not allowed as heritable and thus selectable, information.
If we restrict all known heritable human phenotypes to just
1 million then each gene codes for, on average, 33.3
phenotypes. How is it possible to delete genetic epistasis
from such a situation? Clearly nature is not just using one
polypeptide within one selectable phenotype she is being
much more efficient. If such events remain regarded as
"inherited" but "not heritable" and thus "selectable", how
can the system work with just 30,000 or so genes?

RAGLAND:
LR. Edser have you asked Moran what his views on genetic
epistasis are? I get the impression Dr. Moran doesn't
beleve in genetic epistasis from reading your response.
I have not read what Dr, Moran's views are on this so it
would be helpful for him to respond to your tar and
feathering.

RJK:- Prominent among these were two Rockville, Md.-based
companies, Celera, under the leadership of J. Craig Venter,
and Human Genome Sciences, led by William Haseltine. But
when the first draft of the human genome sequence was
published in the spring of 2001, the unexpectedly low gene
count (less than 30,000) elicited a hasty reevaluation of
this business model. On a genetic level, humans, it seems,
are not all that different from flies and worms.

LS:- No experts were surprised at this result.

JE:- Dr Moran's comment is simply not credible. Haldane's
dilemma was only finally solved, after the human genome
project demonstrated that gene centric calculations based on
Fisher and Haldane's assumptions: only additive gene
associations are heritable and thus selectable (requiring an
enormous genome to be able to code for all the heritable
differences between man and chimp), was discovered to be
redundant. A tiny genome more efficiently used, i.e. that
allowed more than one gene that codes for one polypeptide to
be used within more than just one selected phenotype is the
only possible solution if DNA/RNA is alone considered to
provide genetic code. Of course it has been known for over
40 years that more than just DNA/RNA systems provides a
genetic code. Sonniborn demonstrated that the cell cortex
can provide heritable information that was not based on
DNA/RNA. He rearranged a patch cilia in single celled forms
to be cut out and reversed so the cell swam in circles. This
was passed on over countless generations. Prions form a
"prima face" case for proteins coding for protein folding
information. If a 2nd layer of heritable material exists
above the DNA/RNA level then the two systems acting
_together_ would provide a _levered_ system of inheritance,
i.e. a system where tiny changes provide many different
codes only requiring a tiny DNA/RNA base. The blinkered view
of gene centric Neo Darwinists that bean bag population
genetics can provide all the answers is not credible. Such
models are useful but have been painfully misused.

RJS:- Or maybe they are, if we can assume that genes are not
strictly deterministic. As Venter et al. reported in their
genome manuscript: "A single gene may give rise to multiple
transcripts, and thus multiple distinct proteins with
multiple functions by means of alternative splicing and
alternative transcription initiation and termination
sites."2 The industry shakeup was predictable. Celera, Human
Genome Sciences, and most of the other genomic sequencing
firms refocused their business plans and downsized. Venter
resigned as president of Celera, and Haseltine has indicated
his intention to do the same.

LT:- I think Venter and Haseltine were probably kidnapped by
aliens or maybe they've been murdered by the Masons. It's
certain that there has to be some kind of world-wide
conspiracy in order to explain all these strange
happenings.

JE:- No, just gene centric Neo Darwinistic intransigence. Dr
Moran refuses to take a non biased view and allows non
testable theory as science to maitain his position.

RAGLAND: Perhaps the human genome project hasn't delivered
as some thought it would. These things take time. I think
there is much that we don't know. Undoubtedly, some of what
we think is correct today will have to be revised in the
future. The important thing is not to be like the flat
earth believers and when science does make new discoveries
attempt to suppress it because it doesn't fit our
preconceived notions.

RJS:- Read the rest at The Scientist http://www.the-
scientist.com/yr2004/may/research3_040524.html

LU:- The Scientist is not a credible magazine.

JE:- Yes, only the non testable dictates of Dr Moran et al
are allowed as credible.

RAGLAND:
LV. Moran can come across as arrogant and belittling but he
should, if he cares to, to respond to your accusations
against him.

Michael Ragland wrote:
>
>
> RJS:- Rethinking Genetic Determinism With only 30,000
> genes, what is it that makes humans human? By Paul H.
> Silverman For more than 50 years scientists have operated
> under a set of seemingly incontrovertible assumptions
> about genes, gene expression, and the consequences
> thereof. Their mantra: One gene yields one protein; genes
> beget messenger RNA, which in turn begets protein; and
> most critically, the gene is deterministic in gene
> expression and can therefore predict disease propensities.
>
> LM:- This is total nonsense. I've been teaching about
> genes that don't make mRNA or proteins for 25 years and
> I learned about them long before that.
>
> RJS:- One gene can only yield one polypeptide, but these
> polypeptides can be woven into more than just the one
> protein. Many proteins commonly constitute one selectable
> phenotype, e.g. haemoglobin the red pigment found in the
> blood which carries both oxygen and carbon dioxide. Thus
> most protein phenotypes are coded for by more than one
> gene. Since selection is only possible at the _phenotypic_
> level, mostly, groups of genes are _dependently_ selected
> (selected using the same phenotype). Thus, for the
> overwhelming majority of genomic genes being "selfish"
> cannot pay unless that gene's selfishness is mutual to at
> least all the other genes that code for the one phenotype
> being selected.
>

Maybe it is easier to ask: if the genes contribute to a
useful phenotype, then how would they avoid being selected?
Possibly most easily by not exhibiting fully the mutual
selfishness described. It then remains to be shown how
otherwise are they selected?

> RJK:- Yet during the last five years, data have revealed
> inadequacies in this theory. Unsettling results from the
> Human Genome Project (HGP) in particular have thrown the
> deficiencies into sharp relief. Some genes encode more
> than one protein; others don't encode proteins at all.
>
> LM:- I've also been teaching students about genes that
> encode more than one protein for 25 years. JE:-
> Incorrect. One gene codes for one polypeptide. As Dr
> Moran well knows, a protein is not the same biological
> entity as a polypeptide. More than one polypeptide
> normally constitutes a protein and mostly, more than
> one protein constitutes one selectable phenotype.
>

To me this is like the gene selecting a program on a washing
machine, unaware it is chained to many levels of washing
machines all connected together and then asking "is the wash
on the right cycle?"!

> RAGLAND: The article states, "One gene can only yield one
> polypeptide, but these polypeptides can be woven into more
> than just the one protein." Is this true? Is the question
> one gene can only yield one polypeptide framed incorrectly
> in light of genetic epistasis? If genes are not the
> causative factor in selecting phenotype then how can we
> possibly be able to unravel the secrets of our DNA? Isn't
> it likely at least with some genetic diseases the "gene-
> centric" model will prove itself? Perhaps some traits are
> more epistatic than others. For example, traits such as
> aggression and intelligence are arguably epistatic based.
> Certainly, it can be argued science will come up with
> genetic engineering which will eliminate certain genetic
> diseases before we can genetically engineer certain
> aspects of intelligence and aggression.
>

Even in the clear-cut case this may be partly dreaming.

For one recessive gene and one dominant, my Punnet square
gave ~25% of offspring had traits determined, 75% it was pot-
luck (amongst all the combined possibilities).

> JE: Gene centric Neo Darwinists prefer to oversimplify
> this situation in their attempt to delete epistasis which
> is defined as _non_ additive. This just means all the
> genes that _must_ be selected _together_ because they code
> for the one selectable phenotype. Apparently, these should
> not be confused with separate somatic phenotypes which are
> regarded as selectively independent, i.e."additive", e.g.
> polygenes for human height.

That's interesting though because how would that be known
at meiosis.

Of course it may look like that in a population, but that's
like saying because a gas looks continuous there can't be
atoms (Brownian motion?).

I feel here that must is a little strong an assertion...
overall genes would tend to group together but that is why
it is selection not determination.

> Thus the genes that code for the proteins that constitute
> the protein haemoglobin are _dependently_ selected at that
> phenotype but the proteins that form the walls of the
> artery are supposed to constitute an _independent_ somatic
> phenotype. Clearly this is the case re: body phenotypes
> but is not the case re: gene fitness because haemoglobin
> and the proteins that form an artery wall are FITNESS
> DEPENDENT on each other. A good haemoglobin protein in a
> blocked artery is selected against because that artery may
> reduce the _total_ number of _fertile_ forms reproduced
> into _one_ population by the unfortunate Darwinian
> selectee who has the faulty artery. A clean artery is
> selected against by sickle cell anemia for a similar
> reason. In fact ALL then proteins that form one Darwinian
> selectee (one fertile form) are FITNESS DEPENDENT. This is
> clearly seen when two phenotypes incorporate the same gene
> that coded for just the one polypeptide. Here, just that
> one gene would be independently selected at TWO separate
> phenotypes as well as being dependently selected at two
> phenotypes if more than one gene was requited to code for
> each independent phenotype. Since the human genome only
> has 30,000 or so genes but has millions of heritable and
> thus selectable phenotypes, the same genes must be
> dependently selected at more than just one phenotype, i.e.
> genetic epistasis must dominate entirely, human genetics.
> Yet, non epistasis is still regarded as "inherited" but
> "not heritable" and thus, "non selectable".
>

????

> RAGLAND: You write, "Yet non-epistasis is still regarded
> as "inherited" but not "heritable" and thus "non-
> selectable". Don't you mean epistasis is still regarded as
> inherited but not heritable and thus non-selectable? What
> is the difference between inherited and heritable? Isn't
> this splitting hairs?
>
> JE: Like it or not, genomic genes form _dependent_
> selective _webs_ and not just independent selective
> chains. The Neo Darwinistic model of independently
> selectable genomic genes is not real. Not a single
> independently selectable genomic gene has ever been
> documented within nature.
>

Mendel's peas were bred pure first which is almost
never the case.

Co-dominance and incomplete dominance could occur even for
independently selectable genes (and could be important
unexpectedly).

So even independent selection would not produce definite
results in all cases.

> RAGLAND: What about the gene for sickle cell anemia?
>
>
> JE: The Neo Darwinian model of independently selectable
> genes gave birth to the model that just random events that
> change gene freq. of such genes can now be regarded as
> "evolution", e.g. genetic drift. They cannot. Such changes
> can only be validly regarded as temporal variation.
>
> RAGLAND: What is the difference between random genetic
> drift and temporal variation?
>

Temporal variation would probably occur naturally and
keep a population in a non-equilibrium state (not random,
not homogeneous, but ORDERED) that may allow it to adapt
more quickly.

Random genetic drift (if it is allowed at all, perhaps in
the presence of strong mutagens) would confer a poorer
ability to adapt unless the population was lucky a) in the
degree of drift b) in the particular effects of the drift.

> JE: To do so is to _grossly_ misuse an oversimplified
> model. A model is not a theory, it is always, a
> simplification/over simplification of an existing theory.
> Such a model can never be validly used to contest and win
> against the theory it was simplified from. To do so is to
> turn science into a Mad Hatter's Tea Party.
>

Yes to the extent that it is impossible to produce anything
remotely approaching truly random genetic drift even
experimentally never mind theoretically.

However a model (even very simplified) that includes
"crossover" etc. can be shown to behave in quantifiably
different ways to mutate-and-select alone.

Such a model can hint (only), however, that a theory may be
correct and sometimes models are the best we can do until we
have understood more (which the model can help).

> RKS:- These findings help refine evolutionary theory by
> explaining an explosion of diversity from relatively
> little starting material.
>
> LM:- Really?
>
> JE:- The argument is that genetic epistasis must provide
> the basis for genetic fitness. The gene centric Neo
> Darwinistic view that fitness epistasis is "inherited" but
> "not heritable" must be discarded. Redefining ftness
> epistasis as additive simply deletes all fitness epistasis
> and is yet another Mad Hatter solution because not a
> single independent in fitness genomic gene has ever been
> documented within nature.
>

If it is essentially deterministic mutate-and-select, models
have convinced me nature can do better! Interesting because
by making a gross simplification, you can sometimes avoid a
grosser one!

> RAGLAND" I think sickle cell anemia is an exception. It
> conferred protection against malaria. I tend to agree with
> what your saying but the reply is "So what"? Science is
> currently not advanced enough to understand genetic
> epistasis and to be able to influence it. It's much like
> my writing about aggression. We know hardly nothing about
> its biological underpinnings. Perhaps you are writing to
> attempt to create a shift in attitude away from the neo-
> Darwinian gene-centric view but I would argue that will
> only come when enough scientific discoveries have been
> made it discredit it.
>
> RKS:- We therefore need to rethink our long-held beliefs:
> A reevaluation of the genetic determinism doctrine,
> coupled with a new systems biology mentality, could help
> consolidate and clarify genome-scale data, enabling us
> finally to reap the rewards of the genome sequencing
> projects.
>
> LM:- This soounds a lot like new-age doublespeak. Who is
> this guy?
>
> JE:- It is Dr Moran who employs "new-age doublespeak",
> i.e. who employs post modern epistemology because he
> regards just a random process as being testably causative
> to something when it remains impossible to test for such
> causation.
>

Why not put it to the test, then rethink?

Race a deterministic genome against a less
deterministic one...?

(it may involve making a model)

> RAGLAND: What are Dr. Moran's views on genetic epistasis
> versus neo-Darwinian gene-centrism. Does he take sides or
> does he accomodate both views. Can both views be
> reconciled with each other?
>
> JE: At all times, random patterns can validly be supposed
> to be caused by _either_ random or non random processes.
> Thus the observation of just a random pattern such as a
> random genetic drift is NEVER definitive to just a random
> process.
>
> RAGLAND: I think Dr. Moran understands natural selection
> and random drift are not necessarily mutually exclusive
> processes.
>

But random drift would certainly NOT map one-to-one onto
selected traits, since we don't see random
characteristics...

So the question really is whether random drift is a good
NULL hypothesis even if we don't believe it. And it may well
be as good as we can get. However it is difficult to do
science with.

Beginner.