[tt] [wta-talk] Common Sense for our Genomes

[Eugen Leitl]

----- Forwarded message from James Clement <clementlawyer at hotmail.com> -----

From: James Clement <clementlawyer at hotmail.com>
Date: Wed, 17 Oct 2007 15:39:56 -0700
To: 'World Transhumanist Association Discussion List' <wta-talk at transhumanism.org>
Subject: [wta-talk] Common Sense for our Genomes
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Reply-To: World Transhumanist Association Discussion List <wta-talk at transhumanism.org>

THIS EXCELLENT ARTICLE WAS BROUGHT TO MY ATTENDTION BY DR. STEVE COLES, OF
THE GRG (WWW.GRG.ORG):



Commentary:

"Common Sense for Our Genomes"
by
Steven E. Brenner 1
Nature, Vol. 449, pp. 783-4 (October 18, 2007) 
Steven E. Brenner is at the Department of Plant and Microbial Biology 
111 Koshland Hall 
University of California 
Berkeley, CA 94720; USA 
Abstract:

    A personal DNA sequence is not yet practically useful. But it could be,
argues Steven E. Brenner, if we had the right resources available to
interpret genomes.
 

R. WOODWARD/GETTY

    Revelation of the complete DNA sequences of James D. Watson and J. Craig
Venter elicited headlines in recent months, but most press reports struggled
to offer meaningful interpretations. The most noted observation was that
Venter has a particular gene variant predisposing him to cardiac disease,
although his family history was enough to let him know about this general
risk. If the genome is so revealing, why was so little revealed?

    It is telling that Venter said he learned about the cardiac disease gene
in a newspaper report. Put simply, even we in the scientific community 
can't easily come to grips with what we know. The effects of gene variations
are scattered in hundreds of databases, across hundreds of 
interpretative reports in clinical laboratories, and among millions of
manuscripts and patent applications. And although some papers discuss 
the precise effects of a single DNA base change, many analyses offer simple
rules of thumb rather than specific guidance.

    Moreover, even as we celebrate the advent of personal genome sequencing,
we should maintain realistic expectations. Given that most common drug
prescriptions don't even consider a patient's weight, it is unclear how many
future therapies will depend on the minutiae of our genomic make-up. Indeed,
it remains to be seen whether we will typically learn anything more
important from our genomes than the need to use sunscreen, eat better and
exercise more. However, I believe that if we don't seize the initiative and
develop the necessary resources to interpret our genomes, the Venter and
Watson genomes will be seen as missed opportunities.

    Even the scientific paper reporting Venter's genome revealed less than
it might 1. The gene variants described in the initial analysis, intended to
engage a wider audience, could have been selected to elicit guffaws,
touching on associations with alcoholism, obesity, novelty-seeking, and
antisocial behavior. However, these are all statistical likelihoods, and
their relevances are hard to decipher.

    Yet, after learning of the genetic variations that render him
susceptible to cardiac disease, Craig Venter reportedly assumed a new level
of personal responsibility by altering his diet and taking a
cholesterol-lowering statin. So personal genomes may offer a way to
translate genomic knowledge into better preventive medicine.

    Even now, further analyses of the Venter genome 2 could reveal more
useful gene variants. For example, Cytochrome P450 isozymes determine how
rapidly individuals metabolize various drugs, and the US Food and Drug
Administration has approved a microarray test for genotyping these enzymes.
Venter's Cytochrome P450 gene variants were not reported, but these
variations can inform drug dosages.

 It remains to be seen whether we will learn anything more important from
our genomes than the need to use sunscreen, eat better, and exercise more. 

    We are still waiting to learn if the analysis of Watson's genome will
reveal more or less than Venter's. Watson's sequence is available online 3
and a small number of gene variants have been automatically annotated using
the On-line Mendelian Inheritance in Man (OMIM) database. OMIM has 18,000
entries summarizing the literature related to human genes and genetic
disorders (see table below). But because such mutations and their effects
are described textually, only 133 of the 18,000 could be linked directly to
a unique single-nucleotide substitution 4.

Full table

    Visionary geneticists have long contemplated building a resource to
consolidate our understanding of genome variation. However, academic
squabbles and misunderstandings caused the most comprehensive effort -
involving hundreds of scientists backed with millions of dollars - to
founder 5. Perhaps they were premature? Until recently, it was rarely
productive to look beyond a single gene known to be of research or clinical
interest. Today, the situation has changed radically. With the prospect of
inexpensive personal genome sequences, there is profound impetus for
integrating our knowledge of genetic variation and its effect on a genomic
scale.

Covering the Bases

    Many of the foundations for describing human genome variation and
integrating this knowledge are already in place. The Human Genome Variation
Society has defined a standard nomenclature for precisely describing small
variants, which makes it possible, for example, to consistently ascertain
whether two polymorphisms are the same or different. Central publicly funded
databases have repositories of genetic variation information and offer
reference genes and genomes on which the variation can be mapped. Among
these, dbGaP is an example of a database of genotype-phenotype relationships
generated largely from genome-wide association studies. There are also more
than 600 locus-specific databases that focus on narrow areas of the genome.
But merging these databases with dbGaP, and other data sources, would be a
complex task.

    I propose establishing a Genome Commons, a public knowledgebase of human
genetic variation and its effect, culled from databases, diagnostic
laboratories, and the scientific literature. Ultimately, such a repository
of our common human inheritance would be a vast resource for research,
medicine and understanding ourselves.

    There are many ways in which the Genome Commons could be constructed,
but I offer some general guiding principles. It would certainly build on the
curation of hundreds of small locus-specific and other databases today. This
is an often used and successful model, employed for example at GeneTests, a
reference database of thousands of gene and disease tests for diagnostic
use. The editors of GeneTests benefit from contributions by hundreds of
experts who volunteer their knowledge. Similarly, quality controls in the
Genome Commons would be provided by experts overseeing entries in their
domain of expertise, typically a set of genes or diseases. In addition to
their own contributions, they would collate and review entries that could be
submitted by anyone with access to academic journals and appropriate
training.


Share and Share Alike


    To work on a genomic scale, the Genome Commons would need to be
carefully structured, incorporating statistical details about data quality
and the strength of associations for researchers, as well as clinical
references for eventual use by medical practitioners. It is essential that
the Genome Commons be open for remixing, augmentation and redistribution of
content. It is only in this way that researchers can fully share their
knowledge and allow others to build on it.

    An individual genome will typically have millions of differences when
compared with a reference genome; most differences are of little
consequence, but some single mutations can be fatal. The Genome Commons
itself need not contain any individual's information and thus raises few
ethical or privacy concerns. However, both for research purposes and for
clinical interpretation, we will need a navigation tool to relate each
individual's variations to the knowledge compiled in the Genome Commons.

    But sequenced genomes do not come indexed for easy analysis and our
knowledge is so multilayered, that it presents a technical challenge. At one
extreme, for Sickle-Cell Anemia, we understand the molecular mechanism by
which mutation leads to disease. In many more instances, however, there is a
single-gene association, without any mechanistic understanding. In general,
we are happy to find any significant association of phenotype with a genetic
marker. Most variations have never been phenotypically characterized -
Venter's genome had more than a million variants never seen before - and
analyzing these will require predictive approaches. Moreover, variations
appear on different scales in the genome, ranging from small substitutions,
insertions and deletions, to large-scale chromosomal restructuring.

    Initially, I imagine that a Genome Commons navigator would amalgamate
observed variation, and propose phenotypic interpretations. This first step
would allow researchers to assess the challenge and promise of these data,
and to design further research and analysis methods. Later versions of
navigators will incorporate the best methods from many research groups. But
to truly interpret a genome, we face the more daunting challenge of sifting
through the millions of variations and ranking them so that we are not
deluged with genomic marginalia. The navigator would eventually present a
status report focusing on genetic differences of greatest medical or
personal importance.

    Private enterprise would play a vital part by providing an interface
between the Genome Commons and the wider community. Researchers would access
the Genome Commons directly, but companies would mediate its delivery to
patients and physicians. Just as clinical laboratories are used by
physicians to perform diagnostic testing today, I would expect clinical labs
to perform large-scale genome sequencing in the future. I envisage these
labs - and new companies such as 23andMe and Navigenics - using the Genome
Commons navigator as a reference tool for producing diagnostic reports.

    Much genomic variation information is not free, or is encumbered with
intellectual-property protection. To be fully successful, companies must
also contribute discoveries to the Genome Commons. As a central clearing
house of intellectual property, the Genome Commons could reduce transaction
costs. Companies could contribute information and accept a standard
agreement for diagnostic use, making it easier for clinical laboratories to
license large quantities of intellectual property with minimal overheads. In
this way, more assays become accessible and affordable to patients.

    The cost to create and maintain the Genome Commons will be considerable,
even if many volunteers assist the effort. Extrapolating from the costs of
other resources, such as OMIM, PharmGKB and GeneTests, the core
knowledgebase may require millions of dollars in support each year. Most of
this would be spent on salaries for curators and staff overseeing the
informatics.

    Ideally, the Genome Commons would be primarily funded as a government
resource or by a major charity, although many companies will have strategic
economic reasons to financially support an open resource. If a public Genome
Commons fails to emerge, we may instead get a private resource with similar
content, but whose licensing requirements stymie research and innovation. A
single private resource would also lead to monopoly pricing for diagnostic
information. After the huge investments made to ensure that a human genome
sequence was public and free, additional outlays for the Genome Commons seem
prudent so that genomes can be readily interpreted for medical practice and
research.

    The challenges of building a Genome Commons and navigator are not
trivial, but this resource could affect us all personally. In a world where
we all face limited time, resources and personal restraint, an open Genome
Commons would eventually enable productive use of the wealth of information
available, helping us to prioritize healthy activities and therapies to give
us the most productive and enjoyable lifespans.

Join the discussion at http://www.GenomeCommons.org 


References:
Levy S, et al. PLoS Biol. 5, e254 (2007). 
http://www.jcvi.org/research/huref/ 
http://jimwatsonsequence.cshl.edu/cgi-perl/gbrowse/jwsequence/ 
https://mice.cs.columbia.edu/getTechreport.php?techreportID=448&format=pdf 
Maurer, S. M. Res. Policy 35, 839-853 (2006).

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Eugen* Leitl <a href="http://leitl.org">leitl</a> http://leitl.org
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