BREAKTHROUGH OF THE
YEAR
1. It's All About Me
2. Human Genetic
Variation
1. It's
All About Me
Jocelyn Kaiser
Along with
the flood of discoveries in human genetics, 2007 saw the birth of a new
industry: personal genomics. Depending on your budget, you can either buy a
rough scan of your genome or have the whole thing sequenced. The companies say
the information will help customers learn about themselves and improve their
health. But researchers worry that these services open up a Pandora's box of ethical issues.
At $300,000 to
$1 million per genome, sequencing all 3 billion base pairs is still too costly
for all but a few. Although dozens more personal genomes will probably be
sequenced in the coming year, most will be done by public and private research
organizations--including the institute run by genome maverick J. Craig Venter,
whose personal genome was one of three completed in 2007 in the United States
and China. In a lower-budget effort, Harvard's George Church this month will
deliver initial DNA sequences for the protein-coding sections (1% of the
genome) to the first 10 volunteers for his Personal Genome Project. Meanwhile,
a new company called Knome is offering full-genome
sequencing to 20 customers willing to pay $350,000.
A glimpse
of one's genome is already within the reach of ordinary people, thanks to
several companies. They include 23andMe, which has financing from Google and
may let users link to others with shared traits; Navigenics,
which will screen for about 20 medical conditions; and deCODE
Genetics in
Although
many customers may view this exercise as a way to learn fun facts about
themselves--recreational genomics, some call it--bioethicists
are wary. Most common disease markers identified so far raise risks only
slightly, but they could cause needless worry. At the same time, some people
may be terrified to learn they have a relatively high risk for an incurable
disease such as Alzheimer's.
The rush
toward personal genome sequences also sharpens long-held worries about
discrimination. A bill to prevent insurers and employers from misusing genetic
data is stalled in Congress. Complicating matters, your genetic information
exposes your relatives' DNA, too.
The most
profound implications of having one's genome analyzed may not be what it
reveals now--which isn't much--but what it may show later on. Perhaps to
sidestep such questions, some companies will limit which markers to disclose.
Others, however, will hand customers their entire genetic identity, along with
all the secrets it may hold.
Papers and articles related
to personal genomics
A.L. McGuire, "The
Future of Personal Genomics," Science 317, 1687 (2007)
S. Levy et al., "The
Diploid Genome Sequence of an Individual Human," PLoS
Biology 5, e254 (2007)
J. Cohen, "Venter's
Genome Sheds New Light on Human Variation," Science 317,
1311 (2007)
C. Holden, "Long-Awaited
Genetic Nondiscrimination Bill Headed for Easy Passage," Science
316, 676 (2007)
Interesting Websites
Knome, Inc.
Personal genomics company that offers whole-genome sequencing and analysis
services for individuals.
23andMe, Inc.
Company dedicated to helping individuals understand their own genetic
information using recent advances in DNA analysis technologies and web-based
interactive tools.
Navigenics,
Inc.
Provides customers with information about their genetic
predispositions for certain diseases.
deCODE
Genetics, Inc.
A biopharmaceutical company applying its discoveries in human
genetics to the development of drugs and diagnostics for common diseases.
2. Human
Genetic Variation
Elizabeth Pennisi
The unveiling of the human genome almost 7 years ago cast the first faint light on our complete genetic makeup. Since then, each new genome sequenced and each new individual studied has illuminated our genomic landscape in ever more detail. In 2007, researchers came to appreciate the extent to which our genomes differ from person to person and the implications of this variation for deciphering the genetics of complex diseases and personal traits.
Less than a
year ago, the big news was triangulating variation between us and our primate
cousins to get a better handle on genetic changes along the evolutionary tree
that led to humans. Now, we have moved from asking
what in our DNA makes us human to striving to know what in my DNA makes me me.
Techniques
that scan for hundreds of thousands of genetic differences at once are linking
particular variations to particular traits and diseases in ways not possible
before. Efforts to catalog and assess the effects of insertions and deletions
in our DNA are showing that these changes are more common than expected and
play important roles in how our genomes work--or don't work. By looking at
variations in genes for hair and skin color and in the "speech" gene,
we have also gained a better sense of how we are similar to and different from Neandertals.
Already, the
genomes of several individuals have been sequenced, and rapid improvements in
sequencing technologies are making the sequencing of "me" a real
possibility. The potential to discover what contributes to red hair, freckles,
pudginess, or a love of chocolate--let alone quantifying one's genetic risk for
cancer, asthma, or diabetes--is both exhilarating and terrifying. It comes not
only with great promise for improving health through personalized medicine and
understanding our individuality but also with risks for discrimination and loss
of privacy.
Turning
on the flood lamps
Even with most of the 3 billion DNA bases lined up in
the right order, there was still much that researchers couldn't see in the
newly sequenced human genome in 2001. Early comparative studies threw conserved
regulatory regions, RNA genes, and other features into relief, bringing meaning
to much of our genome, including the 98% that lies outside protein-coding
regions. These and other studies, including a pilot study called ENCODE,
completed this year, drove home how complex the genome
is.
There are
an estimated 15 million places along our genomes where one base can differ from
one person or population to the next. By mid-2007, more than 3 million such
locations, known as single-nucleotide polymorphisms (SNPs),
had been charted. Called the HapMap, this catalog has
made the use of SNPs to track down genes involved in
complex diseases--so-called genome-wide association studies--a reality. More
than a dozen such studies were published this year.
Traditionally,
geneticists have hunted down genes by tracking the inheritance of a genetic
disease through large families or by searching for suspected problematic genes
among patients. Genome-wide association studies go much further. They compare
the distribution of SNPs--using arrays that can
examine some 500,000 SNPs at a time--in hundreds or
even thousands of people with and without a particular disease. By tallying
which SNPs co-occur with symptoms, researchers can
determine how much increased risk is associated with each SNP.
In the
past, such links have been hard-won, and most have vanished on further study.
This year, however, researchers linked variants of more than 50 genes to
increased risk for a dozen diseases. Almost all the variants exert relatively
small effects, in concert with many other genetic factors and environmental
conditions, and in many cases the variant's real role has not yet been pinned
down. But the sheer numbers of people studied have made even skeptics hopeful
that some of these genetic risk factors will prove real and will help reveal
underlying causes.
The Wellcome Trust, the
Several large
studies have also pinpointed type 2 diabetes genes. One French study involving nonobese diabetics found that a version of a gene for a protein
that transports zinc in the pancreas increased the risk of this disease. Three
simultaneous reports involving more than 32,000 participants
uncovered four new diabetes-associated gene variants, bringing to 10 the number
of known non-Mendelian genetic risk factors for type
2 diabetes. These finds strongly point to pancreatic beta cells as the source
of this increasingly common chronic disorder.
New gene
associations now exist for heart disease, breast cancer, restless leg syndrome,
atrial fibrillation, glaucoma, amyotrophic lateral
sclerosis, multiple sclerosis, rheumatoid arthritis, colorectal cancer, ankylosing spondylitis, and
autoimmune diseases. One study even identified two genes in which particular
variants can slow the onset of AIDS, demonstrating the potential of this
approach for understanding why people vary in their susceptibility to
infectious diseases.
Genomic
hiccups
Genomes can differ in many other ways. Bits of DNA ranging from a few to many
thousands, even millions, of bases can get lost, added, or turned around in an
individual's genome. Such revisions can change the number of copies of a gene
or piece of regulatory DNA or jam two genes together, changing the genes'products or shutting them down. This year marked a
tipping point, as researchers became aware that these changes, which can alter
a genome in just a few generations, affect more bases than SNPs.
In one
study, geneticists discovered 3600 so-called copy number variants among 95
individuals studied. Quite a few overlapped genes, including some implicated in
our individuality--blood type, smell, hearing, taste, and metabolism, for
example. Individual genomes differed in size by as many as 9 million bases.
This fall, another group performed an extensive analysis using a technique,
called paired-end mapping, that can quickly uncover
even smaller structural variations.
These
differences matter. One survey concluded that in some populations almost 20% of
differences in gene activity are due to copy-number variants; SNPs account for the rest. People with high-starch
diets--such as in
New
technologies that are slashing the costs of sequencing and genome analyses will
make possible the simultaneous genome-wide search for SNPs
and other DNA alterations in individuals. Already, the unexpected variation
within one individual's published genome has revealed that we have yet to fully
comprehend the degree to which our DNA differs from one person to the next.
Such structural and genetic variety is truly the spice of our individuality.
Papers and Articles
related to Human Genetic Variation
R. Saxena
et al., "Genome-Wide
Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride
Levels," Science 316, 1331 (2007)
E. Zeggini
et al., "Replication
of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2
Diabetes," Science 316, 1336 (2007)
L.J. Scott et al., "A
Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple
Susceptibility Variants," Science 316, 1341 (2007)
V. Steinthorsdottir
et al., "A
Variant in CDKAL1 Influences Insulin Response and Risk of Type 2
Diabetes," Nature Genet. 39, 770 (2007)
R. Sladek
et al., "A
Genome-Wide Association Study Identifies Novel Risk Loci for Type 2
Diabetes," Nature 445, 881 (2007)
J. Sebat
et al., "Strong
Association of De Novo Copy Number Mutations with Autism," Science
316, 445 (2007)
A.J. de Smith et al., "Array
CGH Analysis of Copy Number Variation Identifies 1284 New Genes Variant in
Healthy White Males: Implications for Association Studies of Complex
Diseases," Hum. Mol. Genet. 16, 2783 (2007)
J.O. Korbel
et al., "Paired-End
Mapping Reveals Extensive Structural Variation in the Human Genome," Science
318, 420 (2007)
K.K. Wong et
al., "A
Comprehensive Analysis of Common Copy-Number Variations in the Human
Genome," Am. J. Hum. Genet. 80, 91 (2009)
G.H. Perry et
al., "Diet
and the Evolution of Human Amylase Gene Copy Number Variation," Nature
Genet. 39,
1256 (2007)
C.M. Egan et
al., "Recurrent
DNA Copy Number Variation in the Laboratory Mouse," Nature Genet. 39, 1384 (2007)
The International HapMap Consortium, "A
Second Generation Human Haplotype Map of Over 3.1
Million SNPs," Nature 449, 851
(2007)
B.E.
Stranger et al., "Population
Genomics of Human Gene Expression," Nature Genet. 39, 1217 (2007)
B.E. Stranger et al., "Relative
Impact of Nucleotide and Copy Number Variation on Gene Expression
Phenotypes," Science 315, 848 (2007)
The Wellcome
Trust Case Control Consortium, "Genome-Wide
Association Study of 14,000 Cases of Seven Common Diseases and 3,000 Shared
Controls," Nature 447, 661 (2007)
J. Fellay
et al., "A
Whole-Genome Association Study of Major Determinants for Host Control of
HIV-1," Science 317, 944 (2007)
C. Lalueza-Fox
et al., "A Melanocortin 1 Receptor Allele Suggests Varying
Pigmentation Among Neanderthals," Science
318, 1453 (2007)
J. Krause et al., "The
Derived FOXP2 Variant of Modern Humans Was Shared with Neandertals," Current Biol. 17, 1908
(2007)
M.N. Weedon
et al., "A Common
Variant of HMGA2 is Associated with Adult and Childhood Height in the
General Population," Nature Genet. 39, 1245 (2007)
P. Sulem
et al., "Genetic
Determinants of Hair, Eye and Skin Pigmentation in Europeans," Nature
Genet. 39, 1443 (2007)
R. McPherson et al., "A
Common Allele on Chromosome 9 Associated with Coronary Heart Disease,"
Science 316, 1488 (2007)
News, Reviews, and
Perspectives
J. Couzin
and J. Kaiser, "Closing
the Net on Common Disease Genes," Science 316, 820
(2007)
J. Novembre
et al., "Adaptive
Drool in the Gene Pool," Nature Genet. 39, 1188 (2007)
J. Cohen, "DNA Duplications
and Deletions Help Determine Health," Science 317, 1315
(2007)
X. Estivill
and L. Armengol, "Copy
Number Variants and Common Disorders: Filling the Gaps and Exploring Complexity
in Genome-Wide Association Studies," PLoS
Genetics 3, e190 (2007)
Interesting Websites
Human
Genetic Variation: An NIH Curriculum Supplement
A creative, inquiry-based instruction program,
designed to promote active learning and stimulate student interest in medical
topics.
International HapMap
Project
A multi-country effort to identify and catalog genetic similarities and
differences in human beings.
Database of Genotype and
Phenotype (dbGaP)
Developed to archive and distribute the results of studies that have
investigated the interaction of genotype and phenotype, including genome-wide
association studies, medical sequencing, and molecular diagnostic assays.
Genetic Association Information
Network (GAIN)
A public-private partnership that aims to understand the genetic factors
influencing risk for complex diseases.
ENCODE (Encyclopedia of DNA Elements)
Project launched by the National Human Genome
Research Institute (NHGRI) that aims to identify all functional elements in
the human genome sequence.
SNPs:
A Science Primer
An introduction to single nucleotide polymorphisms, provided by the National Center for Biotechnology
Information.
SNPedia
A web site for sharing information about the effects of DNA variations on
traits and disease.
The Human Genome: Your Genes, Your Health,
Your Future
A comprehensive resource on the human genome, its role in health and medicine,
and the broader social impact of unravelling its
mysteries; produced by the Wellcome Trust.