This annual editorial from Genome Medicine's Section Editors highlights the most exciting
research from the past year and the potential of these advances for medicine. Last
year, we noted that medical 'omics continued its inexorable move towards the clinic;
in 2012 it has truly arrived. DNA capture technologies and sequencing continue to
lead the way, with implications for human genomics, personalized medicine, pharmacogenomics
and drug labeling, public health screening, and public policy already apparent. There
have also been technological advances in proteomics and other 'omic approaches, and
in the integration of these approaches to provide more informative molecular signatures
of health and susceptibility to disease.
De novo mutations: from complexity to the clinic
Genomic approaches to human disease have exploded during 2012, and the number of diseases
for which the genes are being identified by exome sequencing are too numerous to list
and too exciting to highlight any one study over another. Of particular interest is
the ability of genomic analysis to reveal complex patterns of inheritance. The thrombocytopenia
absent radius (TAR) syndrome was previously associated with either de novo or inherited
deletion of 1q21.1; however, evidence suggested that variation at an additional locus
was necessary for disease expression. Exome sequencing revealed that low-frequency
regulatory single-nucleotide polymorphisms for RBM8A (which maps to the 1q21.1 region
and encodes a component of the exon-junction complex), in combination with a 1q21.1
deletion, are necessary and sufficient to cause TAR syndrome [1]. Exome sequencing
also revealed that a form of fascioscapulohumeral muscular dystrophy (FSHD2) results
from digenic inheritance of an allele of the D4Z4 microsatellite array on chromosome
4, which is permissive for the expression of the embedded DUX4 gene, and single-nucleotide
variation (SNV) at the SMCHD1 locus (encoding structural maintenance of chromosomes
flexible hinge domain containing 1) [2]. Thus, an SNV or point mutation allele in
SMCHD1 on chromosome 18 acts as an epigenetic, epistatic modifier of the D4Z4 allele
and acts as a genetic determinant underlying the FSHD2 disease trait [3].
2012 may perhaps be remembered as the year of de novo mutation (DNM). Three different
approaches applied genomic sequencing to directly measure intergenerational DNM rates
[4-6]. DNMs were experimentally measured to occur at about half the previously estimated
rate of about 2.5 × 10-8. Furthermore, these studies confirm and quantify a long-held
observation of a paternal effect on DNM rates [7]. The DNM rate for SNV in the paternal
germline is about four times greater than that in the maternal germline; it increases
linearly by about two DNMs per year in line with spermatogonial stem cell turnover
after puberty [7]. No such maternal age effect was observed. Thus, while maternal
age has long been known to be associated with risk of aneuploidy and developmental
disorders, DNM with paternal aging may have a similar impact on the risk of developmental
disorders in progeny.
Genomics is rapidly being deployed in the clinic, as evidenced by two remarkable papers
from Switzerland and the Netherlands [8,9] showing that a substantial percentage of
sporadic intellectual disability of unknown etiology can be molecularly diagnosed
using an exome sequencing 'trio-based' strategy, comparing the patient with their
parents to identify DNMs. This has immediate clinical implications for counseling
about the risk of recurrence and may eventually provide prognostic information and
potentially genotype-directed therapeutic intervention. Genomic medicine is no longer
the future - it has arrived!
James Lupski, Section Editor, Genomics and epigenomics of disease
Fifteen years of public health genomics
Public health genomics is a multidisciplinary field that deals with the effective
and responsible translation of genome-based science to improve population health [10].
In 2012, the Centers for Disease Control and Prevention (CDC) [11] and the PHG Foundation
[12] marked 15 years of public health genomics in the US and the UK, respectively.
In addition, the European Public Health Genomics Network completed its second cycle
with a scientific symposium in Rome, Italy [13].
What has the past 15 years produced, and where are we going next? A major achievement
has been a better dialog between basic, clinical and population sciences. The principles
of medicine and public health are increasingly converging on a foundation of evidence
that can be applied to the translation of genome-based discoveries into population
health benefits [10]. There is also increased emphasis on policy, training of the
workforce, surveillance and epidemiology [10]. With rapid improvements in genomic
and related technologies, we are seeing the leading edge of the applications of whole-genome
sequencing (WGS) in practice in both pathogen [14] and human genomics [15]. However,
much of the field will be work in progress for quite some time.
In 2012, the CDC Office of Public Health Genomics developed and implemented an evidence-based
classification schema for human genomic applications, taking a population perspective
so that public health programs can start to supplement clinical practice [16]. For
hereditary breast and ovarian cancer (BRCA), Lynch syndrome and familial hypercholesterolemia
(FH), public health programs can use counseling and testing to identify people at
increased genetic risk for cancer and heart disease [17]. There are more than 2 million
people affected with one of these three conditions in the USA, who are at increased
risk for early heart attacks and stroke (FH), breast and ovarian cancer (BRCA) or
colorectal cancer (Lynch syndrome), but most affected individuals and their relatives
do not know they are affected [8]. Therefore, a public health approach of cascade
screening (an active process to find individuals with a certain disease in families,
starting with an affected proband and cascading to relatives) may complement the clinical
approach of promoting access to genetic evaluation and preventive interventions. These
three conditions are only the tip of the iceberg. The facts that there are now more
than 2,500 Mendelian diseases with an available genetic test and more than 100 available
pharmacogenetic tests, and that personal genomic testing services are now available
directly to consumers, means that there will be challenges and opportunities for genomic
implementation for years to come [16].
Muin J Khoury, Section editor, Genomic epidemiology and public health genomics
a
The 'hype' of pharmacogenomics that might be justified
In recent years, the personalized approach of pharmacogenomics-guided treatment has
been acclaimed as one of the most promising innovative concepts in medicine and one
of the first broad clinical applications of genomic medicine. In the mean time, however,
concerns and reservations have arisen as to whether genomic medicine will indeed substantially
improve patient care or change treatment decisions towards targeted, personalized
therapeutic options in clinical practice. Francis Collins' vision in 1999 of a genetically
based, individualized preventive medicine was exciting, suggesting that by 2010, genetic
tests might provide risk information for several diseases for which preventive strategies
are available [18]. The pharmacogenomics hype recently gained support from extraordinary
research activities demonstrating that specific host genotypes are important in the
treatment of chronic hepatitis C (CHC) and cystic fibrosis (CF). In 2011, the US Food
and Drug Administration (FDA) included pharmacogenomic information to the label of
peginterferon alfa-2b and the labels of the direct acting antivirals boceprevir and
telaprevir for treatment of CHC [19], given that several studies provided evidence
that consideration of polymorphisms in the interleukin -28B (IL28B) gene can significantly
improve the efficacy of these drugs [20]. In 2012 the first targeted pharmacogenomic
therapy for CF patients became reality following the approval of the new agent ivacaftor
by the FDA and European Medicines Agency. In patients carrying the CFTR
G551D variant, which results in normal production of the CF transmembrane conductance
regulator CFTR but abnormal chloride channel transport, ivacaftor specifically increases
the channel gating activity of CFTR at the cell surface, thereby enhancing chloride
transport and subsequently improving lung function in CF patients [21].
Yet it is notable that the progress of personalized therapy in clinical practice using
pharmacogenomic information is taking place in small steps. This cannot be explained
solely by the challenges of translational research partnerships or by the lack of
prospective data on the clinical utility of new pharmacogenomic biomarkers. Knowledge
from this past year about the enormous potential of an integrative personal 'omics
profile of the individual patient indicates that we are just beginning to understand
complex phenotypes such as drug responses, which may also change over time [22]. More
intensive research activities are warranted to establish pharmacogenomic signatures
with high predictive value to identify patients at risk of drug failure and/or drug-related
side effects. Only those signatures better than isolated genetic variants will obtain
high acceptance rates in clinical practice [23], thereby promoting the progress of
personalized medicine. This means that pharmacogenomic research should profit from
more comprehensive information provided by clinical and 'omics resources.
Matthias Schwab, Section Editor, Pharmacogenomics and personalized medicine
Top-down proteomics arrives
Proteomics has been dominated by bottom-up approaches, in which proteins are digested
into peptides before mass spectrometry (MS) identification. Although this strategy
has been effective, it effectively 'scrambles' the proteome before MS analysis, adding
uncertainty in how to put the pieces back together. There are advantages to measuring
proteins intact, but such top-down approaches have languished behind bottom-up methods
because of issues related to fractionation, MS instrumentation and software. To many
scientists, top-down proteomics is effective at identifying isolated proteins or confirming
the identity of a protein, but its application to global discovery has been limited.
This past year, however, we have seen tremendous advances in the ability to characterize
complex proteomes using top-down methods.
What may be unexpected is that the major advances were not centered on the mass spectrometer
but involved the way in which the intact proteins were fractionated before MS analysis.
Kelleher and colleagues used a tube-gel electrophoresis (TGE) device to separate intact
proteins by molecular mass before top-down MS identification [24]. Proteins were extracted
from Saccharomyces cerevisiae and those in the 0 to 50 kDa molecular weight range
were separated into 12 fractions using TGE. Each of these fractions of intact proteins
was analyzed in triplicate using nanocapillary liquid chromatography tandem MS. Within
72 hours, a time period comparable to that required using bottom-up approaches, 530
unique proteins and 1,103 distinct protein species (including isoforms) were identified.
This report [24] built upon a previous study [25] in which this group identified over
3,000 proteins from human cells using top-down MS. In this earlier study [24], however,
a four-dimensional separation strategy was required. These reports represent the largest
yeast and human proteome coverages demonstrated so far, and the yeast study [24] specifically
showed that top-down proteomics can be conducted with the throughput capabilities
and timescale of bottom-up approaches. These studies signify important advances in
bringing the characterization of intact proteins, and their isoforms, to proteomic
laboratories worldwide.
Timothy Veenstra, Section Editor, Proteomics and metabolomics
The move from reactive to proactive medicine is under way
Integration of an ever-increasing variety and quantity of biological, clinical, epidemiological,
environmental, functional, genetic, genomic, pathological and physiological data through
systems approaches is the cornerstone for the personalized treatment of individuals,
the ultimate goal of doctors since the Greek founders of medicine. In its modern form,
personalized medicine is empowered by technological advances in experimental and computational
platforms, triggering the transition from the current reactive practice of medicine
to a more proactive mode of 'P4' (predictive, preventive, personalized and participatory)
systems medicine [26]. A fundamental limiting factor in this process is our ability
to distinguish causative, explanatory and actionable relationships from the wide range
of correlations revealed, for example, in genome-wide association studies or clinical
trials that require assessment of hundreds to thousands of patients and control participants
to extract meaningful information [27]. This explains why very few of the large number
of promising biomarkers and drug targets make their way to effective clinical practice,
and thus why costs in drug development and healthcare have escalated [28].
During the past year, great advances have been made in overcoming these hurdles, as
witnessed by two reports on the longitudinal follow-up of individuals and integration
of extensive datasets [29,30]. In the first case, an integrated, dynamic 'omics profile
for one person was recorded regularly over more than a year, combining genomic, transcriptomic,
metabolomic and immunological profiles. It revealed a risk for type 2 diabetes and
pathways and molecular mechanisms distinctive to the healthy and disease states for
that individual [29]. The second case is a report on a decade-long quantitative recording
of blood and stool biomarkers, tracking of nutrition, exercise, sleep and stress,
combined with personal genetics and microbiome assessment of one individual. It detected
a persistent source of inflammation that turned out to be an early pre-symptomatic
sign of the development of late-onset inflammatory bowel disease [30]. These are important
steps for these individuals, who were alerted on their potential or actual health
risks earlier than they would have been in a classical medical situation. Most importantly,
the two studies indicate that collection of datasets in regular time series and their
combination with background genetic or genomic data on single individuals is sufficiently
powerful to overcome the hurdles discussed above. Such findings should, in turn, inform
studies in pharmacogenomics so as to tailor personalized treatments for larger groups
of patients [23]. They should also facilitate the development of panels of indicators
for disease control as part of decision-support systems for the monitoring of prominent
complex diseases, such as chronic obstructive pulmonary disease, by patients and their
physicians [31]. The P4 medicine that seemed to be a long-term possibility is thus
now becoming a reality [32].
Charles Auffray, Section Editor, Systems medicine and informatics
The policy challenges of inexpensive whole-genome sequencing
Although many of the most common ethical, legal and social issues continued to stir
debate - including the issues associated with human gene patents, return of results
and consent for participation in biobanks - the challenges associated with inexpensive
and efficient WGS attracted a significant amount of policy attention in 2012.
Because of the rapid increase in the speed and efficiency of sequencing technologies,
it has long been speculated that routine WGS was a near-future inevitability. Over
the past year, a range of developments, including the use of whole-genome technology
in the prenatal context [33], have pushed the issue beyond mere speculation and heightened
policy debates on the social implications of the technology. For example, there are
emerging questions about the actual health value of routine WGS [34] and its potential
adverse impact - from, for example, a cost perspective - on the health care system
[35]. There seems little doubt that the technology will, among other effects, advance
genomic research and our understanding of a range of diseases and help in the diagnosis
of rare diseases. However, the limited predictive value of most genomic information
(particularly in the context of common chronic diseases) [34], coupled with the fact
that most health care providers seem ill equipped to use the information, has resulted
in a call for more research and health policy analysis on how WGS technology can be
used in a clinically beneficial and cost effective manner [36]. The prospect of cheap
WGS has also heightened, rightly or not, concerns about privacy [37,38]. This is due,
in part, to the vast amount of personal information (albeit largely uninterpretable)
generated, the enduring perception that genetic information is unique and the related
idea that genomic data will have biological relevance. This latter issue has raised
interesting questions about the possible need to obtain consent from relatives prior
to the public release of genomic information. Although all of these issues are worthy
of further analysis, it is the use of this technology in the context of non-invasive
prenatal genetic tests that generated the most controversy [39]. Indeed, Scientific
American selected genome sequencing of fetuses as one of the world-changing developments
of 2012 [40]. These developments seem certain to generate both intense social debate
and a range of regulatory responses [41].
Timothy Caulfield, Section Editor, Ethical, legal and social issues
Abbreviations
CDC: Centers for Disease Control; CHC: chronic hepatitis C; CF: cystic fibrosis; CFTR:
cystic fibrosis transmembrane receptor; DNM: de novo mutation; FDA: US Food and Drug
Administration; P4: predictive, preventive, personalized and participatory; SNV: single
nucleotide polymorphism; TAR: thrombocytopenia absent radius; TGE: tube-gel electrophoresis;
WGS: whole-genome sequencing.
Competing interests
The authors declare that they have no competing interests.
Endnote
a The views expressed here are those of the authors and not necessarily those of the
US Department of Health and Human Services.