Whole human genomic data readily available (Auton et

Whole genome sequencing (WGS) are
relatively new, incredibly potent tools in the quest for human gene discovery
and in furthering putative genetic epidemiological association. Until very
recently, the limiting factor in any sequencing project was the cost and
throughput of Sanger sequencing. The Human Genome project (HGP), completed in
2004, cost approximately $300 million and was completed over several years,
utilizing several hundred capillary sequencers (Tabor et al., 2011). The cost
of sequencing per base is decreasing in what is best described by a logarithmic
function, and as a result it didn’t take long to complete the $10 million
genome. Now, we are closing in on the $1000 genome (Robertson, 2003). Given
that the cost of human WGS is dwindling rapidly, we are going to see a proportionally
large surge in the number of genomes being sequenced. At this time, the genomes
of several thousand persons have been sequenced, initially predominantly resulting
from testing different computational methodologies, analytical methods and
sequencing platforms (Tabor et al., 2011). However, with projects like the 1000
Genomes Project we are seeing an unprecedented increase in the amount of human
genomic data readily available (Auton et al., 2015). The emerging field of
pharmacogenomics has not yet reached commercial clinical maturity. Despite
this, WGS have been used to identify causal variants for certain monogenic
syndromes. Additionally, WGS are now being utilized in studying variants
underlying more common, mundane phenotypes like diabetes and autism. Here in
the United Kingdom, the Wellcome Trust are creating large genomic databases
with a clear aim to provide context in the association between phenotypic
traits and the underlying genotype. As a consequence of the departure from
targeted genetic studies and the torrent of data produced in WGS, the
established norms pertaining to ethical research conduct are being strained – consequently,
concerns of privacy and consent have to be brought up again (Lunshof et al.,


The development and subsequent
application of novel sequencing techniques marks a paradigm shift in the long-standing
status-quo of human genetic research, with the arrival of the next generation
of sequencers and computational analysis tools, a considerably greater quantity
of data is produced. “There are no conditions under which an offer of
disclosure of research results should not be made” (Fernandez et. al., 2003).

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The former quote is dangerous as it conveys a sense of absolutism, and indeed
ignorance in the perceived capabilities of pioneering researchers. Since the
norm has long been for research participants to receive clinical trial results,
a departure from this model is going to be difficult and policy-ridden. If participants
were to receive probabilistic disease results, they may be misled to overestimate
their significance (Bookman et al., 2006) (Trikalinos et al., 2004).


Traditional sequencing based
approaches may have generated hundreds, thousands or even millions of
polymorphisms, most of these are for non-coding regions of DNA, and impose next
to none functional implication. In a juxtaposition, WGS offer functional
information on effectively all protein-coding gene variants in the genome of
the subject. However, the information gathered is probabilistic and hard
conclusions should not be drawn, neither by researchers nor by participants. As
one group so eloquently puts it “…the difficulty in deciding whether to return
research results lies in the fact that exploratory genetic factors have not yet
reached the point of general clinical acceptance” (Renegar et al., 2006). This
quote is now over eleven years old – and we have to consider that significant technological
advances have been made, the surrounding ethical framework remains relatively
static, comparatively.


Since the international ethical
consensus, and subsequent statutes is based on the foregone paradigm of human
genetic research; this essay aims to describe how WGS studies puts the long-standing
ethical framework used by geneticists to a test. We devote distinctive emphasis
to certain integral segments of this framework: the process of acquiring
consent, Y and Z. It is not our goal to criticize the ethical practices of
present WGS studies, but rather to elucidate the current state of these studies
and technologies with an ethically inclined viewpoint –  and to consider where further development in
the field of human genomic research might lead us so that future ethical qualms
may be prevented.




In the month of May, 2007, Nobel
laureate James Watson peered into his own genome for the very first time. The
hard drive he was endowed with, contained the first genome to be sequenced for
less than $1 million (Check, 2007). Although Dr. Watson is a renowned scientist
with a deep academic connection to the personal genome project, at that time he
was also a subject in a genomic research initiative. In a stark contrast to Dr.

Watson, whose strong academic background allows him to make sense of the
contents of the hard drive, is the vast majority of those that will have their
genomes sequenced for medical purposes.


In literature, it has been
stipulated that the responsibility researchers bear regarding disclosure of
genetic research results varies depending on “the type of study, the clinical
significance and reliability of the information, and whether the study involves
patients, genetically ‘at-risk’ families for a tested predisposition or healthy
volunteers” (Knoppers et. al., 2006). Although the former statement is
informative, it is ridden with ambiguity. Additionally, at present time there
are many jurisdictions in which there are no clear policies pertaining to
ethical research conduct. There is a strong plea from the international
genomics community to create standardized approach to issues concerning
consent, disclosure of results and eventual obligations to genetic relatives.


When considering the prospect of
consent and disclosure documents to be used in WGS studies, several issues have
to be tackled. Traditionally, consent and disclosure documents have been used
in genetic research projects, if the aims and scope of the novel research is dissimilar;
the degree of- and implications of which has to be considered. Secondly, if the
hazards and potential gains of the WGS study is of a particular nature,
partakers may require an extensive account to make a properly informed decision
concerning involvement in the project. Thirdly, partakers may need to be
briefed specifically on the nature of WGS studies conducive to sustaining
transparency and credence in the research venture.


Generally, the aim of a WGS study
is to detect genes and variants that present a risk for an unambiguous disease
or variant. Thus, the magnitude of incongruity of the aims pales in comparison
to the technical differences of the research methodology. However, the
convention is not to disclose research approaches and methodology to the
subject, as they are not relevant in their informed decision to partake or not.

 In studies where the goal may be paralleled
to conventional genetic research, a similar standard- pertaining to consent and
disclosure, may be applied. In studies where the scope and aims are
significantly different, this discrepancy should be mirrored in the consent and
disclosure documents.


Genome wide sequence studies have
been gaining popularity for some time now, and as more commercial ventures
relating to genome sequencing becomes more readily available (www.23andMe.com) –
the international GWS community should expect subjects to desire disclosure of
results to an increasing degree. Additionally, the individual nature of GWS
studies will indubitably increase the propensity of subjects’ plea to access
their results. With the former statements in mind, it’s clear that numerous ethical
and protocol concerns must be tackled prior to any return of results.  


Due to the width of GWS studies, it
has a much higher probability of uncovering unexpected variants that may be of
clinical relevance to the subject. Depending on the individual, this could be
viewed either as a positive or negative consequence of the study. Ideally, the
researchers should decide on whether or not they will be reporting results back
to the subject, either immediately or in the future – as the accessibility of
which may impact the subjects’ willingness to partake. Either way, the accessibility,
potential extent of- and mode of returning results should be reflected in
consent and disclosure documents.

Another risk inherent to genomics
and WGS results from the norm of sharing data on rare alleles, regardless of
the perceived clinical or personal value (Auton et al., 2015). The degree to
which allele sharing distresses participants is undetermined, as it is certainly
dependant on the individual. Nevertheless, participants should be apprised on
this- and the consent document should consequently include the research
enterprises’ plan regarding data sharing. The
discrepancy concerning what the research enterprise is legally obligated to inform
subjects of- and what would be perceived as ethical research conduct can lead
to issues of distrust in the enterprise. If the subject is not informed on the open-access
nature of the study, the implications of results and data-sharing obligations
may leave participants with a sense of deceit.


that consent and disclosure documents are to be used in WGS studies, there is
an inherent ambiguity regarding the extent of comprehensiveness. Regardless of
the amount of detail, there will be difficulty understanding the complex information
by the subject. Thus, an ethically coherent alternative mode of delivering the
results may be employed instead. Perhaps a combination of mixed-media and one
on one debriefing with the researcher.   Numerous research projects have established
that individuals in a hypothetical research setting will intuitively tend to
believe researchers will tell them about clinically relevant information-
although the preceding consent documents made no such obligations, or even if
the consent documents unequivocally specified no results would be returned to
the participants (Murphy et al., 2008) (Miller et al., 2008)


Since there is a limited amount of
human genetic data, over the past decade, we have seen a move towards sharing
data to expedite and accelerate genomics research (Tabor et. al., 2011). Researchers
funded by either the National Institute of Health (NIH) or Genome Wide
Association Studies Central (GWAS central) are bound by contract to submit
genomic data of every single one of their subjects to the database of Genotypes
and Phenotypes (dbGaP) (Mailman, 2007). dbGaP aims to create a repository of data relating
to the interaction between genotypes and phenotypes in Humans. The database is
restricted-access and managed by NIH so the immediate data-sharing concerns are
not overwhelming, but it is noteworthy that one organisation should have such
power over global genomic data.




Over the course of
this analysis, we have displayed that WGS and similar studies contest the
status-quo of ethical research conduct which has historically, been primarily
based on concerns pertaining to targeted genetic research approaches. Many of
the issues outlined arise from the non-specific, wide-scoped nature of whole
genome sequencing. Although, WGS based studies are being conducted extensively
at present time, we propose that the prior points should be brought to
attention and indeed be contemplated on, in order to ensure the highest order
of research integrity relating to WGS studies, and increase the likelihood of
advances in the field and mutual content by researchers and participants alike.

In literature,
there is quite a bit of empirical data relating to human genetic research
participants’ concerns regarding consent, reporting back results, implications
of results, future use of results and so forth. We propose an extraordinary
focus of research in this area, such that a repository of data can be amassed
and analysed with the express purpose of developing a standardized tool for
creating consent and disclosure documents. This tool should be proficient and
modular enough to be used over several decades, across continents, and most
importantly – it should be applicable to all sorts of human genetic research
projects. Additionally, and in the meantime, in order to maintain transparency,
we commend and encourage publication of consent and disclosure documents where

Since the current
norm of broad sharing of genomic data is based on genome wide association studies
(GWAS), established by funding- and regulatory agencies, we propose that they
should also initiate this new discussion pertaining to data-sharing policies
specifically for WGS data. In order for the full spectrum of involved parties
to be represented in such a discussion, other stakeholders such as researchers,
participants, ethicists and indeed participants should be present in such a
forum. The fruitfulness and proficiency of such a forum would also emphatically
be enhanced by the formerly described hypothetical repository of empirical data.