Whole genome sequencing (WGS) effectively identify all
functional variants of protein-coding genes in a genome. Projects like the
Human Genome Project (HGP), The $1000 Genome and The 1000 Genomes
Project- has radically increased the pace at which genomics as a field of
commercial and clinical utility has progressed. As such, the prospect of widespread WGS marks the arrival
of a new era in human and medical genetics research. WGS is going to re-invent
what we think possible with genetics research. As genome research progresses,
researchers, participants, regulatory- and funding bodies must necessitate
ethical research conduct. In comparison to the foregone technology: targeted
genetic research approaches, the non-specific nature of WGS demands a
discussion forum where ethical and legal concerns relating to consent,
disclosure, return of results and future uses of results can be discussed.

Although attempts have been made, these apprehensions have not yet been
adequately outlined and addressed. Historically, regulatory agencies and other policy-setting
bodies have tackled these matters as they come rather than having a strong
long-term future-oriented plan for dealing with these concerns methodically. We
elucidate how studies reliant on WGS technology puts the status-quo of ethical
research conduct to a test, with extraneous emphasis on; how consent is
acquired, the proceedings of disclosing results to the subject and to the
international genomics community. We aim to provide context in the analysis of
these issues, discussing their implications for stakeholders and additional
involved parties. Taking the current state of genomics and implications into
account, we provide guidance and some concrete advice on possible routes for
ethical policy development and subsequent research conduct.



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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 thirteen years,
utilizing several hundred capillary sequencers (Bentley et. al., 2008). 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. At present time, we have far surpassed the $1000 genome (Robertson,
2003). As a matter of fact, the price for direct-to-consumer genomic sequencing
is closer to $500, depending on the supplier and quantity of genomes sequenced.

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 (Ayuso et. al., 2013). 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 matured to the point of
widespread commercial clinical utility. 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 (Tabor et. al., 2011). 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 (Caulfield et. al., 2008). 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., 2008).


The field of genomics is
predominantly driven by technological advances, but we are fast approaching a
time when neither cost nor efficiency of genotyping will not be the limiting
factors in the advent of genomic medicine (Sharp, R., 2011).

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). The former quote is potentially daring 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 in a small range of flux.


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, reporting back results and data sharing policies.

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 degree 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) (Kaye et. al., 2009). 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 appropriate.

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, 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 creation of the formerly described
hypothetical repository relating to participants concerns regarding consent,
disclosure, data-sharing and future use of data.

described previously, there are numerous means by which novel WGS studies
challenge the pre-existing framework of results handling and transparency.

Indeed, it would be exemplary if all future WGS studies were carefully designed
well ahead of time. Dejectedly, by virtue of the pace of innovation and
advancement in the field of WGS and genomics in general- this can be
problematic. Additionally, the vast individual differences of WGS studies, such
as geographical location, researchers and type of investigation compounds on
the former. As
the quantity of novel WGS studies and clinical genomic sequencing services
continues to increase, there is an ever-pressing demand for increased ventures
within the field of empirical data collection from study participants and
service receivers. In the future, this kind of empirical data could and should
be used to create models for mass distribution of results, in a manner that
benefits their health and psychological well-being. An inherent function to
this proposed mode of mass distribution should be its ease upscale-ability and
non-specific usefulness.


Conclusively, we think it’s of quintessential importance for
stakeholders and other involved parties to recognise the advent of pervasive
Human whole genome sequencing as an entirely new era in the field of Human
genetics, posing a whole different set of important ethical dilemmas. We urge
everyone involved, from participants and researchers to ethics committees and
funding groups to assume a position of active participation in the discussion
of the coming unforeseen ethical concerns relating to consent, disclosure and
data-sharing of genomic data. By tackling these impending hurdles ahead of
time, extinguishing any qualms 
nay-sayers may have with hard, empirical data – the research community
will be able to further the field of genomics in the most humane and ethical
way possible, while maintaining public trust and transparency.