ABSTRACT___________________________________________________________________________ Whole genome sequencing (WGS) effectively identify allfunctional variants of protein-coding genes in a genome. Projects like theHuman Genome Project (HGP), The $1000 Genome and The 1000 GenomesProject- has radically increased the pace at which genomics as a field ofcommercial and clinical utility has progressed. As such, the prospect of widespread WGS marks the arrivalof a new era in human and medical genetics research. WGS is going to re-inventwhat we think possible with genetics research. As genome research progresses,researchers, participants, regulatory- and funding bodies must necessitateethical research conduct. In comparison to the foregone technology: targetedgenetic research approaches, the non-specific nature of WGS demands adiscussion 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 beenadequately outlined and addressed.
Historically, regulatory agencies and other policy-settingbodies have tackled these matters as they come rather than having a stronglong-term future-oriented plan for dealing with these concerns methodically. Weelucidate how studies reliant on WGS technology puts the status-quo of ethicalresearch conduct to a test, with extraneous emphasis on; how consent isacquired, the proceedings of disclosing results to the subject and to theinternational genomics community. We aim to provide context in the analysis ofthese issues, discussing their implications for stakeholders and additionalinvolved parties. Taking the current state of genomics and implications intoaccount, we provide guidance and some concrete advice on possible routes forethical policy development and subsequent research conduct. Go to:INTRODUCTION___________________________________________________________________________ Whole genome sequencing (WGS) arerelatively new, incredibly potent tools in the quest for human gene discoveryand in furthering putative genetic epidemiological association. Until veryrecently, the limiting factor in any sequencing project was the cost andthroughput of Sanger sequencing. The Human Genome Project (HGP), completed in2004, cost approximately $300 million and was completed over thirteen years,utilizing several hundred capillary sequencers (Bentley et.
al., 2008). Thecost of sequencing per base is decreasing in what is best described by a logarithmicfunction, and as a result it didn’t take long to complete the $10 milliongenome.
At present time, we have far surpassed the $1000 genome (Robertson,2003). As a matter of fact, the price for direct-to-consumer genomic sequencingis 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 proportionallylarge surge in the number of genomes being sequenced (Ayuso et. al., 2013). Atthis 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, withprojects like the 1000 Genomes Project we are seeing an unprecedented increasein the amount of human genomic data readily available (Auton et al.
, 2015). Theemerging field of pharmacogenomics has not yet matured to the point ofwidespread commercial clinical utility. Despite this, WGS have been used to identifycausal variants for certain monogenic syndromes.
Additionally, WGS are now beingutilized in studying variants underlying more common, mundane phenotypes likediabetes and autism (Tabor et. al., 2011).
Here in the United Kingdom, theWellcome Trust are creating large genomic databases with a clear aim to providecontext in the association between phenotypic traits and the underlyinggenotype (Caulfield et. al., 2008). As a consequence of the departure fromtargeted genetic studies and the torrent of data produced in WGS, theestablished norms pertaining to ethical research conduct are being strained –consequently, concerns of privacy and consent have to be brought up again (Lunshofet al., 2008). The field of genomics ispredominantly driven by technological advances, but we are fast approaching atime when neither cost nor efficiency of genotyping will not be the limitingfactors in the advent of genomic medicine (Sharp, R., 2011). The development and subsequentapplication of novel sequencing techniques marks a paradigm shift in thelong-standing status-quo of human genetic research, with the arrival of thenext generation of sequencers and computational analysis tools, a considerablygreater quantity of data is produced.
“There are no conditions under which anoffer of disclosure of research results should not be made” (Fernandez et. al.,2003). The former quote is potentially daring as it conveys a sense ofabsolutism, and indeed ignorance in the perceived capabilities of pioneeringresearchers.
Since the norm has long been for research participants to receiveclinical trial results, a departure from this model is going to be difficultand policy-ridden. If participants were to receive probabilistic diseaseresults, they may be misled to overestimate their significance (Bookman et al.,2006) (Trikalinos et al., 2004). Traditional sequencing basedapproaches may have generated hundreds, thousands or even millions ofpolymorphisms, most of these are for non-coding regions of DNA, and impose nextto none functional implication. In a juxtaposition, WGS offer functionalinformation on effectively all protein-coding gene variants in the genome ofthe subject. However, the information gathered is probabilistic and hardconclusions should not be drawn, neither by researchers nor by participants. Asone group so eloquently puts it “…the difficulty in deciding whether to returnresearch results lies in the fact that exploratory genetic factors have not yetreached the point of general clinical acceptance” (Renegar et al.
, 2006). Thisquote is now over eleven years old – and we have to consider that significanttechnological advances have been made, the surrounding ethical frameworkremains relatively static in a small range of flux. Since the international ethicalconsensus, and subsequent statutes is based on the foregone paradigm of humangenetic research; this essay aims to describe how WGS studies puts thelong-standing ethical framework used by geneticists to a test. We devotedistinctive emphasis to certain integral segments of this framework: theprocess 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 technologieswith an ethically inclined viewpoint – and to consider where further development in the field of human genomicresearch might lead us so that future ethical qualms may be prevented. CONSENT AND HANDLINGOF RESULTS___________________________________________________________________________ In the month of May, 2007, Nobellaureate James Watson peered into his own genome for the very first time. Thehard drive he was endowed with, contained the first genome to be sequenced forless than $1 million (Check, 2007). Although Dr.
Watson is a renowned scientistwith a deep academic connection to the personal genome project, at that time hewas 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 thecontents of the hard drive, is the vast majority of those that will have theirgenomes sequenced for medical purposes. In literature, it has beenstipulated that the responsibility researchers bear regarding disclosure ofgenetic research results varies depending on “the type of study, the clinicalsignificance and reliability of the information, and whether the study involvespatients, genetically ‘at-risk’ families for a tested predisposition or healthyvolunteers” (Knoppers et. al., 2006). Although the former statement isinformative, it is ridden with ambiguity. Additionally, at present time thereare many jurisdictions in which there are no clear policies pertaining toethical research conduct.
There is a strong plea from the internationalgenomics community to create standardized approach to issues concerningconsent, disclosure of results and eventual obligations to genetic relatives. When considering the prospect ofconsent and disclosure documents to be used in WGS studies, several issues haveto be tackled. Traditionally, consent and disclosure documents have been usedin genetic research projects, if the aims and scope of the novel research isdissimilar; 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 decisionconcerning involvement in the project. Thirdly, partakers may need to bebriefed specifically on the nature of WGS studies conducive to sustainingtransparency and credence in the research venture. Generally, the aim of a WGS studyis to detect genes and variants that present a risk for an unambiguous diseaseor variant. Thus, the magnitude of incongruity of the aims pales in comparisonto the technical differences of the research methodology.
However, theconvention is not to disclose research approaches and methodology to thesubject, as they are not relevant in their informed decision to partake or not. In studies where the goal may be paralleledto conventional genetic research, a similar standard- pertaining to consent anddisclosure, may be applied. In studies where the scope and aims aresignificantly different, this discrepancy should be mirrored in the consent anddisclosure documents. Genome wide sequence studies havebeen gaining popularity for some time now, and as more commercial venturesrelating to genome sequencing becomes more readily available (www.23andMe.
com)– the international GWS community should expect subjects to desire disclosureof results to an increasing degree. Additionally, the individual nature of GWSstudies will indubitably increase the propensity of subjects’ plea to accesstheir results. With the former statements in mind, it’s clear that numerousethical and protocol concerns must be tackled prior to any return of results. Due to the width of GWS studies, ithas a much higher probability of uncovering unexpected variants that may be ofclinical relevance to the subject.
Depending on the individual, this could beviewed either as a positive or negative consequence of the study. Ideally, theresearchers should decide on whether or not they will be reporting results backto the subject, either immediately or in the future – as the accessibility ofwhich may impact the subjects’ willingness to partake. Either way, theaccessibility, potential extent of- and mode of returning results should bereflected in consent and disclosure documents. Another risk inherent to genomicsand WGS results from the norm of sharing data on rare alleles, regardless ofthe perceived clinical or personal value (Auton et al., 2015).
The degree towhich allele sharing distresses participants is undetermined, as it iscertainly dependant on the individual. Nevertheless, participants should beapprised on this- and the consent document should consequently include the researchenterprises’ plan regarding data sharing. Thediscrepancy concerning what the research enterprise is legally obligated toinform subjects of- and what would be perceived as ethical research conduct canlead to issues of distrust in the enterprise. If the subject is not informed onthe open-access nature of the study, the implications of results anddata-sharing obligations may leave participants with a sense of deceit.
Giventhat consent and disclosure documents are to be used in WGS studies, there isan inherent ambiguity regarding the degree of comprehensiveness. Regardless ofthe amount of detail, there will be difficulty understanding the complexinformation by the subject. Thus, an ethically coherent alternative mode ofdelivering the results may be employed instead. Perhaps a combination ofmixed-media and one on one debriefing with the researcher. Numerous research projects have establishedthat individuals in a hypothetical research setting will intuitively tend tobelieve researchers will tell them about clinically relevant information-although the preceding consent documents made no such obligations, or even ifthe consent documents unequivocally specified no results would be returned tothe participants (Murphy et al., 2008) (Miller et al., 2008) Since there is a limited amount ofhuman genetic data, over the past decade, we have seen a move towards sharingdata to expedite and accelerate genomics research (Tabor et. al.
, 2011).Researchers funded by either the National Institute of Health (NIH) or GenomeWide Association Studies Central (GWAS central) are bound by contract to submitgenomic data of every single one of their subjects to the database of Genotypesand Phenotypes (dbGaP) (Mailman, 2007) (Kaye et. al., 2009). dbGaP aims to createa repository of data relating to the interaction between genotypes andphenotypes in Humans. The database is restricted-access and managed by NIH sothe immediate data-sharing concerns are not overwhelming, but it is noteworthythat one organisation should have such power over global genomic data.
NEXT STEPS ___________________________________________________________________________Over the course of this analysis, we have displayed thatWGS and similar studies contest the status-quo of ethical research conductwhich has historically, been primarily based on concerns pertaining to targetedgenetic research approaches. Many of the issues outlined arise from thenon-specific, wide-scoped nature of whole genome sequencing. Although, WGSbased studies are being conducted extensively at present time, we propose thatthe prior points should be brought to attention and indeed be contemplated on,in order to ensure the highest order of research integrity relating to WGSstudies, and increase the likelihood of advances in the field and mutualcontent by researchers and participants alike. In literature, there is quite a bit of empirical datarelating to human genetic research participants’ concerns regarding consent,reporting back results, implications of results, future use of results and soforth.
We propose an extraordinary focus of research in this area, such that arepository of data can be amassed and analysed with the express purpose ofdeveloping a standardized tool for creating consent and disclosure documents.This tool should be proficient and modular enough to be used over severaldecades, across continents, and most importantly – it should be applicable toall sorts of human genetic research projects. Additionally, and in themeantime, in order to maintain transparency, we commend and encouragepublication of consent and disclosure documents where appropriate. Since the current norm of broad sharing of genomic datais based on genome wide association studies (GWAS), established by funding- andregulatory agencies, we propose that they should also initiate this new discussionpertaining to data-sharing policies specifically for WGS data. In order for thefull spectrum of involved parties to be represented in such a discussion, otherstakeholders such as researchers, ethicists and indeed participants should bepresent in such a forum. The fruitfulness and proficiency of such a forum wouldalso emphatically be enhanced by the creation of the formerly describedhypothetical repository relating to participants concerns regarding consent,disclosure, data-sharing and future use of data.Asdescribed previously, there are numerous means by which novel WGS studieschallenge the pre-existing framework of results handling and transparency.Indeed, it would be exemplary if all future WGS studies were carefully designedwell ahead of time.
Dejectedly, by virtue of the pace of innovation andadvancement in the field of WGS and genomics in general- this can beproblematic. Additionally, the vast individual differences of WGS studies, suchas geographical location, researchers and type of investigation compounds onthe former. Asthe quantity of novel WGS studies and clinical genomic sequencing servicescontinues to increase, there is an ever-pressing demand for increased ventureswithin the field of empirical data collection from study participants andservice receivers. In the future, this kind of empirical data could and shouldbe used to create models for mass distribution of results, in a manner thatbenefits their health and psychological well-being. An inherent function tothis proposed mode of mass distribution should be its ease upscale-ability andnon-specific usefulness. Conclusively, we think it’s of quintessential importance forstakeholders and other involved parties to recognise the advent of pervasiveHuman whole genome sequencing as an entirely new era in the field of Humangenetics, posing a whole different set of important ethical dilemmas.
We urgeeveryone involved, from participants and researchers to ethics committees andfunding groups to assume a position of active participation in the discussionof the coming unforeseen ethical concerns relating to consent, disclosure anddata-sharing of genomic data. By tackling these impending hurdles ahead oftime, extinguishing any qualms nay-sayers may have with hard, empirical data – the research communitywill be able to further the field of genomics in the most humane and ethicalway possible, while maintaining public trust and transparency.