WEDNESDAY, 20 DECEMBER 2023A research group at Stanford University has sequenced the human genome in a record-breaking time of under 6 hours. Unbelievably, this is twice as fast as the previous record. Advancements in genomics are changing healthcare as we know it, for better or for worse. Welcome to the Genomic Revolution.
WHAT IS GENOME SEQUENCING?
Genome sequencing allows medical specialists to view the complete set of genetic material in an individual. Now, in as little as a few hours, genomic data is widely accessible and available. The information from the genome is instrumental in identifying rare inherited disorders, characterising mutations that drive cancer progression, and as evidenced by the recent pandemic, tracking disease outbreaks. The interpretation of genetic data requires high-throughput computational analysis which is often time-consuming, expensive, and subjective. Advancements in genomics have been critical for advancing scientific policy and have increased support for the open-sharing of scientific data. However, this has raised many ethical issues surrounding the use of genetic data, particularly in medicine. Who should have access to this data? What could the data incidentally reveal? And how do we communicate this information to patients?
A BRIEF HISTORY OF SEQUENCING
As incredible as it may seem, genome sequencing is a relatively new technology. It all began in 1977 when Frederick Sanger developed the first sequencing method and was awarded a Nobel Prize for his revolutionary work. The first DNA based genome was sequenced in the same year — the genome of a bacteriophage which infects E. coli.
Jumping to the year 2000, the full genomic sequence of the fruitfly was completed. In the same year, the first plant genome was also sequenced.
The launch of the 1990 Human Genome Project set out to sequence the entire genome of humans, and 15 years later established the first ‘complete’ human genome.
Following this, the HapMap Project in 2005 aimed to describe common patterns of human sequence variation, a major stepping stone for large-scale human genome projects such as the 1000 Genome Project.
2009 saw an explosion of new computational tools. Increasing affordability and accessibility to genome sequencing meant that new tools to accommodate the requirements of large-scale genomic projects were required.
The 100,000 Genome Project was the next major stepping stone, a UK initiative to sequence and study the roles of genes in health and disease. The research and analysis of this initiative is still ongoing. Most recently, the Newborn Genomes Programme was introduced. It aims to explore how, and when, offering whole genome sequencing to newborns is appropriate.
Here, we will focus on two important examples of genomic sequences by looking back and reflecting on the aims and outcomes of the Human Genome Project, and looking forward to see how the Newborn Genomes Programme may change the future of healthcare.
GENOME SEQUENCING: ITS PROMISES
THE HUMAN GENOME PROJECT
It is difficult to attend any biological lecture or read any textbook without the Human Genome Project being mentioned in some capacity. In many ways, it has allowed us to gain a complete understanding of the human genome, remarkably reducing the basis of our existence to a sequence of letters on a page. But is our understanding really complete? Although labs all over the world have access to the human genome at their fingertips, each breakthrough presents us with further unanswered questions and reveals an additional layer of complexity.
The Human Genome Project was set up in 1990 with the initial promise of decoding the human genome down to its sequence of base pairs and annotating the genes. It is clear that the scientists involved in the project, and those who funded it, believed that the success of this project would be a momentous step in modern biology and would have an impact on many disciplines, from physiology and medicine to pharmaceutical design. There was also a great amount of excitement from the media and general public about how we would be able to read the secrets of our own lives in an accessible way. Many thought that this project promised to decode the base sequence of our genome and, in doing so, promised to easily identify all disease causing genes, find genes that set humans apart from other great apes, and explain every aspect of our phenotype. It is difficult in hindsight to distinguish between what the scientists ‘promised’ and what the media and general public expected.
The first draft of the human genome project was published in 2003. For many scientists working in the field today, having access to the human genome is as vital to the lab as test tubes and petri dishes. Because of the Human Genome Project, geneticists have a reference genome that they can compare to the genomes of other humans to identify areas of variation, and use to find similarities and differences between our own DNA, and the DNA of other species. The Human Genome Project was a landmark project in many other ways, not least for its public data publishing and the collaboration between multiple labs working towards a common goal.
The data collected from the Human Genome Project has had a significant impact, in the field of genetics and beyond. This is seen both in its direct use and indirectly in subsequent projects that have used similar or adapted experimental techniques. The Human Genome Project has revealed a lot in terms of our past evolution and relationships to other organisms in the evolutionary tree of life. We have been able to disprove suggestions that the more DNA an organism has, the more complex it is — this is the concept of the so-called ‘C-value enigma’. For example, humans and mice have a similar number of genes while some plants, like corn, have many more genes than we do. Through careful analysis of the Human Genome Project data and the 1000 Genomes initiative, we have been able to identify SNPs or small non-coding polymorphisms. These are bases that are different in different people, for example, 80% of a population may have an A nucleotide at a specific position while the other 20% have a C.
HAVE THE PROMISES OF THE HUMAN GENOME PROJECT BEEN FULFILLED?
The Human Genome Project made many claims during its initial stages about its possible future impact on the biosciences and many of these have stood the test of time. However, almost 20 years on from its completion, we must reflect and ask if all these promises have been met. It is very clear that to know the nucleotide sequence of the human genome is to know the human blueprint. But, in the same way a script can only tell us so much about the final film, the base sequence is not the whole story.
The genome is not simply a string of letters to be read chronologically. In reality, DNA is highly compacted through the involvement of histone proteins and nuclear scaffolds. Some parts are highly repressed and are not actively transcribed while other parts are more accessible to the transcription machinery. The more accessible a gene is, the higher the rate of transcription will be. It should be noted that, for a large proportion of the genome, its state of compaction is dynamic and dependent on the immediate needs of the cell. In contrast, genes that are not needed by a cell (for example, liver enzymes in a muscle cell) may be entirely and almost irreversibly repressed. The fact that a neuron, epithelial cell, and muscle cell are so disparate in structure and role while containing the same genetic information proves that knowing the underlying blueprint is limited in its ability to determine how a cell and organism will look and function.
Epigenetics is currently a very fashionable area of research and one that, arguably, is deserving of the attention it attracts. Epigenetic modifications refer to heritable changes to the genome that do not alter the underlying base sequence (and were therefore not sequenced as part of the Human Genome Project). This could be the addition of chemical groups, such as an acetyl group, to histone proteins, or the addition of a methyl group to cytosine nucleotides in the DNA sequence. These modifications can alter how accessible the DNA is and therefore alter gene expression. When we ask seemingly simple questions like ‘why do genetically identical twins who grew up in the same environment develop different diseases?’, we confirm the nucleotide sequence cannot possibly be the whole story. It is probable that epigenetic divergence plays a part in the different phenotypes of genetically identical individuals.
Even if we briefly ignore the issues that gene expression presents, why is it that we have not been able to clearly identify all the genes in the genome and match gene sequence to function? It is clear this process is not as simple as one might have predicted when the Human Genome Project began. Less than 1.5% of the human genome codes for proteins meaning they must be searched for amongst a desert of non-coding sections of DNA. Introns are non-coding regions of genes that are removed from mRNA transcripts by splicing. They appear frequently and can be up to 200 Kb long. To add a layer of further complexity, the term ‘gene’ is actually very difficult to define. Genes can be nested in other genes by being located in an intron. In addition, a ‘gene’ can encode different proteins if the transcript is post-transcriptionally modified in different ways — this is known as differential splicing. Simply knowing the sequence of A,T,G, and C nucleotides is of limited value without an understanding of the proteins they encode and the regulation of their transcription. However, there have been many advancements in transcriptomics (the analysis of the mRNA transcribed from the DNA sequence) through experimental techniques such as microarrays, for which the sequencing of the human genome was necessary for its creation. It cannot be denied that sequencing the human genome was a crucial step in understanding our genetics and was a necessary foundation for subsequent advancements in both knowledge and technology.
We must be aware when discussing the ‘success’ of the original Human Genome Project that the media greatly exaggerated the claims of the scientists involved. The project was fundamentally a success as it succeeded in completing its primary goal — to sequence the human genome. The notion that the Human Genome Project would revolutionise the biosciences did not come from geneticists but rather the journalists of the time. The difficulty in understanding the complexities of the decoded genome could not have been predicted at the outset of the project. Perhaps presenting unanswered questions and lines of further research is as valuable as giving direct insights.
NEWBORN GENOMES PROGRAMME
Fast-forward to 2021, a public dialogue on the use of whole genome sequencing in newborn screening was released. The dialogue’s main findings are summarised below. The recent Newborn Genomes Programme aims to utilise whole genome sequencing in newborns to expand screening from the current nine conditions offered to many more rare diseases.
Professional guidance and advice on whole genome sequencing of seriously ill infants is conflicting. This creates wide-spread controversy on whether the new screening programme is considered acceptable or not. The British Society for Genetic Medicine believes that testing the whole genome is unlikely to be controversial when testing aids immediate medical management. Conversely, the European Society of Human Genetics believe it is preferable to use a targeted screening approach (such as targeting specific genes) to avoid unsolicited or uninterpretable findings. If a reliable method to detect a serious genetic disorder earlier exists, is it not our responsibility to use it? The professional moral imperative of beneficence — doing good to others, including moral obligation — would have you believe so. However, overwhelming patients with complicated genetic results, riddled with uncertainties, may hinder the professional duty of nonmaleficence — to do no harm. The European Society of Human Genetics raises valid concerns regarding potential incidental findings. Whole genome sequencing of newborn babies may reveal unexpected abnormalities, and this raises questions on how, or even if, we report these findings. Despite initial reservations, the design of Genomics England Newborn Genomes Programme is currently underway.
The programme broadly aims to identify rare diseases in babies; to understand how genomic data could be used to improve knowledge and treatments; and to explore the potential risk and benefits of storing an individual's genome over their lifetime. If successful, the programme could provide early diagnosis for childhood-onset rare genetic conditions. In theory, this is a no-brainer. Improving diagnosis and immediate care for infants whilst building a comprehensive genomic database to inform research and knowledge; what could go wrong? In reality, our understanding of the genome is far from perfect and whole genome sequencing in newborns raises many questions. Who will be affected by whole genome sequencing? What information will be shared to patients and to big data sources? And what are the implications for wider society?
A summary of the public dialogue from the Newborn Genome Programme
1) It would be acceptable to use Whole Genome Sequencing (WGS) to identify a wider set of conditions than current NHS newborn screening programmes provided:
- The condition impacts infants in early childhood.
- Treatments and/or interventions are available to cure, prevent or slow progression of the conditions.
2) Genetic Counselling and Mental health support must be available to those who receive a diagnosis.
3) A comprehensive genetic database should be established so ethnic minority backgrounds are not disadvantaged by receiving more uncertain or less accurate diagnoses.
4) The complexities of WGS must be recognised during the design of the consent process. Including:
- Implications of WGS for the wider family.
- That parents consent on behalf of children, but the children may have different views when they grow up.
- The screening tests have the potential to look for more conditions than current newborn screening.
GENOME SEQUENCING: ITS IMPACT
THE HUMAN GENOME PROJECT
Having a reference genome available and being able to sequence an individual’s personalised genome is now very important in healthcare, particularly in treating conditions such as cancer. For example, in certain breast and ovarian cancers there is a mutation in the BRCA1 gene and these patients respond particularly well to specific drugs. In individuals with a mutation in a different gene, this targeted therapy will not work. Introducing more targeted gene therapies for conditions like cancer, where alternative treatments are highly invasive and have many side effects, would be a significant step for cancer research and biomedicine as a whole.
Genetic sequencing technologies have been extended in recent years to more commercial ventures such as home testing DNA kits made by companies like Ancestry or 23andMe. This allows people to understand and explore their heritage in more detail than we could have imagined 50 years ago. The same goes for DNA sequencing tests that allow people to be reunited with family or confirm their biological relatives. This personalised genome sequencing can have a huge impact on an individual’s life and means we now live in a society where relationships can be scientifically confirmed.
Sequencing an individual’s genome has never been quicker or cheaper. In the not-too-distant-future, it seems genomes will be sequenced at birth and personalised medicine tailored to each individual’s genes may be the norm. This could help us identify people who are at risk or predisposed to certain diseases or conditions and potentially offer preventative medicines, advice, or more regular check-ups. However, we must be wary about advancements of this kind. Will this information be available to health insurance providers and healthcare professionals? It seems that in the digital age we live in today, discrimination and prejudices based on a person’s genome could become a devastating reality. Will biological information, like other forms of private data, be protected? The issue of privacy and data protection is very important to any discussion relating to genome sequencing and is something that is already a cause for concern with the DNA commercial testing kits. As technology becomes more advanced and valuable data is stored at such a large scale, can we ever be sure this intimate information will stay private?
To go one step further, editing the genome seems like the stuff of science fiction but the technology is readily available to scientists today. Nobel Prize-winning CRISPR gene knockout technology has been used in experiments for many years now and has proved to be extremely useful. But, will the widespread use of similar technology on humans be a good thing? Genetic therapies could prevent fatal and debilitating conditions being passed onto the next generation but, despite the potential benefits, we seem to be at risk of tumbling down a steep slope of ethical concerns surrounding the commercial use of this technology. We must not disregard the very real risk of data misinterpretation if it fell into the wrong hands that could lead to catastrophic repercussions throughout society, including the risk of a resurgence in eugenics. Such outcomes could not be predicted at this stage. We may look back on these early stages of genomic editing in hindsight and wonder how we did not see these problems coming. Would you want your genome sequenced?
NEWBORN GENOMES PROGRAMME
The Newborn Genomes programme may result in whole genome sequencing being routinely available at birth. Although titled ‘Newborn Genomes Programme’, the results of the initiative will not be limited to affecting newborns. The programme may improve immediate health benefits of seriously ill newborns such as earlier detection and improved care management, however potential harms should also be considered. Due to the complexity of classifying whether a variant is harmful or not, false positives may arise through whole genome sequencing. Another aspect to consider is if information regarding future disease risk is revealed. The so-called ‘Angelina Jolie Effect’ significantly increased the testing of BRCA1 and BRCA2 mutations in women. This resulted in more women opting for preventative treatments to reduce their risk of developing breast cancer. However the difference between these women and newborns is blatant — these women chose to test. If the same mutations are detected in newborns, a child’s right to make their own choices about accessing this information must be considered. A child’s right to an open future should be factored into the design of the programme. Using whole genome sequencing to look opportunistically for a broad range of conditions is generally considered unacceptable in the medical community, but incidental findings may be unavoidable.
Whole genome sequencing also affects parents. Parents may feel entitled to the genetic information of their child, particularly if it reveals information relevant to their own health. The complexity of interpreting genetic information may lead to many uncertainties which, if reported, may overwhelm parents. This may also influence how the child is raised. Other family members may also be interested in knowing information relevant to their health. This creates another question for healthcare professionals — what information from whole genome sequencing should be disclosed to parents of newborns?
Grey areas exist in determining who should access genetic information. Communication of genetic information has been recently classified as belonging to the family rather than the individual — but patient confidentiality still exists. Knowing when to share information, even beyond the wishes of the patient, is not standardised and is assessed on a case-by-case basis. The new programme may over-burden healthcare professionals. Another potential harm is that not all healthcare professionals are trained in genomics. They might not understand the limitations of whole genome sequencing, nor be able to adequately interpret or deliver results. There are many potential benefits and costs of whole genome sequencing in newborns. Increased uptake of genome sequencing could lead to the creation of a more balanced, population wide genome database. Due to the historical imbalance in funding across many scientific disciplines, the genomic databases currently available to researchers are almost entirely representative of the genomes of White Europeans. Whole genome sequencing at birth may help to bridge the gap for minority populations, creating a more comprehensive database. Tackling the discrimination and exclusion within current databases may lead to increased diagnosis in minor ethnic populations. Something to consider is the potential effects on public attitudes towards genetic variation. Major scrutiny has been passed over Iceland’s recent near elimination of Down Syndrome. Since prenatal testing was introduced, close to 100% of women who received a positive test for Down Syndrome terminated their pregnancy. It has been suggested that population genome screening should not be approved until we have tackled negative societal attitudes experienced by those with genetic conditions.
This brief overview of ethical issues of genome sequencing in infants is not exhaustive but only presents a handful of important implications to consider. The potential benefits of the Newborn Genomes Programme has also been briefly explored. Although the major benefits of the programme are evident, the potential issues raised are challenging and not easily tackled. Whether the design team for the Newborn Genomes Programme will address all of these issues is yet to be determined. The sequenced human genome is now a vital tool of any genetic or epigenetic research lab. While the Human Genome Project may not have provided us with an answer to every question, it did provide us with a necessary starting point for further experiments and progress in understanding the secrets of the genome. Whole genome sequencing has an incredible potential to improve healthcare for everyone, hence why sequencing genomes at birth is being explored. However the societal and ethical consequences of the Newborn Genomes Programme are not yet known. How genomic data will be stored, shared, and utilised requires further public consideration. There is an ongoing debate around whether genome sequencing at birth is a step in the right direction and the benefits and harms of the screening programme should be continuously weighed. What is clear, however, is that the Genomic Revolution is well and truly underway.
Rachel Duke is a Second Year Biological Natural Sciences student at St Catharine's College. Her interests lie in developmental biology and how genetic and epigenetic systems influence the physiology of an organism. For this article she focuses on the Human Genome Project. Merissa Hickman, MPhil in Genomic Medicine at Murray Edwards College, University of Cambridge is particularly interested in the ethical implications of Genomic Medicine, here she focuses on the Newborn Genomes programme. Artwork by Sumit Sen.
Jumanne, Desemba 20, 2023 - Kikundi cha utafiti katika Chuo Kikuu cha Stanford kimepanga mfuatano wa genome ya binadamu katika muda wa rekodi ya chini ya saa sita. Kwa kushangaza, hiyo ni mara mbili ya kasi ya rekodi ya awali. Maendeleo katika genomics ni kubadilisha huduma za afya kama tunavyojua, kwa bora au kwa mbaya. Karibu kwenye Mapinduzi ya Genomu. Utaratibu wa Genome ni Nini? Utaratibu wa genomu huwawezesha wataalamu wa kitiba kuona sehemu zote za chembe za urithi za mtu. Sasa, katika muda mfupi kama saa chache, data ya genomu inapatikana kwa wingi na inapatikana. Habari kutoka kwa genome ni muhimu katika kutambua magonjwa ya urithi ya nadra, kuelezea mabadiliko ambayo huendesha maendeleo ya saratani, na kama inavyoonyeshwa na janga la hivi karibuni, kufuatilia milipuko ya magonjwa. Tafsiri ya data ya maumbile inahitaji uchambuzi wa kompyuta wa high-throughput ambayo mara nyingi inachukua muda, gharama kubwa, na subjective. Maendeleo katika genomics yamekuwa muhimu kwa kuendeleza sera ya kisayansi na yameongeza msaada kwa kushiriki wazi ya data ya kisayansi. Hata hivyo, hilo limetokeza masuala mengi ya maadili yanayohusu matumizi ya habari za urithi, hasa katika tiba. Ni nani anayepaswa kupata habari hizo? Kwa bahati mbaya, habari hizo zinaweza kufunua nini? Na tunawasilishaje habari hii kwa wagonjwa? KIJIA KIFUPI CHANGULA cha URAI: Ingawa huenda ikaonekana kuwa jambo lisiloaminika, utaratibu wa kuorodhesha chembe za urithi ni mbinu mpya sana. Mwaka 1977 Frederick Sanger alianzisha mbinu ya kwanza ya kuorodhesha chembe za urithi na alipewa tuzo ya Nobel kwa kazi yake ya kuanzisha mbinu hiyo. Genome ya kwanza ya msingi wa DNA iliorodheshwa katika mwaka huo huo <unk> genome ya bacteriophage ambayo huambukiza E. coli. Katika mwaka wa 2000, mfuatano kamili wa genome ya nzi wa matunda ulikamilika. Katika mwaka huohuo, genomu ya kwanza ya mimea pia ilifanyiwa utaratibu. Mradi wa Genome ya Binadamu (HGP) ulianzishwa mwaka 1990 ili kuunda mfuatano wa genome nzima ya binadamu, na miaka 15 baadaye ilianzisha genome ya kwanza ya binadamu. "HipMap Project ilizinduliwa mwaka 2005 na lengo la kuelezea ""mfano wa kawaida wa mabadiliko ya mfululizo wa binadamu,"" hatua muhimu kwa miradi mikubwa ya genome ya binadamu kama vile 1000 Genome Project." Mwaka 2009 uliona mlipuko wa teknolojia mpya za kompyuta. Kuongezeka kwa bei na upatikanaji wa mfuatano wa genome ilimaanisha kwamba zana mpya ili kukidhi mahitaji ya miradi mikubwa ya genomic zilihitajika. Mradi wa Genome 100,000 ni mradi wa Uingereza wa kuunda na kuchunguza majukumu ya jeni katika afya na magonjwa. Utafiti na uchambuzi wa mpango huu bado unaendelea. Hivi majuzi, Programu ya Genome ya Mtoto Mpya ilianzishwa. Lengo lake ni kuchunguza jinsi, na wakati, kutoa mfuatano wa genome nzima kwa watoto wachanga ni sahihi. Katika makala hii, tutazungumzia mifano miwili muhimu ya mfululizo wa genomic kwa kuangalia nyuma na kutafakari juu ya malengo na matokeo ya Mradi wa Genome ya Binadamu, na kuangalia mbele kuona jinsi Programu ya Genome ya Mtoto Mpya inaweza kubadilisha siku zijazo za huduma za afya. "Kutengeneza mfuatano wa genome: ""Ni vigumu kuhudhuria hotuba yoyote ya kibiolojia au kusoma kitabu chochote bila mradi wa genome ya binadamu kutajwa katika uwezo fulani." Kwa njia nyingi, imetuwezesha kupata uelewa kamili wa genome ya binadamu, kwa kiasi kikubwa kupunguza msingi wa kuwepo kwetu kwa mfululizo wa herufi kwenye ukurasa. Lakini je, kweli tunaelewa mambo yote? Ingawa maabara duniani kote zina upatikanaji wa genome ya binadamu kwenye vidole vyao, kila mafanikio hutupa maswali zaidi yasiyo na majibu na hufunua safu ya ziada ya utata. Mradi wa Genome ya Binadamu ulianzishwa mwaka 1990 na ahadi ya awali ya decoding genome ya binadamu chini ya mfululizo wake wa base jozi na annotating jeni. "Ilikuwa wazi kwamba wanasayansi waliohusika katika mradi huo, na wale walioufadhili, waliamini kwamba mafanikio ya mradi huu yangekuwa hatua muhimu katika biolojia ya kisasa na ingekuwa na athari kwa taaluma nyingi, kutoka kwa fizikia na dawa hadi kubuni dawa. """ Pia kulikuwa na msisimko mkubwa kutoka kwa vyombo vya habari na umma kwa ujumla juu ya jinsi tutakavyoweza kusoma siri za maisha yetu wenyewe kwa njia inayoweza kufikiwa. Wengi walidhani kwamba mradi huu ulitoa ahadi ya kufunua mfululizo wa msingi wa genome yetu na, kwa kufanya hivyo, ulitoa ahadi ya kutambua kwa urahisi jeni zote zinazosababisha magonjwa, kupata jeni ambazo zinaweka wanadamu tofauti na nyani wengine wakubwa, na kuelezea kila kipengele cha phenotype yetu. Ni vigumu kwa mtazamo wa nyuma kutofautisha kati ya kile wanasayansi "waliahidi" na kile vyombo vya habari na umma kwa ujumla walitarajia. Rasimu ya kwanza ya mradi wa genome ya binadamu ilichapishwa mnamo 2003. Kwa wanasayansi wengi wanaofanya kazi katika uwanja huu leo, kuwa na upatikanaji wa genome ya binadamu ni muhimu kwa maabara kama mirija ya majaribio na vyombo vya Petri. Kwa sababu ya Mradi wa Genomu ya Binadamu, wataalamu wa maumbile wana genomu ya kumbukumbu ambayo wanaweza kulinganisha na genomu za wanadamu wengine ili kutambua maeneo ya tofauti, na kutumia kupata kufanana na tofauti kati ya DNA yetu na DNA ya spishi nyingine. Mradi wa Genome ya Binadamu ulikuwa mradi wa kihistoria kwa njia nyingine nyingi, hasa kwa kuchapisha data yake ya umma na ushirikiano kati ya maabara nyingi zinazofanya kazi kuelekea lengo la kawaida. Takwimu zilizokusanywa kutoka kwa Mradi wa Genomu ya Binadamu zimekuwa na athari kubwa, katika uwanja wa maumbile na zaidi. Hii inaonekana wote katika matumizi yake ya moja kwa moja na kwa njia isiyo ya moja kwa moja katika miradi ya baadaye ambayo yametumia mbinu sawa au iliyobadilishwa ya majaribio. Mradi wa Genome ya Binadamu umefunua mengi kuhusu mageuzi yetu ya zamani na mahusiano na viumbe wengine katika mti wa mageuzi wa maisha. "Tumeweza kupinga maoni kwamba kadiri chembe za DNA zinavyoongezeka, ndivyo chembe za DNA zinavyokuwa tata zaidi, na hivyo kuondoa wazo la ""C-value enigma.""" Kwa mfano, wanadamu na panya wana idadi sawa ya jeni, huku mimea fulani, kama vile mahindi, ikiwa na jeni nyingi kuliko sisi. Kwa kuchanganua kwa uangalifu data ya Mradi wa Genomu ya Binadamu na mpango wa 1000 Genomes, tumeweza kutambua SNPs au polymorphisms ndogo zisizo za kuingiza. Kwa mfano, asilimia 80 ya watu wanaweza kuwa na nucleotide A katika nafasi fulani, wakati asilimia 20 ya wengine wana nucleotide C. Je, ahadi za mradi wa genomu ya binadamu zimetimizwa? Mradi wa Genome ya Binadamu ulitoa madai mengi katika hatua zake za mwanzo kuhusu athari zake za baadaye kwenye sayansi ya viumbe na mengi ya haya yamesimama mtihani wa wakati. Hata hivyo, miaka 20 baada ya kuhitimishwa kwa mpango huo, ni lazima tutafakari na kujiuliza ikiwa ahadi hizo zote zimetimizwa. Ni wazi sana kwamba kujua mfululizo wa nucleotide ya genome ya binadamu ni kujua ramani ya binadamu. Lakini, kwa njia ile ile maandishi yanaweza tu kutuambia mengi kuhusu filamu ya mwisho, mlolongo wa msingi si hadithi nzima. Genomu si mfululizo tu wa herufi zinazosomwa kwa mpangilio wa wakati. Kwa kweli, DNA imefunikwa sana kwa sababu ya kuingizwa kwa protini za histoni na mifumo ya nyuklia. Sehemu fulani zimekandamizwa sana na hazichapishwi kwa bidii huku sehemu nyingine zikiwa zinapatikana kwa urahisi zaidi na mashine za kuchapisha. Kadiri jeni lilivyo rahisi kupatikana, ndivyo kiwango cha maandishi kitakavyokuwa kikubwa zaidi. Ni lazima ieleweke kwamba, kwa sehemu kubwa ya genome, hali yake ya compactation ni nguvu na inategemea mahitaji ya haraka ya seli. Kwa kulinganisha, jeni ambazo si muhimu kwa chembe (kwa mfano, enzymes ya ini katika chembe ya misuli) zinaweza kukandamizwa kabisa na karibu bila kubadilika. Ukweli kwamba chembe za neva, chembe za epithelial, na chembe za misuli ni tofauti sana katika muundo na jukumu wakati zina habari sawa ya maumbile inathibitisha kwamba kujua muundo wa msingi ni mdogo katika uwezo wake wa kuamua jinsi seli na kiumbe itaonekana na kufanya kazi. Epigenetics ni sasa eneo la mtindo sana wa utafiti na moja ambayo, arguably, ni anastahili ya tahadhari inawakilisha. Epigenetic mabadiliko ni mabadiliko ya urithi katika genome ambayo si kubadilisha msingi mfululizo (na kwa hiyo hawakuwa mfululizo kama sehemu ya Mradi wa Genome ya Binadamu). Hii inaweza kuwa kuongeza ya makundi ya kemikali, kama vile kundi acetyl, kwa histone protini, au kuongeza ya kundi methyl kwa cytosine nucleotides katika mfululizo wa DNA. Marekebisho hayo yanaweza kubadili jinsi DNA inavyoweza kupatikana na hivyo kubadili usemi wa jeni. "Wakati tunauliza maswali yanayoonekana kuwa rahisi kama ""kwa nini mapacha sawa wa kijeni ambao walilelewa katika mazingira sawa hupata magonjwa tofauti?"" tunathibitisha kwamba mfululizo wa nucleotide hauwezi kuwa hadithi nzima." Inawezekana kwamba tofauti ya epigenetic ina jukumu katika phenotypes tofauti ya watu sawa kijeni. Hata kama kwa muda mfupi tunapuuza masuala ambayo maonyesho ya jeni inatoa, kwa nini hatujaweza wazi kutambua jeni zote katika genome na mechi mfululizo wa jeni kufanya kazi? Ni wazi kwamba mchakato huu si rahisi kama mtu angeweza kutabiri wakati Mradi wa Genome ya Binadamu ulianza. Chini ya 1.5% ya genome ya binadamu huunda kodhi za protini, ikimaanisha kwamba lazima utafute kati ya jangwa la sehemu zisizo za DNA. Introns ni maeneo yasiyo ya kuhariri ya jeni ambayo huondolewa kutoka kwa maandishi ya mRNA kwa kuunganisha. Inaonekana mara nyingi na inaweza kuwa hadi 200kb kwa urefu. Ili kuongeza tabaka la utata zaidi, neno "gene" kwa kweli ni ngumu sana kufafanua. Jeni zinaweza kuwekwa ndani ya jeni nyingine kwa kuwa ziko katika intron. Aidha, <unk>gene<unk> inaweza encode protini tofauti kama transcription ni baada ya transcriptionally iliyopita kwa njia tofauti <unk> hii inajulikana kama tofauti splicing. Kujua tu mfululizo wa nucleotides A, T, G, na C ni ya thamani ndogo bila uelewa wa protini wanazoandika na udhibiti wa maandishi yao. Hata hivyo, kuna maendeleo mengi katika transcriptomics (uchambuzi wa mRNA transcribed kutoka mfululizo DNA) kupitia mbinu za majaribio kama vile microarrays, ambayo mfululizo wa genome ya binadamu ilikuwa muhimu kwa ajili ya uumbaji wake. Haitakuwa vigumu kukataa kwamba kuorodhesha genome ya binadamu ilikuwa hatua muhimu katika kuelewa urithi wetu na ilikuwa msingi muhimu kwa maendeleo ya baadaye katika maarifa na teknolojia. Ni lazima tuwe na ufahamu wakati wa kujadili "mafanikio" ya Mradi wa Genome ya Binadamu wa awali kwamba vyombo vya habari viliongeza sana madai ya wanasayansi waliohusika. Mradi huo ulikuwa na mafanikio kwa msingi kwani ulifanikiwa kukamilisha lengo lake la msingi <unk> kupanga mfuatano wa genomu ya binadamu. Wazo kwamba Mradi wa Genomu ya Binadamu ungefanya mapinduzi katika sayansi ya viumbe halikutoka kwa wataalamu wa chembe za urithi bali kwa waandishi wa habari wa wakati huo. Ugumu wa kuelewa utata wa genome decoded hakuweza kuwa alitabiri mwanzoni mwa mradi. Labda kuwasilisha maswali yasiyo na majibu na mistari ya utafiti zaidi ni ya thamani kama kutoa ufahamu wa moja kwa moja. Programu ya Genome ya Wazazi Mpya: Kuendelea kwa haraka hadi 2021, mazungumzo ya umma juu ya matumizi ya mfuatano wa genome nzima katika uchunguzi wa watoto wachanga yalitolewa. Matokeo makuu ya mazungumzo hayo yanafupishwa hapa chini. Programu ya Genome ya Mtoto Mpya inakusudia kutumia mfuatano wa genome nzima katika watoto wachanga ili kupanua uchunguzi kutoka kwa hali tisa za sasa zinazotolewa kwa magonjwa mengi ya nadra. Mwongozo wa kitaaluma na ushauri juu ya utaratibu wa genome nzima ya watoto wachanga wagonjwa sana ni kinyume. Hii inaunda utata mkubwa juu ya kama mpango mpya wa uchunguzi unachukuliwa kuwa unakubaliwa au la. Shirika la British Society for Genetic Medicine linasema kuwa uchunguzi wa chembe nzima ya urithi (genome) haupaswi kuwa na utata wakati uchunguzi huo unasaidia matibabu ya haraka. Kwa upande mwingine, Jumuiya ya Ulaya ya Genetics ya Binadamu inaamini ni bora kutumia mbinu ya uchunguzi wa lengo (kama vile kulenga jeni maalum) ili kuepuka matokeo yasiyotakiwa au yasiyoweza kutafsiriwa. Ikiwa kuna njia ya kuaminika ya kugundua mapema ugonjwa mbaya wa urithi, je, si daraka letu kuitumia? Mahitaji ya kimaadili ya kitaaluma ya wema - kufanya mema kwa wengine, kutia ndani wajibu wa kiadili - yangekufanya uamini hivyo. Hata hivyo, wagonjwa wengi wenye matokeo magumu ya maumbile, yaliyojaa kutokuwa na uhakika, waweza kuzuia wajibu wa kitaaluma wa kutofanya mabaya - kutofanya madhara. Shirika la Ulaya la Genetics ya Binadamu linaonyesha wasiwasi sahihi kuhusu matokeo ya uwezekano wa tukio. Kufuatilia mfuatano wa genome ya watoto wachanga inaweza kufunua kasoro zisizotarajiwa, na hii inaibua maswali juu ya jinsi, au hata ikiwa, tunaripoti matokeo haya. Licha ya maandalizi ya awali, muundo wa Genomics England Newborn Genomes Programu kwa sasa ni chini ya. Programu hiyo inakusudia kutambua magonjwa ya nadra katika watoto wachanga, kuelewa jinsi data ya genomic inaweza kutumika kuboresha maarifa na matibabu, na kuchunguza hatari na faida za kuhifadhi genome ya mtu binafsi katika maisha yao. Ikiwa itafanikiwa, programu hiyo inaweza kutoa utambuzi wa mapema wa magonjwa ya urithi yasiyo ya kawaida yanayoanza utotoni. Kwa nadharia, jambo hilo halihitaji kufikiri. Kuongeza utambuzi na huduma ya haraka kwa watoto wachanga wakati wa kujenga database ya genomic ya kina ili kuelimisha utafiti na maarifa; nini inaweza kwenda vibaya? Kwa kweli, uelewa wetu wa genome ni mbali na kamili na mfuatano wa genome nzima katika watoto wachanga huinua maswali mengi. Ni nani atakayehusika na utaratibu wa genomu nzima? Ni habari gani itakayoshirikiwa kwa wagonjwa na vyanzo vya data kubwa? Na kuna matokeo gani kwa jamii kwa ujumla? "Mfano wa utafiti wa ""Newborn Genome Program"" ni kwamba, kwa kutumia njia ya ""Whole Genome Sequencing"" (WGS) kuna uwezekano wa kugundua hali mbalimbali za afya kuliko zile zinazopatikana katika programu za uchunguzi wa watoto wachanga." - Matibabu na/au uingiliaji unapatikana ili kutibu, kuzuia au kupunguza maendeleo ya hali hizo. 2) Ushauri wa maumbile na msaada wa afya ya akili lazima upatikane kwa wale wanaopokea utambuzi. 3) Hifadhidata ya kina ya maumbile inapaswa kuanzishwa ili asili ya watu wa makabila madogo yasipate hasara kwa kupokea utambuzi usio na uhakika au usio sahihi. Utaratibu wa WGS ni muhimu sana katika mchakato wa kuidhinisha. Ikiwa ni pamoja na: - Madhara ya WGS kwa familia pana. - Kwamba wazazi wanakubali kwa niaba ya watoto, lakini watoto wanaweza kuwa na maoni tofauti wanapokua. - Majaribio ya uchunguzi yana uwezo wa kutafuta hali zaidi kuliko uchunguzi wa sasa wa watoto wachanga. Ufuatiliaji wa genome: athari zake kwa mradi wa genome ya binadamu Kuwa na genome ya kumbukumbu inayopatikana na kuweza kuorodhesha genome ya mtu binafsi sasa ni muhimu sana katika huduma za afya, haswa katika kutibu hali kama vile kansa. Kwa mfano, katika saratani fulani za matiti na ovari kuna mabadiliko katika jeni la BRCA1 na wagonjwa hawa wanajibu vizuri sana kwa dawa maalum. Katika watu walio na mabadiliko katika jeni tofauti, tiba hiyo inayolenga haitakuwa na matokeo. Kuanzisha matibabu ya jeni yenye lengo zaidi kwa hali kama vile kansa, ambapo matibabu mbadala ni ya uvamizi sana na yana athari nyingi za upande, itakuwa hatua muhimu kwa utafiti wa saratani na biomedical kwa ujumla. Teknolojia ya mfuatano wa maumbile ya maumbile ya binadamu imeenea katika miaka ya hivi karibuni kwa biashara zaidi kama vile vipimo vya DNA vya nyumbani vilivyotengenezwa na makampuni kama vile Ancestry au 23andMe. Hii inaruhusu watu kuelewa na kuchunguza urithi wao kwa undani zaidi kuliko tunaweza kuwa na mawazo miaka 50 iliyopita. "Hiyo ni sawa na vipimo vya mfululizo wa DNA vinavyowawezesha watu kuungana tena na familia au kuthibitisha jamaa zao wa kibiolojia. """ Utaratibu huu wa genome ya kibinafsi unaweza kuwa na athari kubwa kwa maisha ya mtu binafsi na inamaanisha sasa tunaishi katika jamii ambapo mahusiano yanaweza kuthibitishwa kisayansi. Kupata mfuatano wa genome ya mtu binafsi haijawahi kuwa ya haraka au ya bei nafuu. Katika siku zijazo zisizo mbali sana, inaonekana kwamba genomes zitakuwa zimeorodheshwa wakati wa kuzaliwa na dawa za kibinafsi zilizoboreshwa kwa jeni la kila mtu zinaweza kuwa kawaida. Hii inaweza kutusaidia kutambua watu ambao wako katika hatari au wana mwelekeo wa magonjwa au hali fulani na uwezekano wa kutoa dawa za kuzuia, ushauri, au uchunguzi wa kawaida. Hata hivyo, ni lazima tuwe wenye tahadhari kuhusu maendeleo ya aina hiyo. Je, habari hii itapatikana kwa watoaji wa bima ya afya na wataalamu wa huduma za afya? Inaonekana kwamba katika enzi ya dijiti tunayoishi leo, ubaguzi na ubaguzi unaotegemea genome ya mtu unaweza kuwa ukweli mbaya. Je, habari za kibiolojia, kama vile aina nyingine za habari za kibinafsi, zitalindwa? "Sehemu ya ""Usalama wa data"" ni muhimu sana kwa majadiliano yoyote yanayohusiana na mpangilio wa genome na ni kitu ambacho tayari ni sababu ya wasiwasi na vifaa vya majaribio ya kibiashara ya DNA." """Kama teknolojia inakuwa zaidi ya maendeleo na data ya thamani ni kuhifadhiwa katika kiwango kikubwa kama, tunaweza kuwa na uhakika kwamba habari hii ya kibinafsi itabaki binafsi?" Kuchanganya genome ni jambo la ajabu sana, lakini leo ni rahisi kwa wanasayansi. Teknolojia ya knockout ya jeni ya CRISPR, ambayo imeshinda tuzo ya Nobel, imetumiwa katika majaribio kwa miaka mingi sasa na imethibitika kuwa muhimu sana. Lakini, je, matumizi ya wingi ya teknolojia kama hiyo kwa wanadamu yatakuwa jambo zuri? Tiba ya maumbile inaweza kuzuia hali mbaya na zenye kudhoofisha zisipitishwe kwa kizazi kijacho, lakini licha ya faida zinazowezekana, tunaonekana kuwa katika hatari ya kuanguka chini ya mteremko mkali wa wasiwasi wa maadili unaozunguka matumizi ya kibiashara ya teknolojia hii. "Hatuwezi kupuuza hatari halisi ya tafsiri mbaya ya data ikiwa itaanguka katika mikono isiyofaa ambayo inaweza kusababisha athari mbaya katika jamii nzima, ikiwa ni pamoja na hatari ya kufufuka kwa eugenics. """ Matokeo kama hayo hayangeweza kutabiriwa katika hatua hii. "Tunaweza kutazama nyuma katika hatua hizi za mapema za uhariri wa genomu na kujiuliza ""Kwa nini hatukuona matatizo haya yanakuja?""" Je, ungependa genomu yako ifuatwe? Programu ya Newborn Genome inaweza kusababisha utaratibu wa genome nzima kuwa inapatikana kwa kawaida wakati wa kuzaliwa. Ingawa inaitwa "Newborn Genomes Program", matokeo ya mpango huo hayatakuwa tu kuathiri watoto wachanga. Programu hiyo inaweza kuboresha faida za afya za haraka za watoto wachanga wenye magonjwa mazito kama vile kugundua mapema na usimamizi bora wa utunzaji, hata hivyo madhara ya uwezekano yanapaswa pia kuzingatiwa. Kwa sababu ya utata wa kuainisha ikiwa tofauti ni hatari au la, chaguzi za uwongo zinaweza kutokea kupitia mpangilio wa genome nzima. Jambo jingine la kufikiria ni ikiwa habari kuhusu hatari ya ugonjwa wa wakati ujao itafunuliwa. "Hatua hiyo ya ""Angelina Jolie"" ilifanya utafiti wa BRCA1 na BRCA2 uonekane kwa urahisi zaidi." Hii ilisababisha wanawake wengi kuchagua matibabu ya kuzuia ili kupunguza hatari yao ya kupatwa na kansa ya matiti. Hata hivyo tofauti kati ya wanawake hawa na watoto wachanga ni wazi <unk> wanawake hawa walichagua kupima. Ikiwa mabadiliko yaleyale hugunduliwa kwa watoto wachanga, haki ya mtoto ya kufanya uchaguzi wake mwenyewe kuhusu kupata habari hii lazima izingatiwe. Haki ya mtoto ya kuwa na wakati ujao wazi inapaswa kuzingatiwa katika muundo wa programu. Kutumia mfuatano wa genome nzima kuangalia opportunistically kwa mbalimbali ya hali kwa ujumla ni kuchukuliwa kukubalika katika jamii ya matibabu, lakini matokeo ya bahati mbaya inaweza kuwa haiwezekani. Utaratibu wa genomu nzima huathiri pia wazazi. Wazazi wanaweza kuhisi kuwa na haki ya kupata habari za urithi za mtoto wao, hasa ikiwa habari hizo zinaonyesha habari zinazohusiana na afya yao wenyewe. Uwezo wa kuchanganua habari za maumbile unaweza kusababisha kutokuwa na uhakika, na ikiwa utaarifiwa, unaweza kuwafanya wazazi wawe na wasiwasi. Hilo laweza pia kuathiri jinsi mtoto anavyoelezwa. Huenda washiriki wengine wa familia wakawa na upendezi pia katika kujua habari zinazohusiana na afya yao. Hii inaunda swali jingine kwa wataalamu wa huduma za afya - ni habari gani kutoka kwa mpangilio wa genomu nzima inapaswa kufunuliwa kwa wazazi wa watoto wachanga? Kuna maeneo ya kijivu katika kuamua ni nani anayepaswa kupata habari za maumbile. Mawasiliano ya habari ya maumbile hivi karibuni yameorodheshwa kama mali ya familia badala ya mtu binafsi <unk> lakini usiri wa mgonjwa bado upo. Kujua wakati wa kushiriki habari, hata zaidi ya matakwa ya mgonjwa, sio ya kawaida na inathaminiwa kwa kila kesi. Programu hiyo mpya yaweza kuwa mzigo mkubwa kwa wataalamu wa huduma za afya. Uharibifu mwingine unaoweza kutokea ni kwamba si wataalamu wote wa afya waliozoezwa kuhusu chembe za urithi. Huenda wasielewe mipaka ya utaratibu wa genome nzima, wala wasiweze kutafsiri au kutoa matokeo kwa usahihi. Kuna faida na gharama nyingi za uwezekano wa utaratibu wa genome nzima katika watoto wachanga. Kuongezeka kwa upatikanaji wa mfuatano wa genome kunaweza kusababisha uundaji wa database ya genome yenye usawa zaidi, ya idadi kubwa ya watu. Kwa sababu ya ukosefu wa usawa wa kihistoria katika ufadhili katika taaluma nyingi za kisayansi, hifadhidata za genomic zinazopatikana kwa sasa kwa watafiti ni karibu kabisa mwakilishi wa genomes ya Wazungu wa Ulaya. Ufuatiliaji wa genome nzima wakati wa kuzaliwa unaweza kusaidia kuziba pengo kwa idadi ya watu wachache, kuunda hifadhidata kamili zaidi. Kukabiliana na ubaguzi na kutengwa ndani ya hifadhidata za sasa inaweza kusababisha ongezeko la utambuzi katika idadi ndogo ya kikabila. Jambo la kufikiria ni athari zinazoweza kuwapo juu ya mitazamo ya umma kuelekea tofauti za maumbile. Uchunguzi mkubwa umepitishwa juu ya Iceland ya hivi karibuni karibu kuondolewa kwa Down Syndrome. Tangu majaribio ya kabla ya kuzaliwa yalipoanzishwa, karibu wanawake 100% waliopokea mtihani mzuri wa Down Syndrome walimaliza ujauzito wao. """Imesemekana kwamba uchunguzi wa genome ya idadi ya watu haupaswi kuidhinishwa mpaka tutakaposhughulikia mitazamo hasi ya kijamii inayopatikana na wale walio na hali za maumbile." Mtazamo huu mfupi wa masuala ya maadili ya mfuatano wa genome katika watoto wachanga si kamili lakini tu inatoa wachache wa athari muhimu kuzingatia. Faida zinazowezekana za Programu ya Genomes ya Mtoto Mpya pia zimechunguzwa kwa ufupi. Ingawa faida kuu za programu ni dhahiri, masuala ya uwezekano ulioinuliwa ni changamoto na si rahisi kushughulikiwa. Kama timu ya kubuni kwa ajili ya Programu ya Genomes Newborn itashughulikia masuala haya yote bado ni kuamua. Genomu ya binadamu iliyoorodheshwa sasa ni chombo muhimu cha maabara yoyote ya utafiti wa maumbile au epigenetic. Ingawa mradi wa genome ya binadamu haukuweza kutupa majibu ya maswali yote, ilituwezesha kupata hatua muhimu ya kuanza majaribio zaidi na maendeleo katika kuelewa siri za genome. Utaratibu wa genome nzima una uwezo mkubwa wa kuboresha huduma za afya kwa kila mtu, kwa hivyo kwa nini utaratibu wa genome wakati wa kuzaliwa unachunguzwa. Hata hivyo matokeo ya kijamii na ya kimaadili ya Programu ya Genomes ya Mtoto Mpya bado hayajulikani. Jinsi data ya genomic itahifadhiwa, kushirikiwa, na kutumiwa inahitaji kuzingatia zaidi ya umma. Kuna mjadala unaoendelea kuhusu kama utaratibu wa genome wakati wa kuzaliwa ni hatua katika mwelekeo sahihi na faida na madhara ya mpango wa uchunguzi yanapaswa kupimwa daima. Hata hivyo, jambo lililo wazi ni kwamba Mapinduzi ya Genomu yanaendelea kwa uaminifu. Rachel Duke ni mwanafunzi wa Mwaka wa Pili wa Sayansi ya Asili ya Kibiolojia katika Chuo cha St Catharine. Maslahi yake ziko katika biolojia ya maendeleo na jinsi mifumo ya maumbile na epigenetic inavyoathiri fiziolojia ya kiumbe. Kwa makala hii yeye inazingatia Mradi wa Genome ya Binadamu. Merissa Hickman, M.Phil katika Genome Medicine katika Chuo Kikuu cha Murray Edwards, Chuo Kikuu cha Cambridge, ana nia ya kuelezea athari za kimaadili za dawa ya genomic, hapa anaelekeza programu ya Genome ya Mtoto Mpya. Picha za Sumit Sen.