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Altering the human genome

Altering the human genome


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I recently had a conversation with a rather unusual gentleman who was, let's say, more than a little partial to conspiracy theories. He has this idea that governments are lowering "nanowires" from drones, to inject people with chemicals that modify their genetics in order to reduce their lifespan dramatically, or change their opinions and thoughts.

Clearly this man was a fruitcake, and the complexities of his psychology probably warrant a whole separate debate, but he did get me thinking about the theoretical side of how such a thing might be done.

So, as such, I have a few questions on the matter:

  1. Is it even theoretically possible to alter human genetics using only an injected substance? I'd imagine trying to get a single DNA change to propogate through the entire body without being killed off by the immune system would be near impossible.
  2. Since we are aware of genetic markers that are related to predispositions to certain medical conditions (e.g. heart problems, cancers, high blood pressure, strokes, etc), is it possible to modify human DNA to create these issues in a living person?
  3. Has much research gone into how genetics affects thought and opinion, or the way we perceive and react to situations at an emotional level? If so, is it theoretically possible to alter this at a biological level?

I'm certainly not advocating any of this, and I apologise for the unusual nature of the question, but it's something I certainly find interesting to think about!


First of all it is important to note that, within certain limits, human DNA is not much different than, say, a mouse DNA: it has the same structure, it is constituted by the same bases etc etc. Therefore it is teorethically possible (leaving aside ethical issues, of course) to selectively modify it as you would do for a mouse. There are, however, some technical issues and obviously many ethical ones.

To answer specifically to your questions

Is it even theoretically possible to alter human genetics using only an injected substance?

Yes it is. Aside from the good example of radioactive substances given by Alexander, another good one (and probably one that is more common) is that of chemical mutagens.

It is important to understand that the mutation caused by these substances are random, or only partially selective. For instance, certain substances, called intercalating agents can interpose themselves in between the bases of the DNA, interfering and possibly giving rise to mutations during DNA replication.

Other substances such as alkilating agents are a bit more specific, although still not gene- or locus- specific. For instance ethylnitrosourea (ENU) favours A->T base transversions and AT->GC transitions.

I'd imagine trying to get a single DNA change to propogate through the entire body without being killed off by the immune system would be near impossible.

The immune system would not necessarily kill cells with mutations. Think of what happens during cancer developement. Also, an extremely important point: mutating a somatic cell (i.e. not a sperm or an egg) can induce a mutant phenotype in the individual but it will not be transmitted to his/her progeny.

Since we are aware of genetic markers that are related to predispositions to certain medical conditions (e.g. heart problems, cancers, high blood pressure, strokes, etc), is it possible to modify human DNA to create these issues in a living person?

As Alexander says, there is much research in this field. Some attempts of gene therapy have indeed been made, and some have a big potential. We are, however, still far away for gene therapy to become a routine treatment.

Also, remember that:

  1. not all diseases are genetic diseases
  2. not all genetic diseases are monogenic: some derive from a complex interplay of different factors and hence curing them is not as simple as providing the correct version of the mutated gene.

Has much research gone into how genetics affects thought and opinion, or the way we perceive and react to situations at an emotional level? If so, is it theoretically possible to alter this at a biological level?

Yes, but I would say that we are very very far away from a complete understanding of how thought and emotions are coded in our brain. The very difficult point is that one needs to study these events at multiple scales. We can study a big region of the brain and say that it is involved in fear coding, for instance. But then if you want to go deeper and study what happens at the single cell level you need to look at a lot of different cells to see how they interact between each other. From the other side of the "size scale", it is possible to study biochemical processes in the single neuron, but then again it is difficult to study how these processes are integrated in big networks of cells, especially in vivo.


Concerning the first question, it is very well possible to alter human genetics by injecting a highly radio-active substance that will eventually cause mutations almost all cells. The lifespan will be dramatically reduced, however and the condition is known as "radiation sickness"(link to Wikipedia).

But the person probably means so-called "directed mutations" (link to Wikipedia), when the changes of genetic information is not random, but rather at a certain place and towards a certain function.

Second point, this is the area of extensive research: if we could specifically cure a gene than many diseases that are incurable now (like cystic fibrosis) could be effectively treated. The complete nanotechnology (link to Wikipedia) is all about it.

As to the third point, this is also a very old discussion about the role of nature (=genetics) and nurture (environment). Answering this question in the scope of other questions I can suggest that (genetic) knocking-out some inhibiting receptor systems in brain can lead to certain malfunctions and deceases, including the lymbic system that is responsible for emotions and perception.


Is it even theoretically possible to alter human genetics using only an injected substance? I'd imagine trying to get a single DNA change to propogate through the entire body without being killed off by the immune system would be near impossible.

Yes, it is possible to alter human genetics through injectable carrier. You are also correct that it is currently impossible to make a DNA change to the entire body. It is possible to transform a a few percent of cells in a single tissue.

Since we are aware of genetic markers that are related to predispositions to certain medical conditions (e.g. heart problems,

cancers, high blood pressure, strokes, etc), is it possible to modify human DNA to create these issues in a living person? Yes, in theory. You genetically alter a human embryo… let said embryo grow up to a person. Then harvest that tissue from said living person. Similar to what is done in mice… just on humans. As you can imagine nobody is doing this right now. Breeding human for scientific experiments is very unethical (can slow… who want to wait 9months) and will unlikely to get public funding.

And also no, as in not in the way you are thinking The tech is no there yet.

Has much research gone into how genetics affects thought and opinion, or the way we perceive and react to situations at an emotional level? If so, is it theoretically possible to alter this at a biological level?

Yes there is. https://en.wikipedia.org/wiki/Human_behaviour_genetics But as you can imagine, genetics affect behavior in broad strokes. Genetics does not affect if you are prefer to buy Airbus stock vs Boeing stock. It does affect board things like how much anxiety you can tolerate. How short a temper you have. How much preference do you have to novel experiences.

And upon this broad stock that genetics gives you, you as a person will write if you like challenging jobs, going places, new places, etc.


What are genome editing and CRISPR-Cas9?

Genome editing (also called gene editing) is a group of technologies that give scientists the ability to change an organism's DNA. These technologies allow genetic material to be added, removed, or altered at particular locations in the genome. Several approaches to genome editing have been developed. A recent one is known as CRISPR-Cas9, which is short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. The CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, more accurate, and more efficient than other existing genome editing methods.

CRISPR-Cas9 was adapted from a naturally occurring genome editing system in bacteria. The bacteria capture snippets of DNA from invading viruses and use them to create DNA segments known as CRISPR arrays. The CRISPR arrays allow the bacteria to "remember" the viruses (or closely related ones). If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays to target the viruses' DNA. The bacteria then use Cas9 or a similar enzyme to cut the DNA apart, which disables the virus.

The CRISPR-Cas9 system works similarly in the lab. Researchers create a small piece of RNA with a short "guide" sequence that attaches (binds) to a specific target sequence of DNA in a genome. The RNA also binds to the Cas9 enzyme. As in bacteria, the modified RNA is used to recognize the DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location. Although Cas9 is the enzyme that is used most often, other enzymes (for example Cpf1) can also be used. Once the DNA is cut, researchers use the cell's own DNA repair machinery to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.

Genome editing is of great interest in the prevention and treatment of human diseases. Currently, most research on genome editing is done to understand diseases using cells and animal models. Scientists are still working to determine whether this approach is safe and effective for use in people. It is being explored in research on a wide variety of diseases, including single-gene disorders such as cystic fibrosis, hemophilia, and sickle cell disease. It also holds promise for the treatment and prevention of more complex diseases, such as cancer, heart disease, mental illness, and human immunodeficiency virus (HIV) infection.

Ethical concerns arise when genome editing, using technologies such as CRISPR-Cas9, is used to alter human genomes. Most of the changes introduced with genome editing are limited to somatic cells, which are cells other than egg and sperm cells. These changes affect only certain tissues and are not passed from one generation to the next. However, changes made to genes in egg or sperm cells (germline cells) or in the genes of an embryo could be passed to future generations. Germline cell and embryo genome editing bring up a number of ethical challenges, including whether it would be permissible to use this technology to enhance normal human traits (such as height or intelligence). Based on concerns about ethics and safety, germline cell and embryo genome editing are currently illegal in many countries.


Should We Alter the Human Genome? Let Democracy Decide

In November 2018, a Chinese scientist, He Jiankui, caused an international uproar by announcing the birth of two babies whose DNA he had edited using a tool called CRISPR-Cas9. Human germline genome editing&mdashthat is, making precise changes in human DNA that can be passed down through generations&mdashhas been seen for decades as a line that should not be crossed. This past December, He was sentenced to three years in prison for carrying out an &ldquoillegal medical practice.&rdquo

Yet, as the Chinese experiment shows, the state of technology no longer bars those who are willing to cross it. He&rsquos experiment was a profound scientific and ethical misstep. Not only did he do it before adequate preparatory studies had been undertaken, but he acted unilaterally, deploying a technology with the potential to affect deeply held beliefs about human life all around the planet. His experiment set a dangerous example for other overly eager scientists. In mid-2019, a Russian scientist proposed a similar experiment.

We cannot blame lax oversight on China alone. The scientist who carried out the controversial first experiment in China was trained at U.S. universities using science and technology developed in the U.S., and he consulted with U.S. colleagues before conducting his study. Yet, so far we have largely let prominent scientists and scientific institutions frame the discussion around genome editing.

Whether it is ever acceptable to genetically engineer future children is a question for humanity, not for science. As such, governing the future of this technology is a responsibility for democracy. We the people must ask fundamental questions about the value, the integrity and the meaning of human life. Four years ago, the U.S. National Academies apparently agreed, recommending that human germline editing should proceed only after achieving &ldquobroad societal consensus&rdquo about whether it should be used. The societal deliberation that might lead to such consensus has hardly begun. Nonetheless, in response to the Chinese experiment, the National Academies and the U.K. Royal Society established a commission to develop a framework for a &ldquotranslational pathway&rdquo for editing human embryos in order to produce genetically engineered children. This move prejudges the issue. It takes a question that belongs to all of humanity&mdashshould this work be done at all&mdashand delegates to a small, self-appointed committee of scientists and ethicists the right to decide the conditions under which the work should go ahead. Societal self-reflection demands greater humility on the part of science, coupled with the awareness that there are questions science cannot properly pose, let alone answer fully on its own.

Given the leadership role that U.S.-based science has played in developing genome editing, our democratic institutions should take a corresponding lead in confronting questions of governance. Yet, while limits on this type of experimentation are currently being debated in international circles, our elected representatives have mostly turned the task over to nongovernmental expert bodies like the National Academies.

Many other countries have established laws governing human genetic engineering, backed by robust processes of deliberation and legislation. In the U.S., a ban is in place, but a tenuous one: a rider to the FY2020 Agriculture, Rural Development and Food and Drug Administration House appropriations bill that must be renewed annually. This stopgap measure, though important, is not grounded in the deliberation necessary to identify, let alone resolve, the momentous issues that are at stake.

Senators Dianne Feinstein (D&ndashCalif.), Marco Rubio (R&ndashFla.) and Jack Reed (D&ndashR.I.) have introduced a resolution affirming the importance of this issue. That resolution, which has not yet been brought to the floor for a vote, rightly observes that germline genome editing &ldquotouches on all of humanity.&rdquo The resolution is a valuable first step, and we urge the Senate to take it&mdashand then to give this issue the democratic attention it deserves.

The history of biotechnology shows that scientific self-governance is an imperfect mechanism for securing public trust in the integrity of science. This approach may allow researchers to do what they want in the short run, but in the long run it can create more serious problems for science and industry. The effects of too little public involvement in the early days of biotech, for example, have played out for decades in skepticism and distrust surrounding genetically modified organisms (GMOs). No institution in a democratic society governs itself, and science should not be the exception.

Some scientists worry that He's recklessness will create a &ldquopublic backlash&rdquo against genome editing unless rules are quickly established for how it should be done. This is a misguided justification for rushing ahead. Public trust does not dissolve simply because one scientist takes one wrong step with a new technology. Any powerful technology can be misused, and collective vigilance is needed to make sure that scientists understand and respect important social norms. Broad public discussion helps to inform science about what matters to society and can build a culture of prudent restraint.

Public distrust becomes much more likely when people are shut out of the conversation by an impatient expert community that unilaterally declares what is moral and how far research should go. The Chinese case demonstrates the downsides of allowing that discussion to be framed by those who wish to conduct future experiments. It must include representatives of all those whose lives would be irrevocably affected by efforts to alter the human genome, and that means all of us&mdashparents and children, patients, international citizens, religious communities and future generations

The prospect of genetically engineering future generations touches upon fundamental dimensions of human integrity, meaning and purpose. Manipulating the molecules in our bodies perturbs the ways we relate to one another as social and spiritual beings, reshaping our sense of what lives are worthy of care. If scientists value a &ldquobroad societal consensus&rdquo on these issues, they should, at a minimum, declare a moratorium on research on germline genome editing and seek the involvement of societies&rsquo representatives in guiding and governing this area of research.

Humankind needs greater scientific and moral clarity on germline genome editing. Achieving it requires inclusive, international, democratic deliberation, supported by our democratic institutions. Global deliberation should not rush to satisfy science&rsquos demands for speed or to smooth the pathway for wider use of germline editing. When the future of our genetic heritage is at stake, deliberation can afford to be as slow as it needs to be in order to remain open, thorough and inclusive.

The views expressed are those of the author(s) and are not necessarily those of Scientific American.


There Still Aren’t Any Rules Preventing Scientists From Making Gene-Edited Babies

The anniversary of He Jiankui’s botched experiment brings more questions than answers

While the embryos were not grown past 14 days and were destroyed after the editing experiment, the results provide a warning for future attempts to establish pregnancies with genetically modified embryos and make gene-edited babies. (The findings were posted online to the preprint server bioRxiv on June 5 and have not yet been peer-reviewed.) Such DNA damage described in the paper could cause birth defects or genetic diseases, or lead to cancer later in life.

This is a restraining order for all genome editors to stay the living daylights away from embryo editing.”

Since CRISPR’s debut as a gene-editing tool in 2013, scientists have touted its possibilities for treating all kinds of diseases. CRISPR is not only easier to use but more precise than previous genetic engineering technologies — but it’s not foolproof.

Niakan’s team started with 25 human embryos and used CRISPR to snip out a gene known as POU5F1 in 18 of them. The other seven embryos acted as controls. The researchers then used sophisticated computational methods to analyze all of the embryos. What they found was that of the edited embryos, 10 looked normal but eight had abnormalities across a particular chromosome. Of those, four contained inadvertent deletions or additions of DNA directly adjacent to the edited gene.

A major safety concern with using CRISPR to fix faulty DNA in people has been the possibility for “off-target” effects, which can happen if the CRISPR machinery doesn’t edit the intended gene and mistakenly edits someplace else in the genome. But Niakan’s paper sounds the alarm for so-called “on-target” edits, which result from edits to the right place in the genome but have unintended consequences.

“What that means is that you’re not just changing the gene you want to change, but you’re affecting so much of the DNA around the gene you’re trying to edit that you could be inadvertently affecting other genes and causing problems,” says Kiran Musunuru, a cardiologist at the University of Pennsylvania who uses CRISPR in his lab to research potential heart disease therapies.

If you think of the human genome — a person’s entire genetic code — as a book, and a gene as a page within that book, CRISPR is like “ripping out a page and gluing a new one in,” Musunuru says. “It’s a very crude process.” He says CRISPR often creates small mutations that are probably not worrisome, but in other cases, CRISPR can delete or scramble large sections of DNA.

This isn’t the first time scientists have used CRISPR to tweak the DNA of human embryos in a lab. Chinese scientists carried out the first successful attempt in 2015. Then, in 2017, researchers at the Oregon Health and Science University in Portland and Niakan’s lab in London reported that they’d carried out similar experiments.

Ever since, there have been fears that a rogue scientist might use CRISPR to make babies with edited genomes. That fear became reality in November 2018, when it was revealed that Chinese researcher He Jiankui used CRISPR to modify human embryos, then established pregnancies with those embryos. Twin girls, dubbed Lulu and Nana, were born as a result, sending shockwaves throughout the scientific community. Editing eggs, sperm, or embryos is known as germline engineering, which results in genetic changes that can be passed on to future generations. Germline editing is different from the CRISPR treatments currently being tested in clinical trials, where the genetic modification only affects the person being treated.

While many scientists have opposed the use of germline editing to create gene-edited babies, some say it could be a way to allow couples at high risk of passing on certain serious genetic conditions to their children to have healthy babies. Beyond preventing disease, the ability to edit embryos has also raised the possibility of creating “designer babies” made to be healthier, taller, or more intelligent. Scientists almost universally condemned He’s experiment because it was done in relative secrecy and it wasn’t meant to fix a genetic defect in the embryos. Instead, he tweaked a healthy gene in an attempt to make the resulting babies resistant to HIV.

In the United States, establishing a pregnancy with an embryo that has been genetically modified is prohibited by law. More than two dozen other countries directly or indirectly prohibit gene-edited babies. But many countries have no such laws. Since He’s fateful gene-editing experiment became public, a researcher in Russia, Denis Rebrikov, has expressed interest in editing embryos from deaf couples in an attempt to provide them with babies that can hear.

Niakan could not be reached for comment, but in a December 2019 editorial in the journal Nature, she argued that much more work on the basic biology of human development is needed before gene editing can be used to create babies. “One must ensure that the outcome will be the birth of healthy, disease-free children, without any potential long-term complications,” she wrote.

The embryos edited by Niakan and her team were never intended to be used to start a pregnancy. In February 2016, her lab became the first in the U.K. to receive permission to use CRISPR in human embryos for research purposes. The embryos used are left over from fertility treatments and donated by patients.

Niakan’s paper comes as the U.S. National Academies, U.K.’s Royal Society, and the World Health Organization are contemplating international standards around the use of germline genome editing in response to the global outcry over He’s experiment. The committees are expected to release recommendations this year or in 2021. But because these organizations have no enforcement power, it will be up to individual governments to adopt such standards and make them law.

Urnov says the new findings should influence those committee’s decisions in a substantial way.

Musunuru agrees. “Nobody has any business using genome editing to try to make modifications in the germline,” he says. “We’re nowhere close to having the scientific ability to do this in a safe way.”


Materials and Methods

Genome Assembly and Identification of Variants across Humans and Great Apes

The great ape genome data (total number 147) for CMAH and CD33rSIGLECs were derived from three publications ( Prado-Martinez et al. 2013 Xue et al. 2015 de Manuel et al. 2016 Kronenberg et al. 2018). These great ape genomes were mapped to human reference genome (GRCh37/hg19) retrieved from UCSC genome browser, using Burrows–Wheeler aligner and further processed with Picard tool to remove duplicates and variant were called using Genome-analysis toolkit. Moreover, the variants in variant call format of chimpanzee, bonobos, gorilla, and orangutan were visualized in integrative genome viewer with their respective reference genome (Pantro4, Gorgor3, and PonAbe2) and annotation file. All archaic hominins raw and processed files were obtained from the Max Planck Institute for Evolutionary Anthropology ( Reich et al. 2010 Castellano et al. 2014 Prufer et al. 2014 Slon et al. 2018) (http://cdna.eva.mpg.de/neandertal). Bed coordinates of SIGLECs and CMAH genes were provided for each human and ape lineage as supplemental (chimpanzee, gorilla, and orangutan) ( supplementary file 1 , Supplementary Material online). Additionally, bed coordinates of additional polymorphism present in CD33rSIGLECs with allele frequency in great ape population were also provided as supplemental ( supplementary file 2 , Supplementary Material online).

Inference of Strong Archaic Natural Selection

The genes involved in sialic acid biology (67 genes) were overlapped with regions displaying signatures of ancient selective sweeps ( Peyregne et al. 2017). The method used to identify these signatures of archaic selection relies on a hidden Markov model to detect extended regions in the genome where the Neanderthal and Denisovan lineages fall outside the human variation ( Meyer et al. 2012 Prufer et al. 2014). This method can only detect events that occurred between the split of modern and archaic humans around 0.5 Ma ( Prufer et al. 2017) and the split of modern human populations from each other around 0.2 Ma ( Schiffels and Durbin 2014). For events with a selective advantage of 0.5% or larger, with an origin of the beneficial mutation as old as 600,000 years ago, the false positive rate of the method is lower than 0.1% and its true positive rate is larger than 65% ( Peyregne et al. 2017). We also note that signals of positive selection are not detectable if the selection coefficient is smaller than 0.1%. The Ensembl database (release 82) ( Aken et al. 2016) was used to annotate each gene with hg19 coordinates from transcription start to transcription end. Furthermore, L1CAM, PECAM, CMAH, SIGLEC13, SIGLEC16, and SIGLEC17 were excluded because they fall either in filtered regions not considered for the ancient sweep screen or could not be mapped to hg19 coordinates. As regulatory regions may also have been the target of positive selection, we extended the start and end coordinates 1 Mb upstream and downstream, respectively. If a neighboring gene was within 1 Mb, we only extended the coordinates until 5 or 1 kb from the transcription start or end of this neighboring gene. In order to test whether the lack of signatures of ancient selection is statistically significant, the candidate regions of ancient selection were randomly placed in the genome and the random placements of all regions were iterated 1,000 times, counting how often no overlap with genes involved in sialic acid biology was detected. The depletion in selection is not significant (356 sets never overlap P value = 0.356).

Immunohistochemistry of Siglecs

Paraffin sections were deparaffinized in xylene and rehydrated in decreasing concentrations of ethanol and Tris-buffered saline–Tween (TBST). Following this, endogenous binding sites and peroxidases were blocked with 1% bovine serum albumin/TBST and 0.3% H2O2/TBST. This was followed by blocking of endogenous biotin and then heat-induced antigen retrieval was performed in citrate buffer pH 6. Primary antibodies (mouse anti-Siglec-7 and Rabbit anti-Siglec-13) or mouse IgG were then overlaid at optimal dilutions, and slides were incubated overnight at 4 °C in a humid chamber. Specific binding was detected using a biotinylated anti-mouse or anti-rabbit (for Siglec-13), followed by Horseradish Peroxidase (HRP) streptavidin and then biotinyl tyramide enhancement and then HRP streptavidin. Substrate color was developed, and nuclei were counterstained with hematoxylin and the slides were aqueous mounted for viewing and digital photomicrography using an Olympus BH2 microscope with an Olympus magnafire camera.


SARS‑CoV‑2 Genes Could Integrate Into The Human Genome, Controversial Study Says

A controversial study has demonstrated the possibility that genetic material from SARS-CoV-2 – the virus that causes COVID-19 – could integrate into our genome. The paper, published in Proceedings of the National Academy of Sciences (PNAS), perhaps provides an explanation as to why people who have recovered from COVID-19 can still test positive for the virus months later. It also builds on the findings of a much-disputed preprint by the same authors, which was released in December 2020.

The said preprint received a fair amount of skepticism from within the scientific community, with many branding it ‘dangerous’ amid fears it could spark concern that messenger RNA (mRNA)-based vaccines could alter human DNA. The authors have, however, stressed that neither set of results – preprint or PNAS – suggest this.

Subsequent preprints by other researchers have picked holes in the methodology used one preprint illustrated that the integration of viral DNA reported in the study was likely introduced by the very technique used to detect it, and was not, in fact, a genuine integration by reverse transcription – the process of synthesizing DNA from an RNA template – as originally suggested.

Rudolf Jaenisch, PhD, and Richard Young, PhD, biology professors at the Whitehead Institute and the Massachusetts Institute of Technology, who led the work, have acknowledged and countered these criticisms. The team used three different sequencing techniques to determine whether SARS-CoV-2 RNA could be integrated into the human genome in culture, via reverse transcription, and all three approaches found evidence that it was possible. DNA copies of the viral RNA were present in the host-cells genome and were found to have been integrated by a LINE1-mediated mechanism. LINE-1 elements make up 17 percent of the human genome and are the genetic sequences that encode reverse transcriptase, the enzyme responsible for reverse transcription.

While these results seem to back up the original hypothesis, that a SARS-CoV-2 DNA fragment can be integrated into the human genome via reverse transcription, it should be mentioned that approximately 30 percent of the integrated viral DNA was missing a LINE-1 recognition site. It is possible, therefore, that another method may be responsible for the integration.

As for the clinical relevance of these findings, evidence of integration in patients is yet to be seen. However, the team do report SARS-CoV-2 integration in tissue from living and autopsied COVID-19 patients: “Importantly, such chimeric transcripts are detected in patient-derived tissues,” they write. “Our data suggest that, in some patient tissues, the majority of all viral transcripts are derived from integrated sequences. Our data provide an insight into the consequence of SARS-CoV-2 infections that may help to explain why patients can continue to produce viral RNA after recovery.”

Further research is needed as to the effect potential integration could have on the course of the disease, and also the implications this might have for other disease-causing RNA viruses, such as dengue and influenza virus.


The Human Genome

What makes each one of us unique? You could argue that the environment plays a role, and it does to some extent. But most would agree that your parents have something to do with your uniqueness. In fact, it is our genes that make each one of us unique &ndash or at least genetically unique. We all have the genes that make us human: the genes for skin and bones, eyes and ears, fingers and toes, and so on. However, we all have different skin colors, different bone sizes, different eye colors and different ear shapes. In fact, even though we have the same genes, the products of these genes work a little differently in most of us. And that is what makes us unique.

The human genome is the genome - all the DNA - of Homo sapiens. Humans have about 3 billion bases of information, divided into roughly 20,000 to 22,000 genes, which are spread among non-coding sequences and distributed among 24 distinct chromosomes (22autosomes plus the X and Y sex chromosomes) (below). The genome is all of the hereditary information encoded in the DNA, including the genes and non-coding sequences.

Human Genome, Chromosomes, and Genes. Each chromosome of the human genome contains many genes as well as noncoding intergenic (between genes) regions. Each pair of chromosomes is shown here in a different color.

Thanks to the Human Genome Project, scientists now know the DNA sequence of the entire human genome. The Human Genome Project is an international project that includes scientists from around the world. It began in 1990, and by 2003, scientists had sequenced all 3 billion base pairs of human DNA. Now they are trying to identify all the genes in the sequence. The Human Genome Project has produced a reference sequence of the human genome. The human genome consists of protein-coding exons, associated introns and regulatory sequences, genes that encode other RNA molecules, and other DNA sequences (sometimes referred to as "junk" DNA), which are regions in which no function as yet been identified.

You can watch a video about the Human Genome Project and how it cracked the "code of life" at this link: http://www.pbs.org/wgbh/nova/genome/program.html.

Our Molecular Selves video discusses the human genome, and is available athttp://www.genome.gov/25520211 or http://www.youtube.com/watch?v=_EK3g6px7Ik.Genome, Unlocking Life's Code is the Smithsonian's National Museum of Natural History exhibit of the human genome. See http://unlockinglifescode.org to visit the exhibit.

ENCODE: The Encyclopedia of DNA Elements

In September 2012, ENCODE, The Encyclopedia of DNA Elements, was announced. ENCODE was a colossal project, involving over 440 scientists in 32 labs the world-over, whose goal was to understand the human genome. It had been thought that about 80% of the human genome was "junk" DNA. ENCODE has established that this is not true. Now it is thought that about 80% of the genome is active. In fact, much of the human genome is regulatory sequences, on/off switches that tell our genes what to do and when to do it. Dr. Eric Green, director of the National Human Genome Research Institute of the National Institutes of Health which organized this project, states, "It's this incredible choreography going on, of a modest number of genes and an immense number of . switches that are choreographing how those genes are used."

It is now thought that at least three-quarters of the genome is involved in making RNA, and most of this RNA appears to help regulate gene activity. Scientists have also identified about 4 million sites where proteins bind to DNA and act in a regulatory capacity. These new findings demonstrate that the human genome has remarkable and precise, and complex, controls over the expression of genetic information within a cell.


Chinese Scientist Claims to Use Crispr to Make First Genetically Edited Babies

Ever since scientists created the powerful gene editing technique Crispr, they have braced apprehensively for the day when it would be used to create a genetically altered human being. Many nations banned such work, fearing it could be misused to alter everything from eye color to I.Q.

Now, the moment they feared may have come. On Monday, a scientist in China announced that he had created the world’s first genetically edited babies, twin girls who were born this month.

The researcher, He Jiankui, said that he had altered a gene in the embryos, before having them implanted in the mother’s womb, with the goal of making the babies resistant to infection with H.I.V. He has not published the research in any journal and did not share any evidence or data that definitively proved he had done it.

But his previous work is known to many experts in the field, who said — many with alarm — that it was entirely possible he had.

“It’s scary,” said Dr. Alexander Marson, a gene editing expert at the University of California in San Francisco.

While the United States and many other countries have made it illegal to deliberately alter the genes of human embryos, it is not against the law to do so in China, but the practice is opposed by many researchers there. A group of 122 Chinese scientists issued a statement calling Dr. He’s actions “crazy” and his claims “a huge blow to the global reputation and development of Chinese science.”

If human embryos can be routinely edited, many scientists, ethicists and policymakers fear a slippery slope to a future in which babies are genetically engineered for traits — like athletic or intellectual prowess — that have nothing to do with preventing devastating medical conditions.

While those possibilities might seem far in the future, a different concern is urgent and immediate: safety. The methods used for gene editing can inadvertently alter other genes in unpredictable ways. Dr. He said that did not happen in this case, but it is a worry that looms over the field.

Dr. He made his announcement on the eve of the Second International Summit on Human Genome Editing in Hong Kong, saying that he had recruited several couples in which the man had H.I.V. and then used in vitro fertilization to create human embryos that were resistant to the virus that causes AIDS. He said he did it by directing Crispr-Cas9 to deliberately disable a gene, known as CCR₅, that is used to make a protein H.I.V. needs to enter cells.

Dr. He said the experiment worked for a couple whose twin girls were born in November. He said there were no adverse effects on other genes.

In a video that he posted, Dr. He said the father of the twins has a reason to live now that he has children, and that people with H.I.V. face severe discrimination in China.

Dr. He’s announcement was reported earlier by the MIT Technology Review and The Associated Press.

In an interview with the A.P. he indicated that he hoped to set an example to use genetic editing for valid reasons. “I feel a strong responsibility that it’s not just to make a first, but also make it an example,” he told the A.P. He added: “Society will decide what to do next.”

It is highly unusual for a scientist to announce a groundbreaking development without at least providing data that academic peers can review. Dr. He said he had gotten permission to do the work from t he ethics board of the hospital Shenzhen Harmonicare , but the hospital, in interviews with Chinese media, denied being involved. Cheng Zhen, the general manager of Shenzhen Harmonicare, has asked the police to investigate what they suspect are “fraudulent ethical review materials,” according to the Beijing News.

The university that Dr. He is attached to, the Southern University of Science and Technology, said Dr. He has been on no-pay leave since February and that the school of biology believed that his project “is a serious violation of academic ethics and academic norms,” according to the state-run Beijing News.

In a statement late on Monday, China’s national health commission said it has asked the health commission in southern Guangdong province to investigate Mr. He’s claims.

Many scientists in the United States were appalled by the developments.

“I think that’s completely insane,” said Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University. Dr. Mitalipov broke new ground last year by using gene editing to successfully remove a dangerous mutation from human embryos in a laboratory dish.


Figure (PageIndex<2>): Human Genome, Chromosomes, and Genes. Each chromosome of the human genome contains many genes as well as noncoding intergenic (between genes) regions. Each pair of chromosomes is shown here in a different color.

Scientists now know the sequence of all the DNA base pairs in the entire human genome. This knowledge was attained by the Human Genome Project (HGP), a $3 billion, international scientific research project that was formally launched in 1990. The project was completed in 2003, two years ahead of its 15-year projected deadline.

Determining the sequence of the billions of base pairs that make up human DNA was the main goal of the HGP. Another goal was mapping the location and determining the function of all the genes in the human genome. There are only about 20,500 genes in human beings.

A Collaborative Effort

Funding for the HGP came from the U.S. Department of Energy and the National Institutes of Health as well as from foreign institutions. The actual research was undertaken by scientists in 20 universities in the U.S., United Kingdom, Australia, France, Germany, Japan, and China. A private U.S. company named Celera also contributed to the effort. Although Celera had hoped to patent some of the genes it discovered, this was later denied.

Reference Genome of the Human Genome Project

In 2003, the HGP published the results of its sequencing of DNA as a human reference genome. Figure (PageIndex<4>) illustrates the process of DNA sequencing. The details of this image are out of the scope of this concept and book. The sequence of the human DNA is stored in databases available to anyone on the Internet. The U.S. National Center for Biotechnology Information (NCBI), part of the NIH, as well as comparable organizations in Europe and Japan, maintain the genomic sequences in a database known as Genbank. Protein sequences are also maintained in this database. The sequences in these databases are the combined sequences of anonymous donors, and as such do not yet address the individual differences that make us unique. However, the known sequence does lay the foundation to identify the unique differences among all of us. Most of the currently identified variations among individuals will be single nucleotide polymorphisms or SNPs. An SNP (pronounced "snip") is a DNA sequence variation occurring at a single nucleotide in the genome. For example, two sequenced DNA fragments from different individuals, GGATCTA to GGATTTA, contain a difference in a single nucleotide. If this, base change occurs in a gene, the base change then results in two alleles: the C allele and the T allele. Remember an allele is an alternative form of a gene. Almost all common SNPs have only two alleles. The effect of these SNPs on protein structure and function and any effect on the resulting phenotype are an extensive field of study.

Benefits of the Human Genome Project

The sequencing of the human genome holds benefits for many fields, including molecular medicine and human evolution.

  • Knowing the human DNA sequence can help us understand many human diseases. For example, it is helping researchers identify mutations linked to different forms of cancer. It is also yielding insights into the genetic basis of cystic fibrosis, liver diseases, blood-clotting disorders, and Alzheimer's disease, among others.
  • The human DNA sequence can also help researchers tailor medications to individual genotypes. This is called personalized medicine, and it has led to an entirely new field called pharmacogenomics. Pharmacogenomics, also called pharmacogenetics, is the study of how our genes affect the way we respond to drugs. You can read more about pharmacogenomics in the Feature below.
  • The analysis of similarities between DNA sequences from different organisms is opening new avenues in the study of evolution. For example, analyses are expected to shed light on many questions about the similarities and differences between humans and our closest relatives the nonhuman primates.

Figure (PageIndex<3>): Timeline of the human genome project from 1990 to 2003. The details of this image are out of the scope of this concept and textbook. The full version of the image is visible at the NIH site.

Ethical, Legal, and Social Issues of the Human Genome Project

From its launch in 1990, the HGP proactively established and funded a separate committee to oversee potential ethical, legal, and social issues associated with the project. A major concern was the possible use of the knowledge generated by the project to discriminate against people. One issue was the fear that employers and health insurance companies would refuse to hire or insure people based on their genetic makeup, for instance, if they had genes that increased their risk of getting certain diseases. In response, in 1996, the U.S. passed the Health Insurance Portability and Accountability Act (HIPAA). It protects against unauthorized, nonconsensual release of individually identifiable health information to any entity not actively engaged in providing healthcare to a patient. This was followed in 2008 by the Genetic Information Nondiscrimination Act (GINA), which specifically prohibits genetic discrimination by health insurance companies and workplaces.


Breaking through the unknowns of the human reference genome

Karen H. Miga is at the UC Santa Cruz Genomics Institute, University of California, Santa Cruz, California 95064, USA.

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The release of drafts of the human genome in 2001 was a landmark achievement 1 , 2 . Scientists could, for the first time, study long stretches of each human chromosome, base by base. As such, researchers could begin to understand how individual genes were ordered, and how the surrounding non-protein-coding DNA was structured and organized. Despite this amazing progress, the draft genomes were still incomplete, with more than 150 million bases missing 3 . Technological advances in the intervening years have allowed researchers to add to the draft, with the complete sequencing of a chromosome finally being achieved 4 , 5 in 2020. As a result, new and uncharacterized parts of the human genome are beginning to surface, ushering in another exciting period of biological discovery.

Read the paper: Initial sequencing and analysis of the human genome

What exactly was included in the draft genomes? The original draft contained many previously unexplored intergenic regions. It also encompassed the vast majority of genes. The International Human Genome Sequencing Consortium 1 initially estimated that the genome contained 30,000–40,000 protein-coding genes, although the publication of an updated genome 6 in 2004, along with improved gene-prediction approaches 7 , led the figure to be revised to about 20,000. The 2004 genome gave a high-resolution map of 2.85 billion nucleotides from euchromatin — the more loosely packaged regions of DNA, which are enriched in genes and make up roughly 92% of the human genome.

The reference genome launched the scientific community into an era of genome exploration, shifting the focus from single genes to more-complete, genome-wide studies. However, gaps remained on each of the 23 pairs of human chromosomes, estimated to contain more than 150 megabases of unknown sequence 3 (Fig. 1). The largest gaps were at locations enriched with highly repetitive DNA or sequences for which there are many near-identical copies. These sections were originally difficult to clone, sequence and correctly assemble. As a result, the human genome project intentionally under-represented these repetitive sequences. Although researchers had a very basic idea of the nature of sequences in these regions, the regions’ high-resolution genomic organization remained elusive.

Figure 1 | Filling in the missing sequence in the human genome. a, The 2001 draft human genome 1 , 2 covered most of the gene-rich DNA, which is loosely packaged in the nucleus. But many gaps remained in tightly packaged regions rich in repetitive DNA sequences, which are often untranscribed (the overall extent of the gaps is exaggerated here, for ease of interpretation). b, Thanks to advances in sequencing and bioinformatics, researchers can now study all of these missing sequences. These include the telomere and subtelomere regions that cap chromosomes centromere structures that are essential for cell division and particularly short and highly repetitive chromosome arms known as acrocentric arms. Regions in which DNA is duplicated, either in one location or in a segmented way, can also now be analysed.

Early attempts to close the gaps used long sequence reads to span the repetitive sequences — but such reads were initially highly error-prone. In the 2010s, new opportunities arose, thanks to advances in the ability to read longer stretches of sequence (outlined in refs. 8 and 9, for instance), along with the development of scalable bioinformatic tools. Sequence reads of tens to hundreds of kilobases allowed the study of the genomic organization of many moderately sized gaps. This provided insights into some subtelomeric regions 9 — repeat-rich DNA adjacent to the telomere structures that cap the ends of chromosomes. It also enabled the study of the first centromeric satellite array 10 , in which short sequences are repeated in tandem for about 300 kilobases. A subset of segmental duplications (stretches of sequence that share 90–100% of their bases and are found in multiple locations) was also resolved, many containing genes previously missing from the reference genome 9 , 11 . However, many of the largest, multi-megabase-sized repeat-rich regions remained intractable.

Over the past few years, the combination of both ultra-long reads 9 and highly accurate long-read data 12 has proved a game-changer for resolving these regions 13 , 14 , revealing, for the first time, extremely long tracts of tandem repeats and regions enriched in segmental duplications. By breaking down these technological barriers, scientists are now discovering extensive repeat-rich regions that can span millions of bases, and make up the entire short arms of chromosomes.

Researchers do not yet fully understand why parts of the human genome are organized in this way. But gaining such an understanding will undoubtedly be valuable, because these repeat-rich sequences are often positioned at sites that are crucial for life. For example, long tracts of ribosomal DNA (rDNA) repeats encode RNA components of the cell’s protein-synthesizing machinery and have an important role in nuclear organization 15 . And the repetitive DNA of structures called centromeres is essential for proper chromosome segregation during cell division 16 .

These large swathes of repetitive DNA come with different sets of rules, in terms of their genomic organization and evolution. They are also subject to different epigenetic regulation (molecular modifications to DNA and associated proteins that do not alter the underlying DNA sequence), which leads repetitive DNA to differ from euchromatin in terms of its organization, replication timing and transcriptional activity 17 – 19 . Many genome-wide tools and data sets cannot yet fully capture all this information from extremely repetitive DNA regions, and so scientists do not yet have a complete picture of what transcription factors bind to them, how these regions are spatially organized in the nucleus, or how regulation of these parts of our genome changes during development and in disease states. Now, much like the initial release of the genome decades ago, researchers are faced with a new, unexplored functional landscape in the human genome. Access to this information will drive technology and innovation to be inclusive of these repeat regions, once again broadening our understanding of genome biology.

Repeat DNA expands our understanding of autism spectrum disorder

In the past year, scientists have used extremely long and highly accurate sequence reads to reconstruct entire human chromosomes from telomere to telomere 4 , 5 . Last year also saw the release of a near-complete human reference genome from an effectively ‘haploid’ human cell line, with only five remaining gaps that mark the sites of rDNA arrays (go.nature.com/3rgz93y). In this line, cells have two identical pairs of chromosomes, simplifying the challenge of repeat assembly compared with typical human cells (which are diploid, with different chromosomes inherited from the mother and father). These maps together offer the first high-resolution glimpse of centromeric regions, segmental duplications, subtelomeric repeats and each of the five acrocentric chromosomes, which have very short arms made up almost entirely of highly repetitive DNA at one end.

It is tempting to think scientists are finally approaching the finish line. However, a single genome assembly, even if complete with near-perfect sequence accuracy, is an insufficient reference from which to study the sequence variation that exists across the human population. Existing maps that chart the diversity across the euchromatic parts of the genome must be extended to fully capture repetitive regions, where copy number and repeat organization vary between individuals. Doing so will require the development of strategies for routine production and analysis of complete human diploid genomes. The aspirational goal of reaching a more-complete and comprehensive reference of humanity will undoubtedly improve our understanding of genome structure and its role in human disease, and align with the promise and legacy of the Human Genome Project.

Nature 590, 217-218 (2021)


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