Researchers map 50,000 of DNA's mysterious 'knots' in the human genome

Innovative study of DNA's hidden structures may open up new approaches for treatment and diagnosis of diseases, including cancer.

DNA is well-known for its double helix shape. But the human genome also contains more than 50,000 unusual 'knot'-like DNA structures called i-motifs, researchers at the Garvan Institute of Medical Research have discovered.

Published today in The EMBO Journalis the first comprehensive map of these unique DNA structures, shedding light on their potential roles in gene regulation involved in disease.

In a landmark 2018 study, Garvan scientists were the first to directly visualise i-motifs inside living human cells using a new antibody tool they developed to recognise and attach to i-motifs. The current research builds on those findings by deploying this antibody to identify i-motif locations across the entire genome.

"In this study, we mapped more than 50,000 i-motif sites in the human genome that occur in all three of the cell types we examined," says senior author Professor Daniel Christ, Head of the Antibody Therapeutics Lab and Director of the Centre for Targeted Therapy at Garvan. "That's a remarkably high number for a DNA structure whose existence in cells was once considered controversial. Our findings confirm that i-motifs are not just laboratory curiosities but widespread -- and likely to play key roles in genomic function."

Curious DNA i-motifs could play a dynamic role in gene activity

I-motifs are DNA structures that differ from the iconic double helix shape. They form when stretches of cytosine letters on the same DNA strand pair with each other, creating a four-stranded, twisted structure protruding from the double helix.

The researchers found that i-motifs are not randomly scattered but concentrated in key functional areas of the genome, including regions that control gene activity.

"We discovered that i-motifs are associated with genes that are highly active during specific times in the cell cycle. This suggests they play a dynamic role in regulating gene activity," says Cristian David Peña Martinez, a research officer in the Antibody Therapeutics Lab and first author of the study.

"We also found that i-motifs form in the promoter region of oncogenes, for instance the MYC oncogene, which encodes one of cancer's most notorious 'undruggable' targets. This presents an exciting opportunity to target disease-linked genes through the i-motif structure," he says.

I-motifs hold promise for new type of therapies and diagnostics

"The widespread presence of i-motifs near these 'holy grail' sequences involved in hard-to-treat cancers opens up new possibilities for new diagnostic and therapeutic approaches. It might be possible to design drugs that target i-motifs to influence gene expression, which could expand current treatment options," says Associate Professor Sarah Kummerfeld, Chief Scientific Officer at Garvan and co-author of the study.

Professor Christ adds that mapping i-motifs was only possible thanks to Garvan's world-leading expertise in antibody development and genomics. "This study is an example of how fundamental research and technological innovation can come together to make paradigm-shifting discoveries," he says.

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Researchers fully sequence the Y chromosome for the first time

What was once the final frontier of the human genome -- the Y chromosome -- has just been mapped out in its entirety.

Led by the National Human Genome Research Institute (NHGRI), a team of researchers at the National Institute of Standards and Technology (NIST) and many other organizations used advanced sequencing technologies to read out the full DNA sequence of the Y chromosome -- a region of the genome that typically drives male reproductive development. The results of a study published in Nature demonstrate that this advance improves DNA sequencing accuracy for the chromosome, which could help identify certain genetic disorders and potentially uncover the genetic roots of others.

DNA sequencing isn't as simple as reading genetic material from a genome's beginning to its end. DNA gets chopped up when it is extracted from cells, plus even the best sequencing equipment can only handle relatively small bits of DNA at a time. So, researchers and clinicians rely on special software to piece together fragments of sequenced code in the correct order like a puzzle.

A reference genome is a separate, already pieced-together genome that serves as a guide, similar to the pictures on the front of puzzle boxes. And because 99.9% of our species' genetic code is shared, any human genome would closely match a reference.

Last year, a team from the Telomere-to-Telomere (T2T) consortium, which is made up of experts from dozens of organizations such as NIST, generated the most complete reference genome at the time by using new sequencing technologies to crack previously indecipherable regions of the genome. But cells used in that work did not contain the most puzzling of all, the Y chromosome.

"Chromosomes all contain sections of very repetitive DNA, but well over half of the Y chromosome is like that," said study co-author Justin Zook, who leads NIST's Genome in a Bottle (GIAB) consortium. "If you use the puzzle analogy, a lot of the Y chromosome looks like the backgrounds often do, where all the pieces look really similar."

With this new endeavor, T2T was not starting at zero as the GIAB had already gotten the ball rolling.

The GIAB's mission is to produce test materials, or benchmarks, that can be used to evaluate sequencing technologies or methods. The materials themselves are highly accurate readouts of specific genes that can act as an answer key for checking the results of a particular sequencing method.

NIST has rigorously analyzed several individual human genomes to create their benchmarks. While GIAB has not yet produced a benchmark for the Y chromosome specifically, the consortium has studied one genome extensively, accumulating the largest collection of Y chromosome data prior to the new study.

That data served as a jumping-off point for the new study's authors, who focused their analysis on the best understood GIAB Y chromosome. They examined the sample with a combination of cutting-edge technologies -- namely high fidelity and nanopore sequencing -- that make the DNA fragment puzzle pieces larger and thus easier to assemble.

A machine-learning analysis tool and gamut of other advanced programs helped the team identify and assemble the pieces of the chromosome. More than 62 million letters of genetic code later, the authors had spelled out the GIAB Y chromosome front to back.

The researchers pitted their complete Y chromosome sequence, named T2T-Y, against the most widely used reference genome's Y chromosome parts, which are riddled with stretches of absent code. Using them both as guides for sequencing a diverse group of over 1,200 separate genomes, they found that T2T-Y drastically improved the outcomes.

T2T-Y, in combination with the group's previous reference genome, T2T-CHM13, represents the world's first complete genome for the half of the population with a Y chromosome.

The newest addition could be useful in identifying and diagnosing the few known conditions related to genes in the Y chromosome. But what's more is the new reference's potential to shed light on new genes and their function.

"There are certainly aspects of fertility and some genetic disorders that are connected to genes in the Y chromosome," Zook said. "But because it's been so hard to analyze up to this point, we may not even know yet just how important the Y chromosome is."

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Information 'deleted' from the human genome may be what made us human

What the human genome is lacking compared with the genomes of other primates might have been as crucial to the development of humankind as what has been added during our evolutionary history, according to a new study led by researchers at Yale and the Broad Institute of MIT and Harvard.

The new findings, published April 28 in the journal Science, fill an important gap in what is known about historical changes to the human genome. While a revolution in the capacity to collect data from genomes of different species has allowed scientists to identify additions that are specific to the human genome -- such as a gene that was critical for humans to develop the ability to speak -- less attention has been paid to what's missing in the human genome.

For the new study researchers used an even deeper genomic dive into primate DNA to show that the loss of about 10,000 bits of genetic information -- most as small as a few base pairs of DNA -- over the course of our evolutionary history differentiate humans from chimpanzees, our closest primate relative. Some of those "deleted" pieces of genetic information are closely related to genes involved in neuronal and cognitive functions, including one associated with the formation of cells in the developing brain.

These 10,000 missing pieces of DNA -- which are present in the genomes of other mammals -- are common to all humans, the Yale team found.

The fact that these genetic deletions became conserved in all humans, the authors say, attests to their evolutionary importance, suggesting that they conferred some biological advantage.

"Often we think new biological functions must require new pieces of DNA, but this work shows us that deleting genetic code can result in profound consequences for traits make us unique as a species," said Steven Reilly, an assistant professor of genetics at Yale School of Medicine and senior author of the paper.

The paper was one of several published in Science from the Zoonomia Project, an international research collaboration that is cataloging the diversity in mammalian genomes by comparing DNA sequences from 240 species of mammals that exist today.

In their study, the Yale team found that some genetic sequences found in the genomes of most other mammal species, from mice to whales, vanished in humans. But rather than disrupt human biology, they say, some of these deletions created new genetic encodings that eliminated elements that would normally turn genes off.

The deletion of this genetic information, Reilly said, had an effect that was the equivalent of removing three characters -- "n't" -- from the word "isn't" to create a new word, "is."

"[Such deletions] can tweak the meaning of the instructions of how to make a human slightly, helping explain our bigger brains and complex cognition," he said.

The researchers used a technology called Massively Parallel Reporter Assays (MPRA), which can simultaneously screen and measure the function of thousands of genetic changes among species.

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Oldest human genome from southern Spain

A new study reports on genomic data from a 23,000-year-old individual who lived in what was probably the warmest place of Europe at the peak of the last Ice Age. The oldest human genome recovered from the southern tip of Spain adds an important piece of the puzzle to the genetic history of Europe.

An international team of researchers has analysed ancient human DNA from several archaeological sites in Andalucía in southern Spain. Thestudy reports on the oldest genome to date from Cueva del Malalmuerzo in southern Spain, as well as the 7,000 to 5,000-year-old genomes of early farmers from other well-known sites, such as Cueva de Ardales.

The Iberian Peninsula plays an important role in the reconstruction of human population history. As a geographic cul-de-sac in the southwest of Europe, it is on one hand considered a refuge during the last Ice Age with its drastic temperature fluctuations. On the other hand, it may have been one of the starting points for the recolonisation of Europe after the glacial maximum. Indeed, previous studies had reported on the genomic profiles of 13,000 to 8,000-year-old hunter-gatherers from the Iberian Peninsula and provided evidence for the survival and continuation of a much older Palaeolithic lineage that has been replaced in other parts of Europe and is no longer detectable.

After an organism's death, its DNA is only preserved for a certain period of time and under favourable climatic conditions. Extracting DNA from ancient remains from hot and dry climates is a huge challenge for researchers. In Andalucía, in the south of present-day Spain, climatic conditions are similar to those in North Africa -- however, DNA has successfully been recovered of 14,000-year-old human individuals from a cave site in Morocco. The new study fills crucial temporal and spatial gaps. Researchers can now directly investigate the role of the southern Iberian Peninsula as a refuge for Ice Age populations and potential population contacts across the Strait of Gibraltar during the last Ice Age, when sea-levels were much lower than today.

In the right place at the right time

The genetic ancestry of individuals from central and southern Europe who lived before the Last Glacial Maximum (24,000 to 18,000 years before today) differs from the ones who recolonised Europe afterwards. However, the situation in western Europe has not been clear until now due to a lack of genomic data from critical time periods. The 23,000-year-old individual from Cueva del Malalmuerzo near Granada finally adds data from the time when large parts of Europe were covered by massive ice sheets. The study describes a direct genetic link between a 35,000-year-old individual from Belgium and the new genome from Malalmuerzo. "Thanks to the high quality of our data we were able to detect traces of one of the first genetic lineages that settled Eurasia 45,000 years ago. Importantly, we found similarities with a 35,000-year-old individual from Belgium whose ancestry we can now trace further to the 23,000-year-old individual from southern Iberia," explains first author Vanessa Villalba-Mouco of the Max Planck Institute for Evolutionary Anthropology.

The individual from Cueva del Malalmuerzo not only links to earlier periods of settlement but also to the hunter-gatherers of southern and western Europe who lived long after the last Ice Age. It also confirms the important role of the Iberian Peninsula as a refuge for human populations during the last Ice Age. From there, humans migrated northwards and eastwards once the ice sheets had retreated. "With Malalmuerzo, we managed to find the right place and the right time period to trace a Palaeolithic human group back to one of the proposed Ice Age refugia. It is remarkable to find such a long-lasting genetic legacy on the Iberian Peninsula, especially since this pre-Ice Age ancestry had long since disappeared in other parts of Europe," adds senior author Wolfgang Haak of the Max Planck Institute for Evolutionary Anthropology.

More puzzle pieces of human history

Interestingly, the authors did not find any genetic link between the southern Iberian Peninsula and North Africa -- despite a distance of only 13 kilometres across the Mediterranean Sea, and parallels in the archaeological record. "In Malalmuerzo, we found no evidence of a genetic contribution from North African lineages, and conversely, there is no evidence of a genetic contribution from southern Spain in the genomes of the 14,000-year-old individuals from the Taforalt cave in Morocco," adds Gerd-Christian Weniger from the University of Cologne. "Why the Strait of Gibraltar was a barrier at the end of the last Ice Age is still one of the unresolved questions of archaeological research in the western Mediterranean region."

The study also includes a number of younger individuals from the Neolithic, a time period when the first farmers arrived in Europe from the Near East. The characteristic genetic ancestry of Anatolian Neolithic groups is indeed detectable in the individuals from Andalucía, suggesting that these early farmers spread over large geographic distances. "Neolithic people from southern Iberia, however, show a higher proportion of hunter-gatherer lineages. Hence, interaction between the last hunters and the first farmers may have been much closer than in other regions," says co-author Jose Ramos-Muñoz from Universidad de Cádiz.

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Ancient viral elements embedded in human genome not from fossil retrovirus

Using a next generation sequencing analysis to examine human endogenous retrovirus (HERV) integration sites, researchers from Kumamoto University, the National Institute of Genetics (Japan), and the University of Michigan (USA) have discovered that these ancient retroviruses can undergo retrotransposition (DNA sequence insertion with RNA mediation) into iPS cells. The team believes that their discovery places a spotlight on a possible risk that HERVs pose when using iPS cells in regenerative medicine.

The study of ancient retroviruses embedded in our genome requires knowledge about our coexistence with viral threats throughout history. We know that HERVs occupy approximately 8% of the human genome and obtain mutations and deletions over long periods. HERVs are also expressed in early embryos and play several physiological roles in human development. For example, HERV-W and HERV-FRD Env proteins are important for placental formation, and HERV-K is thought to protect host cells from exogenous retrovirus infection. However, uncontrollable HERV-K expression is also thought to be associated with various diseases, including various cancers and neurological diseases, but the details of this association is not well known in humans.

Since no one has yet discovered replication competent HERVs in our genome, it is thought that they are from an extinct (fossil) virus. In their current work, the research team from Japan and the US discovered that HERV-K is expressed in SOX2-expressing cells, such as those in early embryos, cancer stem cells and iPS cells. They also found that some HERV-K are newly integrated into the host genome in the absence of Env, the viral envelope glycoprotein. This integration was dependent on reverse transcriptase, integrase and protease, thus the researchers hypothesized that the HERV-K embedded in our genome is actually not from a fossil virus, but moves on the genome through the synthesis of proviral DNA reverse transcription. Interestingly, when the researchers compared the HERV-K integration sites between iPS and fibroblast cells from the same donor, they found new HERV-K integration sites in iPS cells. However, the new integration sites were rarely preserved and disappeared during long-term culturing. HERV-K is likely to be randomly integrated into genome, thus the possibility remains that HERV-K retrotransposed-cells predominantly survive depending on their integration site.

The movement of HERV-K on the genome might cause cancer and neurological diseases by altering the gene expression profile. The researchers believe that the risk of HERV-K transposition is low in iPS cells but suggest that monitoring HERV-K integration sites should be seriously considered to improve the safety of regenerative medicine using iPS cells.

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In the race to solve Alzheimer's disease, scientists find more needles in the haystack

21 million. That's the number of genetic variations in the human genome that researchers are sifting to identify patterns predisposing people to Alzheimer's disease.

It's a huge haystack, and Alzheimer's-related genetic variations, like needles, are miniscule in comparison. Sudha Seshadri, MD, and other faculty at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) readily attest to the deep gulf between what is known about Alzheimer's genetics and what is yet to be discovered.

Dr. Seshadri, Habil Zare, PhD, and colleagues at the university's Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases are investigators on a global project to answer the many Alzheimer's riddles. Dr. Seshadri is a founding principal investigator of the International Genomics of Alzheimer's Project, commonly called IGAP. Glenn Biggs Institute faculty contributed data for the newest research from IGAP, published April 4 in Nature Genetics, and helped craft the discussion on implications of the findings, Dr. Seshadri said.

Large sample

Genomic data of half a million people were used in this latest IGAP study, including 30,000 people with confirmed Alzheimer's disease and 47,000 people categorized as proxies. Researchers could not be sure that proxy participants had Alzheimer's clinically, but they were included based on conversations with their children.

"In Alzheimer's disease research you need many samples, because some of these variants are very rare, and if you want to detect them, you need to study many, many people," said Dr. Zare, assistant professor of cell systems and anatomy in the Joe R. and Teresa Lozano Long School of Medicine and an expert in computational biology and bioinformatics. "The only way to get there is through collaboration between centers and consortia, and IGAP was established for such kind of collaboration."

IGAP conducts genome-wide association studies. These studies reveal areas of the genome, the encyclopedia of human genes, that vary between people who have Alzheimer's disease and people who don't.

"We are looking for the genetic basis so as to better understand all the different types of biology that may be responsible for Alzheimer's disease," said Dr. Seshadri, founding director of the Biggs Institute and professor of neurology in the Long School of Medicine. "As we include data from more and more people, we are able to find variants that are fairly rare, that are only seen in about 1% of the population."

Sea change

In 2009, the year of the first genome-wide association studies, researchers knew of one gene, called APOE, associated with late-onset Alzheimer's disease. Before the April 4 journal publication, researchers had a list of 40 such genes. The new paper confirmed 33 of them in a larger population sample and added 42 new genetic variants not described before.

"We've doubled the number of genes that we know are associated with Alzheimer's disease," Dr. Seshadri said. "Each of these genetic variants is a route to understanding the biology and a potential target for treatment."

Emerging pathways of Alzheimer's biology suggest the involvement of inflammation, cell senescence, central nervous system cells called microglia, and many others. Finding genetic variations will shed light on these pathways.

"A certain percentage of them are what are called druggable targets," Dr. Zare said. "Some are considered more likely to yield drugs."

Diversity needed

The study published in Nature Genetics is confined to certain people groups, which makes it impossible to generalize the gene variations worldwide.

One of the challenges with this paper, as well, is it is largely in persons of European ancestry," Dr. Seshadri said. "So, we hope to bring, over the next few years, a much larger sample of Hispanic and other minority populations to further improve gene discovery."

The South Texas Alzheimer's Disease Research Center (ADRC), a collaboration of the Glenn Biggs Institute, UT Health San Antonio and The University of Texas Rio Grande Valley, is on a mission to bring the region's sizable Hispanic population into genetic studies and other initiatives such as clinical trials. ADRCs are National Institute on Aging Centers of Excellence.

Older Hispanic adults are estimated to be at 1.5 times greater risk of Alzheimer's and other dementias than non-Hispanic whites. Dementia is costing individuals, caregivers, families and the nation an estimated $321 billion in 2022, according to the Alzheimer's Association.

"Our South Texas ADRC is here to treat people and make discoveries that lead to better treatments," Dr. Seshadri said.

The needles in the haystack are being located, and this is having results.

"We are part of this international team and are finding a lot of needles in this huge haystack of 21 million variants," Dr. Zare said.

Partners are crucial

Dr. Seshadri said a gene called SP1 is being considered for drug development by industry. SP1 was identified in an earlier study conducted by IGAP.

"That was a clue discovered years ago and now we have more clues, and hopefully we will have more promising targets in the near future," Dr. Zare said.

As the quest to end the suffering endured by individuals and families continues, the researchers acknowledge the partners who play significant roles.

"We would like to thank each of the collaborators within IGAP, and all the patients and families that join such studies, and the National Institute on Aging, which is our funder," Dr. Seshadri said.

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Researchers generate the first complete, gapless sequence of a human genome

Scientists have published the first complete, gapless sequence of a human genome, two decades after the Human Genome Project produced the first draft human genome sequence. According to researchers, having a complete, gap-free sequence of the roughly 3 billion bases (or "letters") in our DNA is critical for understanding the full spectrum of human genomic variation and for understanding the genetic contributions to certain diseases. The work was done by the Telomere to Telomere (T2T) consortium, which included leadership from researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health; University of California, Santa Cruz; and University of Washington, Seattle. NHGRI was the primary funder of the study.

Analyses of the complete genome sequence will significantly add to our knowledge of chromosomes, including more accurate maps for five chromosome arms, which opens new lines of research. This helps answer basic biology questions about how chromosomes properly segregate and divide. The T2T consortium used the now-complete genome sequence as a reference to discover more than 2 million additional variants in the human genome. These studies provide more accurate information about the genomic variants within 622 medically relevant genes.

"Generating a truly complete human genome sequence represents an incredible scientific achievement, providing the first comprehensive view of our DNA blueprint," said Eric Green, M.D., Ph.D., director of NHGRI. "This foundational information will strengthen the many ongoing efforts to understand all the functional nuances of the human genome, which in turn will empower genetic studies of human disease."

The now-complete human genome sequence will be particularly valuable for studies that aim to establish comprehensive views of human genomic variation, or how people's DNA differs. Such insights are vital for understanding the genetic contributions to certain diseases and for using genome sequence as a routine part of clinical care in the future. Many research groups have already started using a pre-release version of the complete human genome sequence for their research.

The full sequencing builds upon the work of the Human Genome Project, which mapped about 92% of the genome, and research undertaken since then. Thousands of researchers have developed better laboratory tools, computational methods and strategic approaches to decipher the complex sequence. Six papers encompassing the completed sequence appear in Science, along with companion papers in several other journals.

That last 8% includes numerous genes and repetitive DNA and is comparable in size to an entire chromosome. Researchers generated the complete genome sequence using a special cell line that has two identical copies of each chromosome, unlike most human cells, which carry two slightly different copies. The researchers noted that most of the newly added DNA sequences were near the repetitive telomeres (long, trailing ends of each chromosome) and centromeres (dense middle sections of each chromosome).

"Ever since we had the first draft human genome sequence, determining the exact sequence of complex genomic regions has been challenging," said Evan Eichler, Ph.D., researcher at the University of Washington School of Medicine and T2T consortium co-chair. "I am thrilled that we got the job done. The complete blueprint is going to revolutionize the way we think about human genomic variation, disease and evolution."

The cost of sequencing a human genome using "short-read" technologies, which provide several hundred bases of DNA sequence at a time, is only a few hundred dollars, having fallen significantly since the end of the Human Genome Project. However, using these short-read methods alone still leaves some gaps in assembled genome sequences. The massive drop in DNA sequencing costs comes hand-in-hand with increased investments in new DNA sequencing technologies to generate longer DNA sequence reads without compromising the accuracy.

Over the past decade, two new DNA sequencing technologies emerged that produced much longer sequence reads. The Oxford Nanopore DNA sequencing method can read up to 1 million DNA letters in a single read with modest accuracy, while the PacBio HiFi DNA sequencing method can read about 20,000 letters with nearly perfect accuracy. Researchers in the T2T consortium used both DNA sequencing methods to generate the complete human genome sequence.

"Using long-read methods, we have made breakthroughs in our understanding of the most difficult, repeat-rich parts of the human genome," says Karen Miga, Ph.D., a co-chair of the T2T consortium whose research group at the University of California, Santa Cruz is funded by NHGRI. "This complete human genome sequence has already provided new insight into genome biology, and I look forward to the next decade of discoveries about these newly revealed regions."

According to consortium co-chair Adam Phillippy, Ph.D., whose research group at NHGRI led the finishing effort, sequencing a person's entire genome should get less expensive and more straightforward in the coming years.

"In the future, when someone has their genome sequenced, we will be able to identify all of the variants in their DNA and use that information to better guide their healthcare," Phillippy said. "Truly finishing the human genome sequence was like putting on a new pair of glasses. Now that we can clearly see everything, we are one step closer to understanding what it all means."

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Potato genome decoded

More than 20 years after the first releasse of the human genome, scientists at the Ludwig-Maximilians-Universität München and the Max Planck Institute for Plant Breeding Research in Cologne, have for the first time decoded the highly complex genome of the potato. This technically demanding study lays the biotechnological foundation to accelerate the breeding of more robust varieties -- a goal in plant breeding for many years and an important step for global food security.

When shopping for potatoes on a market today, buyers may well be going home with a variety that was already available more than 100 years ago. Traditional potato varieties are popular. And yet this example also highlights a lack of diversity among the predominant potato varieties. However, that could soon change: researchers in the group of geneticist Korbinian Schneeberger were able to generate the first full assembly of a potato genome. This paves the way for breeding new, robust varieties:

"The potato is becoming more and more integral to diets worldwide including even Asian countries like China where rice is the traditional staple food. Building on this work, we can now implement genome-assisted breeding of new potato varieties that will be more productive and also resistant to climate change -- this could have a huge impact on delivering food security in the decades to come."

Especially the low diversity makes potato plants susceptible to diseases. This can have stark consequences, most dramatically during the Irish famine of the 1840s, where for several years nearly the entire potato crop rotted in the ground, and millions of people in Europe suffered from starvation simply because the single variety that was grown was not resistant to newly emerging tuber blight. During the Green Revolution of the 1950s and 1960s, scientists and plant breeders succeeded in achieving large increases in the yields of many of our major crop staples like rice or wheat. However, the potato has seen no comparable boost, and efforts to breed new varieties with higher yields have remained largely unsuccessful to the current day.

The reason for this is simple but has proven difficult to tackle -- instead of inheriting one copy of every chromosome from both the father and from the mother (as in humans) potatoes inherit two copies of each chromosome from each parent, making them a species with four copies of each chromosome (tetraploid). Four copies of each chromosome also mean four copies of each gene, and this makes it highly challenging and time-consuming to generate new varieties that harbour a desired combination of individual properties; what's more, multiple copies of each chromosome also make the reconstruction of the potato genome a far greater technical challenge than was the case for the human genome.

The researchers have overcome this longstanding hurdle using a simple yet elegant trick. Instead of trying to differentiate the four, often very similar, chromosome copies from each other, Korbinian Schneeberger together with his colleague Hequan Sun and other co-workers circumvented this problem by sequencing the DNA of large numbers of individual pollen cells. In contrast to all other cells, each pollen cell contains only two random copies of each chromosome; this facilitated the reconstruction of the sequence of the entire genome.

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New stem cell population provides a new way to study the awakening of the human genome

Researchers from the Babraham Institute have today published their latest work in the journal Cell Stem Cell describing a new subset of human embryonic stem cells that closely resemble the cells present at the genomic 'wake up call' of the 8-cell embryo stage in humans. This new stem cell model will allow researchers to map out the key genomic changes during early development, and help move towards a better understanding of the implications of genome activation errors in developmental disorders and embryo loss.

In all mammals, the early embryo undergoes a number of molecular events just after fertilisation that set the stage for the rest of development. During this key 'wake up call' the genome of the embryo takes over control of the cell's activities from the maternal genome. In humans, this happens at the 8-cell stage and is called zygotic genome activation (ZGA). Before the findings of this study, investigating the details of human ZGA could only be done in human embryos; existing human stem cell models represented the embryo only at later stages of the developmental process. In the UK, experiments using embryos are permitted but highly regulated, meaning that research into early development relied in part on alternative, non-human models.

In 2012, cells representing the genome activation stage of development were found in mouse embryonic stem cells (ESCs), allowing researchers to learn more about mammalian ZGA. Almost a decade later, the Reik lab at the Institute have found a human equivalent. The lab's discovery opens up a way to advance our knowledge of the earliest events during preimplantation development.

Dr Jasmin Taubenschmid-Stowers, lead author and Research Fellow in the Reik lab, part of the Institute's Epigenetics research programme , commented: "Studying mouse embryonic stem cells has allowed researchers to learn about the general process of genome activation, but we could learn even more about this important step in human development thanks to our discovery of a human stem cell counterpart."

In order to function, cells take copies of the genome in the form of an RNA code which is translated into proteins. The RNA code output is called the transcriptome and it can be used to identify different populations of cells. In this study, researchers used existing human data sets and information from mouse ESC studies to identify characteristic transcriptome marks that could be linked to genome activation. Using single cell techniques, they started the search for similar cells in their population of human ESCs.

The team found a subset of human ESCs with the right transcriptome marks to be a potential match for the 8-cell stage, when the major wave of genome activation occurs. They called these cells '8-cell like cells' or 8CLCs and used the published human data to further validate and confirm that these cells shared the same molecular outputs indicative of genome activation and could be pursued as a reliable model for future studies.

To further explore the extent of the similarities between their 8CLCs and 8-cell stage in human embryos, the team worked with Professor Jennifer Nichols from the Wellcome -- MRC Cambridge Stem Cell Institute. Together they were able to select and search for proteins present in both sets of cells that were indicative of ZGA. Their results showed that the ZGA-associated proteins of 8CLCs closely matched those seen in human 8-cell embryos.

As Jasmin explains: "The collaboration with Professor Nichols and her team was vital as we could identify selected proteins and really look at those in real, fixed human 8-cell stage embryo cells compared to our new stem cell counterparts. This work confirmed that our 8C-like cells matched at the protein level too, in additional to the transcriptomics data, providing validation that the 8-cell like cells matched embryo cells across multiple molecular layers."

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