̽��ֱ�� of Cambridge - genome

Genetic study reveals hidden chapter in human evolution

sc604 — Tue, 18 Mar 2025 10:00:00 +0000

Using advanced analysis based on full genome sequences, researchers from the ̽��ֱ�� of Cambridge have found evidence that modern humans are the result of a genetic mixing event between two ancient populations that diverged around 1.5 million years ago. About 300,000 years ago, these groups came back together, with one group contributing 80% of the genetic makeup of modern humans and the other contributing 20%.

For the last two decades, the prevailing view in human evolutionary genetics has been that Homo sapiens first appeared in Africa around 200,000 to 300,000 years ago, and descended from a single lineage. However, these latest results, reported in the journal Nature Genetics, suggest a more complex story.

“ ̽��ֱ��question of where we come from is one that has fascinated humans for centuries,” said first author Dr Trevor Cousins from Cambridge’s Department of Genetics. “For a long time, it’s been assumed that we evolved from a single continuous ancestral lineage, but the exact details of our origins are uncertain.”

“Our research shows clear signs that our evolutionary origins are more complex, involving different groups that developed separately for more than a million years, then came back to form the modern human species,” said co-author Professor Richard Durbin, also from the Department of Genetics.

While earlier research has already shown that Neanderthals and Denisovans – two now-extinct human relatives – interbred with Homo sapiens around 50,000 years ago, this new research suggests that long before those interactions – around 300,000 years ago – a much more substantial genetic mixing took place. Unlike Neanderthal DNA, which makes up roughly 2% of the genome of non-African modern humans, this ancient mixing event contributed as much as 10 times that amount and is found in all modern humans.

̽��ֱ��team’s method relied on analysing modern human DNA, rather than extracting genetic material from ancient bones, and enabled them to infer the presence of ancestral populations that may have otherwise left no physical trace. ̽��ֱ��data used in the study is from the 1000 Genomes Project, a global initiative that sequenced DNA from populations across Africa, Asia, Europe, and the Americas.

̽��ֱ��team developed a computational algorithm called cobraa that models how ancient human populations split apart and later merged back together. They tested the algorithm using simulated data and applied it to real human genetic data from the 1000 Genomes Project.

While the researchers were able to identify these two ancestral populations, they also identified some striking changes that happened after the two populations initially broke apart.

“Immediately after the two ancestral populations split, we see a severe bottleneck in one of them—suggesting it shrank to a very small size before slowly growing over a period of one million years,” said co-author Professor Aylwyn Scally, also from the Department of Genetics. “This population would later contribute about 80% of the genetic material of modern humans, and also seems to have been the ancestral population from which Neanderthals and Denisovans diverged.”

̽��ֱ��study also found that genes inherited from the second population were often located away from regions of the genome linked to gene functions, suggesting that they may have been less compatible with the majority genetic background. This hints at a process known as purifying selection, where natural selection removes harmful mutations over time.

“However, some of the genes from the population which contributed a minority of our genetic material, particularly those related to brain function and neural processing, may have played a crucial role in human evolution,” said Cousins.

Beyond human ancestry, the researchers say their method could help to transform how scientists study the evolution of other species. In addition to their analysis of human evolutionary history, they applied the cobraa model to genetic data from bats, dolphins, chimpanzees, and gorillas, finding evidence of ancestral population structure in some but not all of these.

“What’s becoming clear is that the idea of species evolving in clean, distinct lineages is too simplistic,” said Cousins. “Interbreeding and genetic exchange have likely played a major role in the emergence of new species repeatedly across the animal kingdom.”

So who were our mysterious human ancestors? Fossil evidence suggests that species such as Homo erectus and Homo heidelbergensis lived both in Africa and other regions during this period, making them potential candidates for these ancestral populations, although more research (and perhaps more evidence) will be needed to identify which genetic ancestors corresponded to which fossil group.

Looking ahead, the team hopes to refine their model to account for more gradual genetic exchanges between populations, rather than sharp splits and reunions. They also plan to explore how their findings relate to other discoveries in anthropology, such as fossil evidence from Africa that suggests early humans may have been far more diverse than previously thought.

“ ̽��ֱ��fact that we can reconstruct events from hundreds of thousands or millions of years ago just by looking at DNA today is astonishing,” said Scally. “And it tells us that our history is far richer and more complex than we imagined.”

̽��ֱ��research was supported by Wellcome. Aylwyn Scally is a Fellow of Darwin College, Cambridge. Trevor Cousins is a member of Darwin College, Cambridge.

Reference:
Trevor Cousins, Aylwyn Scally & Richard Durbin. ‘A structured coalescent model reveals deep ancestral structure shared by all modern humans.’ Nature Genetics (2025). DOI: 10.1038/s41588-025-02117-1

Modern humans descended from not one, but at least 2 ancestral populations that drifted apart and later reconnected, long before modern humans spread across the globe.

Our history is far richer and more complex than we imagined

Aylwyn Scally

Jose A Bernat Bacete via Getty Images

Plaster reconstructions of the skulls of human ancestors

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

DNA sequencing method lifts ‘veil’ from genome black box

cr696 — Mon, 23 Jan 2023 16:00:00 +0000

In a paper published in the journal Nature Biotechnology, ̽��ֱ�� of Cambridge researchers have outlined a new DNA sequencing method that can detect where and how small molecule drugs interact with the targeted genome.

“Understanding how drugs work in the body is essential to creating better, more effective therapies,” said co-first author Dr Zutao Yu from the Yusuf Hamied Department of Chemistry. “But when a therapeutic drug enters a cancer cell with a genome that has three billion bases, it’s like entering a black box.”

̽��ֱ��powerful method, called Chem-map, lifts the veil of this genomic black box by enabling researchers to detect where small molecule drugs interact with their targets on the DNA genome.

Each year, millions of cancer patients receive treatment with genome-targeting drugs, such as doxorubicin. But despite decades of clinical use and research, the molecular mode of action with the genome is still not well-understood.

“Lots of life-saving drugs directly interact with DNA to treat diseases such as cancer,” said co-first author Dr Jochen Spiegel. “Our new method can precisely map where drugs bind to the genome, which will help us to develop better drugs in the future.”

Chem-map allows researchers to conduct in situ mapping of small molecule-genome interactions with unprecedented precision, by using a strategy called small-molecule-directed transposase Tn5 tagmentation. This detects the binding site in the genome where a small molecule binds to genomic DNA or DNA-associated proteins.

In the study, the researchers used Chem-map to determine the direct binding sites in human leukaemia cells of the widely used anticancer drug doxorubicin. ̽��ֱ��technique also showed how the combined therapy of using doxorubicin on cells already exposed to the histone deacetylase (HDAC) inhibitor tucidinostat could have a potential clinical advantage.

̽��ֱ��technique was also used to map the binding sites of certain molecules on DNA G-quadruplexes, known as G4s. G4s are four-stranded secondary structures that have been implicated in gene regulation, and could be possible targets for future anti-cancer treatments.

“I am so proud that we have been able to solve this longstanding problem – we have established a highly efficient approach which will open many paths for new research,” said Yu.

Professor Sir Shankar Balasubramanian, who led the research, said: “Chem-map is a powerful new method to detect the site in the genome where a small molecule binds to DNA or DNA-associated proteins. It provides enormous insights on how some drug therapies interact with the human genome, and makes it easier to develop more effective and safer drug therapies.”

Reference:
Zutao Yu, Jochen Spiegel et al. 'Chem-map profiles drug binding to chromatin in cells.' Nature Biotechnology (2023). DOI: 10.1038/s41587-022-01636-0

Many life-saving drugs directly interact with DNA to treat diseases such as cancer, but scientists have struggled to detect how and why they work – until now.

KTSDESIGN/SCIENCE PHOTO LIBRARY via Getty Images

Illustration of DNA molecules

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Largest study of whole genome sequencing data reveals new clues to causes of cancer

sc604 — Thu, 21 Apr 2022 18:00:00 +0000

In the biggest study of its kind, a team of scientists led by Professor Serena Nik-Zainal from Cambridge ̽��ֱ�� Hospitals (CUH) and the ̽��ֱ�� of Cambridge, analysed the complete genetic make-up or whole-genome sequences (WGS) of more than 12,000 NHS cancer patients.

Because of the vast amount of data provided by whole genome sequencing, the researchers were able to detect patterns in the DNA of cancer, known as ‘mutational signatures’, that provide clues about whether a patient has had a past exposure to environmental causes of cancer such as smoking or UV light, or has internal, cellular malfunctions.

̽��ֱ��team were also able to spot 58 new mutational signatures, suggesting that there are additional causes of cancer that we don't yet fully understand. ̽��ֱ��results are reported in the journal Science.

̽��ֱ��genomic data were provided by the 100,000 Genomes Project: an England-wide clinical research initiative to sequence 100,000 whole genomes from around 85,000 patients affected by rare disease or cancer.

“WGS gives us a total picture of all the mutations that have contributed to each person’s cancer,” said first author Dr Andrea Degasperi, from Cambridge’s Department of Oncology. “With thousands of mutations per cancer, we have unprecedented power to look for commonalities and differences across NHS patients, and in doing so we uncovered 58 new mutational signatures and broadened our knowledge of cancer.”

“ ̽��ֱ��reason it is important to identify mutational signatures is because they are like fingerprints at a crime scene - they help to pinpoint cancer culprits,” said Serena Nik-Zainal, from the Department of Medical Genetics and an honorary consultant in clinical genetics at CUH. “Some mutational signatures have clinical or treatment implications – they can highlight abnormalities that may be targeted with specific drugs or may indicate a potential ‘Achilles heel’ in individual cancers.

“We were able to perform a forensic analysis of over 12,000 NHS cancer genomes thanks to the generous contribution of samples from patients and clinicians throughout England. We have also created FitMS, a computer-based tool to help scientists and clinicians identify old and new mutational signatures in cancer patients, to potentially inform cancer management more effectively.”

Michelle Mitchell, chief executive of Cancer Research UK, which funded the research, said:

“This study shows how powerful whole genome sequencing tests can be in giving clues into how the cancer may have developed, how it will behave and what treatment options would work best. It is fantastic that insight gained through the NHS 100,000 Genomes Project can potentially be used within the NHS to improve the treatment and care for people with cancer.”

Professor Matt Brown, chief scientific officer of Genomics England said:

“Mutational signatures are an example of using the full potential of WGS. We hope to use the mutational clues seen in this study and apply them back into our patient population, with the ultimate aim of improving diagnosis and management of cancer patients.”

Professor Dame Sue Hill, chief scientific officer for England and Senior Responsible Officer for Genomics in the NHS said:

“ ̽��ֱ��NHS contribution to the 100,000 Genomes Project was vital to this research and highlights how data can transform the care we deliver to patients, which is a cornerstone of the NHS Genomic Medicine Service.”

Reference:
Andrea Degasperi et al. ‘Substitution mutational signatures in whole-genome–sequenced cancers in the UK population.’ Science (2022). DOI: 10.1126/science.abl9283

Adapted from a CUH press release.

DNA analysis of thousands of tumours from NHS patients has found a ‘treasure trove’ of clues about the causes of cancer, with genetic mutations providing a personal history of the damage and repair processes each patient has been through.

̽��ֱ��reason it is important to identify mutational signatures is because they are like fingerprints at a crime scene - they help to pinpoint cancer culprits

Serena Nik-Zainal

Largest dataset of cancer whole genome sequences | Serena Nik-Zainal

Isaac Brownell, National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH

Merkel Cell Carcinoma

Yes

Licence type:

Public Domain

Genomes front and centre of rare disease diagnosis

Anonymous — Wed, 24 Jun 2020 16:15:38 +0000

A research programme pioneering the use of whole genome sequencing in the NHS has diagnosed hundreds of patients and discovered new genetic causes of disease. Whole genome sequencing is the technology used by the 100,000 Genomes Project, a service set up by the government to introduce routine genetic diagnostic testing in the NHS.

̽��ֱ��results of the study, published in the journal Nature, demonstrate that sequencing the whole genomes of large numbers of individuals in a standardised way can improve the diagnosis and treatment of patients with rare diseases. It was led by researchers at the ̽��ֱ�� of Cambridge together with Genomics England.

̽��ֱ��researchers studied the genomes of groups of patients with similar symptoms, affecting different tissues, such as the brain, eyes, blood or the immune system. They identified a genetic diagnosis for 60% of individuals in one group of patients with early loss of vision.

̽��ֱ��programme offered whole-genome sequencing as a diagnostic test to patients with rare diseases across an integrated health system, a world first in clinical genomics. ̽��ֱ��integration of genetic research with NHS diagnostic systems increases the likelihood that a patient will receive a diagnosis and the chance that a diagnosis will be provided within weeks rather than months.

“Around 40,000 children are born each year with a rare inherited disease in the UK alone. Sadly, it takes more than two years, on average, for them to be diagnosed,” said Willem Ouwehand, Professor of Experimental Haematology at Cambridge, the National Institute for Health Research BioResource and NHS Blood and Transplant Principal Investigator. “We felt it was vital to shorten this odyssey for patients and parents.

“This research shows that quicker and better genetic diagnosis will be possible for more NHS patients.”

In the study, funded principally by the National Institute for Health Research, the entire genomes of almost 10,000 NHS patients with rare diseases were sequenced and searched for genetic causes of their conditions. Previously unobserved genetic differences causing known rare diseases were identified, in addition to genetic differences causing completely new genetic diseases.

̽��ֱ��team identified more than 172 million genetic differences in the genomes of the patients, many of which were previously unknown. Most of these genetic differences have no effect on human health, so the researchers used new statistical methods and powerful supercomputers to search for the differences which cause disease – a few hundred ‘needles in the haystack’.

“Our study demonstrates the value of whole-genome sequencing in this context and provides a suite of new diagnostic tools, some of which have already led to improved patient care,” said Professor Adrian Thrasher of the UCL Great Ormond Street Institute of Child Health (ICH) in London.

Using a new analysis method developed specifically for the project, the team identified 95 genes in which rare genetic differences are statistically very likely to be the cause of rare diseases. Genetic differences in at least 79 of these genes have been shown definitively to cause disease.

̽��ֱ��team searched for rare genetic differences in almost all of the 3.2 billion DNA letters that make up the genome of each patient. This contrasts with current clinical genomics tests, which usually examine a small fraction of the letters, where genetic differences are thought most likely to cause disease. By searching the entire genome researchers were able to explore the ‘switches and dimmers’ of the genome – the regulatory elements in DNA that control the activity of the thousands of genes.

̽��ֱ��team showed that rare differences in these switches and dimmers, rather than disrupting the gene itself, affect whether or not the gene can be switched on at the correct intensity. Identifying genetic changes in regulatory elements that cause rare disease is not possible with the clinical genomics tests currently used by health services worldwide. It is only possible if the whole of the genetic code is analysed for each patient.

“We have shown that sequencing the whole genomes of patients with rare diseases routinely within a health system provides a more rapid and sensitive diagnostic service to patients than the previous fragmentary approach, and, simultaneously, it enhances genetics research for the future benefit of patients still waiting for a diagnosis,” said Dr Ernest Turro from the ̽��ֱ�� of Cambridge and the NIHR BioResource.

“Thanks to the contributions of hundreds of physicians and researchers across the UK and abroad, we were able to study patients in sufficient numbers to identify the causes of even very rare diseases.”

Although individual rare diseases affect a very small proportion of the population, there exist thousands of rare diseases and, together, they affect more than three million people in the UK. To tackle this challenge, the NIHR BioResource created a network of 57 NHS hospitals which focus on the care of patients with rare diseases. Nearly 1000 doctors and nurses working at these hospitals made the project possible by asking their patients and, in some cases, the parents of affected children to join the NIHR BioResource.

“In setting up the NIHR BioResource Project, we were taking uncharted steps in a determined effort to improve diagnosis and treatment for patients in the NHS and further afield” said Dr Louise Wood, Director of Science, Research and Evidence at the Department of Health and Social Care.“This research has demonstrated that patients, their families and the health service can all benefit from placing genomic sequencing at the forefront of clinical care in appropriate settings.

Based on the emerging data from the present NIHR BioResource study and other studies by Genomics England, the UK government announced in October 2018 that the NHS will offer whole-genome sequencing analysis for all seriously ill children with a suspected genetic disorder, including those with cancer. ̽��ֱ��sequencing of whole genomes will expand to one million genomes per year by 2024.

Whole-genome sequencing will be phased in nationally for the diagnosis of rare diseases as the ‘standard of care’, ensuring equivalent care across the country.

̽��ֱ��benefits include a faster diagnosis for patients, reduced costs for health services, improved understanding of the reasons they suffer from disease for patients and their carers and improved provision of treatment.

Reference:
Turro E et al. ‘Whole-genome sequencing of patients with rare diseases in a national health system.’ Nature (2020). DOI: 10.1038/s41586-020-2434-2

Adapted from an NIHR press release.

Cambridge-led study discovers new genetic causes of rare diseases, potentially leading to improved diagnosis and better patient care.

This research shows that quicker and better genetic diagnosis will be possible for more NHS patients

Willem Ouwehand

National Human Genome Research Institute, National Institutes of Health

DNA Double Helix

Yes

Licence type:

Public Domain

Identification of viruses and bacteria could be sped up through computational methods

sc604 — Mon, 30 Mar 2020 19:00:00 +0000

̽��ֱ��researchers, led by the ̽��ֱ�� of Edinburgh, with colleagues from Cambridge, London, Slovenia and China, used a combination of theoretical and experimental methods to develop a strategy to detect the DNA of infectious diseases. ̽��ֱ��results are reported in the Proceedings of the National Academy of Sciences.

̽��ֱ��current coronavirus pandemic highlights the need for fast and accurate detection of infectious diseases. Importantly, viral infections like coronavirus and bacterial infections like those associated with antimicrobial resistance (AMR) need to be distinguished. This is usually done by using a complementary sequence that binds selectively to the genome of interest. Normally, this is done by targeting a single, long DNA sequence that is unique to the pathogen.

However, the researchers believe that much higher selectivities can be achieved by simultaneously targeting many shorter sequences that occur with a higher frequency in the pathogen of interest than in the DNA of other organisms that may be present in the patient samples.

"This approach exploits a phenomenon called ‘multivalency’, and the extensive numerical calculations, based on real bacterial and viral DNA sequences show that this approach should significantly outperform current approaches," said co-author Professor Erika Eiser from Cambridge’s Cavendish Laboratory. "Even though the individual shorter sequences bind more weakly to the target DNA than a single, longer sequences, the strength of the multivalent binding increases much faster than linearly with the number of short sequences."

In other words, instead of designing molecular probes that bind strongly to one place on the target DNA, researchers should, counterintuitively, design probes that bind weakly all over the target DNA. Making such relatively short probe sequences is, at present, a standard procedure and the sequences can be ordered online.

̽��ֱ��experimental part of the project started with experiments in Cambridge, showing that the method can work in principle on a mixture of viral DNA and colloids coated with short complementary strands. Then the simulations took over to predict what combination of probe sequences would give the highest selectivity.

This part of the project has so far only been tested in computer models. ̽��ֱ��next step is to carry out experiments on real mixtures of viral and bacterial DNA.

"Experiments are needed to test how well this works in practice – but it is exciting work, given the urgent need for fast, reliable disease detection methods, especially those that can be applied in countries with a weak health infrastructure," said Professor Rosalind Allen from the ̽��ֱ�� of Edinburgh, who led the research.

This work was performed before the COVID-19 pandemic. However, the current emergency illustrates the need for robust and highly selective methods to quickly identify specific viruses – particularly in ‘low-tech’ environments.

̽��ֱ��research was funded in part by the Royal Society and the European Research Council.

Reference:
Tine Curk et al. ‘Computational design of probes to detect bacterial genomes by multivalent binding.’ PNAS (2020). DOI: 10.1073/pnas.1918274117

Adapted from a ̽��ֱ�� of Edinburgh press release.

How you can support Cambridge's COVID-19 research effort

Donate to support COVID-19 research at Cambridge

A new multinational study has shown how the process of distinguishing viruses and bacteria could be accelerated through the use of computational methods.

Yes

Genome editing reveals role of gene important for human embryo development

sc604 — Wed, 20 Sep 2017 17:00:00 +0000

̽��ֱ��team used genome editing techniques to stop a key gene from producing a protein called OCT4, which normally becomes active in the first few days of human embryo development. After the egg is fertilised, it divides until at about 7 days it forms a ball of around 200 cells called the ‘blastocyst’. ̽��ֱ��study found that human embryos need OCT4 to correctly form a blastocyst.

“We were surprised to see just how crucial this gene is for human embryo development, but we need to continue our work to confirm its role” says Dr Norah Fogarty from the Francis Crick Institute, first author of the study. “Other research methods, including studies in mice, suggested a later and more focussed role for OCT4, so our results highlight the need for human embryo research.”

Dr Kathy Niakan from the Francis Crick Institute, who led the research adds, “One way to find out what a gene does in the developing embryo is to see what happens when it isn’t working. Now we have demonstrated an efficient way of doing this, we hope that other scientists will use it to find out the roles of other genes. If we knew the key genes that embryos need to develop successfully, we could improve IVF treatments and understand some causes of pregnancy failure. It will take many years to achieve such an understanding, our study is just the first step.”

̽��ֱ��research was published in Nature and led by scientists at the Francis Crick Institute, in collaboration with colleagues at Cambridge ̽��ֱ��, Oxford ̽��ֱ��, the Wellcome Trust Sanger Institute, Seoul National ̽��ֱ�� and Bourn Hall Clinic. It was chiefly funded by the UK Medical Research Council, Wellcome and Cancer Research.

̽��ֱ��team spent over a year optimising their techniques using mouse embryos and human embryonic stem cells before starting work on human embryos. To inactivate OCT4, they used an editing technique called CRISPR/Cas9 to change the DNA of 41 human embryos. After seven days, embryo development was stopped and the embryos were analysed.

̽��ֱ��embryos used in the study were donated by couples who had undergone IVF treatment, with frozen embryos remaining in storage; the majority were donated by couples who had completed their family, and wanted their surplus embryos to be used for research. ̽��ֱ��study was done under a research licence and strict regulatory oversight from the Human Fertilisation and Embryology Authority (HFEA), the UK Government's independent regulator overseeing infertility treatment and research.

As well as human embryo development, OCT4 is thought to be important in stem cell biology. ‘Pluripotent’ stem cells can become any other type of cell, and they can be derived from embryos or created from adult cells such as skin cells. Human embryonic stem cells are taken from a part of the developing embryo that has high levels of OCT4.

“We have the technology to create and use pluripotent stem cells, which is undoubtedly a fantastic achievement, but we still don’t understand exactly how these cells work,” explains Dr James Turner, co-author of the study from the Francis Crick Institute. “Learning more about how different genes cause cells to become and remain pluripotent will help us to produce and use stem cells more reliably.”

Sir Paul Nurse, Director of the Francis Crick Institute, says: “This is exciting and important research. ̽��ֱ��study has been carried out with full regulatory oversight and offers new knowledge of the biological processes at work in the first five or six days of a human embryo’s healthy development. Kathy Niakan and colleagues are providing new understanding of the genes responsible for a crucial change when groups of cells in the very early embryo first become organised and set on different paths of development. ̽��ֱ��processes at work in these embryonic cells will be of interest in many areas of stem cell biology and medicine.”

Dr. Kay Elder, study co-author from the Bourn Hall Clinic, says: "Successful IVF treatment is crucially dependent on culture systems that provide an optimal environment for healthy embryo development. Many embryos arrest in culture, or fail to continue developing after implantation; this research will significantly help treatment for infertile couples, by helping us to identify the factors that are essential for ensuring that human embryos can develop into healthy babies.”

Dr Ludovic Vallier, co-author on the study from the Wellcome Trust Sanger Institute and the Wellcome - MRC Cambridge Stem Cell Institute, said: “This study represents an important step in understanding human embryonic development. ̽��ֱ��acquisition of this knowledge will be essential to develop new treatments against developmental disorders and could also help understand adult diseases such as diabetes that may originate during the early stage of life. Thus, this research will open new fields of opportunity for basic and translational applications.”

Reference:
Norah M.E. Fogarty et al. 'Genome editing of OCT4 reveals distinct mechanisms of lineage specification in human and mouse embryos.' Nature (2017). DOI: 10.1038/nature24033.

Adapted from a Francis Crick Institute press release.

Researchers have used genome editing technology to reveal the role of a key gene in human embryos in the first few days of development. This is the first time that genome editing has been used to study gene function in human embryos, which could help scientists to better understand the biology of our early development.

This knowledge will be essential to develop new treatments against developmental disorders and could also help understand adult diseases such as diabetes that may originate during the early stage of life.

Ludovic Vallier

Dr Kathy Niakan/Nature

Day 2 embryo

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Snip, snip, cure: correcting defects in the genetic blueprint

lw355 — Fri, 14 Jul 2017 08:01:02 +0000

Dr James Thaventhiran points to a diagram of a 14-year-old boy’s family tree. Some of the symbols are shaded black.

“These family members have a very severe form of immunodeficiency. ̽��ֱ��children get infections and chest problems, the adults have bowel problems, and the father died from cancer during the study. ̽��ֱ��boy himself had a donor bone marrow transplant when he was a teenager, but he remains very unwell, with limited treatment options.”

To understand the cause of the immunodeficiency, Thaventhiran, a clinical immunologist in Cambridge’s Department of Medicine, has been working with colleagues at the Great Northern Children’s Hospital in Newcastle, where the family is being treated.

Theirs is a rare disease, which means the condition affects fewer than 1 in 2,000 people. Most rare diseases are caused by a defect in the genetic blueprint that carries the instruction manual for life. Sometimes the mistake can be as small as a single letter in the three billion letters that make up the genome, yet it can have devastating consequences.

When Thaventhiran and colleagues at the National Institute for Health Research (NIHR) BioResource in Cambridge carried out whole genome sequencing on the boy’s DNA, they discovered a defect that could explain the immunodeficiency. “We believe that just one wrong letter causes a malfunction in an immune cell called a dendritic cell, which is needed to detect infections and cancerous cells.”

Now, hope for an eventual cure for family members affected by the faulty gene is taking shape in the form of ‘molecular scissors’ called CRISPR-Cas9. Discovered in bacteria, the CRISPR-Cas9 system is part of the armoury that bacteria use to protect themselves from the harmful effects of viruses. Today it is being co-opted by scientists worldwide as a way of removing and replacing gene defects.

One part of the CRISPR-Cas9 system acts like a GPS locator that can be programmed to go to an exact place in the genome. ̽��ֱ��other part – the ‘molecular scissors’ – cuts both strands of the faulty DNA and replaces it with DNA that doesn’t have the defect.

“It’s like rewriting DNA with precision,” explains Dr Alasdair Russell. “Unlike other forms of gene therapy, in which cells are given a new working gene but without being able to direct where it ends up in the genome, this technology changes just the faulty gene. It’s precise and it’s ‘scarless’ in that no evidence of the therapy is left within the repaired genome.”

Russell heads up a specialised team in the Cancer Research UK Cambridge Institute to provide a centralised hub for state-of-the-art genome-editing technologies.

“By concentrating skills in one area, it means scientists in different labs don’t reinvent the wheel each time and can keep pace with the field,” he explains. “At full capacity, we aim to be capable of running up to 30 gene-editing projects in parallel.

“What I find amazing about the technology is that it’s tearing down traditional barriers between different disciplines, allowing us to collaborate with clinicians, synthetic biologists, physicists, engineers, computational analysts and industry, on a global scale. ̽��ֱ��technology gives you the opportunity to innovate, rather than imitate. I tell my wife I sometimes feel like Q in James Bond and she laughs.”

Russell’s team is using the technology both to understand disease and to treat it. Together with Cambridge spin-out DefiniGEN, they are rewriting the DNA of a very special type of cell called an induced pluripotent stem cell (iPSC). These are cells that are taken from the skin of a patient and ‘reprogrammed’ to act like one of the body’s stem cells, which have the capacity to develop into almost any other cell of the body.

In this case, they are turning the boy’s skin cells into iPSCs, using CRISPR-Cas9 to correct the defect, and then allowing these corrected cells to develop into the cell type that is affected by the disease – the dendritic cell. “It’s a patient-specific model of the cure in a Petri dish,” says Russell.

̽��ֱ��boy’s family members are among a handful of patients worldwide who are reported to have the same condition and among around 3,500 in the UK who have similar types of immunodeficiency caused by other gene defects. With such a rare group of diseases, explains Thaventhiran, it’s important to locate other patients to increase the chance of understanding what happens and how to treat it.

He and Professor Ken Smith in the Department of Medicine lead a programme to find, research and provide diagnostic services to these patients. So far, 2,000 patients (around 60% of the total affected in the UK) have been recruited and sequenced by the NIHR Bioresource, making it the largest worldwide cohort of patients with primary immunodeficiency."

“We’ve now made 12 iPSC lines from different patients with immunodeficiency,” adds Thaventhiran, who has started a programme for gene editing all of the lines. “This means that for the first time we’ll be able to investigate whether correcting the mutation corrects the defect – it’ll open up new avenues of research into the mechanisms underlying these diseases.”

But it’s the possibility of using the gene-edited cells to cure patients that excites Thaventhiran and Russell. They explain that one option might be to give a patient repeated treatments of their own gene-edited iPSCs. Another would be to take the patient’s blood stem cells, edit them and then return them to the patient.

̽��ֱ��researchers are quick to point out that although the technologies are converging on this possibility of truly personalised medicine, there are still many issues to consider in the fields of ethics, regulation and law.

Dr Kathy Liddell, who leads the Cambridge Centre for Law, Medicine and Life Sciences, agrees: “It’s easy to see the appeal of using gene editing to help patients with serious illnesses. However, new techniques could be used for many purposes, some of which are contentious. For example, the same technique that edits a disease in a child could be applied to an embryo to stop a disease being inherited, or to ‘design’ babies. This raises concerns about eugenics.

“ ̽��ֱ��challenge is to find systems of governance that facilitate important purposes, while limiting, and preferably preventing, unethical purposes. It’s actually very difficult. Rules not only have to be designed, but implemented and enforced. Meanwhile, powerful social drivers push hard against ethical boundaries, and scientific information and ideas travel easily – often too easily – across national borders to unregulated states.”

A further challenge is the business case for carrying out these types of treatments, which are potentially curative but are costly and benefit few patients. One reason why rare diseases are also known as orphan diseases is because in the past they have rarely been adopted by drug companies.

Liddell adds: “CRISPR-Cas9 patent wars are just warming up, demonstrating some of the economic issues at stake. Two US institutions are vigorously prosecuting their own patents, and trying to overturn the others. There will also be cross-licensing battles to follow.”

“ ̽��ֱ��obvious place to start is by correcting diseases caused by just one gene; however, the technology allows us to scale up to several genes, making it something that could benefit many, many different diseases,” adds Russell. “At the moment, the field as a whole is focused on ensuring the technology is safe before it moves into the clinic. But the advantage of it being cheap, precise and scalable should make CRISPR attractive to industry.”

In ten years or so, speculates Russell, we might see bedside ‘CRISPR on a chip’ devices that screen for mutations and ‘edit on the fly’. “I’m really excited by the frontierness of it all,” says Russell. “We feel that we’re right on the precipice of a new personalised medical future.”

Gene editing using ‘molecular scissors’ that snip out and replace faulty DNA could provide an almost unimaginable future for some patients: a complete cure. Cambridge researchers are working towards making the technology cheap and safe, as well as examining the ethical and legal issues surrounding one of the most exciting medical advances of recent times.

I’m really excited by the frontierness of it all. We feel that we’re right on the precipice of a new personalised medical future.

Alasdair Russell

̽��ֱ��District

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First complete genome data extracted from ancient Egyptian mummies

sc604 — Tue, 30 May 2017 14:32:42 +0000

An international team of researchers have successfully recovered and analysed ancient DNA from Egyptian mummies dating from approximately 1400 BCE to 400 BCE, including the first genome-wide data from three individuals. ̽��ֱ��study found that modern Egyptians share more ancestry with sub-Saharan Africans than ancient Egyptians did, whereas ancient Egyptians were found to be most closely related to ancient people from the Middle East and Western Asia.

This study counters prior scepticism about the possibility of recovering reliable ancient DNA from Egyptian mummies. Despite the potential issues of degradation and contamination caused by climate and mummification methods, the authors were able to use high-throughput DNA sequencing and robust authentication methods to ensure the ancient origin and reliability of the data. ̽��ֱ��study, published in the journal Nature Communications, shows that Egyptian mummies can be a reliable source of ancient DNA, and can contribute to a more accurate and refined understanding of Egypt’s history.

Egypt is a promising location for the study of ancient populations. It has a rich and well-documented history, and its geographic location and many interactions with populations from surrounding areas, in Africa, Asia and Europe, make it a dynamic region. Recent advances in the study of ancient DNA present an opportunity to test existing understandings of Egyptian history using ancient genetic data.

However, genetic studies of ancient Egyptian mummies are rare due to methodological and contamination issues. Although some of the first extractions of ancient DNA were from mummified remains, scientists have raised doubts as to whether genetic data, especially the nuclear DNA which encodes for the majority of the genome, from mummies would be reliable, and whether it could be recovered at all.

“ ̽��ֱ��potential preservation of DNA has to be regarded with scepticism,” said Johannes Krause, Director at the Max Planck Institute for the Science of Human History and senior author of the study. “ ̽��ֱ��hot Egyptian climate, the high humidity levels in many tombs and some of the chemicals used in mummification techniques, contribute to DNA degradation and are thought to make the long-term survival of DNA in Egyptian mummies unlikely.”

For this study, the team, led by the ̽��ֱ�� of Tübingen and the Max Planck Institute for the Science of Human History in Germany, and including researchers from the ̽��ֱ�� of Cambridge, looked at genetic differentiation and population continuity over a 1,300 year timespan, and compared these results to modern populations.

̽��ֱ��team sampled 151 mummified individuals from the archaeological site of Abusir el-Meleq, along the Nile River in Middle Egypt, from two anthropological collections hosted and curated at the ̽��ֱ�� of Tübingen and the Felix von Luschan Skull Collection at the Museum of Prehistory of the Staatliche Museen zu Berlin, Stiftung Preussicher Kulturbesitz.

In total, the authors recovered partial genomes from 90 individuals, and genome-wide datasets from three individuals. They were able to use the data gathered to test previous hypotheses drawn from archaeological and historical data, and from studies of modern DNA.

“In particular, we were interested in looking at changes and continuities in the genetic makeup of the ancient inhabitants of Abusir el-Meleq,” said Alexander Peltzer, one of the lead authors of the study from the ̽��ֱ�� of Tübingen.

̽��ֱ��team wanted to determine if the investigated ancient populations were affected at the genetic level by foreign conquest and domination during the time period under study, and compared these populations to modern Egyptian comparative populations.

“There is literary and archaeological evidence for foreign influence at the site, including the presence of individuals with Greek and Latin names and the use of foreign material culture,” said co-author W. Paul van Pelt from Cambridge’s Division of Archaeology. “However, neither of these provides direct evidence for the presence of foreigners or of individuals with a migration background, because many markers of Greek and Roman identity became ‘status symbols’ and were adopted by natives and foreigners alike. ̽��ֱ��combined use of artefacts, textual evidence and ancient DNA data allows a more holistic study of past identities and cultural exchange or ‘entanglement’.”

̽��ֱ��study found that the inhabitants of Absur el-Meleq were most closely related to ancient populations in the Levant, and were also closely related to Neolithic populations from the Anatolian Peninsula and Europe. “ ̽��ֱ��genetics of the Abusir el-Meleq community did not undergo any major shifts during the 1,300 year timespan we studied, suggesting that the population remained genetically relatively unaffected by foreign conquest and rule,” said Wolfgang Haak, group leader at the Max Planck Institute for the Science of Human History, and a co-author of the paper.

̽��ֱ��data shows that modern Egyptians share approximately 8% more ancestry on the nuclear level with sub-Saharan African populations than the inhabitants of Abusir el-Meleq, suggesting that an increase in sub-Saharan African gene flow into Egypt occurred within the last 2,000 years. Possible causal factors may have been improved mobility down the Nile River, increased long-distance trade between sub-Saharan Africa and Egypt, and the trans-Saharan slave trade that began approximately 1,300 years ago.

Reference:
Verena J. Schuenemann et al. ‘Ancient Egyptian mummy genomes suggest an increase of Sub-Saharan African ancestry in post-Roman periods.’ Nature Communications (2017). DOI: 10.1038/ncomms15694

Adapted from a press release from the Max Planck Institute for the Science of Human History.

Study finds that ancient Egyptians were most closely related to ancient populations from the Middle East and Western Asia.

̽��ֱ��combined use of artefacts, textual evidence and ancient DNA data allows a more holistic study of past identities and cultural exchange.

W. Paul van Pelt

Will Scullin

Usermontu Mummy

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