̽��ֱ�� of Cambridge - genome sequencing

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.

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Beethoven’s genome sequenced from locks of his hair

ta385 — Wed, 22 Mar 2023 15:01:00 +0000

A Cambridge scientist has played a leading role in sequencing Ludwig van Beethoven’s genome, revealing clues to the composer’s health and family history.

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

̽��ֱ��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.

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̽��ֱ��microbiologist tackling humanity’s next biggest killer

cg605 — Wed, 17 Nov 2021 12:43:31 +0000

Since childhood Stephen Baker says he had a grim fascination with poo. He caught the bug for microbiology and spent 12 years in Vietnam researching bacteria that cause diarrhoea. Stephen thinks that antibiotic-resistant bacteria is likely to be humanity’s biggest killer in the future. But says that if we keep doing the science, we have hope.

Whole genome sequencing increases diagnosis of rare disorders by nearly a third

ta385 — Thu, 04 Nov 2021 06:00:00 +0000

Mitochondrial disorders affect around 1 in 4,300 people and cause progressive, incurable diseases. They are amongst the most common inherited diseases but are difficult for clinicians to diagnose, not least because they can affect many different organs and resemble many other conditions.

Current genetic testing regimes fail to diagnose around 40% of patients, with major implications for patients, their families and the health services they use.

A new study, published in the BMJ, offers hope to families with no diagnosis, and endorses plans for the UK to establish a national diagnostic programme based on whole genome sequencing (WGS) to make more diagnoses faster.

While previous studies based on small, highly selected cohorts have suggested that WGS can identify mitochondrial disorders, this is the first to examine its effectiveness in a national healthcare system – the NHS.

̽��ֱ��study, led by researchers from the MRC Mitochondrial Biology Unit and Departments of Clinical Neuroscience and Medical Genetics at the ̽��ֱ�� of Cambridge, involved 319 families with suspected mitochondrial disease recruited through the 100,000 Genomes Project which was set up to embed genomic testing in the NHS, discover new disease genes and make genetic diagnosis available for more patients.

In total, 345 participants – aged 0 to 92 with a median age of 25 years – had their whole genome sequenced. Through different analyses, the researchers found that they could make a definite or probable genetic diagnosis for 98 families (31%). Standard tests, which are often more invasive, failed to reach these diagnoses. Six possible diagnoses (2% of the 98 families) were made. A total of 95 different genes were implicated.

Surprisingly, 62.5% of the diagnoses were actually non-mitochondrial disorders, with some having specific treatments. This happened because so many different diseases resemble mitochondrial disorders, making it very difficult to know which are which.

Professor Patrick Chinnery from the MRC Mitochondrial Biology Unit and the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, said:

“We recommend that whole genome sequencing should be offered early and before invasive tests such as a muscle biopsy. All that patients would need to do is have a blood test, meaning that this could be offered across the whole country in an equitable way. People wouldn’t need to travel long distances to multiple appointments, and they would get their diagnosis much faster.”

Dr Katherine Schon from the MRC Mitochondrial Biology Unit and the Departments of Clinical Neuroscience and Medical Genetics, said:

“A definitive genetic diagnosis can really help patients and their families, giving them access to tailored information about prognosis and treatment, genetic counselling and reproductive options including preimplantation genetic diagnosis or prenatal diagnosis.”

̽��ֱ��researchers made 37.5% of their diagnoses in genes known to cause mitochondrial disease. These diagnoses were nearly all unique to a particular participant family, reflecting the genetic diversity found in these disorders. ̽��ֱ��impairment of mitochondrial function tends to affect tissues with high energy demand such as the brain, the peripheral nerves, the eye, the heart and the peripheral muscles. ̽��ֱ��study offers a valuable new resource for the discovery of future mitochondrial disease genes.

̽��ֱ��majority of the team’s diagnoses (62.5%) were, however, of non-mitochondrial disorders which had features resembling mitochondrial diseases. These disorders would have been missed if the participants had only been investigated for mitochondrial disorders through muscle biopsy and/or a specific mitochondrial gene panel. These participants were living with a range of conditions including developmental disorders with intellectual disability, severe epileptic conditions and metabolic disorders, as well as heart and neurological diseases.

Chinnery said: “These patients were referred because of a suspected mitochondrial disease and the conventional diagnostic tests are specifically for mitochondrial diseases. Unless you consider these other possibilities, you won't diagnose them. Whole genome sequencing isn’t restricted by that bias.”

A small number of newly diagnosed participants are already receiving treatments as a result. ̽��ֱ��team identified potentially treatable disorders in six participants with a mitochondrial disorder and nine with a non-mitochondrial disorder, but the impact of the treatments has yet to be determined.

Chinnery said: “Diagnostic services are fragmented and unevenly distributed across the UK, and that creates major challenges for people with rare diseases and their families. By delivering a national programme based on this genome-wide approach, you can offer the same level of service to everyone."

Schon said: “If we can create a national platform of families with rare diseases, we can give them the opportunity to engage in clinical trials so we can get definitive evidence that new treatments work.”

̽��ֱ��study points out that the relatively high number of patients with probable or possible diagnoses reflects the need for greater investment into the analysis of functional effects of new genetic variants which could be the cause of disease, but it is not certain at present.

It also argues that rapid trio whole genome sequencing should be offered to all acutely unwell individuals with suspected mitochondrial disorders, so that results can help guide clinical management. Currently in the UK, this is only available for acutely unwell children.

Dr Ellen Thomas, Clinical Director and Director of Quality at Genomics England, said:

“We are very pleased to see significant research like this being enabled by data generously donated by participants of the 100,000 Genomes Project. It is clear from these results how their contributions to a rich and, importantly, secure dataset is critical in facilitating the genomic research that leads to insights like these that then have the potential to return value to the NHS and their patients. We look forward to seeing how these findings could support future care for patients with suspected mitochondrial disorders.”

Reference

KR Schon et al., ‘Use of whole genome sequencing to determine the genetic basis of suspected mitochondrial disorders: a cohort study’, BMJ (2021). DOI: 10.1136/ bmj-2021-066288

Funding

National Institute for Health Research, NHS England, Wellcome, Cancer Research UK and the Medical Research Council within UK Research and Innovation

Whole genome sequencing from a single blood test picks up 31% more cases of rare genetic disorders than standard tests, shortening the ‘diagnostic odyssey’ that affected families experience, and providing huge opportunities for future research.

A definitive genetic diagnosis can really help patients and their families

Patrick Chinnery

Belova59 via Pixabay

Gloved hand holding two blood samples

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Track and trace in Sierra Leone

cjb250 — Thu, 30 Sep 2021 13:17:39 +0000

Professor Ian Goodfellow played a crucial role in helping to bring the Ebola epidemic in Sierra Leone to a close in 2014. His team's work helped inform technology used today in the majority of SARS-CoV-2 sequencing, which is keeping us safe in the current pandemic.

Cambridge researchers awarded the Millennium Technology Prize

sc604 — Tue, 18 May 2021 14:32:48 +0000

̽��ֱ�� of Cambridge chemists Shankar Balasubramanian and David Klenerman have been jointly awarded the 2020 Millennium Technology Prize, one of the world’s most prestigious science and technology prizes, by Technology Academy Finland (TAF).

̽��ֱ��global prize, awarded at two-year intervals since 2004 to highlight the impact of science and innovation on society, is worth €1 million. Of the nine previous winners of the Millennium Technology Prize, three have subsequently gone on to win a Nobel Prize. This is the first time that the prize has been awarded to more than one recipient for the same innovation, celebrating the significance of collaboration. ̽��ֱ��announcement of the 2020 award was delayed due to the COVID-19 pandemic.

Professors Balasubramanian and Klenerman co-invented Solexa-Illumina Next Generation DNA Sequencing (NGS), technology that has enhanced our basic understanding of life, converting biosciences into ‘big science’ by enabling fast, accurate, low-cost and large-scale genome sequencing – the process of determining the complete DNA sequence of an organism’s make-up. They co-founded the company Solexa to make the technology available to the world.

̽��ֱ��technology has had – and continues to have – a transformative impact in the fields of genomics, medicine and biology. One measure of the scale of change is that it has allowed a million-fold improvement in speed and cost when compared to the first sequencing of the human genome. In 2000, sequencing of one human genome took over 10 years and cost more than a billion dollars: today, the human genome can be sequenced in a single day at a cost of $1,000. More than a million human genomes are sequenced at scale each year, thanks to the technology co-invented by Professors Balasubramanian and Klenerman, meaning we can understand diseases much better and much more quickly.

Professor Sir Shankar Balsubramanian FRS from the Yusuf Hamied Department of Chemistry, Cancer Research UK Cambridge Institute and a Fellow of Trinity College, said: “I am absolutely delighted at being awarded the Millennium Technology Prize jointly with David Klenerman, but it’s not just for us, I’m happy on behalf of everyone who has contributed to this work.”

Professor Sir David Klenerman FMedSci FRS from the Yusuf Hamied Department of Chemistry, and a Fellow of Christ’s College, said: “It’s the first time that we’ve been internationally recognised for developing this technology. ̽��ֱ��idea came from Cambridge and was developed in Cambridge. It’s now used all over the world, so I’m delighted largely for the team of people who worked on this project and contributed to its success.”

Next-generation sequencing involves fragmenting sample DNA into many small pieces that are immobilized on the surface of a chip and locally amplified. Each fragment is then decoded on the chip, base-by-base, using fluorescently coloured nucleotides added by an enzyme. By detecting the colour-coded nucleotides incorporated at each position on the chip with a fluorescence detector – and repeating this cycle hundreds of times – it is possible to determine the DNA sequence of each fragment.

̽��ֱ��collected data is then analysed using computer software to assemble the full DNA sequence from the sequence of all these fragments. ̽��ֱ��NGS method’s ability to sequence billions of fragments in a parallel fashion makes the technique fast, accurate and cost-efficient. ̽��ֱ��invention of NGS was a revolutionary approach to the understanding of the genetic code in all living organisms.

Next-generation sequencing provides an effective way to study and identify new coronavirus strains and other pathogens. With the emergence of the COVID-19 pandemic, the technology is now being used to track and explore mutations in the coronavirus. This work has helped the creation of multiple vaccines now being administered worldwide and is critical to the creation of new vaccines against new dangerous viral strains. ̽��ֱ��results will also be used to prevent future pandemics.

̽��ֱ��technology is also allowing scientists and researchers to identify the underlying factors in individuals that contribute to their immune response to COVID-19. This information is essential to unravelling the reason behind why some people respond much worse to the virus than others.

NGS technology has revolutionised global biological and biomedical research and has enabled the development of a broad range of related technologies, applications and innovations. Due to its efficiency, NGS is widely adopted in healthcare and diagnostics, such as cancer, rare diseases, infectious medicine, and sequencing-based non-invasive prenatal testing.

It is increasingly used to define the genetic risk genes for patients with a rare disease and to define new drug targets for disease in defined patient groups. NGS has also contributed to the creation of new and powerful biological therapies like antibodies and gene therapies.

In the field of cancer, NGS is becoming the standard analytical method for defining personalised therapeutic treatment. ̽��ֱ��technology has dramatically improved our understanding of the genetic basis of many cancers and is often used both for clinical tests for early detection and diagnostics both from tumours and patients’ blood samples.

In addition to medical applications, NGS has also had a major impact on all of biology as it allows the clear identification of thousands of organisms in almost any kind of sample, which is important for agriculture, ecology and biodiversity research.

Academy Professor Päivi Törmä, Chair of the Millennium Technology Prize Selection Committee, said: “ ̽��ֱ��future potential of NGS is enormous and the exploitation of the technology is still in its infancy. ̽��ֱ��technology will be a crucial element in promoting sustainable development through personalisation of medicine, understanding and fighting killer diseases, and hence improving the quality of life. Professor Balasubramanian and Professor Klenerman are worthy winners of the prize.”

Professor Marja Makarow, Chair of Technology Academy Finland said: “Collaboration is an essential part of ensuring positive change for the future. Next Generation Sequencing is the perfect example of what can be achieved through teamwork and individuals from different scientific backgrounds coming together to solve a problem.

“ ̽��ֱ��technology pioneered by Professor Balasubramanian and Professor Klenerman has also played a key role in helping discover the coronavirus’s sequence, which in turn enabled the creation of the vaccines – itself a triumph for cross-border collaboration – and helped identify new variants of COVID-19.”

Tomorrow (19 May 2021) Professors Balasubramanian and Klenerman will deliver the Millennium Technology Prize Lecture, talking about their innovation, at 14:30 at the Millennium Innovation Forum. ̽��ֱ��lecture can be accessed here.

British duo Professor Shankar Balasubramanian and Professor David Klenerman have been awarded the Millennium Technology Prize for their development of revolutionary DNA sequencing techniques.

Journeys of Discovery: Rapid genome sequencing

Millennium Technology Prize

David Klenerman and Shankar Balasubramanian receiving the MTP prize

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Hunting for COVID-19 variants

cjb250 — Mon, 22 Mar 2021 11:06:50 +0000

Professor Sharon Peacock explains the story behind the UK's world-leading SARS-CoV-2 genomics capability.