̽��ֱ�� of Cambridge - Human Genome Project

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

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Genetic roulette in a new world

gm349 — Fri, 17 Aug 2012 17:00:56 +0000

In 2003 it was a sensation. No really – it’s probably true that in medicine only the first human heart transplant operation back in 1967 has generated as much publicity. That was in the pre-web dark age but, nevertheless, the South African surgeon Christiaan Barnard was immortalized as a global hero: even the patient’s name was on everyone’s lips (Louis Washkansky if you’re struggling to recall) and you can re-live the whole event at the Groote Schuur Hospital museum in Capetown. But, although 2003 was just a decade ago, in today’s world sensations fade almost with the following dawn, whether they are pop groups or life-changing scientific advances.

So if now you mention “ ̽��ֱ��Human Genome Project” to a man on the Clapham omnibus you are likely to elicit only a puzzled look. What happened in 2003 was of course that the genetic code – that is the sequence of bases in DNA – was revealed for the entire human genome. And an astonishing triumph it was, not least because, in contrast to almost everything else in history with a major British component, it was completed within schedule and under cost.

̽��ֱ��feat was deservedly greeted with a fanfare of public interest unprecedented for any scientific project short of the early space missions. President Bush in the White House was hooked-up live to whoever was living in No. 10 at the time, the leading British scientists in this amazing project dropped in for tea and Mike Dexter, then Chairman of ̽��ֱ��Wellcome Trust and a restrained and conservative fellow – being a scientist – described it somewhat inelegantly as “… the outstanding achievement not only of our lifetime, but in terms of human history.”

However, even more remarkable is what happened next. ̽��ֱ��ensuing decade has brought technical advances so breathtaking as to almost overshadow the original human genome project itself. This quite staggering revolution has seen the introduction of fully automated, high throughput flow cells that simultaneously carry out hundreds of millions of separate sequencing reactions – just say that slowly. In the jargon it’s called ‘massively parallel sequencing’. ̽��ֱ��upshot of this stunning technology is that sequencing speed has gone up by 100 million times whilst, almost unbelievably, the cost has dropped by a factor of 10,000. Even computing science can’t match that progress!

One consequence of this incredible, though relatively unpublicised, revolution is that genomes can be now be sequenced on an industrial scale and in the years to come that is going to impact on every facet of mankind’s existence. Thus far the field of cancer has been the foremost recipient of this technological broadside with thousands of tumour genomes now sequenced. This has unveiled the almost incomprehensible panoply of genetic changes that cells can sustain and yet emerge still capable of proliferating. One of the first cancer genomes to be sequenced was that of a female who had died from leukemia. ̽��ֱ��work was carried out by ̽��ֱ��Genome Institute at Washington ̽��ֱ�� in St. Louis, Missouri and since then, under its Director Richard Wilson, this group has continued to be a world leader in genomics and in particular in unravelling the extraordinary complexity of the group of cancers collectively called leukemias.

Wilson and his colleagues know, of course, that they are at the forefront of the most extraordinary transformation in medicine – because eventually it will affect everyone –though Rick Wilson himself is as improbable a revolutionary as you could imagine: a gentle, soft-spoken American, he’s what on this side of the pond would be called a thoroughly nice chap.

However, if they had any doubts about the direction in which their science was leading the world, these would have been dispelled when one of their own community, Lukas Wartman, was diagnosed with a very rare form of leukemia. This had first appeared ten years ago when Lukas was a student completing his medical degree at Washington ̽��ֱ��, and at that time it had been treated with chemotherapy and a bone-marrow transplant.

In the following years, Dr. Wartman had pursued his career goal of becoming a practicing oncologist specializing in leukemia until, in July 2011 the disease returned and he went into relapse. As his condition deteriorated rapidly and only one outcome seemed possible, those treating him turned in desperation from conventional approaches to local expertise. They applied genomic analysis to his cancer cells. From the vast number of disruptions identified, one in particular stood out: an abnormally expressed gene that had previously been associated with other types of leukemia but is very rare in the form Wartman had developed.

By an unlikely chance there is a drug available that can knockout the activity of the protein made by that gene. Its effect was phenomenal, restoring the normal blood count and achieving complete remission. This wonderful outcome does not mean that Dr. Wartman is cured for life – but for now he is alive and well – and a co-author of the group’s latest paper – on leukemia.

He had been a desperately unlucky in that the genetic roulette that is life generated in him a hand of mutations that drove the development of a rare and almost invariably lethal form of leukemia. But life also smiled on Lukas Wartman in that circumstances found him at the heart of the genomics revolution that is ushering in a new world of medicine. His isn’t the first life to be saved through the use of this fabulous technology but he is one of the first few who will, in years to come, be followed by many as these marvellous methods for diagnosis and the design of treatment come into widespread use.

Dr Robin Hesketh, Senior Lecturer in the Department of Biochemistry and author of Betrayed by Nature, explains how advances in inexpensive, rapid gene sequencing and expression analysis is revolutionising cancer research and the development of new treatments.

MJ/TR (´???) from Flickr

DNA

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Superfast genomes move a step closer to reality

bjb42 — Thu, 20 Nov 2008 00:00:00 +0000

̽��ֱ��genome sequence of three individuals, from China, Nigeria and a cancer patient, are only the third, fourth and fifth complete genomes to be decoded and the first using Solexa sequencing on the Illumina Genome Analyzer (Illumina purchased Solexa in 2007).

Their completion amounts to a major step to the goal of tailor-made profiles of individual genomes.

Each of the sequences cost a fraction of the first human genome sequenced by the Human Genome Project which finished in 2004 at a cost of $300 million. Each of these genomes cost less than $250,000.

This is the first time that the technology has been used to sequence an entire DNA sequence of a human. Next year Illumina expects the cost to fall to around $10,000.

This technology overcomes the limitations that have held back previous attempts to sequence a complete human genome. Previous sequencing approaches could only read 10 to 100 bases per step/cycle. This technique can sequence more than 10 million bases at a time.

̽��ֱ��phenomenal increase in the number of bases that can be read is because of the novel technology used - reverse terminator chemistry. Human DNA is randomly cut up into small pieces and immobilised to a surface. Each molecule of DNA is copied 100s of times so that a forest of sequences builds up from each original sequence. It is then possible to process more than 10 million samples at a time.

With all the molecules attached to a surface, an enzyme attaches coloured blocks to the first base of the sequence. Each of the four bases of DNA (A,T,C,G) has a coloured fluorescent block that equates to it; red, green, blue and green. With the coloured blocks attached an image is taken of the surface and the base at the first position is determined. To ensure that only one coloured block is incorporated at a time, a protecting group blocks incorporation of any more fluorescent blocks.

A process then clips off the colour block and the blocking group at that position, hence reversible terminator sequencing. Using the same process, each base in the sequence is read to provide a colour coded sequence. This assembled colour sequence can then be translated to provide the DNA sequence.

̽��ֱ��process builds up a picture of the sequence using short reads of 35 base pairs for each cut segment. Although each read is very short, the sheer number of molecules allows the sequences to be stitched together to form the complete genome sequence.

̽��ֱ��three anonymous genomes join those of the distinguished geneticists James Watson and Craig Venter as the only people to have their personal genome made publicly available.

When Professors Shankar Balasubramanian and David Klenerman began their research into DNA sequencing 10 years ago, the Human Genome Project was less than half way through when they had the lofty goal of generating over a billion bases of DNA sequence at a time. In a decade that work has surpassed their original expectations, and the resulting spin out company, Solexa.

Commenting on this successful application of research, Dr Richard Jennings, Director of Technology Transfer & Consultancy Services, Cambridge Enterprise said:

"This remarkable technology which started as a researchers conversation and a sketch on a whiteboard, shows how the ̽��ֱ�� of Cambridge and its inventors can help translate the results of fundamental research into applications with outstanding societal benefits."

Recent work by Illumina has increased the number of bases that the technique can read to more than 100 bases at a time and it can process upto 20 billion bases per run. This research takes another step towards the aim of the $1,000 genome that could allow each of us to discover our unique genome that could lead to tailor made treatments for a wide range of diseases.

This year it is anticipated that many more human genomes will be sequenced using this technique.

Since its commercial release in 2007, more than 130 original research projects have been published in peer reviewed journals using the Illumina Genome Analyzer.

̽��ֱ��process has been used to analyse genetic variation between individuals. It has also been used assemble miRNA profiles in cancers that could lead to diagnostic and therapeutic benefits.

̽��ֱ��first Asian and African human genomes have been deciphered using a technique originally invented by Professors Shankar Balasubramanian and David Klenerman at the ̽��ֱ�� of Cambridge's Department of Chemistry and developed by the spin-out Solexa.

This remarkable technology which started as a researchers conversation and a sketch on a whiteboard, shows how the ̽��ֱ�� of Cambridge and its inventors can help translate the results of fundamental research into applications with outstanding societal benefits.

Dr Richard Jennings

Maria Keays from Flickr

DNA sculpture at Centre for Life

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Finding the ‘genetic signposts’ of disease

ns480 — Sat, 01 Sep 2007 11:57:45 +0000

̽��ֱ��Wellcome Trust Case Control Consortium (WTCCC) brought together 50 research groups from dozens of institutions in the UK, including the Wellcome Trust Sanger Institute at Hinxton, Cambridge, and the ̽��ֱ�� of Cambridge. ̽��ֱ��success of the project depended both on capitalising on the knowledge built by the Human Genome Project and the HapMap Project, two consortia in which the Sanger Institute was a major partner, and also on the sheer size of the collaboration across the UK.

Dr Panos Deloukas, who led the team at the Sanger Institute, explains: ‘This was unprecedented in the UK. ̽��ֱ��sharing of samples and data on this scale has changed the ethos of the research community – through working with 50 laboratories across the country and conducting large-scale disease genetics at a level that has never been done before.’

̽��ֱ��collaborators contributed their large national collections of DNA samples collected from different patient groups – totalling an incredible 17,000 samples across the UK (2000 patients for each of the diseases studied plus 3000 healthy controls) – allowing over 10 billion pieces of genetic information to be analysed by genome scan using the Affymetrix GeneChip assay. Tiny genetic variations between individuals that predispose to type 1 and type 2 diabetes, Crohn’s disease, bipolar disorder, coronary heart disease, hypertension and rheumatoid arthritis were sought. By identifying these ‘genetic signposts’, scientists might understand which people are most at risk and why.

‘We have found 24 genomic regions with very strong evidence of harbouring variants that underlie six of the phenotypes we studied and we saw a spectrum of genetic architectures among these common diseases,’ explains Dr Deloukas. ‘Once we had these findings then the medical collaborators provided insight into the significance of the gene associations and tried to replicate them.’

Significant new breakthroughs have been made for Crohn’s disease and type 1 diabetes, and a link between the two diseases has been discovered. Dr Miles Parkes (Gastroenterology Unit, Addenbrooke’s Hospital, Cambridge) and Professor John Todd (Department of Medical Genetics, ̽��ֱ�� of Cambridge), both participants in the WTCCC, are now leading studies to follow up these findings. ‘It’s rewarding to see that the highly significant genetic associations are now being replicated in independent samples,’ says Dr Deloukas. ‘ ̽��ֱ��framework set up by the WTCCC clearly works.’

Dr Mark Walport, Director of the Wellcome Trust, views the WTCCC as a success: ‘It is an excellent illustration of the importance of knowing the human genome sequence and cataloguing its variations. Hopefully, with the insight gained into these diseases we will be able to make real progress in combating them.’

For more information on the Wellcome Trust Sanger Institute and the WTCCC (including a full list of participants), please go to www.sanger.ac.uk and www.wtccc.org.uk

One of the biggest projects ever undertaken to identify genetic variants that predispose some people to certain diseases was begun in 2005, thanks to £9 million funding from the Wellcome Trust. ̽��ֱ��ground-breaking results of this study were published in June this year.

It is an excellent illustration of the importance of knowing the human genome sequence and cataloguing its variations. Hopefully, with the insight gained into these diseases we will be able to make real progress in combating them.

Dr Mark Walport, Director of the Wellcome Trust

S.A.Mossman from Flickr

Sign Post

̽��ֱ��Wellcome Trust

<div> <p> ̽��ֱ��Wellcome Trust is well known as the leading funder of biomedical research in the UK, spending many millions on major research projects that have tangible impacts on health and disease.</p> <p>This ethos is abundantly evident in the £9 million support given to the Wellcome Trust Case Control Consortium, a collaboration of leading human geneticists across the UK, to analyse thousands of DNA samples and identify genetic predispositions to common diseases. ̽��ֱ��Trust also embraces studies on how biomedical research affects people and society; the funding of a research project being undertaken in the ̽��ֱ�� of Cambridge’s Centre for Family Research is an example of this rounded view.</p> <p> ̽��ֱ��Wellcome Trust is the UK’s largest source of funds for biomedical research and the second largest medical research charity in the world. Spending around £500 million each year in the UK and internationally, the mission of the Trust is to support the brightest scientists with the best ideas, and to ‘respond flexibly to medical needs and scientific opportunities’. Through support of a broad portfolio of biomedical research from immunology and infectious diseases to physiological sciences, the Trust aims to make a difference by advancing understanding of the processes that underpin health and disease. And, as the leading funder of translation research in the UK, the Trust is also committed to translating research innovations into health benefits. Technology Transfer at the Trust can help bridge the gap between fundamental research and commercial application by funding research that is sometimes deemed ‘too early’ or ‘too high-risk’ to be pursued by the corporate healthcare or investment sectors.</p> <p>Perhaps less well known are the Trust’s funding streams across medical humanities and public engagement. Through these, the importance is recognised of engaging with society to foster an informed climate within which biomedical research can flourish. This understanding can inform many things, from the ethical conduct of research, to the development of public policy and regulatory environments, to the enlightened debate about biomedical science, its achievements, applications and implications.</p> </div>

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