From The University of Cambridge (UK): “New route to evolution – how DNA from our mitochondria gets into our genomes”

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From The University of Cambridge (UK)

10.5.22
Craig Brierley

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Mitochondria surrounded by cytoplasm. Credit: Dr David Furness.

Scientists have shown that in one in every 4,000 births, some of the genetic code from our mitochondria – the ‘batteries’ that power our cells – inserts itself into our DNA, revealing a surprising new insight into how humans evolve.

In a study published today in Nature [below], researchers at the University of Cambridge and Queen Mary University of London show that mitochondrial DNA also appears in some cancer DNA suggesting that it acts as a sticking plaster to try and repair damage to our genetic code.

Mitochondria are tiny ‘organelles’ that sit within our cells, where they act like batteries, providing energy in the form of the molecule ATP to power the cells. Each mitochondrion has its own DNA – mitochondrial DNA – that is distinct to the rest of the human genome which is comprised of nuclear DNA.

Mitochondrial DNA is passed down the maternal line – that is, we inherit it from our mothers, not our fathers. However, a study published in PNAS [below] in 2018 from researchers at the Cincinnati Children’s Hospital Medical Center in the USA reported evidence that suggested some mitochondrial DNA had been passed down the paternal line.

To investigate these claims, the Cambridge team looked at the DNA from over 11,000 families recruited to Genomics England’s 100,000 Genomes Project, searching for patterns that looked like paternal inheritance. The Cambridge team found mitochondrial DNA ‘inserts’ in the nuclear DNA of some children that were not present in that of their parents. This meant that the US team had probably reached the wrong conclusions: what they had observed were not paternally-inherited mitochondrial DNA, but rather these inserts.

Now, extending this work to over 66,000 people, the team showed that the new inserts are actually happening all the time, showing a new way our genome evolves.

Professor Patrick Chinnery, from the Medical Research Council Mitochondrial Biology Unit and Department of Clinical Neurosciences at the University of Cambridge, explained: “Billions of years ago, a primitive animal cell took in a bacterium that became what we now call mitochondria. These supply energy to the cell to allow it to function normally, while removing oxygen, which is toxic at high levels. Over time, bits of these primitive mitochondria have passed into the cell nucleus, allowing their genomes to talk to each other.

“This was all thought to have happened a very long time ago, mostly before we had even formed as a species, but what we’ve discovered is that that’s not true. We can see this happening right now, with bits of our mitochondrial genetic code transferring into the nuclear genome in a measurable way.”

The team estimate that mitochondrial DNA transfers to nuclear DNA in around one in every 4,000 births. If that individual has children of their own, they will pass these inserts on – the team found that most of us carry five of the new inserts, and one in seven of us (14%) carry very recent ones. Once in place, the inserts can occasionally lead to very rare diseases, including a rare genetic form of cancer.

It is not clear exactly how the mitochondrial DNA inserts itself – whether it does so directly or via an intermediary, such as RNA – but Professor Chinnery says it is likely to occur within the mother’s egg cells.

When the team looked at sequences taken from 12,500 tumour samples, they found that mitochondrial DNA was even more common in tumour DNA, arising in around one in 1,000 cancers, and in some cases, the mitochondrial DNA inserts actually causes the cancer.

“Our nuclear genetic code is breaking and being repaired all the time,” said Professor Chinnery. “Mitochondrial DNA appears to act almost like a Band-Aid, a sticking plaster to help the nuclear genetic code repair itself. And sometimes this works, but on rare occasions if might make things worse or even trigger the development of tumours.”

More than half (58%) of the insertions were in regions of the genome that code for proteins. In the majority of cases, the body recognizes the invading mitochondrial DNA and silences it in a process known as methylation, whereby a molecule attaches itself to the insert and switches it off. A similar process occurs when viruses manage to insert themselves into our DNA. However, this method of silencing is not perfect, as some of the mitochondrial DNA inserts go on to be copied and move around the nucleus itself.

The team looked for evidence that the reverse might happen – that mitochondrial DNA absorbs parts of our nuclear DNA – but found none. There are likely to be several reasons why this should be the case.

Firstly, cells only have two copies of nuclear DNA, but thousands of copies of mitochondrial DNA, so the chances of mitochondrial DNA being broken and passing into the nucleus are much greater than the other way around.

Secondly, the DNA in mitochondria is packaged inside two membranes and there are no holes in the membrane, so it would be difficult for nuclear DNA to get in. By contrast, if mitochondrial DNA manages to get out, holes in the membrane surrounding nuclear DNA would allow it pass through with relative ease.

Professor Sir Mark Caulfield, Vice Principal for Health at Queen Mary University of London, said: “I am so delighted that the 100,000 Genomes Project has unlocked the dynamic interplay between mitochondrial DNA and our genome in the cell’s nucleus. This defines a new role in DNA repair, but also one that could occasionally trigger rare disease, or even malignancy.”

The research was mainly funded by the Medical Research Council, Wellcome, and the National Institute for Health Research.

Science papers:
Nature
PNAS 2018
See the science papers for instructive material.

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The University of Cambridge (UK) [legally The Chancellor, Masters, and Scholars of the University of Cambridge] is a collegiate public research university in Cambridge, England. Founded in 1209 Cambridge is the second-oldest university in the English-speaking world and the world’s fourth-oldest surviving university. It grew out of an association of scholars who left the University of Oxford (UK) after a dispute with townsfolk. The two ancient universities share many common features and are often jointly referred to as “Oxbridge”.

Cambridge is formed from a variety of institutions which include 31 semi-autonomous constituent colleges and over 150 academic departments, faculties and other institutions organized into six schools. All the colleges are self-governing institutions within the university, each controlling its own membership and with its own internal structure and activities. All students are members of a college. Cambridge does not have a main campus and its colleges and central facilities are scattered throughout the city. Undergraduate teaching at Cambridge is organized around weekly small-group supervisions in the colleges – a feature unique to the Oxbridge system. These are complemented by classes, lectures, seminars, laboratory work and occasionally further supervisions provided by the central university faculties and departments. Postgraduate teaching is provided predominantly centrally.

Cambridge University Press a department of the university is the oldest university press in the world and currently the second largest university press in the world. Cambridge Assessment also a department of the university is one of the world’s leading examining bodies and provides assessment to over eight million learners globally every year. The university also operates eight cultural and scientific museums, including the Fitzwilliam Museum, as well as a botanic garden. Cambridge’s libraries – of which there are 116 – hold a total of around 16 million books, around nine million of which are in Cambridge University Library, a legal deposit library. The university is home to – but independent of – the Cambridge Union – the world’s oldest debating society. The university is closely linked to the development of the high-tech business cluster known as “Silicon Fe”. It is the central member of Cambridge University Health Partners, an academic health science centre based around the Cambridge Biomedical Campus.

By both endowment size and consolidated assets Cambridge is the wealthiest university in the United Kingdom. In the fiscal year ending 31 July 2019, the central university – excluding colleges – had a total income of £2.192 billion of which £592.4 million was from research grants and contracts. At the end of the same financial year the central university and colleges together possessed a combined endowment of over £7.1 billion and overall consolidated net assets (excluding “immaterial” historical assets) of over £12.5 billion. It is a member of numerous associations and forms part of the ‘golden triangle’ of English universities.

Cambridge has educated many notable alumni including eminent mathematicians; scientists; politicians; lawyers; philosophers; writers; actors; monarchs and other heads of state. As of October 2020, 121 Nobel laureates; 11 Fields Medalists; 7 Turing Award winners; and 14 British prime ministers have been affiliated with Cambridge as students; alumni; faculty or research staff. University alumni have won 194 Olympic medals.

History

By the late 12th century, the Cambridge area already had a scholarly and ecclesiastical reputation due to monks from the nearby bishopric church of Ely. However, it was an incident at Oxford which is most likely to have led to the establishment of the university: three Oxford scholars were hanged by the town authorities for the death of a woman without consulting the ecclesiastical authorities who would normally take precedence (and pardon the scholars) in such a case; but were at that time in conflict with King John. Fearing more violence from the townsfolk scholars from the University of Oxford started to move away to cities such as Paris; Reading; and Cambridge. Subsequently enough scholars remained in Cambridge to form the nucleus of a new university when it had become safe enough for academia to resume at Oxford. In order to claim precedence, it is common for Cambridge to trace its founding to the 1231 charter from Henry III granting it the right to discipline its own members (ius non-trahi extra) and an exemption from some taxes; Oxford was not granted similar rights until 1248.

A bull in 1233 from Pope Gregory IX gave graduates from Cambridge the right to teach “everywhere in Christendom”. After Cambridge was described as a studium generale in a letter from Pope Nicholas IV in 1290 and confirmed as such in a bull by Pope John XXII in 1318 it became common for researchers from other European medieval universities to visit Cambridge to study or to give lecture courses.

Foundation of the colleges

The colleges at the University of Cambridge were originally an incidental feature of the system. No college is as old as the university itself. The colleges were endowed fellowships of scholars. There were also institutions without endowments called hostels. The hostels were gradually absorbed by the colleges over the centuries; but they have left some traces, such as the name of Garret Hostel Lane.

Hugh Balsham, Bishop of Ely, founded Peterhouse – Cambridge’s first college in 1284. Many colleges were founded during the 14th and 15th centuries but colleges continued to be established until modern times. There was a gap of 204 years between the founding of Sidney Sussex in 1596 and that of Downing in 1800. The most recently established college is Robinson built in the late 1970s. However, Homerton College only achieved full university college status in March 2010 making it the newest full college (it was previously an “Approved Society” affiliated with the university).

In medieval times many colleges were founded so that their members would pray for the souls of the founders and were often associated with chapels or abbeys. The colleges’ focus changed in 1536 with the Dissolution of the Monasteries. Henry VIII ordered the university to disband its Faculty of Canon Law and to stop teaching “scholastic philosophy”. In response, colleges changed their curricula away from canon law and towards the classics; the Bible; and mathematics.

Nearly a century later the university was at the centre of a Protestant schism. Many nobles, intellectuals and even commoners saw the ways of the Church of England as too similar to the Catholic Church and felt that it was used by the Crown to usurp the rightful powers of the counties. East Anglia was the centre of what became the Puritan movement. In Cambridge the movement was particularly strong at Emmanuel; St Catharine’s Hall; Sidney Sussex; and Christ’s College. They produced many “non-conformist” graduates who, greatly influenced by social position or preaching left for New England and especially the Massachusetts Bay Colony during the Great Migration decade of the 1630s. Oliver Cromwell, Parliamentary commander during the English Civil War and head of the English Commonwealth (1649–1660), attended Sidney Sussex.

Modern period

After the Cambridge University Act formalized the organizational structure of the university the study of many new subjects was introduced e.g. theology, history and modern languages. Resources necessary for new courses in the arts architecture and archaeology were donated by Viscount Fitzwilliam of Trinity College who also founded the Fitzwilliam Museum. In 1847 Prince Albert was elected Chancellor of the University of Cambridge after a close contest with the Earl of Powis. Albert used his position as Chancellor to campaign successfully for reformed and more modern university curricula, expanding the subjects taught beyond the traditional mathematics and classics to include modern history and the natural sciences. Between 1896 and 1902 Downing College sold part of its land to build the Downing Site with new scientific laboratories for anatomy, genetics, and Earth sciences. During the same period the New Museums Site was erected including the Cavendish Laboratory which has since moved to the West Cambridge Site and other departments for chemistry and medicine.

The University of Cambridge began to award PhD degrees in the first third of the 20th century. The first Cambridge PhD in mathematics was awarded in 1924.

In the First World War 13,878 members of the university served and 2,470 were killed. Teaching and the fees it earned came almost to a stop and severe financial difficulties followed. As a consequence, the university first received systematic state support in 1919 and a Royal Commission appointed in 1920 recommended that the university (but not the colleges) should receive an annual grant. Following the Second World War the university saw a rapid expansion of student numbers and available places; this was partly due to the success and popularity gained by many Cambridge scientists.