̽��ֱ�� of Cambridge - Peter Forster

COVID-19: genetic network analysis provides ‘snapshot’ of pandemic origins

Anonymous — Thu, 09 Apr 2020 04:25:32 +0000

UPDATED on Thursday April 30th 2020 with the following statement from Dr Peter Forster: "Our analysis published in the Proceedings of the National Academy of Sciences (PNAS) looked at the early spread of the virus in humans. Our analysis was not designed to investigate rumours suggesting the virus itself came from outside China. It is a misinterpretation of our research to suggest that the novel coronavirus originated outside China."

Researchers from Cambridge, UK, and Germany have reconstructed the early 'evolutionary paths' of SARS-CoV-2 in humans – as infection spread from Wuhan out to Europe and North America – using genetic network techniques.'

By analysing the first 160 complete virus genomes to be sequenced from human patients, the scientists have mapped some of the original spread of the new coronavirus through its mutations, which creates different viral lineages.

“There are too many rapid mutations to neatly trace a SARS-CoV-2 family tree. We used a mathematical network algorithm to visualise all the plausible trees simultaneously,” said geneticist Dr Peter Forster, lead author from the ̽��ֱ�� of Cambridge.

“These techniques are mostly known for mapping the movements of prehistoric human populations through DNA. We think this is one of the first times they have been used to trace the infection routes of a coronavirus like COVID-19.”

̽��ֱ��team used data from virus genomes sampled from across the world between 24 December 2019 and 4 March 2020. ̽��ֱ��research revealed three distinct 'variants' of SARS-CoV-2, consisting of clusters of closely related lineages, which they label ‘A’, ‘B’ and ‘C’.

Forster and colleagues found that the closest type of SARS-CoV-2 to the one discovered in bats – type ‘A’, the “original human virus genome” – was present in Wuhan, but surprisingly was not the city’s predominant virus type.

Versions of ‘A’ were seen in Chinese individuals, and Americans reported to have lived in Wuhan, and mutated versions of ‘A’ were found in patients from the USA and Australia.

Wuhan’s major virus type, ‘B’, was prevalent in patients from across East Asia. However, the variant didn’t travel much beyond the region without further mutations – implying a 'founder event' in Wuhan, or 'resistance' against this type of coronavirus outside East Asia, say researchers.

̽��ֱ��‘C’ variant is the major European type, found in early patients from France, Italy, Sweden and England. It is absent from the study’s Chinese mainland sample, but seen in Singapore, Hong Kong and South Korea.

̽��ֱ��new analysis also suggests that one of the earliest introductions of the virus into Italy came via the first documented German infection on 27 January, and that another early Italian infection route was related to a 'Singapore cluster'.

Importantly, the researchers say that their genetic networking techniques accurately traced established infection routes: the mutations and viral lineages joined the dots between known cases.

As such, the scientists argue that these 'phylogenetic' methods could be applied to the very latest coronavirus genome sequencing to help predict future global hot spots of disease transmission and surge.

“Phylogenetic network analysis has the potential to help identify undocumented COVID-19 infection sources, which can then be quarantined to contain further spread of the disease worldwide,” said Forster, a fellow of the McDonald Institute of Archaeological Research at Cambridge, as well as the ̽��ֱ��’s Institute of Continuing Education.

̽��ֱ��findings are published today in the journal Proceedings of the National Academy of Sciences (PNAS). ̽��ֱ��software used in the study, as well as classifications for over 1,000 coronavirus genomes and counting, is available free at www.fluxus-technology.com.

Variant ‘A’, most closely related to the virus found in both bats and pangolins, is described as 'the root of the outbreak' by researchers. Type ‘B’ is derived from ‘A’, separated by two mutations, then ‘C’ is in turn a “daughter” of ‘B’.

Researchers say the localisation of the ‘B’ variant to East Asia could result from a 'founder effect': a genetic bottleneck that occurs when, in the case of a virus, a new type is established from a small, isolated group of infections.

Forster argues that there is another explanation worth considering. “ ̽��ֱ��Wuhan B-type virus could be immunologically or environmentally adapted to a large section of the East Asian population. It may need to mutate to overcome resistance outside East Asia. We seem to see a slower mutation rate in East Asia than elsewhere, in this initial phase.”

He added: “ ̽��ֱ��viral network we have detailed is a snapshot of the early stages of an epidemic, before the evolutionary paths of COVID-19 become obscured by vast numbers of mutations. It’s like catching an incipient supernova in the act.”

Since today’s PNAS study was conducted, the research team has extended its analysis to 1,001 viral genomes. While yet to be peer-reviewed, Forster says the latest work suggests that the first infection and spread among humans of SARS-CoV-2 occurred between mid-September and early December.

̽��ֱ��phylogenetic network methods used by researchers – allowing the visualisation of hundreds of evolutionary trees simultaneously in one simple graph – were pioneered in New Zealand in 1979, then developed by German mathematicians in the 1990s.

These techniques came to the attention of archaeologist Professor Colin Renfrew, a co-author of the new PNAS study, in 1998. Renfrew went on to establish one of the first archaeogenetics research groups in the world at the ̽��ֱ�� of Cambridge.

Study charts the 'incipient supernova' of SARS-CoV-2 through genetic mutations as it spread from China and Asia to Australia, Europe and North America. Researchers say their methods could be used to help identify undocumented infection sources.

Phylogenetic network analysis has the potential to help identify undocumented COVID-19 infection sources

Peter Forster

Forster et al

Figure from the PNAS paper showing the transmission routes using phylogenetic networks.

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Yes

Study finds increased DNA mutations in children of teenage fathers

fpjl2 — Wed, 18 Feb 2015 09:49:59 +0000

A genetic study of over 24,000 parents and their children has shown that the children of teenage fathers have unexpectedly high levels of DNA mutations.

Mutations, the result of DNA copying errors during cell division, can occur in different cells of the body and at different times during life. Some, such as those that occur in 'germ cells' – which create sperm or eggs – cause changes affecting the individual's offspring.

Previously, it was thought that germ cells in both boys and girls go through a similar number of cell divisions, and should have roughly the same rates of DNA mutation by the time an individual reaches puberty.

Now, a new study shows that the number of cell divisions – and consequently DNA mutation rates – experienced by the germ cells of teenage boys is six times higher than for those of girls, and that DNA mutations passed down to the children of teenage fathers are higher as a result.

Researchers say the increased DNA mutations in the reproductive cells of adolescent boys could explain why the children of teenage fathers have a higher risk for disorders such as autism, schizophrenia and spina bifida.

Men produce germ cells throughout their lives, and it was previously assumed that DNA mutation in germ cells increased as men get older – more cell division and greater DNA mutation has occurred as men age.

However, the latest results show that the germ cells of adolescent boys are an exception to this aging rule.

Researchers have shown that male germ cells go through around 150 cell divisions by puberty, compared to the 22 cell divisions experienced by female oocytes (immature egg cells). This raises in tandem the rates of DNA mutation incurred by cell division in the germ cells of teenage boys – creating higher chances of hereditary disease in children conceived by adolescent fathers.

̽��ֱ��researchers say that this could be the result of unknown cell divisions during male childhood or a spike in DNA error during puberty – although the reasons are currently unclear.

Prior to the new findings, male germ cells were thought to undergo 30 divisions by puberty. ̽��ֱ��results overturn previous notions that the younger the man, the less cell division and the less risk of DNA mutations in germ – and later sperm – cells.

In fact, researchers say that – while more work needs to be done – these initial findings furthermore indicate that sperm cells in teenagers have approximately 30% higher rates of DNA mutation than those of young men in their twenties, and that teenage boys have similar levels of DNA mutation in their sperm cells to men aged in their late thirties and forties.

“It appears that the male germ cells accumulate DNA errors unnoticed during childhood, or commit DNA errors at an especially high level at the onset of puberty. However, the reason for this is not yet clear,” said geneticist Dr Peter Forster, a Fellow of Murray Edwards College and the McDonald Institute at the ̽��ֱ�� of Cambridge, who conducted the study with colleagues from the Institute of Forensic Genetics in Münster, Germany.

“Possibly the DNA copying mechanism is particularly error-prone at the beginning of male puberty. Or, sperm production in boys may undergo dozens more cell cycles – and therefore DNA copying errors – than has previously been suspected,” he said.

Either way, the textbooks may well need to be rewritten as a result of the new findings, says Forster, which are published today in the journal Proceedings of the Royal Society B.

̽��ֱ��research team used DNA from blood and saliva samples taken from 24,097 normal parents and their validated biological children from areas of Germany, Austria, the Middle East and West Africa.

̽��ֱ��researchers analysed a type of DNA known as ‘microsatellites’ – simple, repetitive sequences of DNA that only mutate as a result of cell replication, providing the team with a natural ‘cell-cycle counter’ which they used to track the number of times a cell divides, and consequently the rate of mutations through DNA copying error.

Through comparative analysis, the research team discovered the increased DNA mutations in children of teenage fathers, and that mutations are six times higher in male sperm cells during onset of puberty than in female oocytes.

While this means that the children of teenage fathers have increased chance of abnormality, Forster points out that the risk is still very small: perhaps around 2% as opposed to a general average abnormality risk of 1.5%.

̽��ֱ��team hope to develop the cell-cycle counter technique used in the study and apply it to cancers, in order to better estimate the age of such conditions in individuals, and the number of cell divisions between the initial cellular malfunction and tumour growth.

New research reveals that the sperm cells of adolescent boys have more than six times the rate of DNA mutations as the equivalent egg cells in adolescent girls, resulting in higher rates of DNA mutation being passed down to children of teenage fathers. ̽��ֱ��findings suggest that the risk of birth defects is higher in the children of teenage fathers as a consequence.

Sperm production in boys may undergo dozens more cell cycles – and therefore DNA copying errors – than has previously been suspected

Peter Forster

Professor Stefan Schlatt, ̽��ֱ�� of Muenster

Section of normal testes of a young man

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Yes

Richard III – case closed after 529 years

fpjl2 — Tue, 02 Dec 2014 17:46:44 +0000

An international research team has provided overwhelming evidence that the skeleton discovered under a car park in Leicester indeed represents the remains of King Richard III - closing what is probably the oldest forensic case solved to date.

Analysis of all the available evidence confirms identity of King Richard III to the point of 99.999% (at its most conservative).

̽��ֱ��team of researchers, including geneticist Dr Peter Forster from Murray Edwards College and the McDonald Institute for Archaeological Research, and led by Cambridge graduate Dr Turi King have published their findings online today in the journal Nature Communications.

̽��ֱ��researchers collected DNA from living relatives of Richard III and analysed several genetic markers, including the complete mitochondrial genomes, inherited through the maternal line, and Y-chromosomal markers, inherited through the paternal line, from both the skeletal remains and the living relatives.

While the Y-chromosomal markers differ, the mitochondrial genome shows a genetic match between the skeleton and the maternal line relatives. ̽��ֱ��former result is not unsurprising as the chances for a false-paternity event is fairly high after so many generations.

Forster said: “Although the false paternity means we cannot look forward in time, we can trace King Richard’s Y lineage back into prehistory. Historically, the male line of the Plantagenets is recorded back until AD1028 in N France. Using King Richard’s genetic profile, we can go back much further: Richard’s G2a type traces back to the first farmers who migrated from the Near East and Anatolia (modern Turkey) to Europe about 8000 years ago, quickly spreading along the Mediterranean and into Central Europe and France by 5500BC.

"These pioneer farmers carried predominantly G2a types, which today are quite rare, around 1 percent in Europe (see map). And one of these Anatolian farmers was King Richard’s immigrant male ancestor. Incidentally, the descendants of the Plantagenets not only became Kings of England but also of Jerusalem, bringing the migration of this Y chromosome type full circle.”

Map shows locations of 14 living men who are close genetic matches to King Richard – their G2a type is quite rare, around 1 percent in Europe today.

Analysis of the mitochondrial DNA shows a match between Richard III and modern female-line relatives Michael Ibsen and Wendy Duldig. ̽��ֱ��male line of descent is broken at one or more points in the line between Richard III and living male-line relatives descended from Henry Somerset, 5th Duke of Beaufort.

This paper is also the first to carry out a statistical analysis of all the evidence together to prove beyond reasonable doubt that Skeleton 1 from the Greyfriars site in Leicester is indeed the remains of King Richard III.

̽��ֱ��researchers also used genetic markers to determine hair and eye colour of Richard III and found that with probably blond hair - at least during childhood - and almost certainly blue eyes, Richard III looked most similar to his depiction in one of the earliest portraits of him that survived, that in the Society of Antiquaries in London.

“Our paper covers all the genetic and genealogical analysis involved in the identification of the remains of Skeleton 1 from the Greyfriars site in Leicester and is the first to draw together all the strands of evidence to come to a conclusion about the identity of those remains,” said Dr Turi King from the ̽��ֱ�� of Leicester, who lead the research.

“Even with our highly conservative analysis, the evidence is overwhelming that these are indeed the remains of King Richard III, thereby closing an over 500 year old missing person’s case.”

Historically, the male line of the Plantagenets is recorded until Hugues, Count of Perche (documented AD1028 in N France).
Prehistorically, Richard’s male ancestor, carrying a G2a-type, arrived with the first farmers from the Near East and Anatolia (modern Turkey) to Europe about 8000 years ago, quickly spreading along the Mediterranean and into Central Europe and France by 5500BC.

̽��ֱ��research team now plans to sequence the complete genome of Richard III to learn more about the last English king to die in battle.

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

DNA and genealogical study confirms identity of remains found in Leicester and uncovers new truths about his appearance and Plantagenet lineage.

Although the false paternity means we cannot look forward in time, we can trace King Richard’s Y lineage back into prehistory

Peter Forster

̽��ֱ�� of Leicester/Carl Vivian

Skull and bones of Richard III

Yes

Identity of Pompeii’s mystery horse revealed

ns480 — Fri, 17 Dec 2010 15:25:23 +0000

Academics initially believed that they had unearthed a new, now-extinct, breed of horse when they analysed DNA sequences from skeletons found at a house in the ancient Roman town in 2004.

But Susan Gurney, working with Dr Peter Forster on horse genetics at the ̽��ֱ�� of Cambridge, revisited the study and found that their initial excitement was misplaced.

Writing in the new issue of the Journal of Cellular Biochemistry, Gurney, from the ̽��ֱ��'s Institute of Continuing Education, explains that there appears to have been a mix-up in the lab, which resulted in horse DNA being combined with that of a donkey to create an artificial hybrid.

̽��ֱ��research could still prove important, however, as the newly identified donkey may well be the first proof that the "Somali" ass lineage normally found in Italy dates back to at least Roman times.

̽��ֱ��original study six years ago analysed the skeletons of equids that belonged to a rich Roman household in Pompeii. All five were well preserved by the volcanic ash which covered Pompeii and the nearby settlement of Herculaneum when Mount Vesuvius erupted in AD79.

They were found in the stables at the house of the Casti Amanti (chaste lovers), so-called because its walls have frescoes depicting a romantic scene. This house was probably owned by Caius Iulius Polybius, a wealthy politician and baker in ancient Pompeii - as shown by the fact that the house contains an open oven and four wheat grindstones.

̽��ֱ��team looked at the mitochondrial DNA sequences (mtDNA) of each of the horses. Four standard mtDNA types were quickly identified, but the fifth "horse" appeared to be of an exotic and mysterious DNA type no longer found today.

In a subsequent paper, the researchers reported that this must be from a different, unknown breed of horse, which had perhaps since disappeared.

When Susan Gurney re-examined the research, however, she realised that they had made an error in the laboratory, accidentally combining a donkey mtDNA sequence with that of a horse, and thus generating a hybrid which had actually never existed at all.

In her journal article, she explains that the first 177 nucleotides (molecules which form the structural units of a DNA sequence) match existing patterns for donkeys. ̽��ֱ��remaining 193 nucleotides match those of an existing breed of horse.

"Looking at the research with hindsight, it's possible to recognise two separate strands of horse and donkey DNA," she said. "In addition, the horse DNA that appears to have been inadvertently mixed in with the donkey's genetic information is the same type as that found in another Herculaneum horse, which might be the source of the mistake."

Despite the erroneous conclusion, however, the finding is still an important one: ̽��ֱ��donkey DNA finds its closest match with the DNA of domestic donkeys that are related to the Somali wild ass, typically found in Italy today.

In other European countries, asses are often descended from the Nubian lineage instead.

As a result, the ancient Pompeiian donkey DNA sequence, if confirmed, may well represent the origins of that division, and provide valuable early evidence that the Somali breed appeared in Italy at least as early as Roman times.

̽��ֱ��identity of a mysterious breed of “horse” which has baffled experts since its remains were uncovered at Pompeii has been resolved by a Cambridge ̽��ֱ�� researcher – who realised it was a donkey.

̽��ֱ��horse DNA that appears to have been inadvertently mixed in with the donkey's genetic information is the same type as that found in another Herculaneum horse, which might be the source of the mistake.

Susan Gurney

̽��ֱ�� of Cambridge

Pompeii's mystery horse

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Yes