̽��ֱ�� of Cambridge - genetic mutation

̽��ֱ��master of mutations

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Dr Alex Cagan – illustrator, geneticist and explorer of animal DNA – is offering a new perspective on the tapestry of life. His work has profound implications for the pursuit of healthy ageing and the possibilities of cancer resistance.

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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Order matters: sequence of genetic mutations determines how cancer behaves

cjb250 — Wed, 11 Feb 2015 22:00:00 +0000

Most of the genetic mutations that cause cancer result from environmental ‘damage’ (for example, through smoking or as a result of over-exposure to sunlight) or from spontaneous errors as cells divide. In a study published today, researchers at the Department of Haematology, the Cambridge Institute for Medical Research and the Wellcome Trust/Medical Research Council Stem Cell Institute show for the first time that the order in which such mutations occur can have an impact on disease severity and response to therapy.

̽��ֱ��researchers examined genetically distinct single stem cells taken from patients with myeloproliferative neoplasms (MPNs), a group of bone marrow disorders that are characterised by the over-production of mature blood cells together with an increased risk of both blood clots and leukaemia. These disorders are identified at a much earlier stage than most cancers because the increased number of blood cells is readily detectable in blood counts taken during routine clinical check-ups for completely different problems.

Approximately one in ten of MPN patients carry mutations in both the JAK2 gene and the TET2 gene. By studying these individuals, the research team was able to determine which mutation came first and to study the effect of mutation order on the behaviour of single blood stem cells.

Using samples collected primarily from patients attending Addenbrooke’s Hospital, part of the Cambridge ̽��ֱ�� Hospitals, researchers showed that patients who acquire mutations in JAK2 prior to those in TET2 display aberrant blood counts over a decade earlier, are more likely to develop a more severe red blood cell disease subtype, are more likely to suffer a blood clot, and their cells respond differently to drugs that inhibit JAK2.

Dr David Kent, one of the study’s lead authors, says: “This surprising finding could help us offer more accurate prognoses to MPN patients based on their mutation order and tailor potential therapies towards them. For example, our results predict that targeted JAK2 therapy would be more effective in patients with one mutation order but not the other.”

Professor Tony Green, who led the study, adds: “This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy. These results show how study of the MPNs provides unparalleled access to the earliest stages of tumour development (inaccessible in other cancers, which usually cannot be detected until many mutations have accumulated). This should give us powerful insights into the origins of cancer.”

Work in the Green Lab is supported in part by Leukaemia and Lymphoma Research and Cancer Research UK.

Dr Matt Kaiser, Head of Research at Leukaemia & Lymphoma Research, said: “We are becoming more and more aware that a cancer’s genetic signature can vary from patient to patient, and we are becoming better at personalising treatment to match this. ̽��ֱ��discovery that the order in which genetic errors occur can have such a big impact on cancer progression adds an important extra layer of complexity that will help tailor treatment for patients with MPNs. ̽��ֱ��technology to do this sort of study has been available only recently and it shows once again how pioneering research into blood cancers can reveal fundamental insights into cancer in general.”

Dr Áine McCarthy, Science Information Officer at Cancer Research UK, says: “ ̽��ֱ��methods used in this pioneering research could help improve our understanding of how cancer cells develop mutations and when they do so. This interesting study suggests that the order in which genetic faults appear can affect how patients respond to different drugs – this insight could help doctors personalise treatment to make it more effective for each patient.”

Reference
Ortmann, CA and Kent, DG et al. ̽��ֱ��Impact of Mutation Order on Myeloproliferative Neoplasms. NEJM; 11 Feb 2015

Additional funding came from the Kay Kendall Leukaemia Fund; the NIHR Cambridge Biomedical Research Centre; the Cambridge Experimental Cancer Medicine Centre; the Leukemia & Lymphoma Society of America; the Canadian Institutes of Health Research; and the Lady Tata Memorial Trust.

̽��ֱ��order in which genetic mutations are acquired determines how an individual cancer behaves, according to research from the ̽��ֱ�� of Cambridge, published today in the New England Journal of Medicine.

This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy

Tony Green

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Red blood cells (illustration)

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Novel genetic mutations cause low metabolic rate and obesity

sj387 — Fri, 25 Oct 2013 07:43:45 +0000

Researchers from the ̽��ֱ�� of Cambridge have discovered a novel genetic cause of severe obesity which, although relatively rare, demonstrates for the first time that genes can reduce basal metabolic rate – how the body burns calories.

Previous studies (performed by David Powell and colleagues at Lexicon Pharmaceuticals in Texas) demonstrated that when the gene KSR2 (Kinase Suppressor of Ras 2) was deleted in mice, the animals became severely obese. As a result of this research, Professor Sadaf Farooqi from the ̽��ֱ�� of Cambridge’s Wellcome Trust-MRC Institute of Metabolic Science decided to explore whether KSR2 mutations might also lead to obesity in humans.

In collaboration with Dr Ines Barroso’s team at the Wellcome Trust Sanger Institute, the researchers sequenced the DNA from over 2,000 severely obese patients and identified multiple mutations in the KSR2 gene. ̽��ֱ��research was published online today, 24 October, in the journal Cell.

KSR2 belongs to a group of proteins called scaffolding proteins which play a critical role in ensuring that signals from hormones such as insulin are correctly processed by cells in the body to regulate how cells grow, divide and use energy. To investigate how KSR2 mutations might lead to obesity, Professor Farooqi’s team performed a series of experiments which showed that many of the mutations disrupt these cellular signals and, importantly, reduce the ability of cells to use glucose and fatty acids.

Patients who had the mutations in KSR2 had an increased drive to eat in childhood, but also a reduced metabolic rate, indicating that they have a reduced ability to use up all the energy that they consume. A slow metabolic rate can be found in people with an underactive thyroid gland, but in these patients thyroid blood tests were in the normal range - eliminating this as a possible explanation for their low metabolic rate. People have speculated for a long time that some individuals may burn calories more slowly than others. ̽��ֱ��findings in this study provide the first evidence that defects in a particular gene, KSR2, can affect a person’s metabolic rate and how their bodies processed calories.

Professor Farooqi said: “Up until now, the genes we have identified that control body weight have largely affected appetite. However, KSR2 is different in that it also plays a role in regulating how energy is used in the body. In the future, modulation of KSR2 may represent a useful therapeutic strategy for obesity and type 2 diabetes.”

Changes in diet and levels of physical activity underlie the recent increase in obesity in the UK and worldwide. However, there is a lot of variation in how much weight people gain. This variation between people is largely influenced by genetic factors, and many of the genes involved act in the brain. ̽��ֱ��discovery of a new obesity gene, KSR2, adds another level of complexity to the body’s mechanisms for regulating weight. ̽��ֱ��Cambridge team is continuing to study the genetic factors influencing obesity, findings which they hope to translate into beneficial therapies in the future.

Professor Farooqi’s research was funded by the Wellcome Trust.

Researchers believe the gene could be a useful therapeutic target for treating obesity and type 2 diabetes

In the future, modulation of KSR2 may represent a useful therapeutic strategy for obesity and type 2 diabetes

Sadaf Farooqi

Shaury Nash

DNA code

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Scientists discover genetic disease which causes recurrent respiratory infections

sj387 — Fri, 18 Oct 2013 08:36:28 +0000

Cambridge scientists have discovered a rare genetic disease which predisposes patients to severe respiratory infections and lung damage. Because the scientists also identified how the genetic mutation affects the immune system, they are hopeful that new drugs that are currently undergoing clinical trials to treat leukaemia may also be effective in helping individuals with this debilitating disease.

For the study, led by the ̽��ֱ�� of Cambridge in collaboration with the Babraham Institute and the MRC Laboratory for Molecular Biology, the researchers first examined genetic information from individuals who suffer from immunodeficiency and are predisposed to infections. From this group, the scientists identified a unique genetic mutation in 17 patients that suffer from severe respiratory infections and rapidly develop lung damage.

̽��ֱ��researchers, who were primarily funded by the Wellcome Trust, MRC, BBSRC and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, found that the mutation increases activity of an enzyme called Phosphoinositide 3-Kinase δ (PI3Kδ). ̽��ֱ��enzyme is present in immune cells and regulates their function. However, constantly activated PI3Kδ impairs work of these immune cells, preventing them from responding efficiently to infection and providing long-lasting protection. Consequently, patients with this mutation have severe and recurrent infections.

“Patients with this mutation have a defect in the immune cells, so their protection from infections is weak and inefficient,” said Sergey Nejentsev, Wellcome Trust Senior Research Fellow from the ̽��ֱ�� of Cambridge who led the research. “We called this newly identified disease Activated PI3K- δ Syndrome (APDS) after the enzyme in the immune system that is affected by the genetic mutation.”

̽��ֱ��researchers believe that it may be possible to treat APDS in future. There are currently drugs in clinical trials for leukaemia that were designed specifically to inhibit the PI3Kδ enzyme. ̽��ֱ��researchers have already shown that these drugs reduce activity of the mutant protein.

Alison Condliffe, joint senior author on the paper from the ̽��ֱ�� of Cambridge, said: “We are very excited by the prospect of using these drugs to help patients with APDS. We believe that they may be able to restore functions of immune cells, thereby reducing infections and preventing lung damage.”

Although the prevalence of the disease is not yet known, the scientists believe that it is relatively frequent compared to other immunodeficiencies and may underpin immunodeficiencies and chronic lung disorders in a substantial fraction of patients.

“It is very important that doctors consider a possibility of APDS in their patients,” said Dr Nejentsev. “A simple genetic test can tell if the patient has the mutation or not. We believe that now many more APDS patients will be identified all over the world.”

̽��ֱ��research was published by Science Express (the electronic publication of selected Science papers).

Discovery could lead to new treatments for this genetic disorder.

We believe that now many more APDS patients will be identified all over the world

Sergey Nejentsev

Chikumaya

X-ray photo of a chest

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Folic acid deficiency can affect the health of great, great grandchildren

gm349 — Thu, 26 Sep 2013 00:07:14 +0000

Folic acid deficiency can cause severe health problems in offspring, including spina bifida, heart defects and placental abnormalities. A study out today reveals that a mutation in a gene necessary for the metabolism of folic acid not only impacts the immediate offspring but can also have detrimental health effects on the next several generations. ̽��ֱ��new research, which also sheds light on the molecular mechanism of folic acid (also known as folate) during development, was published today in the journal Cell.

“Although our research focused on genetic mutations which disrupts the break down and metabolism of folic acid, we believe that folic acid deficiency in the diet would have a similar multi-generational impact on health,” said Dr Erica Watson from the Centre for Trophoblast Research at the ̽��ֱ�� of Cambridge, who led the study.

̽��ֱ��detrimental effects of folic acid deficiency on development are quite well known. As a result, many countries, to include Canada and the US, have implemented folate fortification programmes which require folic acid to be added to cereal products. However, until now, very little was known about how folic acid deficiency caused the diverse range of health problems in offspring.

“Fortification programmes have reduced the risk of health effects but not eliminated them completely,” said Dr Watson. “Based on our research, we now believe that it may take more than one generation to eliminate the health problems caused by folate deficiency.”

̽��ֱ��researchers, from the Universities of Cambridge and Calgary, used mice for the study as they metabolize folic acid very similarly to humans and because folic acid deficiency or mutations in the same genes required to break down folic acid in humans result in similar developmental abnormalities and diseases in mice. This enabled the researchers to explore how the molecular mechanism of folic acid deficiency impacted development, thereby causing health problems.

For the study, the scientists used mice in which a gene called Mtrr was specifically mutated. ̽��ֱ��gene is key to the normal progression of the folic acid cycle and, when mutated, it results in abnormal folic acid metabolism causing similar effects to dietary folic acid deficiency. ̽��ֱ��researchers found that when either the maternal grandmother or the maternal grandfather had this Mtrr mutation, their genetically normal grandchildren were at risk of a wide spectrum of developmental abnormalities. These developmental abnormalities were also seen in the fourth and fifth generations of mice.

Through another experiment which involved transferring the embryo from the third generation into a normal healthy female mouse, they discovered that these developmental abnormalities were not passed down genetically. Instead, the serious defects were the result of epigenetic changes which had been inherited.

Epigenetics is a system which turns genes on and off. It occurs when chemicals, such as methyl groups, bind to the DNA at specific locations to control which genes are expressed and when they are expressed. (Interestingly, the folic acid cycle is required to make sure that the cell has enough methyl groups for normal gene expression.) Epigenetic inheritance refers to the passing of these epigenetic marks from one generation to the next – despite the epigenome, for the most part, being ‘wiped clean’ after each generation.

̽��ֱ��researchers hypothesize that, for a yet unknown reason, some of these abnormal epigenetic marks caused by the Mtrr mutation may escape this normal erasure and are inherited by the next generation. If these abnormal epigenetic marks that regulate genes important for development are inherited, then these generations may develop abnormalities as a result of the wrong genes being turned on or off.

“It surprised us to find that the great, great grandchildren of a parent who has had a folic acid deficiency could have health problems as a result - suggesting that the ‘sins of your maternal grandparents’ can have an effect on your development and your risk for disease,” said Dr Watson.

“More importantly, our research shows that disease in general can be inherited through epigenetic means rather than genetic means, which has huge implications for human health. Environmental factors that influence epigenetic patterns - e.g., diet, epigenetic disruptors in the environment such as chemicals, etc. - may also have long term, multigenerational effects.”

Deficiencies associated with spina bifida, heart defects and placental abnormalities.

It surprised us to find that the great, great grandchildren of a parent who has had a folic acid deficiency could have health problems as a result.

Dr Erica Watson

Folic acid deficiency can affect the health of great, great grandchildren

Dr Erica Watson

Mouse embryos half-way through gestation (embryonic day 10.5). From left to right: normal size, growth restricted and growth enhanced.

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