Environment and Human Genetics? Does this affect Greyhounds?
Dec 30, 2018 14:02:16 GMT 10
Post by Tom Meulman on Dec 30, 2018 14:02:16 GMT 10
There is far more to genetics than the sequence of building blocks in the DNA molecules that make up our genes and chromosomes. The "more" is known as epigenetics.
What is epigenetics?
Epigenetics, literally "on" genes, refers to all modifications to genes other than changes in the DNA sequence itself. Epigenetic modifications include addition of molecules, like methyl groups, to the DNA backbone. Adding these groups changes the appearance and structure of DNA, altering how a gene can interact with important interpreting (transcribing) molecules in the cell's nucleus.
How do epigenetic modifications affect genes?
Genes carry the blueprints to make proteins in the cell. The DNA sequence of a gene is transcribed into RNA, which is then translated into the sequence of a protein. Every cell in the body has the same genetic information; what makes cells, tissues and organs different is that different sets of genes are turned on or expressed.
Because they change how genes can interact with the cell's transcribing machinery, epigenetic modifications, or "marks," generally turn genes on or off, allowing or preventing the gene from being used to make a protein. On the other hand, mutations and bigger changes in the DNA sequence (like insertions or deletions) change not only the sequence of the DNA and RNA, but may affect the sequence of the protein as well. (Mutations in the sequence can prevent a gene from being recognized, amounting to its being turned off, but only if the mutations affect specific regions of the DNA.)
There are different kinds of epigenetic "marks," chemical additions to the genetic sequence. The addition of methyl groups to the DNA backbone is used on some genes to distinguish the gene copy inherited from the father and that inherited from the mother. In this situation, known as "imprinting," the marks both distinguish the gene copies and tell the cell which copy to use to make proteins.
What is "imprinting?"
"Imprinted genes" don't rely on traditional laws of Mendelian genetics, which describe the inheritance of traits as either dominant or recessive. In Mendelian genetics, both parental copies are equally likely to contribute to the outcome. The impact of an imprinted gene copy, however, depends only on which parent it was inherited from. For some imprinted genes, the cell only uses the copy from the mother to make proteins, and for others only that from the father.
Imprinting in genetics is not new, but it is gaining visibility as it is linked to more diseases and conditions that affect humans. Centuries ago, mule breeders in Iraq noted that crossing a male horse and a female donkey created a different animal than breeding a female horse and a male donkey. In the modern scientific era, however, the initial evidence for parent-of-origin effects in genetics didn't appear until the mid 1950s or so.
Then, in the mid 1980s, scientists studying mice discovered that inheritance of genetic material from both a male and a female parent was required for normal development. The experiments also revealed that the resulting abnormalities changed depending on whether the inherited genetic material was all male in origin or all female.
Around the same time, others discovered that the effects of some transgenes in mice differed when they were passed from the male or female parent. The first naturally occurring example of an imprinted gene was the discovery of imprinting in the IGF-2 gene in mice in 1991, and currently about 50 imprinted genes have been identified in mice and humans.
Why should it matter which parent donated the gene copy?
Why imprinting evolved in animals is unclear, but one hypothesis is that imprinting represents a genetic "battle of the sexes," since many imprinted genes regulate embryonic growth. Maternally-expressed imprinted genes (for which the copy from mom is always used) usually suppress growth, while paternally expressed genes usually enhance growth.
The "battle of the sexes" hypothesis is partly based on studies in animals that suggest growth-promoting imprinted genes help ensure the continuation of the father's genes, a particularly important issue for species in which more than one male can contribute to a single litter of offspring. The mother, however, is more interested in maintaining her own health, biologically speaking, and hence her genes "fight" the paternal genes and limit the size of the embryo or fetus.
What role does imprinting play in disease?
Because of their growth-related aspects, imprinted genes likely play a major role in the development of cancer and other conditions in which cell and tissue growth are abnormal. Imprinted genes in which the copy from the mother is turned on (maternally expressed) usually suppress growth, while paternally expressed genes usually stimulate growth (see above).
In cancer, some tumor suppressor genes are actually maternally expressed genes that are mistakenly turned off, preventing the growth-limiting protein from being made. Likewise, many oncogenes -- growth-promoting genes -- are paternally expressed genes for which a single dose of the protein is just right for normal cell proliferation. However, if the maternal copy of the oncogene loses its epigenetic marks and is turned on as well, uncontrolled cell growth can result.
In the collection of birth defects known as Beckwith-Wiedemann syndrome (BWS), abnormal epigenetics leads to abnormal growth of tissues, overgrowth of abdominal organs, low blood sugar at birth and cancers. Similiarly, in the imprinting disorder Prader-Willi syndrome, abnormal epigenetics causes short stature and mental retardation as well as other syndromic features.
There's also evidence in mice that some imprinted genes may play a role in behavior, particularly in nurturing and social situations.
How does imprinting get messed up?
Just as mutations in the sequence of DNA can be acquired as a cell copies its DNA, changes in a cell's epigenetics can be acquired as well, although how those errors occur isn't as well understood. Scientists do know that epigenetic alterations can be caused by environmental changes, such as the laboratory conditions used for growing cells, but the details are murky.
For example, researchers are still trying to understand the process by which cells maintain or change their gene's imprinting marks. In sperm and egg, for instance, imprinted gene copies have to be re-imprinted. Imagine one copy of a paternally imprinted gene passed from a father to his daughter (the copy is paternally inherited and will be "on") and then to her child (it's now a maternally inherited copy and will be "off").
Many scientists believe that "incorrect" epigenetic changes to tumor suppressor genes and oncogenes are some of the first steps in cancer initiation. Determining when and how imprinting marks get re-written during egg and sperm development is crucial in figuring out whether imprinting abnormalities could be corrected in cancer.
What's next for imprinting research?
As more is learned about what role abnormal imprinting plays in biology and disease, it's important to continue learning about exactly how imprinting works. What marks distinguish maternal and paternal gene copies, and are they the same for all imprinted genes? How and when during conception or formation of sperm and egg are the tell-tale marks changed?
Can epigenetics be manipulated to return normal control to cells in tumors?
To find answers to these and other questions, imprinting in early stage embryos will need to be studied. Hopkins researchers recently created a mouse model in which the paternal and maternal gene copies are easily distinguished in order to help answer these questions. The true test will be one day evaluating the questions in humans, although such experiments are not currently permitted.
The Ghost in Your Genes
The scientists who believe your genes are shaped in part by your ancestors' life experiences.
Biology stands on the brink of a shift in the understanding of inheritance. The discovery of epigenetics – hidden influences upon the genes – could affect every aspect of our lives.
At the heart of this new field is a simple but contentious idea – that genes have a 'memory'. That the lives of your grandparents – the air they breathed, the food they ate, even the things they saw – can directly affect you, decades later, despite your never experiencing these things yourself. And that what you do in your lifetime could in turn affect your grandchildren.
The conventional view is that DNA carries all our heritable information and that nothing an individual does in their lifetime will be biologically passed to their children. To many scientists, epigenetics amounts to a heresy, calling into question the accepted view of the DNA sequence – a cornerstone on which modern biology sits.
Epigenetics adds a whole new layer to genes beyond the DNA. It proposes a control system of 'switches' that turn genes on or off – and suggests that things people experience, like nutrition and stress, can control these switches and cause heritable effects in humans.
In a remote town in northern Sweden there is evidence for this radical idea. Lying in Överkalix's parish registries of births and deaths and its detailed harvest records is a secret that confounds traditional scientific thinking. Marcus Pembrey, a Professor of Clinical Genetics at the Institute of Child Health in London, in collaboration with Swedish researcher Lars Olov Bygren, has found evidence in these records of an environmental effect being passed down the generations. They have shown that a famine at critical times in the lives of the grandparents can affect the life expectancy of the grandchildren. This is the first evidence that an environmental effect can be inherited in humans.
In other independent groups around the world, the first hints that there is more to inheritance than just the genes are coming to light. The mechanism by which this extraordinary discovery can be explained is starting to be revealed.
Professor Wolf Reik, at the Babraham Institute in Cambridge, has spent years studying this hidden ghost world. He has found that merely manipulating mice embryos is enough to set off 'switches' that turn genes on or off.
For mothers like Stephanie Mullins, who had her first child by in vitro fertilisation, this has profound implications. It means it is possible that the IVF procedure caused her son Ciaran to be born with Beckwith-Wiedemann Syndrome – a rare disorder linked to abnormal gene expression. It has been shown that babies conceived by IVF have a three- to four-fold increased chance of developing this condition.
And Reik's work has gone further, showing that these switches themselves can be inherited. This means that a 'memory' of an event could be passed through generations. A simple environmental effect could switch genes on or off – and this change could be inherited.
His research has demonstrated that genes and the environment are not mutually exclusive but are inextricably intertwined, one affecting the other.
The idea that inheritance is not just about which genes you inherit but whether these are switched on or off is a whole new frontier in biology. It raises questions with huge implications, and means the search will be on to find what sort of environmental effects can affect these switches.
After the tragic events of September 11th 2001, Rachel Yehuda, a psychologist at the Mount Sinai School of Medicine in New York, studied the effects of stress on a group of women who were inside or near the World Trade Center and were pregnant at the time. Produced in conjunction with Jonathan Seckl, an Edinburgh doctor, her results suggest that stress effects can pass down generations.
Meanwhile research at Washington State University points to toxic effects – like exposure to fungicides or pesticides – causing biological changes in rats that persist for at least four generations.
This work is at the forefront of a paradigm shift in scientific thinking. It will change the way the causes of disease are viewed, as well as the importance of lifestyles and family relationships. What people do no longer just affects themselves, but can determine the health of their children and grandchildren in decades to come. "We are," as Marcus Pembrey says, "all guardians of our genome."
Epigenetics
Epigenetics refers to the covalent modifications found in chromatin, on both the DNA and the accompanying histone proteins. The narrowest definition would encompass only those modifications that can be transmitted down cellular generations, but the term is more commonly used to describe all such alterations, whether these are heritable or transient. Indeed, much of the current research focus in the field is on the relatively transient changes because of the importance of these changes in influencing gene expression and hence cellular activity.
A wide range of epigenetic modifications (or “marks”) have been identified. Methylation is the commonest change in DNA, but a much greater range of modifications has been found on histone proteins including methylation, acetylation, phosphorylation, neddylation, SUMOlation and ubiquitinylation.
The establishment or removal of these marks is a complex and dynamic process, and is also processive as the presence or absence of a particular modification on a histone protein influences the other modifications that can be achieved.
The control of epigenetic modifications and their downstream effects on gene expression operates at all levels of the cellular machinery. Stimuli are converted into signalling pathways leading to the nucleus, where they influence the enzymes that modify chromatin. Differentially modified chromatin binds different complexes of proteins which affect gene transcription. Multiple epigenetic affectors and effectors will be present and active in a cell at any given moment, operating in complex and interacting networks. These networks may be further modulated by the actions of non-coding RNAs including microRNAs.
Members of CellCentric’s network of scientists are investigating all levels of the epigenetic pathways, from a variety of technological and biological angles, leading to new opportunities in drug discovery.
Heavy going but contains some interesting ideas.
Tom
What is epigenetics?
Epigenetics, literally "on" genes, refers to all modifications to genes other than changes in the DNA sequence itself. Epigenetic modifications include addition of molecules, like methyl groups, to the DNA backbone. Adding these groups changes the appearance and structure of DNA, altering how a gene can interact with important interpreting (transcribing) molecules in the cell's nucleus.
How do epigenetic modifications affect genes?
Genes carry the blueprints to make proteins in the cell. The DNA sequence of a gene is transcribed into RNA, which is then translated into the sequence of a protein. Every cell in the body has the same genetic information; what makes cells, tissues and organs different is that different sets of genes are turned on or expressed.
Because they change how genes can interact with the cell's transcribing machinery, epigenetic modifications, or "marks," generally turn genes on or off, allowing or preventing the gene from being used to make a protein. On the other hand, mutations and bigger changes in the DNA sequence (like insertions or deletions) change not only the sequence of the DNA and RNA, but may affect the sequence of the protein as well. (Mutations in the sequence can prevent a gene from being recognized, amounting to its being turned off, but only if the mutations affect specific regions of the DNA.)
There are different kinds of epigenetic "marks," chemical additions to the genetic sequence. The addition of methyl groups to the DNA backbone is used on some genes to distinguish the gene copy inherited from the father and that inherited from the mother. In this situation, known as "imprinting," the marks both distinguish the gene copies and tell the cell which copy to use to make proteins.
What is "imprinting?"
"Imprinted genes" don't rely on traditional laws of Mendelian genetics, which describe the inheritance of traits as either dominant or recessive. In Mendelian genetics, both parental copies are equally likely to contribute to the outcome. The impact of an imprinted gene copy, however, depends only on which parent it was inherited from. For some imprinted genes, the cell only uses the copy from the mother to make proteins, and for others only that from the father.
Imprinting in genetics is not new, but it is gaining visibility as it is linked to more diseases and conditions that affect humans. Centuries ago, mule breeders in Iraq noted that crossing a male horse and a female donkey created a different animal than breeding a female horse and a male donkey. In the modern scientific era, however, the initial evidence for parent-of-origin effects in genetics didn't appear until the mid 1950s or so.
Then, in the mid 1980s, scientists studying mice discovered that inheritance of genetic material from both a male and a female parent was required for normal development. The experiments also revealed that the resulting abnormalities changed depending on whether the inherited genetic material was all male in origin or all female.
Around the same time, others discovered that the effects of some transgenes in mice differed when they were passed from the male or female parent. The first naturally occurring example of an imprinted gene was the discovery of imprinting in the IGF-2 gene in mice in 1991, and currently about 50 imprinted genes have been identified in mice and humans.
Why should it matter which parent donated the gene copy?
Why imprinting evolved in animals is unclear, but one hypothesis is that imprinting represents a genetic "battle of the sexes," since many imprinted genes regulate embryonic growth. Maternally-expressed imprinted genes (for which the copy from mom is always used) usually suppress growth, while paternally expressed genes usually enhance growth.
The "battle of the sexes" hypothesis is partly based on studies in animals that suggest growth-promoting imprinted genes help ensure the continuation of the father's genes, a particularly important issue for species in which more than one male can contribute to a single litter of offspring. The mother, however, is more interested in maintaining her own health, biologically speaking, and hence her genes "fight" the paternal genes and limit the size of the embryo or fetus.
What role does imprinting play in disease?
Because of their growth-related aspects, imprinted genes likely play a major role in the development of cancer and other conditions in which cell and tissue growth are abnormal. Imprinted genes in which the copy from the mother is turned on (maternally expressed) usually suppress growth, while paternally expressed genes usually stimulate growth (see above).
In cancer, some tumor suppressor genes are actually maternally expressed genes that are mistakenly turned off, preventing the growth-limiting protein from being made. Likewise, many oncogenes -- growth-promoting genes -- are paternally expressed genes for which a single dose of the protein is just right for normal cell proliferation. However, if the maternal copy of the oncogene loses its epigenetic marks and is turned on as well, uncontrolled cell growth can result.
In the collection of birth defects known as Beckwith-Wiedemann syndrome (BWS), abnormal epigenetics leads to abnormal growth of tissues, overgrowth of abdominal organs, low blood sugar at birth and cancers. Similiarly, in the imprinting disorder Prader-Willi syndrome, abnormal epigenetics causes short stature and mental retardation as well as other syndromic features.
There's also evidence in mice that some imprinted genes may play a role in behavior, particularly in nurturing and social situations.
How does imprinting get messed up?
Just as mutations in the sequence of DNA can be acquired as a cell copies its DNA, changes in a cell's epigenetics can be acquired as well, although how those errors occur isn't as well understood. Scientists do know that epigenetic alterations can be caused by environmental changes, such as the laboratory conditions used for growing cells, but the details are murky.
For example, researchers are still trying to understand the process by which cells maintain or change their gene's imprinting marks. In sperm and egg, for instance, imprinted gene copies have to be re-imprinted. Imagine one copy of a paternally imprinted gene passed from a father to his daughter (the copy is paternally inherited and will be "on") and then to her child (it's now a maternally inherited copy and will be "off").
Many scientists believe that "incorrect" epigenetic changes to tumor suppressor genes and oncogenes are some of the first steps in cancer initiation. Determining when and how imprinting marks get re-written during egg and sperm development is crucial in figuring out whether imprinting abnormalities could be corrected in cancer.
What's next for imprinting research?
As more is learned about what role abnormal imprinting plays in biology and disease, it's important to continue learning about exactly how imprinting works. What marks distinguish maternal and paternal gene copies, and are they the same for all imprinted genes? How and when during conception or formation of sperm and egg are the tell-tale marks changed?
Can epigenetics be manipulated to return normal control to cells in tumors?
To find answers to these and other questions, imprinting in early stage embryos will need to be studied. Hopkins researchers recently created a mouse model in which the paternal and maternal gene copies are easily distinguished in order to help answer these questions. The true test will be one day evaluating the questions in humans, although such experiments are not currently permitted.
The Ghost in Your Genes
The scientists who believe your genes are shaped in part by your ancestors' life experiences.
Biology stands on the brink of a shift in the understanding of inheritance. The discovery of epigenetics – hidden influences upon the genes – could affect every aspect of our lives.
At the heart of this new field is a simple but contentious idea – that genes have a 'memory'. That the lives of your grandparents – the air they breathed, the food they ate, even the things they saw – can directly affect you, decades later, despite your never experiencing these things yourself. And that what you do in your lifetime could in turn affect your grandchildren.
The conventional view is that DNA carries all our heritable information and that nothing an individual does in their lifetime will be biologically passed to their children. To many scientists, epigenetics amounts to a heresy, calling into question the accepted view of the DNA sequence – a cornerstone on which modern biology sits.
Epigenetics adds a whole new layer to genes beyond the DNA. It proposes a control system of 'switches' that turn genes on or off – and suggests that things people experience, like nutrition and stress, can control these switches and cause heritable effects in humans.
In a remote town in northern Sweden there is evidence for this radical idea. Lying in Överkalix's parish registries of births and deaths and its detailed harvest records is a secret that confounds traditional scientific thinking. Marcus Pembrey, a Professor of Clinical Genetics at the Institute of Child Health in London, in collaboration with Swedish researcher Lars Olov Bygren, has found evidence in these records of an environmental effect being passed down the generations. They have shown that a famine at critical times in the lives of the grandparents can affect the life expectancy of the grandchildren. This is the first evidence that an environmental effect can be inherited in humans.
In other independent groups around the world, the first hints that there is more to inheritance than just the genes are coming to light. The mechanism by which this extraordinary discovery can be explained is starting to be revealed.
Professor Wolf Reik, at the Babraham Institute in Cambridge, has spent years studying this hidden ghost world. He has found that merely manipulating mice embryos is enough to set off 'switches' that turn genes on or off.
For mothers like Stephanie Mullins, who had her first child by in vitro fertilisation, this has profound implications. It means it is possible that the IVF procedure caused her son Ciaran to be born with Beckwith-Wiedemann Syndrome – a rare disorder linked to abnormal gene expression. It has been shown that babies conceived by IVF have a three- to four-fold increased chance of developing this condition.
And Reik's work has gone further, showing that these switches themselves can be inherited. This means that a 'memory' of an event could be passed through generations. A simple environmental effect could switch genes on or off – and this change could be inherited.
His research has demonstrated that genes and the environment are not mutually exclusive but are inextricably intertwined, one affecting the other.
The idea that inheritance is not just about which genes you inherit but whether these are switched on or off is a whole new frontier in biology. It raises questions with huge implications, and means the search will be on to find what sort of environmental effects can affect these switches.
After the tragic events of September 11th 2001, Rachel Yehuda, a psychologist at the Mount Sinai School of Medicine in New York, studied the effects of stress on a group of women who were inside or near the World Trade Center and were pregnant at the time. Produced in conjunction with Jonathan Seckl, an Edinburgh doctor, her results suggest that stress effects can pass down generations.
Meanwhile research at Washington State University points to toxic effects – like exposure to fungicides or pesticides – causing biological changes in rats that persist for at least four generations.
This work is at the forefront of a paradigm shift in scientific thinking. It will change the way the causes of disease are viewed, as well as the importance of lifestyles and family relationships. What people do no longer just affects themselves, but can determine the health of their children and grandchildren in decades to come. "We are," as Marcus Pembrey says, "all guardians of our genome."
Epigenetics
Epigenetics refers to the covalent modifications found in chromatin, on both the DNA and the accompanying histone proteins. The narrowest definition would encompass only those modifications that can be transmitted down cellular generations, but the term is more commonly used to describe all such alterations, whether these are heritable or transient. Indeed, much of the current research focus in the field is on the relatively transient changes because of the importance of these changes in influencing gene expression and hence cellular activity.
A wide range of epigenetic modifications (or “marks”) have been identified. Methylation is the commonest change in DNA, but a much greater range of modifications has been found on histone proteins including methylation, acetylation, phosphorylation, neddylation, SUMOlation and ubiquitinylation.
The establishment or removal of these marks is a complex and dynamic process, and is also processive as the presence or absence of a particular modification on a histone protein influences the other modifications that can be achieved.
The control of epigenetic modifications and their downstream effects on gene expression operates at all levels of the cellular machinery. Stimuli are converted into signalling pathways leading to the nucleus, where they influence the enzymes that modify chromatin. Differentially modified chromatin binds different complexes of proteins which affect gene transcription. Multiple epigenetic affectors and effectors will be present and active in a cell at any given moment, operating in complex and interacting networks. These networks may be further modulated by the actions of non-coding RNAs including microRNAs.
Members of CellCentric’s network of scientists are investigating all levels of the epigenetic pathways, from a variety of technological and biological angles, leading to new opportunities in drug discovery.
Heavy going but contains some interesting ideas.
Tom