Ancestors Effect
Bonding, Belonging, & Shaking the Limbs
https://books.google.com/books?id=3blTkK3IMVIC&printsec=frontcover#v=onepage&q&f=false
Bonding, Belonging, & Shaking the Limbs
https://books.google.com/books?id=3blTkK3IMVIC&printsec=frontcover#v=onepage&q&f=false
What Are They Remembering For Us?
And Us For Them?
Our history is our collective transgenerational memory. No people can successfully live outside of their memory. In the West the past plays one of the most critical roles in Western civilization. but it is so embedded, so obvious that it becomes invisible. Experiences change sperm and egg prints and epigenetic changes in chromosomes. Toxins that affected your great-grandparents could be in your genes.
Most epigenetic regulation is probably not inherited transgenerationally (the definition of epigenetics relates to changes that are heritable through meiosis and mitosis, not sexual reproduction. But transgenerational inheritance IS an epigenetic phenomenon. As far as we know, most epigenetic marks are cleared during embryonic development and somehow reset. We don't really understand why a subset are not reset in certain situations.
This is an area were there are still so many unknowns. Only 2% of the human genome codes for protein-coding genes and this represents about 20,000 protein-coding genes.
When the genome was sequenced and we realized that there were so few protein-coding genes, scientists realized that there must be other mechanisms that we hadn’t identified or recognized the significance of yet. One of these mechanisms that has received increased attention in recent years is epigenetics.
Epigenetics literally means “over the genome”. It encompasses all meiotically and mitotically heritable changes in gene expression that are not coded in the DNA sequence itself. If we break that down, there are some key points to note.
-"Not coded in the DNA":
There is no change in the DNA sequence. Thus, for these to be heritable, there must be mechanisms of inheritance besides DNA replication.
-“changes in gene expression":
The underlying assumption of all epigenetic studies should be that these changes alter gene expression (or change how inducible or repressible gene expression is, but that’s harder to measure)
-"meiotically and mitotically heritable”:
This means heritable through cell division. NOT heritable through generations. The media has focused on epigenetics as evidence for Lamarckian evolution (the inheritance of acquired traits), but this is not necessarily accurate.
Epigenetic mechanisms are, by definition, heritable through cell division, but in mammals, many (maybe most?) of these marks are cleared in gametogenesis and embryogenesis (more on this in a later post). Epigenetic mechanisms can mediate transgenerational inheritance but this is not a necessary part of epigenetic mechanisms (more on this too in a later post.)
Epigenetics generally refers to four mechanisms.
1) Cytosine modifications: direct covalent modifications of cytosines in the DNA sequences. Cytosine is methylated by DNA methyltransferases to 5-methylcytosine (5mC). 5mC can be oxidized by Tet enzymes to 5-hydroxymethylcytosine (5hmC0. These two modifications are thought to be stable. Tet enzymes can also further convert 5hmC to 5-formylcytosine and 5-carboxylcytosine, but they are thought to not be stable and to be intermediates in demethylation (the removal of these cytosine modifications). Modification of cytosines can alter how transcription factors and other DNA binding protein interact with DNA. There are also DNA binding proteins that specifically recognize the different modifications to cytosine and these can recruit their own interacting protein. All of this altered recruitment of proteins affects gene expression.
2) Histone modifications: Histones are proteins that, with DNA, form chromatin, which is the material that makes up chromosomes. The fundamental unit of chromatin is the nucleosome. In each nucleosome, 147 DNA base pairs wrap around an octamer of histone proteins (2 each of the 4 core histones). An additional linker histone binds to the DNA between these octamers. Each histone has a tail that can be covalently modified. Histone modifications are the post-translational methylation, acetylation, phosphorylation or ubiquitination of these histone tails. These modifications are associated with increased or decreased gene expression, depending on the site of the modification. An additional level of regulation comes from the fact that the core histones can also be swapped out for alternate histones.
3) Non-coding RNAs: There are perhaps more genes that code for functional RNAs than there are protein-coding genes in the human genome. These RNAs are involved in many processes including RNA interference, post-transcriptional gene silencing, and specifying regions of heterochromatin.
4) Long range chromatin interactions: In biology, we often forget about the larger 3D arrangements within cells. We now know that, in addition to the arrangement of DNA into chromosomes, chromosomes interact with each other and form functional domains within the nucleus. I shared a recent paper from Cell demonstrating this that I’ll reshare because it’s just so amazing! Really watch it. It’s amazing and made me think about the cell in a way I never thought about it before.
These mechanisms do not exist in isolation. They form a network of mechanisms that all work together to effect gene expression.
Changes from chemicals, pesticides, fungicides, and contaminants (including vaccines) are passed down through the generations. So even if our children have never been exposed to a toxin, their genes are changed because of the toxins their mothers, grandmothers, great grandmothers and so on were exposed to.
Genes aren't the cause of most disease; the cause of most disease alters genetic expression. Epigenetics is revealing the biological transmission of molecular memory.
We can pass down altered stress responses, prenatal exposure, emotional trauma, abuse, violence, adult onset diseases, reproductive and fertility issues, fears and anxieties, endocrine disruption, toxic environmental exposure, metabolic disease, personality disorders, mental illness, addiction, sexual conflict, chemical damage, gene silencing, pharmaceutical side-effects, attachment disorder, DNA methylation, histone modifications and a host of other disorders.
Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring.
During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring, Another measure is 15 cortisol response indices measurable between mothers and infants. Fetal cells influence maternal health during pregnancy (and long after)
The Spent Breath of Millions
Transgenerational trauma is trauma that is transferred from the first generation of trauma survivors to the second and further generations of offspring of the survivors via complex post-traumatic stress disorder mechanisms, including historical and communal trauma.
“Trauma can be transmitted across generations. However, our transgenerational wounds are not the essence of who we are. How do we transcend our identification with history? Healing involves knowing that you are not alone, trusting that there is a path to greater freedom, and a willingness to feel your relationship to the suffering of your family lineage. Releasing the burdens of trauma, our own or those of our family history, we often feel lighter, a greater sense of choice, and an increased experience belonging in the world.”
Researchers showed that exposure to at least 12 harsh punishments annually altered brain volume and function in the prefrontal cortex. BUT, they also have a great extended paragraph on the factors leading up to this, that provides even MORE reason to avoid punitive parenting. They discuss how anticipating parental needs and potential violence (what psychologists call hypervigilance and hippies call empath abilities) is a developmental skill. Some children might have a lag in this development. Which means they will experience MORE punishment. (AKA, those hard to discipline kids will get more discipline.) In turn, their brains will take more damage, and that will be passed down to the next generation.
Just as our human genes were transmitted vertically from our parents and from their parents, and ultimately from our distant primate ancestors, the same holds true for our microbial genes. This intergenerational transfer begins at the moment of birth, when the minimally colonized fetus is exposed to the microbes as it transits out through the birth canal. The infant, covered with Mom’s microbes, swallows some, which become the founders of the intestinal populations. Babies also inoculate Mom’s breast with their new mouth microbes, and she delivers them back, along with constituents in her milk that specifically favor the ancestral microbes. Thus, Mom’s skin and mouth are other important sources of baby’s early microbes.
We all carry and relive the primordial psyche which is reliving the soul of our ancestors. They may be gone, but primordial psyche remains alive within us, and available for interaction. Some live closer to it than others, but we all have creative, rational, and intuitive faculties that are rooted in this primordial ground, an unalterable level of creative imagination, primordial unity, and instinctive participation mystique.
Depression and Inflammation
http://medicalxpress.com/news/2015-11-inflammation-linked-weakened-reward-circuits.html
5 Biotypes of DepressionThe five defined depression biotypes are:
Undermethylated Depression
This type of depression was found in 38 percent of patients in the study. The problem in these cases is low activity at serotonin receptors, apparently due to rapid reabsorbtion after serotonin is released into a synapse.
“It’s not serotonin deficiency, but an inability to keep serotonin in the synapse long enough. Most of these patients report excellent response to SSRI antidepressants, although they may experience nasty side effects,” Walsh said.
Pyrrole Depression
This type was found in 17 percent of the patients studied, and most of these patients also said that SSRI antidepressants helped them. These patients exhibited a combination of impaired serotonin production and extreme oxidative stress.
Copper Overload
Accounting for 15 percent of cases in the study, these patients cannot properly metabolize metals. Most of these people say that SSRIs do not have much of an effect—positive or negative—on them, but they report benefits from normalizing their copper levels through nutrient therapy. Most of these patients are women who are also estrogen intolerant.
“For them, it’s not a serotonin issue, but extreme blood and brain levels of copper that result in dopamine deficiency and norepinephrine overload,” Walsh explained. “This may be the primary cause of postpartum depression.”
Low-Folate Depression
These patients account for 20 percent of the cases studied, and many of them say that SSRIs worsened their symptoms, while folic acid and vitamin B12 supplements helped. Benzodiazepine medications may also help people with low-folate depression.
Walsh said that a study of 50 school shootings over the past five decades showed that most shooters probably had this type of depression, as SSRIs can cause suicidal or homicidal ideation in these patients.
Toxic Depression
This type of depression is caused by toxic-metal overload—usually lead poisoning. Over the years, this type accounted for 5 percent of depressed patients, but removing lead from gasoline and paint has lowered the frequency of these cases.
“We are not the first to suggest that there may be other causes of depression, but we might be the first to identify the other forms of depression, and the first to suggest blood testing to guide the treatment approach,” Walsh said.
A New Way to Diagnose Depression?
A urine test can detect pyrrole depression, while blood testing can identify the other biotypes.
Walsh said a physician-training program is in place to expand the testing throughout the world. Last month, 66 doctors from Australia were trained in the approach, and training for U.S. physicians will take place in October. Walsh's goal is to educate 1,000 doctors on this issue in five years.
“Psychiatrists appear to be the most enthusiastic participants,” he said.
David Brendel, M.D., Ph.D., a Boston-area psychiatrist, said it would be a “significant advance” to diagnose treatable forms of depression with objective medical tests.
“But I don't see adequate evidence that these (or other) researchers are anywhere near accomplishing this,” he said. Brendel added that depression likely has many causes and complex neurophysiological underpinnings. He said the medical community is still “entirely unable” to diagnose it using medical tests, though he said researchers may be closer to having tests, such as gene assays, that can identify the most effective medical treatment for a specific patient.
Mona Shattell, Ph.D., a nurse and professor at DePaul University specializing in mental health, said that being able to diagnose depression with a blood test could potentially increase the number of people diagnosed—and lead to more people being treated for the condition.
“It would also be helpful because depression, and other mental illnesses, are still stigmatizing,” she said. “If depression could be detected via a blood test, it would clearly be in the realm of ‘medical illness’ and therefore a ‘real’ problem that is not due to individual weakness or other equally stigmatizing reasons.”
Behaviour can be affected by events in previous generations which have been passed on through a form of genetic memory, animal studies suggest.
Experiments showed that a traumatic event could affect the DNA in sperm and alter the brains and behaviour of subsequent generations.
A Nature Neuroscience study shows mice trained to avoid a smell passed their aversion on to their "grandchildren".
Experts said the results were important for phobia and anxiety research.
The animals were trained to fear a smell similar to cherry blossom.
The team at the Emory University School of Medicine, in the US, then looked at what was happening inside the sperm.
They showed a section of DNA responsible for sensitivity to the cherry blossom scent was made more active in the mice's sperm.
Both the mice's offspring, and their offspring, were "extremely sensitive" to cherry blossom and would avoid the scent, despite never having experienced it in their lives.
Changes in brain structure were also found.
"The experiences of a parent, even before conceiving, markedly influence both structure and function in the nervous system of subsequent generations," the report concluded.
Family affairThe findings provide evidence of "transgenerational epigenetic inheritance" - that the environment can affect an individual's genetics, which can in turn be passed on.
One of the researchers Dr Brian Dias told the BBC: "This might be one mechanism that descendants show imprints of their ancestor.
"There is absolutely no doubt that what happens to the sperm and egg will affect subsequent generations."
Prof Marcus Pembrey, from University College London, said the findings were "highly relevant to phobias, anxiety and post-traumatic stress disorders" and provided "compelling evidence" that a form of memory could be passed between generations.
He commented: "It is high time public health researchers took human transgenerational responses seriously.
"I suspect we will not understand the rise in neuropsychiatric disorders or obesity, diabetes and metabolic disruptions generally without taking a multigenerational approach."
In the smell-aversion study, is it thought that either some of the odour ends up in the bloodstream which affected sperm production or that a signal from the brain was sent to the sperm to alter DNA.
And Us For Them?
Our history is our collective transgenerational memory. No people can successfully live outside of their memory. In the West the past plays one of the most critical roles in Western civilization. but it is so embedded, so obvious that it becomes invisible. Experiences change sperm and egg prints and epigenetic changes in chromosomes. Toxins that affected your great-grandparents could be in your genes.
Most epigenetic regulation is probably not inherited transgenerationally (the definition of epigenetics relates to changes that are heritable through meiosis and mitosis, not sexual reproduction. But transgenerational inheritance IS an epigenetic phenomenon. As far as we know, most epigenetic marks are cleared during embryonic development and somehow reset. We don't really understand why a subset are not reset in certain situations.
This is an area were there are still so many unknowns. Only 2% of the human genome codes for protein-coding genes and this represents about 20,000 protein-coding genes.
When the genome was sequenced and we realized that there were so few protein-coding genes, scientists realized that there must be other mechanisms that we hadn’t identified or recognized the significance of yet. One of these mechanisms that has received increased attention in recent years is epigenetics.
Epigenetics literally means “over the genome”. It encompasses all meiotically and mitotically heritable changes in gene expression that are not coded in the DNA sequence itself. If we break that down, there are some key points to note.
-"Not coded in the DNA":
There is no change in the DNA sequence. Thus, for these to be heritable, there must be mechanisms of inheritance besides DNA replication.
-“changes in gene expression":
The underlying assumption of all epigenetic studies should be that these changes alter gene expression (or change how inducible or repressible gene expression is, but that’s harder to measure)
-"meiotically and mitotically heritable”:
This means heritable through cell division. NOT heritable through generations. The media has focused on epigenetics as evidence for Lamarckian evolution (the inheritance of acquired traits), but this is not necessarily accurate.
Epigenetic mechanisms are, by definition, heritable through cell division, but in mammals, many (maybe most?) of these marks are cleared in gametogenesis and embryogenesis (more on this in a later post). Epigenetic mechanisms can mediate transgenerational inheritance but this is not a necessary part of epigenetic mechanisms (more on this too in a later post.)
Epigenetics generally refers to four mechanisms.
1) Cytosine modifications: direct covalent modifications of cytosines in the DNA sequences. Cytosine is methylated by DNA methyltransferases to 5-methylcytosine (5mC). 5mC can be oxidized by Tet enzymes to 5-hydroxymethylcytosine (5hmC0. These two modifications are thought to be stable. Tet enzymes can also further convert 5hmC to 5-formylcytosine and 5-carboxylcytosine, but they are thought to not be stable and to be intermediates in demethylation (the removal of these cytosine modifications). Modification of cytosines can alter how transcription factors and other DNA binding protein interact with DNA. There are also DNA binding proteins that specifically recognize the different modifications to cytosine and these can recruit their own interacting protein. All of this altered recruitment of proteins affects gene expression.
2) Histone modifications: Histones are proteins that, with DNA, form chromatin, which is the material that makes up chromosomes. The fundamental unit of chromatin is the nucleosome. In each nucleosome, 147 DNA base pairs wrap around an octamer of histone proteins (2 each of the 4 core histones). An additional linker histone binds to the DNA between these octamers. Each histone has a tail that can be covalently modified. Histone modifications are the post-translational methylation, acetylation, phosphorylation or ubiquitination of these histone tails. These modifications are associated with increased or decreased gene expression, depending on the site of the modification. An additional level of regulation comes from the fact that the core histones can also be swapped out for alternate histones.
3) Non-coding RNAs: There are perhaps more genes that code for functional RNAs than there are protein-coding genes in the human genome. These RNAs are involved in many processes including RNA interference, post-transcriptional gene silencing, and specifying regions of heterochromatin.
4) Long range chromatin interactions: In biology, we often forget about the larger 3D arrangements within cells. We now know that, in addition to the arrangement of DNA into chromosomes, chromosomes interact with each other and form functional domains within the nucleus. I shared a recent paper from Cell demonstrating this that I’ll reshare because it’s just so amazing! Really watch it. It’s amazing and made me think about the cell in a way I never thought about it before.
These mechanisms do not exist in isolation. They form a network of mechanisms that all work together to effect gene expression.
Changes from chemicals, pesticides, fungicides, and contaminants (including vaccines) are passed down through the generations. So even if our children have never been exposed to a toxin, their genes are changed because of the toxins their mothers, grandmothers, great grandmothers and so on were exposed to.
Genes aren't the cause of most disease; the cause of most disease alters genetic expression. Epigenetics is revealing the biological transmission of molecular memory.
We can pass down altered stress responses, prenatal exposure, emotional trauma, abuse, violence, adult onset diseases, reproductive and fertility issues, fears and anxieties, endocrine disruption, toxic environmental exposure, metabolic disease, personality disorders, mental illness, addiction, sexual conflict, chemical damage, gene silencing, pharmaceutical side-effects, attachment disorder, DNA methylation, histone modifications and a host of other disorders.
Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring.
During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring, Another measure is 15 cortisol response indices measurable between mothers and infants. Fetal cells influence maternal health during pregnancy (and long after)
The Spent Breath of Millions
Transgenerational trauma is trauma that is transferred from the first generation of trauma survivors to the second and further generations of offspring of the survivors via complex post-traumatic stress disorder mechanisms, including historical and communal trauma.
“Trauma can be transmitted across generations. However, our transgenerational wounds are not the essence of who we are. How do we transcend our identification with history? Healing involves knowing that you are not alone, trusting that there is a path to greater freedom, and a willingness to feel your relationship to the suffering of your family lineage. Releasing the burdens of trauma, our own or those of our family history, we often feel lighter, a greater sense of choice, and an increased experience belonging in the world.”
Researchers showed that exposure to at least 12 harsh punishments annually altered brain volume and function in the prefrontal cortex. BUT, they also have a great extended paragraph on the factors leading up to this, that provides even MORE reason to avoid punitive parenting. They discuss how anticipating parental needs and potential violence (what psychologists call hypervigilance and hippies call empath abilities) is a developmental skill. Some children might have a lag in this development. Which means they will experience MORE punishment. (AKA, those hard to discipline kids will get more discipline.) In turn, their brains will take more damage, and that will be passed down to the next generation.
Just as our human genes were transmitted vertically from our parents and from their parents, and ultimately from our distant primate ancestors, the same holds true for our microbial genes. This intergenerational transfer begins at the moment of birth, when the minimally colonized fetus is exposed to the microbes as it transits out through the birth canal. The infant, covered with Mom’s microbes, swallows some, which become the founders of the intestinal populations. Babies also inoculate Mom’s breast with their new mouth microbes, and she delivers them back, along with constituents in her milk that specifically favor the ancestral microbes. Thus, Mom’s skin and mouth are other important sources of baby’s early microbes.
We all carry and relive the primordial psyche which is reliving the soul of our ancestors. They may be gone, but primordial psyche remains alive within us, and available for interaction. Some live closer to it than others, but we all have creative, rational, and intuitive faculties that are rooted in this primordial ground, an unalterable level of creative imagination, primordial unity, and instinctive participation mystique.
Depression and Inflammation
http://medicalxpress.com/news/2015-11-inflammation-linked-weakened-reward-circuits.html
5 Biotypes of DepressionThe five defined depression biotypes are:
Undermethylated Depression
This type of depression was found in 38 percent of patients in the study. The problem in these cases is low activity at serotonin receptors, apparently due to rapid reabsorbtion after serotonin is released into a synapse.
“It’s not serotonin deficiency, but an inability to keep serotonin in the synapse long enough. Most of these patients report excellent response to SSRI antidepressants, although they may experience nasty side effects,” Walsh said.
Pyrrole Depression
This type was found in 17 percent of the patients studied, and most of these patients also said that SSRI antidepressants helped them. These patients exhibited a combination of impaired serotonin production and extreme oxidative stress.
Copper Overload
Accounting for 15 percent of cases in the study, these patients cannot properly metabolize metals. Most of these people say that SSRIs do not have much of an effect—positive or negative—on them, but they report benefits from normalizing their copper levels through nutrient therapy. Most of these patients are women who are also estrogen intolerant.
“For them, it’s not a serotonin issue, but extreme blood and brain levels of copper that result in dopamine deficiency and norepinephrine overload,” Walsh explained. “This may be the primary cause of postpartum depression.”
Low-Folate Depression
These patients account for 20 percent of the cases studied, and many of them say that SSRIs worsened their symptoms, while folic acid and vitamin B12 supplements helped. Benzodiazepine medications may also help people with low-folate depression.
Walsh said that a study of 50 school shootings over the past five decades showed that most shooters probably had this type of depression, as SSRIs can cause suicidal or homicidal ideation in these patients.
Toxic Depression
This type of depression is caused by toxic-metal overload—usually lead poisoning. Over the years, this type accounted for 5 percent of depressed patients, but removing lead from gasoline and paint has lowered the frequency of these cases.
“We are not the first to suggest that there may be other causes of depression, but we might be the first to identify the other forms of depression, and the first to suggest blood testing to guide the treatment approach,” Walsh said.
A New Way to Diagnose Depression?
A urine test can detect pyrrole depression, while blood testing can identify the other biotypes.
Walsh said a physician-training program is in place to expand the testing throughout the world. Last month, 66 doctors from Australia were trained in the approach, and training for U.S. physicians will take place in October. Walsh's goal is to educate 1,000 doctors on this issue in five years.
“Psychiatrists appear to be the most enthusiastic participants,” he said.
David Brendel, M.D., Ph.D., a Boston-area psychiatrist, said it would be a “significant advance” to diagnose treatable forms of depression with objective medical tests.
“But I don't see adequate evidence that these (or other) researchers are anywhere near accomplishing this,” he said. Brendel added that depression likely has many causes and complex neurophysiological underpinnings. He said the medical community is still “entirely unable” to diagnose it using medical tests, though he said researchers may be closer to having tests, such as gene assays, that can identify the most effective medical treatment for a specific patient.
Mona Shattell, Ph.D., a nurse and professor at DePaul University specializing in mental health, said that being able to diagnose depression with a blood test could potentially increase the number of people diagnosed—and lead to more people being treated for the condition.
“It would also be helpful because depression, and other mental illnesses, are still stigmatizing,” she said. “If depression could be detected via a blood test, it would clearly be in the realm of ‘medical illness’ and therefore a ‘real’ problem that is not due to individual weakness or other equally stigmatizing reasons.”
Behaviour can be affected by events in previous generations which have been passed on through a form of genetic memory, animal studies suggest.
Experiments showed that a traumatic event could affect the DNA in sperm and alter the brains and behaviour of subsequent generations.
A Nature Neuroscience study shows mice trained to avoid a smell passed their aversion on to their "grandchildren".
Experts said the results were important for phobia and anxiety research.
The animals were trained to fear a smell similar to cherry blossom.
The team at the Emory University School of Medicine, in the US, then looked at what was happening inside the sperm.
They showed a section of DNA responsible for sensitivity to the cherry blossom scent was made more active in the mice's sperm.
Both the mice's offspring, and their offspring, were "extremely sensitive" to cherry blossom and would avoid the scent, despite never having experienced it in their lives.
Changes in brain structure were also found.
"The experiences of a parent, even before conceiving, markedly influence both structure and function in the nervous system of subsequent generations," the report concluded.
Family affairThe findings provide evidence of "transgenerational epigenetic inheritance" - that the environment can affect an individual's genetics, which can in turn be passed on.
One of the researchers Dr Brian Dias told the BBC: "This might be one mechanism that descendants show imprints of their ancestor.
"There is absolutely no doubt that what happens to the sperm and egg will affect subsequent generations."
Prof Marcus Pembrey, from University College London, said the findings were "highly relevant to phobias, anxiety and post-traumatic stress disorders" and provided "compelling evidence" that a form of memory could be passed between generations.
He commented: "It is high time public health researchers took human transgenerational responses seriously.
"I suspect we will not understand the rise in neuropsychiatric disorders or obesity, diabetes and metabolic disruptions generally without taking a multigenerational approach."
In the smell-aversion study, is it thought that either some of the odour ends up in the bloodstream which affected sperm production or that a signal from the brain was sent to the sperm to alter DNA.
So how do our epigenomes become informed about life around us, particularly the epigenome of a fetus or a yet‑to‑be‑conceived child? Most of the science points to our neural, endocrine, and immune systems. Our brains, glands, and immune cells sense the outside world and secrete hormones, growth factors, neurotransmitters, and other biological signaling molecules to tell every organ in the body that it needs to adapt to a changing world.
Soft evolution is like an annotated book. Those who read different annotations of the same book may end up with very different learning.
As we experience stress, love, aging, fear, pleasure, infection, pain, exercise, or hunger, various hormones adjust various physical responses within our bodies. Hormones surge through our blood; changes in cortisol, testosterone, estrogen, interleukin, leptin, insulin, oxytocin, thyroid hormone, growth hormone, and adrenaline make us behave and develop in different ways. And they signal to our epigenomes, “Time to flip some switches!”Genes get shut off or turned on as the world around us changes.
The Book of LifeSoft evolution is analogous to an annotated book. The basic text and argument of the book remain the same. But if the text is gradually surrounded by margin notes and comments, then those who read different annotations of the exact same book may end up with very different learning, depending on who annotated the particular copy they borrowed, how they treated the original text, how the reader decided to interpret the interplay between the original printed text and the annotations, and whether some of the annotations were erased or modified by other readers.
There are multiple ways to add in rapid, inherited epigenetic adaptations without any change in the core DNA code. One basic and common mechanism is DNA methylation: Enzymes in our cells attach a methyl group (CH3) to a cytosine (C) located next to a guanine (G) in our DNA, forming a methylated island. This tells the gene that follows next, “Shhh, do not express yourself.”
One of the key reasons for human diversity is that about 70 percent, or roughly 14,000, of our genes have these “on/off” switches plus random mutations among them, so there are countless combinations of ways that these switches are flipped in the human population.
Sperm and eggs get a nearly fresh start: An estimated 90 percent of the switches are erased before conception occurs, which means most epigenetic memories are lost. But there is still a lot of recent data moving from generation to generation. (Those who described sperm as simple bags of DNA with a tail could never explain why sperm had so many receptors for so many hormones not directly related to reproduction, including leptin, one of the obesity genes, as well as 19 growth factors, cytokines, and neurotransmitters.)
Epigenetic switches can be flipped on and off in sperm, eggs, or embryos, so your kids and grandkids can share your environmental experiences and knowledge, and be better prepared for the environment they will soon be entering. For instance, if you were a male smoker, and your brother was not, 28 epigenetic signals in your sperm would be different from his. Sperm are listening.
At conception, your grandchildren listen to distant tales, and sometimes pass them on.
Reprinted from Evolving Ourselves by Juan Enriquez and Steve Gullans with permission of Current, an imprint of Penguin Publishing Group, a division of Penguin Random House LLC. Copyright (c) Juan Enriquez and Steven Gullans, 2015.
Soft evolution is like an annotated book. Those who read different annotations of the same book may end up with very different learning.
As we experience stress, love, aging, fear, pleasure, infection, pain, exercise, or hunger, various hormones adjust various physical responses within our bodies. Hormones surge through our blood; changes in cortisol, testosterone, estrogen, interleukin, leptin, insulin, oxytocin, thyroid hormone, growth hormone, and adrenaline make us behave and develop in different ways. And they signal to our epigenomes, “Time to flip some switches!”Genes get shut off or turned on as the world around us changes.
The Book of LifeSoft evolution is analogous to an annotated book. The basic text and argument of the book remain the same. But if the text is gradually surrounded by margin notes and comments, then those who read different annotations of the exact same book may end up with very different learning, depending on who annotated the particular copy they borrowed, how they treated the original text, how the reader decided to interpret the interplay between the original printed text and the annotations, and whether some of the annotations were erased or modified by other readers.
There are multiple ways to add in rapid, inherited epigenetic adaptations without any change in the core DNA code. One basic and common mechanism is DNA methylation: Enzymes in our cells attach a methyl group (CH3) to a cytosine (C) located next to a guanine (G) in our DNA, forming a methylated island. This tells the gene that follows next, “Shhh, do not express yourself.”
One of the key reasons for human diversity is that about 70 percent, or roughly 14,000, of our genes have these “on/off” switches plus random mutations among them, so there are countless combinations of ways that these switches are flipped in the human population.
Sperm and eggs get a nearly fresh start: An estimated 90 percent of the switches are erased before conception occurs, which means most epigenetic memories are lost. But there is still a lot of recent data moving from generation to generation. (Those who described sperm as simple bags of DNA with a tail could never explain why sperm had so many receptors for so many hormones not directly related to reproduction, including leptin, one of the obesity genes, as well as 19 growth factors, cytokines, and neurotransmitters.)
Epigenetic switches can be flipped on and off in sperm, eggs, or embryos, so your kids and grandkids can share your environmental experiences and knowledge, and be better prepared for the environment they will soon be entering. For instance, if you were a male smoker, and your brother was not, 28 epigenetic signals in your sperm would be different from his. Sperm are listening.
At conception, your grandchildren listen to distant tales, and sometimes pass them on.
Reprinted from Evolving Ourselves by Juan Enriquez and Steve Gullans with permission of Current, an imprint of Penguin Publishing Group, a division of Penguin Random House LLC. Copyright (c) Juan Enriquez and Steven Gullans, 2015.
Ancestor Syndrome
Bonds, Bondage, & Double-Binds
Information is transmitted transgenerationally by unconscious means without being assimilated because it was never verbalized and was among the unspoken family secrets. This 'black hole' of family life is where the memory lapses, dreams, slip ups, illness, pain, accidents, guilt, unresolved hatred, revenge, false ideas, relics of the past, and impulsive action reside waiting to be acted out along with unresolved grief, loss, and unfulfillment. How many things go without saying? Twisted loyalties, family myths, implicit injunctions, suffered injustices include just a few.
We can approach family issues as part of our genealogical work and attempt to give them meaning or resolution. Those named after lost ones may carry memory-traces or projections of their name-sake. If a family shares a co-consciousness it also shares a co-unconscious. The unconscious communicates in synchronicity and a sort of circular or cyclic time.
Family Constellations (a subset application of Systemic Constellations) is an experiential process that aims to release and resolve profound tensions within and between people. The process diverges from conventional forms of cognitive, behavior and psychodynamic psychotherapy in several key respects. In a single session, a Family Constellation attempts to reveal a previously unrecognized systemic dynamic that spans multiple generations in a given family and to resolve the deleterious effects of that dynamic by encouraging the subject to accept the factual reality of the past.
Practitioners claim that present day problems and difficulties may be influenced by traumas suffered in previous generations of the family, even if those affected now are unaware of the original event in the past. A theoretical foundation for this concept is called The Ancestor Syndrome in psychology.
Recent findings in epigenetics research supports the concept that after-effects of trauma can be passed to subsequent generations. Hellinger referred to the relation between present and past problems which are not caused by direct personal experience as Systemic entanglements, said to occur when unresolved trauma has afflicted a family through an event such as murder, suicide, death of a mother in childbirth, early death of a parent, child, or sibling, war, natural disaster, emigration, or abuse.
Bonds, Bondage, & Double-Binds
Information is transmitted transgenerationally by unconscious means without being assimilated because it was never verbalized and was among the unspoken family secrets. This 'black hole' of family life is where the memory lapses, dreams, slip ups, illness, pain, accidents, guilt, unresolved hatred, revenge, false ideas, relics of the past, and impulsive action reside waiting to be acted out along with unresolved grief, loss, and unfulfillment. How many things go without saying? Twisted loyalties, family myths, implicit injunctions, suffered injustices include just a few.
We can approach family issues as part of our genealogical work and attempt to give them meaning or resolution. Those named after lost ones may carry memory-traces or projections of their name-sake. If a family shares a co-consciousness it also shares a co-unconscious. The unconscious communicates in synchronicity and a sort of circular or cyclic time.
Family Constellations (a subset application of Systemic Constellations) is an experiential process that aims to release and resolve profound tensions within and between people. The process diverges from conventional forms of cognitive, behavior and psychodynamic psychotherapy in several key respects. In a single session, a Family Constellation attempts to reveal a previously unrecognized systemic dynamic that spans multiple generations in a given family and to resolve the deleterious effects of that dynamic by encouraging the subject to accept the factual reality of the past.
Practitioners claim that present day problems and difficulties may be influenced by traumas suffered in previous generations of the family, even if those affected now are unaware of the original event in the past. A theoretical foundation for this concept is called The Ancestor Syndrome in psychology.
Recent findings in epigenetics research supports the concept that after-effects of trauma can be passed to subsequent generations. Hellinger referred to the relation between present and past problems which are not caused by direct personal experience as Systemic entanglements, said to occur when unresolved trauma has afflicted a family through an event such as murder, suicide, death of a mother in childbirth, early death of a parent, child, or sibling, war, natural disaster, emigration, or abuse.
The Genome's Dark MatterEvidence is growing that your DNA sequence does not determine your entire genetic fate. Joseph Nadeau is trying to find out what accounts for the rest.
MIT Technology Review magazine
January/February 2011
Something’s Missing:
Geneticist Joseph Nadeau has been finding examples of what he calls “funky” genetic effects that could help explain the mystery of “missing heritability.”
What we know about the fundamental laws of inheritance began to take shape in a monastery garden in Moravia in the middle of the 19th century, when Gregor Mendel patiently cross-bred pea plants over the course of several years, separated the progeny according to their distinct traits, and figured out the mathematical foundations of modern genetics. Since the rediscovery of Mendel’s work a century ago, the vocabulary of Mendelian inheritance—dominant genes, recessive genes, and ultimately our own era’s notion of disease genes—has colored every biological conversation about genetics. The message boils down to a single premise: your unique mix of physiological traits and disease risks (collectively known as your phenotype) can be read in the precise sequence of chemical bases, or letters, in your DNA (your genotype).
But what if—except in the cases of some rare single-gene disorders like Tay-Sachs disease—the premise ignores a significant portion of inheritance? What if the DNA sequence of an individual explains only part of the story of his or her inherited diseases and traits, and we need to know the DNA sequences of parents and perhaps even grandparents to understand what is truly going on? Before the Human Genome Project and the era of widespread DNA sequencing, those questions would have seemed ridiculous to researchers convinced they knew better. But modern genomics has run into a Mendelian wall.
Large-scale genomic studies over the past five years or so have mainly failed to turn up common genes that play a major role in complex human maladies. More than three dozen specific genetic variants have been associated with type 2 diabetes, for example, but together, they have been found to explain about 10 percent of the disease’s heritability—the proportion of variation in any given trait that can be explained by genetics rather than by environmental influences. Results have been similar for heart disease, schizophrenia, high blood pressure, and other common maladies: the mystery has become known as the “missing heritability” problem. Francis Collins, director of the National Institutes of Health, has sometimes made grudging reference to the “dark matter of the genome”—an analogy to the vast quantities of invisible mass in the universe that astrophysicists have inferred but have struggled for decades to find.
Joseph H. Nadeau has been on a quest to uncover mechanisms that might account for the missing components of heritability. And he is finding previously unsuspected modes of inheritance almost everywhere he looks.
Nadeau, who until recently was chair of genetics at Case Western Reserve University in Cleveland and is now director of research and academic affairs at the Institute for Systems Biology in Seattle, has done studies showing that certain traits in mice are influenced by specific stretches of variant DNA that appeared on their parents’ or grandparents’ chromosomes but do not appear on their own.
“Transgenerational” genetics, as he calls these unusual patterns of inheritance, fit partly under the umbrella of traditional epigenetics—the idea that chemical changes wrought by environmental exposures and experiences can modify DNA in ways that either muffle a normally vocal gene or restore the voice of a gene that had been silenced. Researchers have begun to find that these changes are heritable even though they alter only the pattern of gene expression, not the actual genetic code. Yet it’s both more disconcerting and more profound to suggest, as he does, that genes an ancestor carried but didn’t pass down can influence traits and diseases in subsequent generations.
Consider the results of an experiment Nadeau and his colleague Vicki R. Nelson published last August. They created an inbred strain of mice and then compared two sets of females that were genetically identical except for one small difference: one set had a father whose Y chromosome came from another strain of mouse and contained a different set of genetic variants. That shouldn’t have affected the daughter mice at all, because females don’t inherit the Y chromosome. But the presence of that uninherited DNA in the previous generation exerted a profound effect on many of the more than 100 traits tested in the two sets of female offspring, whose own DNA was exactly the same. These results, Nelson and Nadeau concluded, suggest that “transgenerational genetic effects rival conventional genetics in frequency and strength.”
In a separate but similarly unsettling line of experiments, Nadeau and his collaborators are finding that the impact of any given gene depends on all the other genes surrounding it. Nadeau is hardly the only scientist to identify these complex gene-gene interactions, but he and his colleagues have created a unique set of genetically engineered mice that is giving them and other scientists unprecedentedly precise tools for dissecting these “situational genetics” to show how the variants in a gene’s molecular neighborhood affect the way it behaves.
Findings like these, taken together, could shed light on the missing-heritability problem, but at the cost of upending the dominance of traditional Mendelian ideas about how inheritance works. Sitting on the outside deck of the Institute for Systems Biology one recent afternoon, munching on a sandwich as seaplanes descended toward the skyline of Seattle, Nadeau recalled giving a talk about all this at a conference several years ago and discovering afterward that a prominent Ivy League geneticist in attendance, whom he declined to name, simply couldn’t get the heretical ideas out of his head. “He came up to me after the talk,” Nadeau recalled, “and said, ‘This can’t be true in humans.’ I ran into him at breakfast the next day and he said, ‘This can’t be true in humans.’ And then when the meeting was over, I ran into him at the airport, and he came up to me and said, ‘This can’t be true in humans.’ ” Or as another leading genome scientist once told Nadeau at a meeting in Europe, “If transgenerational effects happen in humans, we’re screwed.”
That is to say, discovering that his findings apply to humans would decouple a person’s DNA sequence from her or his traits, calling into question much of the work scientists have done to find the genetic sources of complex diseases and develop drugs that target them. At a time when companies are analyzing customers’ DNA for a fee, these ideas would make the results much more difficult to interpret medically and much more complicated to assess when trying to make a diagnosis or calculate disease risk.
Eric J. Topol, who heads genomic research at the Scripps Research Institute in La Jolla, California, agrees that genomics has suddenly gotten a lot more complicated. “There’s a lot of non-Mendelian stuff going on,” he says, “and there’s a lot that we’re going to have to sort out that doesn’t have anything to do with the DNA sequence.”
RUINING GENETICS
In 2009, a group of researchers based in the Netherlands published a stunning study on the genetics of human height—stunning because it failed to find much of a genetic component in one of the most obvious of inherited human traits. The group analyzed 54 recently identified genetic locations that statistical analysis suggested were the main contributors to height and discovered that all of them together accounted for only 4 to 6 percent of the height variance in thousands of subjects.
The “missing heritability” in the height study typifies many recent research reports in which large-scale genetic screens, known as genome-wide association studies, have identified a multitude of genes (or at least genetic neighborhoods) that are statistically associated with a biological trait like height or a disease like obesity, yet account for mystifyingly little of its propensity to run in families. What is interesting about Nadeau’s findings is that even though they diminish the significance of single genes and the DNA sequences of individuals, the research preserves—and in some ways increases—the significance of family history, since even the genetic variants that parents and grandparents don’t pass down through DNA seem to influence the traits of their children or grandchildren.
Nadeau, who is silver-haired and cheerful, has been investigating what he sometimes calls “funky” genetic results ever since sophisticated sequencing technologies became available about 10 years ago. Some of those results have been hinted at by traditional epigenetics, which has begun to trace changes that are transmitted from one generation to the next in animals even though the basic DNA sequence remains the same. (For example, researchers have found that rats whose cognitive performance was improved through environmental factors can pass those improvements down to offspring.) But where that field has typically focused on chemical modifications of DNA, Nadeau’s work expands the notion of epigenetics to include genetic effects that may be transmitted by different molecular players: ribonucleic acids (or RNAs), which exert powerful regulatory effects on DNA.
Key evidence for Nadeau’s general views on unconventional modes of inheritance grew out of a dissertation project that one of his students began around 2001. In the long tradition of misguided doctoral advice, everyone told Man-Yee Lam that her project was boring, derivative, and hardly worth doing; for five or six years, nothing in her results suggested otherwise. The focus of the project was testicular germ-cell tumors. It didn’t become clear until much later that the experiment represented the first rigorous demonstration of a transgenerational effect, showing that genetic variations in a parent—even though they were not passed along to offspring—could dramatically change disease risks in those offspring.
Lam set out to see if she could identify interactions between several “modifier” genes—interactions that would increase susceptibility to testicular cancer in mice. She found lots of these interactions (some quite strong), completed her thesis, and graduated. Then, when the group started to write up the results for publication, they noticed something very peculiar: the effects had also occurred in some of the control animals bred from the same original population. In other words, males that had been bred so as not to inherit the disease mutations still had a statistically significant increase in their risk for testicular cancer, simply because the parents possessed a particular genetic variant. The results suggested that there could be patches of DNA in parents that affected the traits of children, even if the children did not inherit this bit of parental DNA.
Even before publication in 2007, Nadeau began describing the findings—to decidedly mixed reviews. He says, “If they were geneticists, there were all sorts of technical [objections] or ‘It’s not fair to talk about this in public. This is just too complicating, too—it’s too everything!’ One even said, ‘Are you trying to ruin genetics?’ ”
“COMPLETELY CRAZY”
Nadeau isn’t trying to ruin genetics, of course, but the other main focus of his research, involving gene-gene interactions in genetically engineered mice, also challenges the assumptions of modern Mendelians. Whereas conventional genomic studies assume that a number of individual genes contribute independently to complex diseases, Nadeau’s group has been investigating how genes can work in concert to produce illness or, surprisingly, suppress it. Certain genetic variants neutralize other disease genes, so that a person’s susceptibility to disease may depend more on the combined effect of all the genes in the background than on the disease genes in the foreground.
If this phenomenon is widespread, it holds significant implications for medicine. While enormous resources are routinely devoted to the search for disease genes, the research on gene-gene interactions—mostly in mice but increasingly in humans—suggests it may be at least as productive to identify protective and neutralizing genetic variants that counteract the effects of pathological variants. Understanding the biology of these protective variants could offer new routes to disease prevention and treatment. The mechanisms through which they exert their effects could even form the basis for new drugs.
To conduct his experiments, Nadeau and his collaborator, genomic pioneer Eric Lander, engineered 22 substrains of a commonly studied mouse strain called Black 6 by systematically replacing a different chromosome in each mouse with the corresponding chromosome from another strain, known as A/J. The idea of all this mixing and matching was to create a highly controlled system for studying gene-gene interactions, in part to determine how much a given gene contributes to the heritability of a disease or trait. By dropping in a “foreign” chromosome while holding everything else constant, the researchers could calculate the influence of each newly introduced gene. As Nadeau and his colleagues inserted one chromosome after another against the otherwise stable background and then measured the genetic effects, they discovered that the extent to which any gene affected the heritability of a given trait was dramatically larger than what more conventional genomic studies would have predicted. The implication is that the potency—and, Nadeau would discover, the action—of disease genes must change with the context created by other genes on other chromosomes.
To illustrate how complicated this idea is, Nadeau hops out of his chair and rushes over to the whiteboard in his office, where he quickly sketches out how these “completely crazy” context-dependent effects can act even within a single chromosome. The experiments focus on a genetic variant they have identified on chromosome 6 in the A/J mice that completely protects the animal against obesity. When they drop the chromosome into Black 6 mice, they too are protected against obesity. But it’s not that simple. When researchers stitch a bit of the DNA from the A/J strain into a large section of chromosome 6 in the Black 6 mice, the resulting mice are obese. When they trim away some of the Black 6 DNA and replace it with more A/J DNA, the resistance gene becomes active and the mice are lean. But when they add even more A/J DNA to this hybrid chromosome, the resistance gene turns off again. This on-off genetics continues even when the researchers add or subtract extremely small portions of chromosome 6. In fact, no matter how small the patch of DNA, nibbling away at it alternately confers and erases resistance to obesity. The reason is not known, but the larger message is that the effect of any variant seems to depend on its genetic surroundings. “We see that effect all the time,” Nadeau says. “All the time! Everywhere, in every trait we look at.”
Nadeau’s group has also begun using these genetically engineered mice to explore transgenerational effects related to obesity. In research published several months ago, David Buchner, a researcher at Case Western Reserve, showed that one of the strains, which possesses a genetic variant that confers resistance to obesity, can pass this resistance to offspring that don’t inherit the variant. The presence of the resistance gene in the paternal line of ancestry—either in the father or in the grandfather—was sufficient to inhibit diet-induced obesity and reduce appetite in mice that were otherwise genetically predisposed to getting fat.
HEALTHY GENES
Could humans also experience non-Mendelian forms of inheritance, particularly the complex gene-gene interplay that Nadeau keeps finding in mice?
Several years ago, Eric Topol launched a systematic attempt to study the genetics of elderly people who were in particularly good health. The researchers sought out subjects who met a series of stringent criteria: they had to be 80 or older, free of chronic diseases, and not taking any long-term medications.
Topol initially suspected a Mendelian explanation for their medical good fortune: he figured that they’d managed to avoid inheriting variant genes, or alleles, known to be associated with disease. Nadeau thought otherwise. He predicted, in fact, that people in the study would possess disease-related mutant genes like everyone else; what conferred their unusual health, he suspected, was the complex gene-gene interactions he’d seen in mice, where certain genetic variants in the background could neutralize the effects of pathological mutations. “The original premise—and Eric and I had a little bet on this—is that when they sequenced them, they would be free of disease-causing genes,” Nadeau recalls. “My argument was, they’ve got the same load of disease-causing mutations as anybody else, but they also have variants that suppress those diseases.”
The study is still going on, and it turns out, as Nadeau predicted, that hundreds of the test subjects possess just as many disease-causing genes as members of the control group, which in this case consists of people who died more than a decade ago. According to conventional Mendelian genetics, people who harbor these “risk alleles” should be more susceptible to disease. And indeed, conventional genetic testing would point to a heightened risk for diseases they never developed. But Topol’s results indicate that you can’t gauge the impact of any given disease variant unless you know what other variants are in the background, potentially including some that either modify disease genes or protect against them. So Nadeau and Topol have advocated a systematic search for “modifier genes” and “protective alleles” that neutralize the deleterious effects of the disease-associated variants that everyone else has been looking for.
It may sound like a dramatic break, but Nadeau says these exceptions to Mendelian patterns should come as no surprise. “Mendel picked the traits where he would get simple genetics,” he explains. “What Mendel said is true. But it’s not the whole truth.”
Stephen S. Hall is a New York-based writer whose recent books include Wisdom: From Philosophy to Neuroscience and Size Matters, which explains the genetics and biology of height.
- By Stephen S. Hall on December 21, 2010
MIT Technology Review magazine
January/February 2011
Something’s Missing:
Geneticist Joseph Nadeau has been finding examples of what he calls “funky” genetic effects that could help explain the mystery of “missing heritability.”
What we know about the fundamental laws of inheritance began to take shape in a monastery garden in Moravia in the middle of the 19th century, when Gregor Mendel patiently cross-bred pea plants over the course of several years, separated the progeny according to their distinct traits, and figured out the mathematical foundations of modern genetics. Since the rediscovery of Mendel’s work a century ago, the vocabulary of Mendelian inheritance—dominant genes, recessive genes, and ultimately our own era’s notion of disease genes—has colored every biological conversation about genetics. The message boils down to a single premise: your unique mix of physiological traits and disease risks (collectively known as your phenotype) can be read in the precise sequence of chemical bases, or letters, in your DNA (your genotype).
But what if—except in the cases of some rare single-gene disorders like Tay-Sachs disease—the premise ignores a significant portion of inheritance? What if the DNA sequence of an individual explains only part of the story of his or her inherited diseases and traits, and we need to know the DNA sequences of parents and perhaps even grandparents to understand what is truly going on? Before the Human Genome Project and the era of widespread DNA sequencing, those questions would have seemed ridiculous to researchers convinced they knew better. But modern genomics has run into a Mendelian wall.
Large-scale genomic studies over the past five years or so have mainly failed to turn up common genes that play a major role in complex human maladies. More than three dozen specific genetic variants have been associated with type 2 diabetes, for example, but together, they have been found to explain about 10 percent of the disease’s heritability—the proportion of variation in any given trait that can be explained by genetics rather than by environmental influences. Results have been similar for heart disease, schizophrenia, high blood pressure, and other common maladies: the mystery has become known as the “missing heritability” problem. Francis Collins, director of the National Institutes of Health, has sometimes made grudging reference to the “dark matter of the genome”—an analogy to the vast quantities of invisible mass in the universe that astrophysicists have inferred but have struggled for decades to find.
Joseph H. Nadeau has been on a quest to uncover mechanisms that might account for the missing components of heritability. And he is finding previously unsuspected modes of inheritance almost everywhere he looks.
Nadeau, who until recently was chair of genetics at Case Western Reserve University in Cleveland and is now director of research and academic affairs at the Institute for Systems Biology in Seattle, has done studies showing that certain traits in mice are influenced by specific stretches of variant DNA that appeared on their parents’ or grandparents’ chromosomes but do not appear on their own.
“Transgenerational” genetics, as he calls these unusual patterns of inheritance, fit partly under the umbrella of traditional epigenetics—the idea that chemical changes wrought by environmental exposures and experiences can modify DNA in ways that either muffle a normally vocal gene or restore the voice of a gene that had been silenced. Researchers have begun to find that these changes are heritable even though they alter only the pattern of gene expression, not the actual genetic code. Yet it’s both more disconcerting and more profound to suggest, as he does, that genes an ancestor carried but didn’t pass down can influence traits and diseases in subsequent generations.
Consider the results of an experiment Nadeau and his colleague Vicki R. Nelson published last August. They created an inbred strain of mice and then compared two sets of females that were genetically identical except for one small difference: one set had a father whose Y chromosome came from another strain of mouse and contained a different set of genetic variants. That shouldn’t have affected the daughter mice at all, because females don’t inherit the Y chromosome. But the presence of that uninherited DNA in the previous generation exerted a profound effect on many of the more than 100 traits tested in the two sets of female offspring, whose own DNA was exactly the same. These results, Nelson and Nadeau concluded, suggest that “transgenerational genetic effects rival conventional genetics in frequency and strength.”
In a separate but similarly unsettling line of experiments, Nadeau and his collaborators are finding that the impact of any given gene depends on all the other genes surrounding it. Nadeau is hardly the only scientist to identify these complex gene-gene interactions, but he and his colleagues have created a unique set of genetically engineered mice that is giving them and other scientists unprecedentedly precise tools for dissecting these “situational genetics” to show how the variants in a gene’s molecular neighborhood affect the way it behaves.
Findings like these, taken together, could shed light on the missing-heritability problem, but at the cost of upending the dominance of traditional Mendelian ideas about how inheritance works. Sitting on the outside deck of the Institute for Systems Biology one recent afternoon, munching on a sandwich as seaplanes descended toward the skyline of Seattle, Nadeau recalled giving a talk about all this at a conference several years ago and discovering afterward that a prominent Ivy League geneticist in attendance, whom he declined to name, simply couldn’t get the heretical ideas out of his head. “He came up to me after the talk,” Nadeau recalled, “and said, ‘This can’t be true in humans.’ I ran into him at breakfast the next day and he said, ‘This can’t be true in humans.’ And then when the meeting was over, I ran into him at the airport, and he came up to me and said, ‘This can’t be true in humans.’ ” Or as another leading genome scientist once told Nadeau at a meeting in Europe, “If transgenerational effects happen in humans, we’re screwed.”
That is to say, discovering that his findings apply to humans would decouple a person’s DNA sequence from her or his traits, calling into question much of the work scientists have done to find the genetic sources of complex diseases and develop drugs that target them. At a time when companies are analyzing customers’ DNA for a fee, these ideas would make the results much more difficult to interpret medically and much more complicated to assess when trying to make a diagnosis or calculate disease risk.
Eric J. Topol, who heads genomic research at the Scripps Research Institute in La Jolla, California, agrees that genomics has suddenly gotten a lot more complicated. “There’s a lot of non-Mendelian stuff going on,” he says, “and there’s a lot that we’re going to have to sort out that doesn’t have anything to do with the DNA sequence.”
RUINING GENETICS
In 2009, a group of researchers based in the Netherlands published a stunning study on the genetics of human height—stunning because it failed to find much of a genetic component in one of the most obvious of inherited human traits. The group analyzed 54 recently identified genetic locations that statistical analysis suggested were the main contributors to height and discovered that all of them together accounted for only 4 to 6 percent of the height variance in thousands of subjects.
The “missing heritability” in the height study typifies many recent research reports in which large-scale genetic screens, known as genome-wide association studies, have identified a multitude of genes (or at least genetic neighborhoods) that are statistically associated with a biological trait like height or a disease like obesity, yet account for mystifyingly little of its propensity to run in families. What is interesting about Nadeau’s findings is that even though they diminish the significance of single genes and the DNA sequences of individuals, the research preserves—and in some ways increases—the significance of family history, since even the genetic variants that parents and grandparents don’t pass down through DNA seem to influence the traits of their children or grandchildren.
Nadeau, who is silver-haired and cheerful, has been investigating what he sometimes calls “funky” genetic results ever since sophisticated sequencing technologies became available about 10 years ago. Some of those results have been hinted at by traditional epigenetics, which has begun to trace changes that are transmitted from one generation to the next in animals even though the basic DNA sequence remains the same. (For example, researchers have found that rats whose cognitive performance was improved through environmental factors can pass those improvements down to offspring.) But where that field has typically focused on chemical modifications of DNA, Nadeau’s work expands the notion of epigenetics to include genetic effects that may be transmitted by different molecular players: ribonucleic acids (or RNAs), which exert powerful regulatory effects on DNA.
Key evidence for Nadeau’s general views on unconventional modes of inheritance grew out of a dissertation project that one of his students began around 2001. In the long tradition of misguided doctoral advice, everyone told Man-Yee Lam that her project was boring, derivative, and hardly worth doing; for five or six years, nothing in her results suggested otherwise. The focus of the project was testicular germ-cell tumors. It didn’t become clear until much later that the experiment represented the first rigorous demonstration of a transgenerational effect, showing that genetic variations in a parent—even though they were not passed along to offspring—could dramatically change disease risks in those offspring.
Lam set out to see if she could identify interactions between several “modifier” genes—interactions that would increase susceptibility to testicular cancer in mice. She found lots of these interactions (some quite strong), completed her thesis, and graduated. Then, when the group started to write up the results for publication, they noticed something very peculiar: the effects had also occurred in some of the control animals bred from the same original population. In other words, males that had been bred so as not to inherit the disease mutations still had a statistically significant increase in their risk for testicular cancer, simply because the parents possessed a particular genetic variant. The results suggested that there could be patches of DNA in parents that affected the traits of children, even if the children did not inherit this bit of parental DNA.
Even before publication in 2007, Nadeau began describing the findings—to decidedly mixed reviews. He says, “If they were geneticists, there were all sorts of technical [objections] or ‘It’s not fair to talk about this in public. This is just too complicating, too—it’s too everything!’ One even said, ‘Are you trying to ruin genetics?’ ”
“COMPLETELY CRAZY”
Nadeau isn’t trying to ruin genetics, of course, but the other main focus of his research, involving gene-gene interactions in genetically engineered mice, also challenges the assumptions of modern Mendelians. Whereas conventional genomic studies assume that a number of individual genes contribute independently to complex diseases, Nadeau’s group has been investigating how genes can work in concert to produce illness or, surprisingly, suppress it. Certain genetic variants neutralize other disease genes, so that a person’s susceptibility to disease may depend more on the combined effect of all the genes in the background than on the disease genes in the foreground.
If this phenomenon is widespread, it holds significant implications for medicine. While enormous resources are routinely devoted to the search for disease genes, the research on gene-gene interactions—mostly in mice but increasingly in humans—suggests it may be at least as productive to identify protective and neutralizing genetic variants that counteract the effects of pathological variants. Understanding the biology of these protective variants could offer new routes to disease prevention and treatment. The mechanisms through which they exert their effects could even form the basis for new drugs.
To conduct his experiments, Nadeau and his collaborator, genomic pioneer Eric Lander, engineered 22 substrains of a commonly studied mouse strain called Black 6 by systematically replacing a different chromosome in each mouse with the corresponding chromosome from another strain, known as A/J. The idea of all this mixing and matching was to create a highly controlled system for studying gene-gene interactions, in part to determine how much a given gene contributes to the heritability of a disease or trait. By dropping in a “foreign” chromosome while holding everything else constant, the researchers could calculate the influence of each newly introduced gene. As Nadeau and his colleagues inserted one chromosome after another against the otherwise stable background and then measured the genetic effects, they discovered that the extent to which any gene affected the heritability of a given trait was dramatically larger than what more conventional genomic studies would have predicted. The implication is that the potency—and, Nadeau would discover, the action—of disease genes must change with the context created by other genes on other chromosomes.
To illustrate how complicated this idea is, Nadeau hops out of his chair and rushes over to the whiteboard in his office, where he quickly sketches out how these “completely crazy” context-dependent effects can act even within a single chromosome. The experiments focus on a genetic variant they have identified on chromosome 6 in the A/J mice that completely protects the animal against obesity. When they drop the chromosome into Black 6 mice, they too are protected against obesity. But it’s not that simple. When researchers stitch a bit of the DNA from the A/J strain into a large section of chromosome 6 in the Black 6 mice, the resulting mice are obese. When they trim away some of the Black 6 DNA and replace it with more A/J DNA, the resistance gene becomes active and the mice are lean. But when they add even more A/J DNA to this hybrid chromosome, the resistance gene turns off again. This on-off genetics continues even when the researchers add or subtract extremely small portions of chromosome 6. In fact, no matter how small the patch of DNA, nibbling away at it alternately confers and erases resistance to obesity. The reason is not known, but the larger message is that the effect of any variant seems to depend on its genetic surroundings. “We see that effect all the time,” Nadeau says. “All the time! Everywhere, in every trait we look at.”
Nadeau’s group has also begun using these genetically engineered mice to explore transgenerational effects related to obesity. In research published several months ago, David Buchner, a researcher at Case Western Reserve, showed that one of the strains, which possesses a genetic variant that confers resistance to obesity, can pass this resistance to offspring that don’t inherit the variant. The presence of the resistance gene in the paternal line of ancestry—either in the father or in the grandfather—was sufficient to inhibit diet-induced obesity and reduce appetite in mice that were otherwise genetically predisposed to getting fat.
HEALTHY GENES
Could humans also experience non-Mendelian forms of inheritance, particularly the complex gene-gene interplay that Nadeau keeps finding in mice?
Several years ago, Eric Topol launched a systematic attempt to study the genetics of elderly people who were in particularly good health. The researchers sought out subjects who met a series of stringent criteria: they had to be 80 or older, free of chronic diseases, and not taking any long-term medications.
Topol initially suspected a Mendelian explanation for their medical good fortune: he figured that they’d managed to avoid inheriting variant genes, or alleles, known to be associated with disease. Nadeau thought otherwise. He predicted, in fact, that people in the study would possess disease-related mutant genes like everyone else; what conferred their unusual health, he suspected, was the complex gene-gene interactions he’d seen in mice, where certain genetic variants in the background could neutralize the effects of pathological mutations. “The original premise—and Eric and I had a little bet on this—is that when they sequenced them, they would be free of disease-causing genes,” Nadeau recalls. “My argument was, they’ve got the same load of disease-causing mutations as anybody else, but they also have variants that suppress those diseases.”
The study is still going on, and it turns out, as Nadeau predicted, that hundreds of the test subjects possess just as many disease-causing genes as members of the control group, which in this case consists of people who died more than a decade ago. According to conventional Mendelian genetics, people who harbor these “risk alleles” should be more susceptible to disease. And indeed, conventional genetic testing would point to a heightened risk for diseases they never developed. But Topol’s results indicate that you can’t gauge the impact of any given disease variant unless you know what other variants are in the background, potentially including some that either modify disease genes or protect against them. So Nadeau and Topol have advocated a systematic search for “modifier genes” and “protective alleles” that neutralize the deleterious effects of the disease-associated variants that everyone else has been looking for.
It may sound like a dramatic break, but Nadeau says these exceptions to Mendelian patterns should come as no surprise. “Mendel picked the traits where he would get simple genetics,” he explains. “What Mendel said is true. But it’s not the whole truth.”
Stephen S. Hall is a New York-based writer whose recent books include Wisdom: From Philosophy to Neuroscience and Size Matters, which explains the genetics and biology of height.
According to shamanic beliefs, when a person dies their spirit goes into the Underworld. There the spirit stays for a period of time and then it becomes an ancestral spirit with the ability to freely travel to other regions of the spirit world such as the Middle World, which is the spirit side of the world we are living in. Virtually all tribal and shamanic traditions had ceremonies and rituals of honoring the ancestors, of feeding them, seeking their advice or appeasing them. Shamans due to their ability to see spirits could usually commune directly with ancestral spirits when in a trance or having imbibed sacred plants.
While the other members of the tribe might not have been able to communicate with ancestors directly, they might have had ancestral contact in dreams for instance. Dreams were given great importance by many tribal cultures, and contrary to our modern Western attitude, were seen as real. I too have had several dreams of my deceased grandmother, which I feel were real experiences on the astral planes. These were very powerful dreams that touched me deeply. Even in our disconnected and dis-spirited times many people speak of feeling their beloved ancestors near and protecting them, or report dreams of deep meaning about relatives who have passed on.
In all ancient cultures it was common knowledge that ancestors could be of great help to the living but also create problems, if they were not honored or when there was an ancestral curse etc. In the Vedic tradition, for example, the ancestors or pitris can hold negative karma that afflicts the living descendants. These karmas can be alleviated or altogether overcome if the living descendants organize sacrificial rituals to certain Vedic deities. This is believed to help both the forefathers and the living descendants and is a very popular and effective Vedic practice. By the way, if the word sacrifice scares you, all Vedic sacrifices are totally non-bloody and vegetarian! The Vedic Gods as very high spiritual beings do not demand blood or harm to innocent creatures as the lesser gods frequently do.
While the other members of the tribe might not have been able to communicate with ancestors directly, they might have had ancestral contact in dreams for instance. Dreams were given great importance by many tribal cultures, and contrary to our modern Western attitude, were seen as real. I too have had several dreams of my deceased grandmother, which I feel were real experiences on the astral planes. These were very powerful dreams that touched me deeply. Even in our disconnected and dis-spirited times many people speak of feeling their beloved ancestors near and protecting them, or report dreams of deep meaning about relatives who have passed on.
In all ancient cultures it was common knowledge that ancestors could be of great help to the living but also create problems, if they were not honored or when there was an ancestral curse etc. In the Vedic tradition, for example, the ancestors or pitris can hold negative karma that afflicts the living descendants. These karmas can be alleviated or altogether overcome if the living descendants organize sacrificial rituals to certain Vedic deities. This is believed to help both the forefathers and the living descendants and is a very popular and effective Vedic practice. By the way, if the word sacrifice scares you, all Vedic sacrifices are totally non-bloody and vegetarian! The Vedic Gods as very high spiritual beings do not demand blood or harm to innocent creatures as the lesser gods frequently do.
%20O.%20Babenko%20et%20al.,%2017%2001%2015.pdf
Epigenetics is also a well-established developmental mechanism that describes cellular memory during a person’s lifetime. Your skin cells, liver cells, neurons – in fact nearly all cell types - have the same genome tucked up inside. Yet each of them has a quite stable memory that tells them that they are skin, liver, or neurons and so forth, and that memory (largely) persists as cells multiply, even in petri dishes outside of the body. Understanding this epigenetic cell memory could help explain how previous life events or exposures in the environment might affect the current health and disease of one individual, and there are many scientists looking into this. Here genetics nearly always underlies these changing features of cellular memory - the theory of epigenetics is an excellent candidate for understanding how the environment and genetics combine, and many researchers are rightfully excited about exploring this further.
However, increasing evidence now shows that phenotypic variation can sometimes occur when environmental factors and genetic variants in previous generations create an epigenetic state that persists across generations in individuals who are not directly exposed to that environment or who do not inherit the original genetic variant [21–26].
Epigenetic changes can range from chemical modifications of histone proteins—such as acetylation and methylation—to modifications made to the DNA itself. Such changes usually cause chromatin compaction, which limits the ability of the RNA polymerase II transcription complex to access DNA, ultimately resulting in reduced messenger RNA (mRNA) and protein output. Many view epigenetics as an annotation or editing of the genome that defines which genes will be silenced in order to streamline protein production or squelch unnecessary redundancy. That annotation, they say, does not and cannot permanently change the original manuscript (i.e., DNA), but merely access to the manuscript.
Just as epigenetics was gaining acceptance within the general scientific community, scientists began reporting observations of a newly identified phenomenon called transgenerational epigenetic inheritance, or the passage of epigenetic changes from a parent to its offspring. Recent experimental work in mice, worms, and pigs has found evidence that some degree of transgenerational epigenetic inheritance may take place.[1. B.T. Heijmans et al., “Persistent epigenetic differences associated with prenatal exposure to famine in humans,” PNAS, 105:17046–49, 2008.],[2. T.B. Franklin et al., “Epigenetic transmission of the impact of early stress across generations,” Biol Psychiatry, 68:408–15, 2010.],[3. O. Rechavi et al., “Transgenerational inheritance of an acquired small RNA-based antiviral response in C. elegans,” Cell, 147:1248–56, 2011.],[4. M. Braunschweig et al., “Investigations on transgenerational epigenetic response down the male line in F2 pigs,” PLoS ONE, 7: e30583, 2012.]
In some cases, environmental exposures lead to heritable epigenetic changes, a phenomenon that we term ‘transgenerational environmental effects’. In other cases, the original genetic variant is sufficient to initiate epigenetic inheritance (transgenerational genetic effects). In addition, environmental effects can lead to heritable epigenetic changes only in genetically predisposed individuals (trans-generational gene–environment interactions). Similarly, interactions can occur between genetically determined epigenetic states in parents and conventional genetic variants in offspring (transgenerational epistasis).
Recent studies suggest an alternative mode of inheritance where genetic variants that are present in one generation affect phenotypes in subsequent generations, thereby decoupling the conventional relations between genotype and phenotype, and perhaps, contributing to ‘missing heritability’. Under some conditions, these transgenerational genetic effects can be as frequent and strong as conventional inheritance, and can persist for multiple generations. Growing evidence suggests that RNA mediates these heritable epigenetic changes. The primary challenge now is to identify the molecular basis for these effects, characterize mechanisms and determine whether transgenerational genetic effects occur in humans.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720237/
However, increasing evidence now shows that phenotypic variation can sometimes occur when environmental factors and genetic variants in previous generations create an epigenetic state that persists across generations in individuals who are not directly exposed to that environment or who do not inherit the original genetic variant [21–26].
Epigenetic changes can range from chemical modifications of histone proteins—such as acetylation and methylation—to modifications made to the DNA itself. Such changes usually cause chromatin compaction, which limits the ability of the RNA polymerase II transcription complex to access DNA, ultimately resulting in reduced messenger RNA (mRNA) and protein output. Many view epigenetics as an annotation or editing of the genome that defines which genes will be silenced in order to streamline protein production or squelch unnecessary redundancy. That annotation, they say, does not and cannot permanently change the original manuscript (i.e., DNA), but merely access to the manuscript.
Just as epigenetics was gaining acceptance within the general scientific community, scientists began reporting observations of a newly identified phenomenon called transgenerational epigenetic inheritance, or the passage of epigenetic changes from a parent to its offspring. Recent experimental work in mice, worms, and pigs has found evidence that some degree of transgenerational epigenetic inheritance may take place.[1. B.T. Heijmans et al., “Persistent epigenetic differences associated with prenatal exposure to famine in humans,” PNAS, 105:17046–49, 2008.],[2. T.B. Franklin et al., “Epigenetic transmission of the impact of early stress across generations,” Biol Psychiatry, 68:408–15, 2010.],[3. O. Rechavi et al., “Transgenerational inheritance of an acquired small RNA-based antiviral response in C. elegans,” Cell, 147:1248–56, 2011.],[4. M. Braunschweig et al., “Investigations on transgenerational epigenetic response down the male line in F2 pigs,” PLoS ONE, 7: e30583, 2012.]
In some cases, environmental exposures lead to heritable epigenetic changes, a phenomenon that we term ‘transgenerational environmental effects’. In other cases, the original genetic variant is sufficient to initiate epigenetic inheritance (transgenerational genetic effects). In addition, environmental effects can lead to heritable epigenetic changes only in genetically predisposed individuals (trans-generational gene–environment interactions). Similarly, interactions can occur between genetically determined epigenetic states in parents and conventional genetic variants in offspring (transgenerational epistasis).
Recent studies suggest an alternative mode of inheritance where genetic variants that are present in one generation affect phenotypes in subsequent generations, thereby decoupling the conventional relations between genotype and phenotype, and perhaps, contributing to ‘missing heritability’. Under some conditions, these transgenerational genetic effects can be as frequent and strong as conventional inheritance, and can persist for multiple generations. Growing evidence suggests that RNA mediates these heritable epigenetic changes. The primary challenge now is to identify the molecular basis for these effects, characterize mechanisms and determine whether transgenerational genetic effects occur in humans.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720237/
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Elusive inheritance:
Transgenerational effects and epigenetic inheritance in human environmental diseaseProgress in Biophysics and Molecular Biology
(Impact Factor: 2.27). 04/2015; 118(1-2). DOI: 10.1016/j.pbiomolbio.2015.02.011
ABSTRACT
Epigenetic mechanisms involving DNA methylation, histone modification, histone variants and nucleosome positioning, and noncoding RNAs regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and DNA. Epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. The idea that environment-induced epigenetic changes in mammals could be inherited through the germline, independent of genetic mechanisms, has stimulated much debate.
Many experimental models have been designed to interrogate the possibility of transgenerational epigenetic inheritance and provide insight into how environmental exposures influence phenotypes over multiple generations in the absence of any apparent genetic mutation. Unexpected molecular evidence has forced us to reevaluate not only our understanding of the plasticity and heritability of epigenetic factors, but of the stability of the genome as well.
Recent reviews have described the difference between transgenerational and intergenerational effects; the two major epigenetic reprogramming events in the mammalian life cycle; these two events making transgenerational epigenetic inheritance of environment-induced perturbations rare, if at all possible, in mammals; and mechanisms of transgenerational epigenetic inheritance in non-mammalian eukaryotic organisms.
This paper briefly introduces these topics and mainly focuses on (1) transgenerational phenotypes and epigenetic effects in mammals, (2) environment-induced intergenerational epigenetic effects, and (3) the inherent difficulties in establishing a role for epigenetic inheritance in human environmental disease.
Copyright © 2015. Published by Elsevier Ltd.
Elusive inheritance: Transgenerational effects and epigenetic
inheritance in human environmental disease.
Available from: http://www.researchgate.net/publication/273372745_Elusive_inheritance_Transgenerational_effects_and_epigenetic_inheritance_in_human_environmental_disease [accessed Nov 20, 2015].
Between the Lines: Healing the Individual & Ancestral Soul with Family.
Nikki Mackay
https://books.google.com/books?id=ygLtBAAAQBAJ&pg=PT84&lpg=PT84&dq=entangled+ancestors&source=bl&ots=nFc0VPwohl&sig=AHbph519ND7J39MjOpxVKhQ-JGc&hl=en&sa=X&ved=0ahUKEwi_nuKrpPvKAhVGkh4KHSqjBk84FBDoAQglMAI#v=onepage&q=entangled%20ancestors&f=false
Transgenerational effects and epigenetic inheritance in human environmental diseaseProgress in Biophysics and Molecular Biology
(Impact Factor: 2.27). 04/2015; 118(1-2). DOI: 10.1016/j.pbiomolbio.2015.02.011
ABSTRACT
Epigenetic mechanisms involving DNA methylation, histone modification, histone variants and nucleosome positioning, and noncoding RNAs regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and DNA. Epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. The idea that environment-induced epigenetic changes in mammals could be inherited through the germline, independent of genetic mechanisms, has stimulated much debate.
Many experimental models have been designed to interrogate the possibility of transgenerational epigenetic inheritance and provide insight into how environmental exposures influence phenotypes over multiple generations in the absence of any apparent genetic mutation. Unexpected molecular evidence has forced us to reevaluate not only our understanding of the plasticity and heritability of epigenetic factors, but of the stability of the genome as well.
Recent reviews have described the difference between transgenerational and intergenerational effects; the two major epigenetic reprogramming events in the mammalian life cycle; these two events making transgenerational epigenetic inheritance of environment-induced perturbations rare, if at all possible, in mammals; and mechanisms of transgenerational epigenetic inheritance in non-mammalian eukaryotic organisms.
This paper briefly introduces these topics and mainly focuses on (1) transgenerational phenotypes and epigenetic effects in mammals, (2) environment-induced intergenerational epigenetic effects, and (3) the inherent difficulties in establishing a role for epigenetic inheritance in human environmental disease.
Copyright © 2015. Published by Elsevier Ltd.
Elusive inheritance: Transgenerational effects and epigenetic
inheritance in human environmental disease.
Available from: http://www.researchgate.net/publication/273372745_Elusive_inheritance_Transgenerational_effects_and_epigenetic_inheritance_in_human_environmental_disease [accessed Nov 20, 2015].
Between the Lines: Healing the Individual & Ancestral Soul with Family.
Nikki Mackay
https://books.google.com/books?id=ygLtBAAAQBAJ&pg=PT84&lpg=PT84&dq=entangled+ancestors&source=bl&ots=nFc0VPwohl&sig=AHbph519ND7J39MjOpxVKhQ-JGc&hl=en&sa=X&ved=0ahUKEwi_nuKrpPvKAhVGkh4KHSqjBk84FBDoAQglMAI#v=onepage&q=entangled%20ancestors&f=false