12:31 PM
Unknown
The spread of social phobia
persons genetic and environment-related.
Genetic determinism:
Implications scientific, medical and ethical
The formulation of the theory of evolution, there are
nearly 150 years, advances in genetics for over a century, and the rise of
molecular genetics that followed the discovery of DNA there are more 50 years
have profoundly changed our vision and understanding of the living world,
health and human diseases.
Ambiguity of the notion of genetic
determinism
Developments in molecular genetics,
genetic engineering, and the draft human genome sequence has facilitated the
dissemination of knowledge in society about the relationship between genes and
diseases. The identification of genetic sequences involved in many diseases
inheritance (Huntington's disease, muscular dystrophy, cystic fibrosis, sickle
cell disease, fragile X, colonic polyposis family familial forms of breast
cancer ...) or occurred spontaneously ( trisomy 21) has led to a better
understanding of the mechanisms responsible for the development of these
diseases, diagnostic tests or predictive, and in some cases, therapeutic
measures for preventive or curative. The proliferation of GMOs (genetically
modified animals or plants by the transformation of a gene, the insertion of an
additional gene or otherwise deletion of a gene) and the discovery of some
spectacular effects of these changes on certain characteristics of these
organizations or their health has reinforced the idea of the importance of
genes in living organisms function. There was even enough showing that genetic
introduced into a bacterium, or an animal cell, a human gene that allows human
cells to produce insulin for the most common bacteria or animal cell produces human
insulin.
These findings have not only resulted
familiarize society with genetics and raise both hopes and concerns to the
increasing development of its applications. They have also helped to strengthen
the society of ancient and widespread notions of genetic determinism according
to which our identity and our future - what we are and what we will become -
are primarily or entirely determined by our genes. In this vision, the destiny
of the individual is, from its conception, already registered in the particular
sequence of its genes. During the past 20 years, work suggesting that violence,
aggression, addiction, fidelity, love, homosexuality, religious faith ... are
related to variations in one or several gene (s) specific (s) have experienced
significant media coverage and widespread popularity. And it is in this context
that are often included expectations regarding the development of a predictive
medicine based on genetic testing.
Three distinct issues emerge that can be
made in the following manner. The first is: the identity and fate of a person
they are already written somewhere, since its conception? It is a question of a
metaphysical nature. The second is: the identity and fate of a person they are,
in part, read somewhere, and if so, where, how, and to what extent? It is a
question of a scientific nature. The third is that the results actually mean
that science gives us, and how we can and we want to reconcile with the very
values that underpin research, medicine, and more broadly, our society? It is
a question of an ethical nature.
If the concept of "any genetic"
began to fade from many researchers (Atlan, 1998), it still leads often to
ignore or neglect the body of research on the complex interactions between
genes and environment - and a more broadly between nature and nurture -
heredity and in the emergence of the uniqueness of each person. The exploration
of this complexity is the field of study of a field of research in full expansion:
epigenetics, which is literally "above" genes, that is to say
upstream of genes, that the control, even in a hierarchical way, what could be
more important than genes.
Old question of heredity
The emphasis on the question of heredity
is probably as old as the history of mankind. Extremely schematic way, we can
consider that this issue has been addressed in two very different ways
throughout history. The first approach was the order of the questions: what are
the respective shares of the innate and acquired - or more broadly the nature
and culture - in the emergence of the unique characteristics of a person? What
is the role of heredity in this part of innate? And what might be the
mechanisms by which hereditary characteristics to transmit, mix, and change
from generation to generation? This approach to questioning, the search order
is that which modern biology began, 150 years, to provide answers more accurate
and often surprising. The second approach has not made an inquiry, but rather
an action based on a presupposition. Starting from the notion that the
essential characteristics and capabilities of a person could only be a priori
related to heredity, it was to ensure that the social role, activities, and
capabilities of a person are intimately linked to heredity: it is a social
process whose examples are endless - the hereditary monarchies, aristocracies,
caste system, arranged marriages ... If we do not take into account the
entanglement between the former two approaches - questioning and, on the other
hand, a priori answer - it is difficult to understand how modern science has
been, and can still sometimes enroll in his questioning assumptions elders in
existing responses that can guide and constrain the interpretation of research
results.
Two ideas blend into effect today in the
belief in a strong genetic determinism or absolute. The ancient idea that the
essential characteristics and capabilities of a person, and an essential part
of the future are determined by heredity and modern avatar of this idea, that a
biological discipline - genetics, science Heredity - alone can account, in a
simple and comprehensive, the uniqueness of a person and its future.
It is in the development of research
using both the old assumptions and technical innovations more modern than the
main risks arise probably drift scientific and ethical part of contemporary
research on the genetic determinism of complex diseases, including complex
diseases and disabilities affecting behavior and social interaction skills. It
is not to prejudge here is that the mere fact that these concepts are old they
are a priori devoid of any scientific basis: the exploration of the unknown
can, by definition, book all sorts of surprises and the history of science is
full of examples of concepts rediscovered the importance of which has long been
ignored, denied, or ignored (Lightman and Gingerich, 1992; Ameisen, 2003). But
it is important to realize that these old concepts concerning heredity not only
a long scientific history: they also had a sometimes tragic history regarding
their ethical implications (Gould, 1981 and 2002, Rothstein, 2005 .
Unethical the notion of
genetic determinism: Social Darwinism to eugenics ...
The extreme views of genetic determinism
have ancient roots. They go back to the theories developed by geneticists and
Haldane Fischer during the first half of the twentieth century, and even before
the (re) discovery of the gene in 1900, a vision of heredity developed in the
late nineteenth century by designers of "social Darwinism" (Gould,
1981). In 1883, twenty-four years after the publication of "From The
Origin of Species", and a year after the death of Darwin
We can not forget had some consequences
of these ideas, whose spread was extremely fast and had a profound influence on
society in the late nineteenth century and the first half of the twentieth
century. For example, the so-called "discovery" of the genetic basis
of a lack of intelligence and "antisocial behavior" among immigrants
from Europe and South East has led the United States in the early twentieth
century, the development of highly restrictive immigration laws with respect to
these populations in order to protect the "health" mental and social
situation. Genetic basis of the alleged crime, mental health and
"antisocial behavior" has also led, in the early twentieth century,
the introduction of compulsory sterilization laws favoring, referred to eugenics
in many democracies Western Europe, and many states in the United States: Tens
of thousands of people were sterilized as well (Gould, 1981 and 2002,
Rothstein, 2005). Some of these concepts were the basis, in Nazi Germany, in
the development of racial laws, euthanasia of the mentally handicapped, and
genocide. And it is in the judgment of Nuremberg
The recurrent temptation to discover a
grid of one-dimensional - the analysis of the shape of the skull, for example,
the anthropology of the early twentieth century, or the gene sequence for
modern genetics - which is enough finally to alone to account for different
levels of complexity of life and the human, often leads to the evolutionist Stephen
Jay Gould called "Mismeasure of Man" (Gould, 1981): Mismeasure a
scientific and Mismeasure ethically.
In 1893, Thomas Henry Huxley, who was one
of the most ardent defenders of Darwin
Today, more than in other fields of
genetics, it is probably genetic diseases that affect behavior, social
interactions, and mental abilities, and genetic traits, which pose not only
ethical problems, but also problems of scientific understanding (Rothstein,
2005(.
Avatars science the notion
of genetic determinism: the modern synthesis selfish gene
...
The mid-twentieth century, the modern
synthesis realized the integration of genetics to Darwin
The reductionist view of biology and
evolution of the single "point of view of the gene" (where the unit
of selection is not so much the body, as Darwin and his early successors, but
the genes that have the organization) has solved many complex problems, sometimes
difficult to understand in the context of classical Darwinian theory presented
in "On the Origin of Species", although the term "sexual
selection" thoroughly developed by Darwin his later work, "The
Descent of Men, and selection in relation to sex," presents the
perspective that can address these problems. This is, for example, the
apparently paradoxical spread of genes whose presence has an adverse effect on
the longevity of individuals (Williams, 1957), or even the survival of the
species, as is the case of phenomena meiotic distortion which can significantly
skew the sex ratio, enough to cause the disappearance of all the individuals of
one sex (Dawkins, 1976; Ridley, 2004). This is Dawkins who popularized with
great talent and a very successful one of the most extreme visions of genetic
determinism offering, 30 years ago, the metaphor of the "selfish
gene", writing in the book of the same name: "... [genes] are safe
inside gigantic robots ... manipulating the world by controlling it remotely.
They [genes] are you and me, they created us, body and spirit, and their
preservation is the ultimate reason for our existence ... "(Dawkins, 1976).
In a subsequent book, which is probably
his most original, "The Extended Phenotype", Dawkins (1982) shows
that this vision "in terms of gene" allows us to reconsider in a new
way, some of the more complex interactions between different agencies, in
particular the interactions between parasites and hosts they colonize. But the
dramatic metaphors about the "selfish gene" favored, despite some
precautions Dawkins, wide dissemination in society of the simplistic idea that
genes have a role not only actors, but also a form of intentionality. This idea
reflects the company sometimes vaguely anthropomorphic notions prédarwiniennes
project and purpose at work in the evolution of life, and very old notions of
vitalism. However, not only the genes have no intentions, but they are not
actors: they are, or are not used by the cells that possess them, and each cell
can generally from ' same gene, produce, depending on the circumstances,
several different proteins by the involvement of mechanisms continue to be
increasingly complex than previously thought (Gingeras, 2006).
These are the proteins that are involved
in the cells, and their effects depend in particular three-dimensional forms
they adopt, which are not only determined by the sequence of the genes from
which they are made, but also depend on the nature and activities of other
proteins present in the cells with which they interact and in particular the
presence and activity of many protein families "chaperones". And
these are proteins (the cell made from some of its genes), which are at work in
the production of other proteins from other genes ... There are therefore no
chain causality and simple way leading from a gene to a protein, a gene to a
"function" or higher because of a gene to the individual ... and the
reductive notion but popular "genetic program" is a notion deeply
ambiguous: "it is a program," wrote 30 years ago Henri Atlan
"who needs the product of his reading and scripts to be read and executed
..." (Atlantic, 1979). Literally "program" means
"pre-writing". But what is "pre-written" in our genes, if
indeed we can use that word, it is not our identity and our future is a set of
opportunities and constraints that the update depends continuously in our
history and our environment.
Can we reduce the complexity of living
metaphor Dawkins, where genes "manipulate the world ..." and
"created us body and mind"? The exterior is at least as, and often
more than the inside: the environment is at least as much as genes, acquired as
much as innate, and in humans and many animal species , culture as much as the
nature. Even if one insists, that there is no reason a priori to choose a point
of view centered on genes - rather than, for example, cells, or individuals -
must be considered in their genes ( s) environment (s). And the notion of
environment (s) is a far more complex than the usually perceives.
"This is about" the environment and its
multiple levels
For each of our genes that reside in the
nucleus of our cells, a first level of environment, it is our 20 000 to 30 000
genes in duplicate, our 40 000 to 60 000 alleles, which surround and we
inherited half of our mother and half from our father. But all our 40 000 to 60
000 alleles, and other areas identified as necessary for our cells to make
proteins from these alleles is not total about 30% to 35% of our DNA. 65% to
70% DNA remaining represent another level environment for our genes. And the
65% to 70% of the DNA, which have long been wrongly considered
"useless", hence the name DNA "trash" are partly used by
the cells, influencing the way they use their genes. For all of our DNA, the
environment is composed by proteins of our chromosomes that surround it. The
environment of each of our 46 chromosomes, it is the entire contents of the
nucleus of each of our cells. For each kernel, the environment is constituted
by the cytoplasm of the cell in which it resides. In the cytoplasm of each of
these cells are present and reproduce the mitochondria, tiny cells within our
cells, which produce energy from oxygen: each of these mitochondria, we inherit
mainly our mother (the mitochondria present in the egg) contains a small number
of genes different from our chromosomal genes. Each of our cells, genetically
identical, belongs to one of the 200 families of our body cells, each differing
by their composition, their structure, their characteristics and properties.
And for each of these cells, the environment is composed by the tens of
trillions of other cells that compose us. And for each of us, the environment,
are the other people around us and the diversity of lifestyles, cultures that
affect this environment and create new environments are animals and plants, and
are germs, viruses, bacteria, and parasites that surround us where we live, and
that change constantly. And for all living beings, another level still, the
environment consists of the non-living environment - landforms, oceans, rivers,
and soil composition of the atmosphere, climate, temperature ... - that living
beings themselves, and in particular humans, constantly transforming ...
Of course, a number of basic features
(our blood groups, our tissue groups, for example) are directly related to the
sequence of some of our genes. But this does not mean that our genes determine
our destiny, or more so, they "manipulate the world." There are genes
and a variety of environments, including levels interpenetrate and influence
each other. In the words of geneticist Richard Lewontin (2000): "The
inside and outside of a living being interpenetrate" and the individual
can be considered both as a place, object, product, and actor interactions.
Development and operating procedures of living imply causality
multidirectional, with feedback effects, amplification or inhibition at
different levels of organization: networks of proteins, cells, networks of
cells, organs, systems organs, individuals, networks of individuals, species
networks, networks of ecological interactions ... And at these levels, which
emerge various forms of interaction and organization, most elements are found
in the words Pascal, "things at once and caused causantes." And more
so that the characteristics we analyze the result of the integration of a large
number of different levels of interaction, as is the case, for example,
behavior.
The notion of "all genetics" -
the notion that the human person can be reduced to a single genome - began to
fade in the world of biomedical research. But it nevertheless continues to be
prevalent in society, and even among many researchers and doctors, as witnessed
debates on "reproductive cloning", and in particular the terms and
concepts of "double" and "copy" , for people who, like
identical twins, share the same genome. Awareness, in 2003, the human genome
did not, contrary to what had been announced some of its proponents,
"reveal human nature" or to understand and treat our illnesses,
played a role in the review of these notions of absolute genetic determinism.
The discovery that we have no more genes than the mouse, not much more than the
fruit fly, and much less than rice, suggesting that the relationship between
our genes and our identity is not limited to a simple relationship linear
causality between a "gene" and "function." Regardless of
the question of numbers, these studies also revealed that our genes shared many
similar sequences with genes of the mouse and the fruit fly ... The sequencing
in 2005 of the chimpanzee genome, confirming that we share more than 98% of the
sequence of our genes, not allowed to reveal to his reading, the nature of
genes or gene sequences that were the specificity of our "human
nature", compared with "nature" our non-human kin (Chimpanzee
Sequencing and Analysis Consortium, 2005). In other words, we know that there
is a link between genes and the development, survival, and behavior
characteristics of living beings: the issue is the nature of this relationship
is that, in most cases, far from simple, unidirectional, rigid and usually we
tend to imagine.
In this issue of the relationship between
the genome and the characteristics of a living species is superimposed another,
that variability even within a species alive. Is there a human genome
"normal"? And if so, what its characteristics? And that may well mean
the term "normal" in the context of the evolution of life and the
continuous mixing of individual variation produced by sexual reproduction?
Gene concept
"normal" gene "abnormal" or "transferred"
Most often, the notion of characteristic
"normal" or "abnormal" for an individual, appears at first
obvious. However, it is a fuzzy concept. It is indeed primarily a statistical
concept, a difference of variation in these characteristics compared to a
hypothetical individual who does not match any particular individual, but to an
average of individuals belonging to the same species. And the statistical
concept appears to prejudge a priori a profit of "adaptive advantage"
it is "normal" and therefore "good" for a bird to have
wings and can fly, it is "normal" and therefore beneficial to a
mammal having no wings, and therefore not able to fly ... But it can also be
"normal" and "good" for a mammal to have wings and can fly,
as This is the case of the bat and a bird have wings and can not fly, as is the
case of the ostrich ... In this context, the concept of gene "normal"
or " abnormal ", although widespread, is also deeply ambiguous.
When we try to go in search of the
origins of the human genome "normal", this journey takes us back
through 4 to 6 million years, until our last non-human primate ancestors we
share with chimpanzees. And recent genetic studies suggest that interfertility
later period between our first human ancestors and forefathers chimpanzees may
have occurred, altering the first human genome in the process of
differentiation (Patterson et al., 2006 ). Paleontology also teaches us that we
are only one human species to which these ancestors gave birth, the only one
not to have disappeared. The essence of "human nature," the
"standard human" is lost in our genealogy: the first human beings
"normal" were, in an apparent paradox, non-human primates
"abnormal".
The genes are in germ cells that give
rise to eggs and sperm, various modifications (mutations, insertions, deletions,
duplications ...) that can then be transmitted from generation to generation,
and that sexual reproduction breaststroke continuously mixtures and diversity.
And these genetic variations accumulate and spread over time that there are, at
any given time, for each gene, several different forms (alleles) whose
distribution in the human species differed and differs Today, according to
history and place (space and time).
Consider, for example, the color of the
skin, a feature whose genetic bases are just beginning to be explored (Lamason
et al., 2005). We do not know the (or) color (s) of original skin (s)
"normal" human beings first. Today, skin tone, rare in one place may
be common in another place, or have been common elsewhere at another time. The
color of the skin is not only a source of diversity, but can also be a source
of disease depending on the environment in the tropics pale skin favors the
development of cancers of the skin, dark skin in the northern hemisphere favors
the development of rickets in children and requires prevention by dietary
vitamin D. But the color of the skin can also be a source of disease due to
causal loops much more complex: not only in terms of the climatic environment,
but also the human environment. The behavior of others, discrimination, by
living conditions that can cause, or the restriction of access to care, may be
a source of diseases whose transmission tree can give the illusion of a cause
inherited, a genetic cause (Duster, 2005(.
Genetic variability and
health
The notion of "normality" is
often associated with the concept of health. However, the World Health
Organization (WHO) defines health not in reference to a "standard"
anyone but "a state of complete physical, mental and social" is not
the healthy person "normal", but the person who feels good. The
relationship between genes and human health should not arise a priori in terms
of allele "normal" or "abnormal", frequent or rare, but in
terms of alleles favoring or not the likelihood of suffering taking into account
the complexity of causal links that may come into play in this area, in
particular those related to the environment. And our vision alleles that favor
the likelihood of suffering - the likelihood of disease - is usually quite
brief. We want to know what are the alleles that would be desirable to be
healthy and what are the alleles that would be undesirable in terms of health.
This question, posed in these terms, probably did not make sense with regard to
the vast majority of our alleles, and the vast majority of diseases. But for a
large number of diseases, most often rare, it has medical implications
essential.
Monogenic hereditary
diseases with Mendelian inheritance and high penetrance: an allele / disease
The notion of genetic determinism is
particularly strong due to the discovery of hereditary diseases that are caused
by the transmission of a particular form of a single allele (single or
duplicate, as appropriate) and for which, If the presence of this allele (or
both alleles) in the genome, the likelihood of the disease (called penetrance)
is strong. These monogenic diseases are numerous, but most rate rare, severely
debilitating and often fatal in the absence of effective treatment and
prevention: Huntington's disease, muscular dystrophy, amyotrophic lateral
sclerosis, phenylketonuria, hemophilia , cystic fibrosis, hemochromatosis ...
(Kasper et al., 2004).
In these monogenic diseases, the allele
(or both alleles) in question is (or are) Legacy (s) under the laws of genetics
described there are more than a century by Mendel. What is it? We have about 20
000 to 30 000 genes, each in duplicate, in most cases, two different alleles
for the same gene, located on our 22 pairs of non-sex chromosomes, and double
or single copy on our two chromosomes sex, as they are symmetrical (XX in
females) or asymmetric (XY in humans). Monogenic diseases are called Mendelian
transmission when only the dominant presence of one particular allele for the
disease develops: the probability, when one parent has the allele to transmit
this allele to one of its children is 50%. Monogenic diseases are called
Mendelian transmission takes two recessive alleles when individuals of the same
gene are present for the disease to develop: in the presence of one of these
alleles, there is often not disease (and in any case not as serious illness),
the other allele, "ordinary", while being sufficient to prevent the
onset of disease. In case of a recessive disease, the probability when each
parent has one allele having a child that has both alleles and risk of
developing the disease is 25%. When a recessive allele is present on the X sex
chromosome, the disease occurs more frequently in men, since man does not have
a second X chromosome that may contain the allele corresponding "ordinary".
A woman who has two X chromosomes (one X being used in each cell, but not the
same as cells), no risk, where disease is recessive to develop the disease if
it has two alleles associated with disease.
Finally, some monogenic hereditary
diseases are caused by variations in mitochondrial genes: they are then
transmitted by the mother, with probabilities that do not correspond to the
laws of Mendel (who studied the transmission of characteristics related to
chromosomal genes).
Dominant hereditary disease, fatal or severely
debilitating in the absence of effective medical treatment, and that the
likelihood is very high (high penetrance) occur generally after the age of
reproduction: in fact, if a disease resulted in death or significant disability
before puberty allele could not be passed from generation to generation. One
example is Huntington's disease, fatal neurodegenerative disease, including age
of onset is variable, but generally after 40 years (Kasper et al., 2004).
However, some recessively inherited
diseases can be fatal or severely debilitating early childhood, without having
prevented the transmission of these alleles through time, to the extent the
transmission of a single copy of the allele s accompanying or any disease, or a
very mild form of disease compatible with survival and reproduction in the
absence of any treatment. Cystic fibrosis is an example of this type of
hereditary monogenic Mendelian recessive theoretical frequency in the general
population, individuals inheriting one of more than a thousand different
alleles (whose presence in duplicate promotes the development of cystic
fibrosis ), and do not develop disease in France is about 1/30. Thus, in the
general population, the theoretical frequency of children at risk of developing
the disease, and who were born to two parents with each of these alleles is
1/30x1/30x1/4, that is to say 1 / 3600 (the introduction in recent years of
neonatal screening for the disease in our country showed that the actual rate
was a bit lower).
The identification and study for over 25
years, thousands of alleles involved in monogenic diseases have high penetrance
revolutionized the understanding of the mechanisms involved in these diseases,
and helped develop diagnostic tests or screening to develop in some cases preventive
or curative treatments and to better understand the functioning of the body and
hence, various other diseases (Kasper et al., 2004; Munnich, 2005). At the same
time, the fact that in many cases of Mendelian diseases and high penetrance,
the presence of one or two particular alleles is frequently accompanied - or
very frequently - the development of the disease has greatly contributed to the
notion of absolute genetic determinism.
But we actually learn Mendelian inherited
diseases with respect, in general, the genetic determinism of disease?
Read the future in the
genes? A metaphor for the risks of overinterpretation
Mendelian inherited diseases in high
penetrance, the mere presence of a particular allele (dominant diseases) or two
particular alleles (recessive diseases) of the same gene, the 20 000 to 30 000
alleles that we have in duplicate (40 000 to 60 000 alleles, say approximately
50 000) is sufficient to predict with high probability the occurrence of a
disease. In other words, if the particular sequence of only 2 per 100 000 (50
000 on one allele for a dominant disease) to 4 per 100 000 (50 000 on both
alleles for a recessive disease) of all our genes is sufficient to predict with
a high probability of occurrence of a disease, it means he that the predictive
power of our genes is huge?
The problem is that predicting the likely
occurrence of a fatal or debilitating disease from the particular sequence of
alleles of a given gene does not necessarily imply that one can read the future
in the genes.
Insofar as the belief in an absolute
genetic determinism derives part of its fascination from some form of vision
that tends to dehumanize, mechanize, and reify the human person, it may be
useful to explore the possibility of overinterpretation of such an approach, to
use a metaphor for a moment mechanics. It is not of course compare a human
being to a machine, but rather to try to understand how a process which aims to
predict the future of life and human assimilating in part to a machine (a
mechanical genetics) may, in the context in which it takes place, leading to
illusions about its predictive capabilities.
Therefore consider an example - schematic
caricature and metaphorical - prediction on a machine. When the space shuttle Columbia exploded after takeoff in 1986, killing the
entire crew, and a teacher she carried on board, a commission of inquiry of the
Congress of the United
States
Did it mean that the study of seals or
other components of a space shuttle can, in general, predict the duration,
direction, travel destination ... a space shuttle? No, of course. But the study
of a particular component, if it reveals the existence of a constraint, will
make a prediction very safe, because it is a constraint that will jeopardize
the integrity of all. The study of the components of a space shuttle does not
in itself predict the future, except in cases where a particular component has
a very high probability of causing a disaster.
In other words, the universe and leaving
to return to living mechanical and human, a simple concept, yet rarely seen, is
the following: the fact that specific sequences, called "abnormal" a
number of alleles predict, in many cases, the occurrence very likely a very
debilitating disease or death does not mean that the sequence of any allele, in
general, allows to predict the future in terms of health and disease. The
sequence of specific genes may have predictive power, more or less, in
probabilistic terms, in the development of a disease. But, apart from these
cases, the analysis of gene sequence, can not - in any case can not now, in the
current state of knowledge - to predict the future of a person.
Genetic abnormalities
"silent" or "talking" and external environment
Even in cases where a particular
sequence, called "abnormal", an allele according to Mendelian
heritable, is associated with a very high probability to the occurrence of a
particular consequence on health, it should be borne in mind two important
concepts.
First, when the disease does not declare
at anyone with the allele (or both alleles) involved when penetrance is strong
but not total, which is most often the case, genetic testing does not predict
the Future of the person: it predicts a probability, more or less, of the
occurrence of the disease. What are the factors that modulate the penetrance?
It may be the nature of the allele, or environmental effects: effects of the
internal environment, genetics, due to the presence of other alleles,
corresponding to other genes, or effects from the external environment.
The second important concept is that, in
some cases, the probability of occurrence can fully depend on the nature of the
external environment with which the child or the person will be in contact: in
a given environment, the probability is very high and in another environment,
it may become zero.
Example of phenyl ketonuria
In many monogenic hereditary diseases and
Mendelian transmission high penetrance (Huntington's disease, amyotrophic
lateral sclerosis, muscular dystrophy ...), in the present state of knowledge,
the presence of one or two allele (s) particular ( s) of a gene is correlated
with a high probability of developing the disease regardless of the environment
in which the person will live after birth. But in some of these diseases
Monogenic Mendelian penetrance strong presence of the allele in question does
not necessarily predict the future regardless of the environment. One example
is a recessive disease phenylketonuria. The presence of two particular alleles
of the same gene causes inability to properly convert an enzyme one of the
amino acids present in the food, phenylalanine, tyrosine, leading to
accumulation of toxic compounds in the brain, and significant mental
retardation in childhood (Kasper et al., 2004; Munnich, 2005). Routine
screening at birth (not by a genetic test, but a test that demonstrates the
operation of the corresponding enzyme) has 30 years to save all the children
who inherited these alleles implementation from birth with a simple diet low in
phenylalanine and tyrosine enriched.
Thus, even when the probability of
occurrence of a disease monogenic Mendelian transmission is extremely strong in
a normal environment, "normal", a change of this environment can make
this probability zero. When there is no change in the familiar environment that
allows to prevent the disease from developing, fate is entirely dictated from
within by certain genes (but even in these cases, there may be questions about
character seemingly unstoppable, see below).
Example of deletion
CCR5-D32 and AIDS
There are some rare allelic variations
(some "anomalies" genetic) transmission and penetrance Mendelian
strong the effect is not to promote the development of a disease, but rather to
protect against disease. One of the most dramatic examples is a variation
consisting of a partial deletion - deletion CCR5-Δ32 - 32 bp of the promoter
(regulatory region) of the CCR5 gene allowing cells to produce the CCR5
receptor. CCR5 protein is a receptor for chemokines, molecules secreted by
other cells which cells expressing this receptor to move in the direction of the
source of secretion of these chemokines, that is to say, in general , to the
site of inflammation. CCR5-Δ32 deletion results in an inability of cells
expressing the receptor on their surface (Murphy, 2001; Kasper et al., 2004).
Approximately 1% of people from the northern hemisphere inherit two copies of
this allele "abnormal" or "defective". These people have no
health disorder detectable, but have an important advantage: they are
protected, in almost all cases against infection by HIV (Murphy, 2001; Kasper
et al., 2004). Indeed, HIV, the AIDS virus uses the CCR5 receptor to enter
cells and infect them. In other words, the absence of such an
"anomaly" genetic (characterized by the presence of two alleles
"abnormal" in the same gene) results for 99% of the northern
hemisphere, and almost all of those other parts of the world (where the
"anomaly" is virtually absent) to expose the infection by the AIDS
virus.
Approximately 10% of people from the
northern hemisphere have a single copy of this allele "abnormal", the
other being a common form, "ordinary". These people are not little or
protected against infection by HIV, the allele "ordinary" for the
production of a sufficient amount of CCR5 for HIV that can infect them. But the
progression of infection to disease is slowed (Murphy, 2001; Kasper et al.,
2004). In other words, the absence of such an "anomaly" genetic
result, 90% of people in the northern hemisphere, and almost all the people
from other parts of the globe, exposing people infected with HIV at a more rapid
development of AIDS.
This "anomaly" monogenic
"protective" is transmitted as Mendelian recessive manner with high
penetrance. It is a mirror image of monogenic recessive Mendelian transmission
and high penetrance that we discussed earlier. But again, let there be no
mistake: this form of genetic determinism, which is closely related to the
nature of the external environment, is of the order of a particular constraint,
allowing the prediction, not a disaster like monogenic Mendelian penetrance
strong, but rather a resistance to a particular disaster.
Be "abnormal" does not
necessarily mean being exposed to a disease to be "abnormal" can also
mean being more resistant than most others to illness.
Variation of genetic
sequences, outdoor environments, and diversity implications
The correlations between the presence of
certain "anomalies" Mendelian genetic transmission and the
probability in a particular environment, develop a disease or otherwise to be
protected are not always unidirectional suggest that the examples come from be
discussed.
Example of sickle cell
anemia and malaria
In 1949, Haldane suggested that the high
frequency in a given population, a particular allele increases the likelihood
of developing a disease, may be related to another effect, protector of the
same allele in some environments.
There are particular alleles which
promote the development of severe recessive diseases when they are present in
duplicate and, when present as a single copy, promote the development of a
moderate form of the same disease, but also the protection against other
diseases, death related to the environment. An example is sickle cell disease
(Kasper et al., 2004). The allele "abnormal" in question results in
the production by the cells form a "abnormal" hemoglobin structure
which causes deformation of red blood cells, causing obstruction of blood
vessels. When this allele is present in duplicate disorders vessel blockage,
and blood clotting disorders that follow can be considerable. When this allele
is present in a single copy, disorders are moderated. People with one copy of
the allele "abnormal" are very numerous in the population of regions
of West Africa where malaria is prevalent:
they are generally protected against serious, fatal malaria, which kills Each
year more than one million children. Encouraging, despite the health problems
it can cause, the survival of those who inherit the frequency of this allele in
these populations is most likely due to the protective effect (Kasper et al.,
2004).
In an environment where there is no
malaria, as the United States ,
the frequent presence of an allele "abnormal" in the African-American
descendants of the inhabitants of these regions of West Africa, which had been
deported to the United
States Africa
infested by malaria, this "anomaly" protects against a deadly disease
common. The presence of this allele is either purely pathological or survival
benefit as a function of the external environment. The allele, as such, is
neither "good" nor "bad." It depends on the environment,
and modern means that we have to protect themselves against malaria.
It is possible that some
"anomalies" gene which we see today in the current environment, that
adverse consequences in terms of hereditary monogenic Mendelian transmission,
have in the past been able to confer benefits in terms of survival or even
health. An example might be alleles whose presence promotes the development of
hemochromatosis, a disease characterized by excessive accumulation of iron in
the body from the diet. Indeed, it is likely that in an environment where food
was low in iron, this storage capacity could be a significant benefit in terms of
survival and health (Brosius and Kreitman, 2000).
Protection or
susceptibility to infectious diseases: back to CCR5-Δ32 deletion
Scarcity, in a population of a particular
allele increases the likelihood of protection against a deadly disease in a
given environment could be linked to the likelihood of developing another
deadly disease in the same environment? CCR5-Δ32 deletion, which protects
against AIDS, and that seems to cause any health problems in the northern
hemisphere, where it is relatively common, expose it to other diseases in other
environments, such as those regions of the southern hemisphere, where the
deletion is virtually absent? Works which have been published suggest: people
who have two copies of the CCR5-Δ32 allele and are therefore protected against
infection with HIV may be more at risk of developing a fatal encephalitis when
infection by a flavivirus transmitted by mosquitoes, West
Nile virus (Glass et al., 2006). This "anomaly"
monogenic which is transmitted as Mendelian recessive manner with high
penetrance, does not, unlike, for example, sickle cell anemia, cause health
problems by itself. But depending on the microbial environment, it faces a
probability of protection against disaster, or could, on the contrary, exhibit
a probability of catastrophe. Again, the allele, as such, is neither
"good" nor "bad." It depends on the particular nature of
the environment.
These concepts have potentially important
therapeutic implications. Indeed, some therapeutic strategies currently being
explored to prevent infection by HIV, or hinder the development of AIDS are
based on the use of drugs to mimic the effects of CCR5-Δ32 deletion, blocking
the receptor CCR5 (Crabb, 2006). If confirmed that such interventions may
promote the development of deadly diseases in case of infection by
flaviviruses, the question of the environment in which the person lives become
an essential element in the risk / benefit ratio of such treatment for
preventive or curative (Glass et al., 2006; Crabb, 2006). Thus, it may be
unrealistic to decide a priori whether a drug, as well as allele is
"good" or "bad" if we do not take into account the environment,
or if you do unknown effects.
Example of HLA polymorphism
There is an example where this is the
same frequency in a human population of an allele, regardless of its particular
sequence, which could be an advantage or a disadvantage in terms of health, for
the person who inherits it. This example concerns the alleles that cells use to
produce the HLA molecules, which constitute the major histocompatibility
complex. In this example, it is the scarcity, the character
"abnormal", the allele that confers a benefit, and its widespread
nature, its "normal", which would present a disadvantage. HLA
molecules play an important role in terms of immune response to microbes, and
thus in our defenses against microbes. There is a very large HLA polymorphism -
very many different alleles - in humans, unrelated individual having a
combination of alleles, and HLA molecules, which is clean, explaining
transplant rejection almost constant in the absence of immunosuppressive
therapy, between unrelated persons (Kasper et al., 2004; Janaway, 2004).
This great polymorphism means that in a
given population, exposed to the same germs, most people respond differently
(using different HLA) to the same microbe, the more likely it is that a
proportion of people possess, by random defense mechanisms that allow them to
survive particularly serious infections. But microbes evolve and change
continuously from generation to generation, on very short time scales. Studies
suggest that people with at a given moment, rare forms of HLA are often better
protected, not because these rare forms allow a more effective defense but
simply because most of the germs that breed in the majority of the population
are not appropriate (Hunter, 2005). If these individuals with rare HLA alleles,
but not particularly efficient, have a significant advantage in terms of
survival, the frequency of these alleles in the population will gradually
increase. Beyond a certain threshold frequency in the population, these alleles
will suddenly lose their protective value: no longer rare, and not particularly
effective, microbes have adapted. Other alleles become rare, will in turn
provide protection against infections
...
This is an interesting example where the
rarity alone could have a beneficial effect on survival and health. It is also
an interesting example of the risks that may be interpreted too narrowly and
too fast the significance of such a correlation between the sequence of a
particular gene and the occurrence of diseases. Indeed, if we analyze this
correlation at a given time in a given population, between HLA alleles and
susceptibility or resistance to infectious diseases, one might be tempted to
assign a priori value inherently "pathological" or conversely
"protective" in the sequence of certain alleles, whereas the
development of the disease or the protection only depends on its frequency in
this population. A person who has some of these alleles, "protective"
because few, emigrated in a region where these alleles are common, and suddenly
lose the protection against infectious diseases they give it. The concepts of
correlation and causation are easy to confuse genetics, as in other fields of
biology.
Beyond changes in the
sequence of genes: genome structure, epistatic interactions and DNA "trash"
The major source of genetic diversity -
genetic polymorphism - in humans is the occurrence and spread in the germ cells
(the cells that produce eggs and sperm) of inheritable mutations are the most
common point mutations, a single base pair of DNA, SNPs (Single Nucleotide
Polymorphisms) (The International Consortium Hapmap, 2003, Hinds et al., 2005).
Other sources of diversity are insertions of additional sequences in a gene,
the deletion of a portion of the gene, or changes not in the sequence of a
gene, but the genome structure (Sharp et al. , 2005; Conrad et al., 2006;
Gingeras, 2006): for example, a polymorphism for deletions of regions
containing genes or not (Conrad et al., 2006) or otherwise duplication of
regions containing one or more genes (s) (Sharp et al., 2005), can lead to 1,
2, 3 ... copies of the same gene.
Effect of changes in the
number of copies of a gene
An example of this type of polymorphism
by duplication of a segment of chromosome, and its consequences for health and
disease, has recently been provided by the study of CCL3L1 gene that is used by
cells to produce a chemokine MIP -1, which binds to the CCR5 receptor (Gonzalez
et al., 2005). This study indicates that people who have multiple copies of the
gene CCL3L1 are firstly less susceptible to HIV infection in a population, that
people with a low number of copies, and secondly, that among adults infected
with HIV in a population, people who have multiple copies of the CCL3L1 gene
evolve more slowly to AIDS (Gonzalez et al., 2005). A greater number of copies
of the gene allows cells to produce a larger quantity of the chemokine MIP-1,
most likely from competing with HIV for binding to CCR5, we saw that it was
necessary to HIV so they can infect cells.
Epistatic interactions:
effect of changes in the sequence of a gene in response to changes in the
sequence of other genes
Among many polymorphisms that influence
the operating procedures of the immune system, there is the great polymorphism
of alleles encoding HLA polymorphism and smaller alleles encoding a receptor
(KIR) that allow some cells killer immune system (cells "natural
killer") to kill cancer cells and cells infected by viruses. Studies have
been conducted in people infected with HIV to explore the possibility that
certain HLA alleles and / or certain KIR alleles can be correlated with the
rapid development of AIDS. The presence in a person infected with HIV, a
particular HLA (HLA-BW4 B-80I) has in itself no consequence in regard to the
rapid development of AIDS, when comparing this person to all people infected
with HIV in a given population. The presence of a particular allele KIR
(KIR-3DS1) is, however, correlated with a faster progression to AIDS. But in
people with both HLA-B BW4-80I allele and KIR-3DS1, progression to AIDS is
significantly slowed (Martin et al., 2002).
Thus, the association of an allele with
the isolated presence has predictive value zero and one allele whose presence
isolated predicts a probability of a poor outcome as a result of a probability
predict favorable evolution. In other words, in this case, and probably in many
others, the predictive power can have the particular sequence of a given allele
depends not only on the nature of the external environment in which a person is
immersed : it also depends on the nature of the internal environment of the
alleles, and the sequence of other genes, and, in a broader sense, the DNA
around them.
Beyond genes: DNA
"trash", microRNA ...
Approximately 95% of our DNA does not
contain genes, in the strict sense of the term, that is to say, does not
contain sequences used by cells to make proteins. Among these DNA regions, some
are located within the same gene (introns), others have been identified as long
regulatory regions schematically forms of switches, called promoters (Gingeras,
2006). Fixing certain proteins - transcription factors - these promoters,
regulatory regions and additional modulates the accessibility of genes to
enzymes that initiate the production from these genes, messenger RNA which will
leave the nucleus of the cell and allow, in the cytoplasm, the manufacture of
the proteins corresponding to the sequence of these genes. Introns and
regulatory regions make up about 30% of the DNA. But the rest of the DNA, that
is to say about 65% to 70% of the DNA has long been considered
"useless", and for this reason, called DNA "trash."
However, since about 5 years it became apparent that some regions of the DNA
"trash" are used by the cells. It seems that about 10% of this DNA
(probably a larger portion of the DNA that constitutes the genes) allows cells
to manufacture micro-RNA, including antisense RNA, which will not lead to the
production of proteins but can destroy or modulate the stability of certain
mRNAs and thus prevent or modify the production of proteins from genes (Mello and
Conte, 2004; Claverie, 2005). And it seems that there are about 10 times more
of these DNA sequences that are used by cells to manufacture these regulatory
RNAs that there are genes (Mattick, 2005).
Thus, knowing the sequence of a
particular gene or genes is not sufficient to predict whether - when or at what
rate - will be used by a particular cell, let alone the whole body, if we do
not know the regulatory sequences of DNA "trash" may modulate its
expression, whose exploration has just begun.
From genetics to epigenetics: effects of the
environment on gene expression
The most common serious diseases in the
rich countries of the northern hemisphere, and in these countries are the main
cause of death and disability are heart disease, cancer, metabolic diseases
such as diabetes, neurodegenerative diseases ... For some of these diseases,
such as breast cancer or colon cancer, or Alzheimer's disease (Price and
Sisodia, 1998), in a small minority of patients, the disease is linked to
particular alleles, and Mendelian transmission high penetrance. But in the vast
majority of people, these alleles are absent: it is not, in these cases,
inherited in Mendelian and high penetrance. But the links between diseases and
gene sequence is not limited to hereditary diseases: cancers represent a
dramatic example of the consequences that may have occurred in a person of some
genetic changes in somatic cells.
In most cases, the development of serious
diseases most frequent in our country is strongly influenced by environment and
lifestyle. The exterior has more often than the interior: the environment and
the lifestyle that heredity genetics, acquired more than innate. The
environment is not just a filter: it has effects on the body that changes the
way the body uses the genes inherited.
Epigenetic memory
The accessibility of a gene in a cell -
that a cell is capable or not use it to make proteins - rests largely on the
presence or absence of chemical modifications of the regulatory sequences of
this gene and changes chemical proteins of chromosomes (histones) surrounding
DNA. Enzymatic reactions which cause methylation of regulatory sequences of
DNA, and enzymatic reactions that cause, for example, a histone deacetylation
prevent the cell to utilize the corresponding gene (Mager and Bartolomei, 2005;
Qiu, 2006; Richards , 2006). These enzymatic reactions depend on the particular
history of the cell and are influenced by their environment: their differential
regulation makes a liver cell does not produce the same proteins that cell of
the heart, when they are genetically identical. And it is a form of
persistence, memory footprint, these particular usage of its genes, a cell has
initiated in response to its environment, which means that, most often, a cell
liver remains a liver cell, and give birth to a liver cell. This phenomenon of
enzymatic modification of DNA or chromatin that explains how the first cells
initially similar that arise from the fertilized egg cell - embryonic stem
cells - are gradually transformed into more than 200 different families of
cells up our bodies (Mager and Bartolomei, 2005; Qiu, 2006; Richards, 2006).
This is also what explains this phenomenon called parental imprinting, the fact
that some alleles will not be used the same way by the cells as they were
transmitted by the father or the mother (Mager and Bartolomei, 2005; Robertson,
2005; Qiu, 2006; Richards, 2006), he also explains that for women, one of the
two X chromosomes is randomly inactivated in each cell (Mager and Bartolomei,
2005 , Robertson, 2005; Qiu, 2006; Richards, 2006). This phenomenon also
explains how the transfer of a nucleus (that is to say the set of chromosomes,
DNA and genes it contains) a skin cell into an egg whose nucleus has been
removed (this is called "cloning") enables the development of an
embryo, while in the environment of the skin cell, this kernel only participate
in the production of skin cells; an egg does not use its genes in the same
manner as a skin cell. But these enzymatic reactions that control the
accessibility of genes can be modulated by the external environment, which may
alter the activity of body cells (Meaney, 2001; Robertson, 2005; Qiu, 2006;
Richards, 2006). And recent studies indicate that two genetically identical
(identical twins) gradually acquire, during their lives, epigenetic
modifications that lead to different ways of using the same genes, thus
contributing to the construction of their singularity, and can be involved in
mismatches risk of developing certain diseases which affect one twin and not the
other (Otto et al., 2005).
It is the exploration of all the effects
of indoor and outdoor environments on how to use genes from the cells, and the
heritability of these changes, in the absence of any change in the sequence of
the DNA through generations of cells, within an individual, and in some cases,
through generations of individuals, which is the field of study of epigenetics
(Meaney, 2001; Qiu, 2006 ). Cells are particularly sensitive to these
environmental changes during the development of the embryo, and the period
after birth. But these effects related to the environment can occur throughout
life. The external environment influences the environment within the body,
which in turn can affect the accessibility of certain genes or not. Know that allele
is present, and know its sequence does not prejudge whether or not to use
cells, and therefore the consequences of its presence.
These epigenetic changes, which are very
different mechanisms are involved in the development of many diseases (Dennis,
2003; Egger et al., 2004; Robertson, 2005; Qiu, 2006; Richards, 2006)
including, for example cancers where epigenetic and genetic changes in somatic
cells both play a significant role (Klein, 2005; Feinberg et al., 2006).
But in the context of epigenetic effects
of the external environment, the most surprising results are perhaps not affect
the development of both diseases, the emergence of some basic physiological
characteristics of organisms, such as how embryonic development, maximum
longevity and aging, and what might be called behavioral traits, such as the
measurable degree of anxiety and memory capabilities measurable. These studies
were conducted in animal models, and we do not know, now, how or to what extent
their results have implications regarding the human being.
Epigenetics and plasticity of embryonic
development
The best known example, the most extreme
and long considered an exception for embryonic development in species far
removed from ours, such as bees. Two egg cells genetically identical bee can,
depending on their external environment (nature of pheromones emitted by
queens, or nature of the food supplied by the workers) develop in two different
ways which give rise either to small workers sterile, who live two months,
either of the queens of large, fertile, who live more than ten years. These
dramatic differences, including longevity "natural" order of a factor
of 60, resulting from different methods of body building, themselves linked to
a differential use of identical genes in that construction.
Epigenetics, aging and longevity
Past ten years, a series of studies has
revealed, in some species, the boundaries of longevity "natural"
maximum were not as rigid as once believed. In very different animal species,
including the last common ancestors back to a period there are about 700
million years - the little transparent worm Caenorhabditis elegans, the fruit
fly Drosophila and the mouse - longevity "natural" maximum
individuals can be increased by at least 30%, and the onset of aging and
diseases of aging much delayed by at least two major types of approaches
(Guarente and Picard, 2005; Kenyon, 2005; Kirkwood 2005 Kurosu et al., 2005).
The first approach is to artificially produce mutations in a particular gene -
to produce new alleles "abnormal" - or delete an allele
"normal", or otherwise increase "abnormally" the number of
copies of an allele "normal ". The second approach is to modify the
external environment - for example, a restriction of calorie rich food. The
simultaneous implementation of these two approaches provides, in most cases, no
additional gain in longevity, suggesting that they exert their effects on the
same process. Thus, a different gene ("abnormal") in a normal
("normal"), or genome normal ("normal") in a different
environment ("abnormal") may have the same effect: delay aging (and
diseases that accompany aging), thus increasing the longevity of an animal that
stays young longer. Change the interior or exterior can have the same effects.
When the notion of genetic inheritance may
be a delusion
There are several mechanisms of very
different nature, which may lead to an "inheritance" - a stable
transmission, do not follow Mendel's laws, through generations of descendants -
some individual characteristics, origin epigenetic regardless of any changes in
the gene sequence.
Internal environment and epigenetic
inheritance
One of these mechanisms is directly
related to the transmission of genes: it is the intergenerational transmission
of certain terms of epigenetic modifications of DNA and / or chromatin that
accompanies the transmission of genes by through germ cells, sperm or eggs,
which may, for example variations in terms of parental imprints (Robertson,
2005; Schubeler and Elgin, 2005; Richards, 2006). Another mechanism, long known
as common in plants, has been identified for the first time in 2006 in a mammal, the
mouse. This mechanism shared with the genetic inheritance that the
intergenerational transmission is through germ cells, sperm or eggs
(Rassoulzadegan et al., 2006). Its peculiarity is that molecules (microRNAs)
that the cells produced in a parent from one allele can be transmitted to the
embryo through the germ cells in the absence of the allele. And amplification
mechanisms can lead remanufacturing of these RNAs and their transmission to the
offspring in the absence of the allele (Rassoulzadegan et al., 2006): it is a
mark of a memory of the presence, in the past, in an ancestor, an allele that
has not been sent. For now, the importance and frequency of such mechanisms in mammals,
particularly humans, are unknown, but have recently been the subject of
assumptions (Krawetz, 2005).
External environment and epigenetic
inheritance behavior
A third mechanism, studied for less than
a decade in mammals, is completely independent of any transmission by germ
cells (Liu et al., 1997, Francis et al., 1999; Meaney, 2001; Dennis, 2003 ,
Francis et al., 2003; Krawetz, 2005; Weaver et al., 2005; Richards, 2006). In
these cases, the propagation of changes is not the result of a transmission,
but a reinitiation by the environment, the offspring from generation to
generation, an epigenetic modification already initiated a similar environment
among the ancestors. It may be, for example, the effect of certain foods
(Dennis, 2003; Richards, 2006): footprint, memory can then be linked to a
particular place or a way of life. But when the environment that initiates
these changes is a particular behavior of animals, it is the community itself
that can reinitiate in every generation, footprint, memory she has received
from his ancestors and that transmits to his descendants (Liu et al., 1997,
Francis et al., 1999 and 2003, Weaver et al., 2004 and 2005).
Obtained in the laboratory by inbreeding,
many strains of mice and rats consist of genetically identical animals, whose
descendants are genetically identical to their parents. Two different strains
of mice or rats genetically identical can be distinguished by differences in
behavior heritable, handed down from generation to generation. For example, an
adult, a measurable level of anxiety more or less important - differences in
how the animal feels and responds to its environment - and different storage
capacities - differences in how the animal prints in him certain components of
its environment, and engages him in this print - correlated with different
levels of expression of receptors for hormones or neurotransmitters in certain
areas of the brain.
The fact that these features are shared
and inherited by genetically identical animals has strengthened the idea of genetic
determinism of behavior, and most of the work in these animal models, as in
many others, have been focused on research alleles determine the sequence of
these differences in behavior. However, a series of research initiated within
the last 10 years some of these strains of rats and mice led to a profound
questioning of these concepts (Liu et al., 1997, Francis et al., 1999 and 2003;
Weaver et al., 2004 and 2005). Work on rat lines revealed that the fact of
giving a newborn a bloodline pure anxious behavior in a surrogate mother
belonging to a bloodline pure calm demeanor, that led to the newborn manifest
in adulthood, behavior (and levels of expression in the brain, receptors for
hormones) identical to those of its parent adoption, not its genetic parents
(Liu et al. , 1997). More surprising if the newborn animal entrusted to a
surrogate mother is a female, she will give birth to itself descendants who, as
adults, have the behaviors and characteristics of their brain grandmother
adoption, not their genetic grandparents (Francis et al., 1999).
Thus, in this case there is inheritance
of "acquired characteristics". The explanation of these results
schematic apparently surprising is the following. In lines of genetically
identical animals to anxious behavior, the way the mother interacts during the
first few days after birth, a newborn, causes methylation (that is to say,
inaccessibility) in cells of certain brain regions, the promoter of a gene that
cells use to produce a receptor for glucocorticoid hormones (Weaver et al.,
2004). How mothers of genetic lineages calm demeanor caring for a newborn leads
to an absence of promoter methylation of this gene, which remains usable by the
cells. Regardless of differences in gene sequence between these two lines, the
type of behavior inherited and passed on to descendants simply depends on the
external environment in which the newborn has been immersed in the days
following birth. More recent studies indicate that if these animals are
subjected, as adults, to experimental treatments that affect the degree of
methylation of their genes, these treatments canceled early epigenetic effects,
changing behavior (Weaver et al., 2004 and 2005), suggesting the possibility
that epigenetic changes may influence behavior in different periods of life.
Other studies conducted in different
lines of genetically identical mice characterized by different behaviors in
adulthood showed that behavior in adulthood could be modified by epigenetic
effects of the environment even before birth (Francis et al., 2003). Briefly,
in this model, mice manifest in adulthood, the behavior of their line of
adoption, not their genetic lineage, provided not only that infants were reared
by their mothers a few days alternative, but have previously been implanted as
embryos in the uterus of the surrogate mother, who play in this case both the
role of surrogate mothers, and mothers after adoption birth (Francis et al.,
2003).
Thus, the widespread idea that a
surrogate mother would be a mere vehicle for the embryo, and would not
influence its development, and in particular on the development of certain
behavioral traits - only have the genes inherited the embryo and the
environment that will be after his birth - is, at least in animals, an
illusion. Epigenetic constraints, such as constraints on the specific nature of
gene starts at conception.
It is important at this stage to make two
remarks. The first is that it is not about the mechanisms involved in disease
development, but variations on behavioral traits of "ordinary" levels
of anxiety, memory skills ... The second point, obviously, is he is not here
but human behavioral traits of animal behavioral traits. And any attempt to
extrapolate these results immediately in humans still has a dimension reductive
must never forget to take into account.
But it is interesting to keep in mind
that such studies suggest a very general way, many approaches currently being
conducted with almost certainty a priori that will identify genetic variants,
alleles, which determine changes in behavior "normal" might be
illusory. There are two risks in these approaches: the first is to reinforce
the idea that every human characteristic is registered and legible from the
design in the gene sequence and the second is to medicalize out all the
components of the uniqueness of personality human (Grandin, 2004; Sacks, 2004).
Epigenetics and animal models of lethal
monogenic Mendelian inheritance and high penetrance
In the case of monogenetic diseases with
Mendelian inheritance and penetrance almost absolute, such as Huntington's
disease, it seems that fate is written in the genes (in one allele) and that
neither the living nor the external environment can not change the development
of the disease. However, recent research, conducted in mice suggest that this
concept could be misleading. Can be induced in mice a disease that has all the
features of Huntington's disease, leading to death by inserting its genome
alleles that cause disease in humans. When these mice maintained under 'normal'
animal, disease and death are triggered reproducibly to the same period in all
genetically identical mice. When "enriched" cages, with objects that
allow exploration, physical activity and mental stimulation, the onset of the
disease, and death, are significantly delayed (Van Dellen et al., 2000). The
same type of experiment was conducted in 2005 with transgenic mice that
accumulate in the brain beta-amyloid deposits characteristic of Alzheimer's
disease virus (Lazarov et al., 2005). It is less clear in this case (unlike the
case of Huntington's disease), these changes actually correspond to those that
lead to Alzheimer's disease in humans. The fact is that when you change, by
"enriching" the environmental conditions, and therefore the lifestyle
of these mice, there is a significant reduction in the formation of
beta-amyloid deposits in the brains of these mice (Lazarov et al., 2005).
It is not known whether these results are
transferable to humans. But it is not impossible that the fatalism with which
we treat people who develop certain diseases is not in some cases a
self-fulfilling prophecy: the belief that nothing in the environment can change
their destiny, we are concerned may be enough of their environment, the first
environment, the human being is the presence of others, and how to relate to
others.
Thus, if the specific nature of genes and
the DNA of an organism affects how the body behaves in its environment and
modifies this environment also affects how the body uses its genes. Innate and
acquired, and in human societies, nature and culture interact in complex causal
relationships, retroactive, now called biology of "causal spiral."
Experiences, particularly in animal models aimed at understanding the role of a
variable trying to keep all other variables constant, can highlight, under the
conditions where the environment is kept constant, the consequences of genetic
diversity. However, the experiments consist of varying environmental reveal
identical genome, the consequences of these environmental changes. The
reductionist approach is essential to try to understand cause-effect
relationships. However, it may be illusory and misleading if it leads to the
conclusion that the causal relationships revealed in specific conditions
summarized alone all causal relationships can be brought into play in complex
and unique individuals, immersed in a changing environment.
Posted in
0 Comments
