APPENDIX ONE: THE MEANING OF GENETIC CAUSATION
by
Elliott Sober
Genes
do two things. They provide a mechanism
of inheritance, and they influence how organisms develop. When genes do the former, they effect a
connection between generations--parents pass genes along to their
children. When genes do the latter,
they participate in processes that occur within a generation; they affect how a
fertilized egg--a single cell--divides and differentiates, and eventually
becomes an adult, who has numerous traits that were not present at conception.
In saying that genes provide a
mechanism of inheritance, the point of the indefinite article is to highlight
the fact that there are nongenetic pathways whereby parents influence the
traits of their children. A child who
hears English spoken while growing up will come to speak English, but this is
not because English-speaking parents transmit a gene for speaking English to
their offspring. Imitation and learning
can lead children to resemble their parents. Cultural context can engender additional similarities that are not
genetically mediated; when children inherit money from their parents, this is
neither genetic transmission nor learning.
When we turn to the second role that
genes play, the indefinite article is again appropriate. Genes are a cause of the traits that
organisms develop, but there are others.
These nongenetic causes are lumped together under the heading of "environment." Genes contribute to an individual's being
tall, but so does the amount of nutrition consumed when young. In discussing how development proceeds, it
is important not to equate "genetic" influences with
"biological" influences. How
many calories you eat is a "biological" influence on your height, but
this is an environmental, not a genetic, factor. To say that "biology" is relevant to a trait is not the
same as saying that "genetics" is relevant. There is more to biology than genetics!
This point is easy enough to grasp in
connection with an example like height, but it seems to get cloudy for many
people when they think about psychological phenotypes. For example, in one controversial study,
Simon LeVay (1993) performed autopsies on
the hypothalmuses of a number of homosexual and heterosexual men, and
claimed to find that a certain region--the INAH-3 nucleus--was smaller in the
former group than in the latter.
LeVay's claims have been disputed for many reasons; for example, the gay
men examined had all died of AIDS, so the question arises as to whether the
size of their nuclei was affected by the disease or by the treatments the
individuals received. However, the
point I want to make about this research concerns the fact that many people
described LeVay's work as showing that there is a genetic basis of homosexuality. No such conclusion follows, even if LeVay is
right that the two groups exhibit this neurological difference. A difference in phenotype may be due to a
genetic difference, an environmental difference, or both; the point does not
change when one focuses on the phenotype of brain structure, or on a
psychological phenotype like sexual orientation.
The two roles played by genes--in
inheritance and in development--are illustrated in the accompanying
figure. Parents transmit genes to
offspring during reproduction (R); genotypes influence phenotypes during
development (D); and parental phenotypes influence offspring phenotypes when
children learn (L) from their parents.
The figure also depicts the fact that genes are not the only players in
the processes in which they participate.
Parent/offspring resemblance may be due to shared genes, to the fact
that parents teach their children, or to the fact that both develop in the same
environment. And the traits that an
organism develops are a joint product of the genes the organism possesses and
the environment in which the organism lives.
------------------
Environment
------------------
--------------------------
-----------------------------
parents'
phenotypes
----------(L)--------> offspring's
phenotype
--------------------------
-----------------------------
(D) (D)
------------------------- ---------------------------
parents'
genotypes
----------(R)--------> offspring's
genotype
-------------------------
---------------------------
Of the two roles that genes play, one
is much better understood than the other.
The rules of genetic transmission are pretty clear. Genes reside in chromosomes, which are found
in the nuclei of cells. Human parents
have forty-six chromosomes in each cell of their bodies; these chromosomes come
in pairs, so there are twenty-three pairs.
When parents produce sperms and eggs, each sperm and each egg receives
one chromosome from each pair; each possesses twenty-three singleton
chromosomes. When these sex cells come
together to form a fertilized egg, the genetic complement of twenty-three pairs
is created anew. There is a great deal
more to the physical processes involved in the formation of sex cells and in
the way that sex cells come together to form a new individual, and some of
these details are the focus of continuing research. Yet, in outline, the way genes behave in the process of
reproduction is a known quantity.
Matters are very different when we ask
how genes participate in the process of development. The initial stages of this process are well understood. Genes are pieces of DNA. Two pieces of DNA are physically different
when they contain different sequences of nucleotides. Development begins with different pieces of DNA constructing
different pieces of messenger RNA, which then are used to construct amino
acids, the building blocks of proteins.
These proteins then help construct still larger and more complex
structures. A zygote has one cell. Genes cause the cell to divide and the
daughter cells to specialize, so that the end product is an organism with
many specialized cells--brain, liver,
heart, etc.--that form up into specialized organ systems. In general, the more downstream
developmental processes are, the less they are understood: a great deal is know
about how genes produce proteins, but we still are vastly ignorant about how
genes construct working livers and brains.
I. Three Modes of
Intervention
In
spite of the fact that development remains a mystery in many respects, the
current molecular revolution in biology is vastly expanding our understanding
of how genes contribute to developmental outcomes. Scientists already are able to intervene into human lives in
various ways, and the precision and pervasiveness of these interventions are
bound to increase as we learn more. We
can use the previous diagram to identify three types of intervention that
knowledge of genetics makes possible.
To see how an individual's phenotype might be modified, consider the
arrows that point, directly or indirectly, to that item in the figure. Two pathways of intervention were in use
before the molecular revolution of the 1980s, though new knowledge will expand
their domains of application. A third
is still in its embryonic stage.
First, understanding which genes
contribute to which traits allows people to control which genes are passed
along from parents to offspring. This
was the dream of the old eugenics movement.
It lives on in the modern guise of genetic counseling. For example, potential parents can be tested
for whether they carry a single copy of the Tay-Sachs gene; if each of them
does, there is a 1 in 4 chance that their child will have two copies and so
will have the disease. Parents, thus
informed, may decide not to have children, or to take the chance and abort the
fetus if it turns out to have two copies.
This intervention does not change the phenotype that a given individual
comes to possess; it merely affects which individuals are conceived and allowed
to be born. The use of this screening
technique has significantly reduced the frequency of Tay Sachs disease--not by
curing it, but by preventing individuals who would have had it from coming into
existence.
Much of what is known about how to
detect the presence of a gene and to predict its phenotypic effects predates
the molecular revolution. Notice that
it is not essential to understand the developmental details to put this
intervention into practice. All that is
needed is a test for whether parents have one copy of a gene that produces the
target phenotypic condition when the gene is found in double dose. Powerful molecular techniques will greatly
enhance this domain of knowledge--more traits in offspring, both good and bad,
will be predictable (in that probabilities will be assigned to their
occurrence) from genetic tests performed on parents.
The second pathway of intervention
involves manipulating the environment.
As we learn more about what genes do, we also learn more about how
environments may be modified to compensate for defective genes. For example,
PKU syndrome (phenylketonuria) is a genetic condition in which people are
unable to digest phenylalanine. If they
receive a normal diet that contains this amino acid, phenylalanine accumulates
in their system, resulting in a severe mental retardation. But if they grow up in a different
environment--one in which the amino acid is not present in their diet--they
develop normally. Cystic fibrosis
provides a second example. It is a
genetic disease. People with cystic
fibrosis often die of lung infections that occur because the mucus in their
lungs is a breeding ground for bacteria.
It has been found that the enzyme DNAase is able to break down the DNA
in this mucus, thus reducing its viscosity.
Here molecular biology has provided a new environmental manipulation,
one that promises to improve the lives of many CF patients.
The third pathway of intervention is
very much in its infancy, but it can be expected to become more and more
available, across an ever widening range of conditions. If individuals lack a gene that is needed to
produce a given protein, then gene replacement therapy may allow working genes
to be inserted into their cells that do the job. Likewise, if individuals have a gene that produces a destructive
protein, new genes may be added that remove the protein, or prevent the protein
from being constructed in the first place.
One version of the condition called
severe combined immune deficiency (SCID) results when two copies of a recessive
mutation are present; the result is that a protein needed by the immune system
is not produced. An experimental
procedure has been tried out on a small number of children; they received DNA
that causes the needed protein to be produced.
The results have varied, but immune response has consistently improved, sometimes
quite dramatically. Another example is
a genetic condition that results in drastically elevated levels of LDL
cholesterol. A young woman with
hypercholesterolemia, who as a result had a history of severe coronary disease,
had her LDL levels significantly reduced by a gene replacement therapy that
involved modifying the genes in some of her liver cells. These two examples are still experimental
procedures, so their general efficacy is at present unknown. It remains to be seen how many other phenotypes
may be modified by similar techniques.
Still, it seems clear that molecular biology will provide an ever
increasing number of such interventions.
Early geneticists had no knowledge of
the physical makeup of genes. The
rediscovery of Mendel's work around 1900 led scientists to think of genes as
hypothetical entities, known only by their effect on the phenotypes of
organisms. The pea plants that Mendel
studied produce smooth and wrinkled peas in predictable proportions; this
allowed the inference that inside of those plants are
entities--"factors"--that combine in certain ways and somehow cause
phenotypes to appear. It was a major
advance when Thomas Hunt Morgan and his school were able to establish in the
early part of this century that genes are located in chromosomes. Even so, it remained true that the existence
and nature of genes was something that could be gleaned only from the
observable phenotypes of organisms.
The way in which genes actually
produce phenotypes remained a mystery and science had no independent access to
their physical makeup. The great leap
forward effected by molecular biology is that the physical nature of genes and
their contribution to developmental processes can be studied more
directly. Genes are no longer thought of
as hypothetical entities; rather, they are "factories." They start and stop work because of
identifiable physical signals and they manufacture products, whose physical
makeup can be analyzed.
In discussing these three possible
types of intervention, which aim to influence the phenotypes that individuals
develop, I have chosen diseases as my examples. Indeed, medical applications of this sort are pretty much the
exclusive focus of present-day genetic counseling, genetically informed
environmental manipulation, and gene replacement therapy. Still, what can be done for abnormal
phenotypes may also be possible for normal ones. Just as science may provide techniques for changing a diseased
phenotype into a healthy one, it also may be able to change a normal phenotype
to one that is "better" than normal.
For example, if some interventions can
prevent certain sorts of mental retardation, it is possible in principle that
other interventions can change normal intelligence to above average intelligence. Not that it is easy to figure out how this
type of intervention might proceed.
Perhaps it is a simpler scientific task to identify genes that
contribute to diseased phenotypes than it is to figure out how normal genes
might be modified to produce "enhanced" phenotypes. And, of course, there may be ethical
objections to interventions of this type.
Still, the ability to intervene in this way is on the horizon as scientific
knowledge expands. The above diagram
applies just as much to "superior" phenotypes as it does to average
or defective ones.
I place the term superior in quotation
marks to signal the fact that it raises problems. Who is to say which traits are better? The Nazis thought in these terms, but their odious form of
"racial biology" has long been exposed as the nonsense it always
was. Although racists will be quick to
use the term "superior," it is important to see that the issue I am
pointing to does not disappear just by disavowing racism. When nonracists say that disease is less
desirable than health, they are applying the terminology of better and worse.
If we try to say why it is better to
be healthy than diseased, we inevitably are led to say that some unusual
phenotypes would be better to have than the average phenotypes found in human
populations. Mental retardation is less
desirable than normal mental function, in part because retardation drastically
contracts the range of worthwhile lives a person might be able to lead. However, this reasoning leads to a further
conclusion--that enhanced mental function can be more desirable than average
mental function if it expands the range of worthwhile options a person
has. Of course, this does not mean that
these two comparisons are equally weighty--that avoiding retardation and being
average is exactly as important as avoiding being average and being a
genius. The point is that if disease is
worse than health, then it is hard to resist the conclusion that some rare
traits would be better to have than traits that are "normal" in the
sense of being average.
My claim is that from the point of
view of biology, it makes sense to think of disease, health, and enhanced
function as all falling on a single continuum.
If intervening in the lives of individuals allows science to move them from
disease to health, science may also be able to move individuals from being
merely healthy to having enhanced function.
The difference between a diseased and a healthy person may be due to
their different genes, different environments, or both; by the same token, the
difference between a normal healthy person and someone who has enhanced
function in some respect (such as better lungs, better eyesight, better memory)
may be genetic, environmental, or both.
II. Four Key Questions
I
now want to analyze more carefully the causal language that is used to describe
the impact of genes and environment on an individual's phenotype. The preceding figure was full of arrows that
represent causal influence. What does
it mean to say that genes are more important than environment (or vice versa)
in the development of some phenotype? I
said earlier that PKU and cystic fibrosis are "genetic" diseases, but
then I described environmental interventions that prevent their development or
ameliorate their symptoms. What does
"genetic" mean in this context?
I also said that speaking English is not a genetic trait, in that people
acquire whatever language they hear while they grow up. But it also is true that individuals without
genes do not end up speaking English, because they do not grow up at all; and a
chicken exposed to spoken English will not end up speaking English, presumably
because of the genes it has. So what
does it mean to say that speaking English is environmental, not genetic?
To address these issues, it will be
useful to consider four questions about the role that genes play in causing
some trait that an individual has:
! Do genes causally contribute
to the trait?
! How much do genes, as
opposed to environment, contribute to the trait?
! Which genes contribute to
the trait?
! How do these genes
contribute to the trait?
These
questions will have different answers, depending on the trait under discussion;
what is true for speaking English is not true for Huntington's disease. The questions are listed in a certain order; typically, to answer a question
further down the list, you have to answer earlier ones. In this sense, later questions are harder
than earlier ones. My goal here is to
clarify what these questions mean; I will not try to provide factual answers to
these questions in connection with any particular trait.
All four questions assume a division
between genes and phenotype on the one hand and between genes and environment
on the other:
Genes
Phenotype
Environment
Phenotype
and environment are defined in biology as "garbage can
categories"--an organism's phenotype is all the traits it has other than
its complement of genes. So all your
morphological, physiological, behavioral, and psychological traits are part of
your phenotype. The fact that someone
is 5' 8" tall, has brown eyes, high blood pressure, a certain blood type,
lives in the Midwest, and likes jazz are all phenotypic traits. Similarly, an organism's environment
includes any trait that it has other than the genes inside its body. How many calories you consume is part of
your environment; your caloric intake, plus your genes, together influence how
tall you grow.
Even things that are inside the
organism's own body can count as part of the "environment" as far as
the development of a given phenotype is concerned. For example, if an individual is born with some degree of
immunity to a certain disease because it received antigens from its mother
contained in the extrachromosomal part of the egg, these antigens are counted
as part of the organism's environment.
The antigens, plus the organism's genes, influence whether and how much
immunity it will exhibit. Possessing a
set of antigens might be considered a part of the environment as far as the
development of immunity is concerned, but having those antigens is also a
phenotypic trait that the organism possesses.
Now let's consider the four questions.
Question (1): Do genes
causally contribute to the trait?
A
set of genes can causally contribute to a trait without it being true that
those genes suffice for the trait. And
it need not be true that those genes are necessary for the trait to be
present. This is a general point about
what the word "cause" means.
Striking a match causally contributes to the match lighting, but the
striking is not by itself sufficient; oxygen has to be present and the match
has to be dry. Similarly, you can get
the match to light without striking it--for example, by using a magnifying
glass to focus light on the head. Here
are two illustrative examples:
! The defective gene in PKU
syndrome causally contributes to the syndrome.
However, a particular environment has to be in place--the presence of
phenylalanine in the diet. So the gene
is not sufficient for the syndrome.
! There is a defective gene
that causes breast cancer. However,
this gene is present in only a small percentage of women who contract breast
cancer. The gene is not a necessary
condition for the cancer.
These examples also show that when a
phenotype has a genetic cause, this does not mean that the phenotype cannot be
modified by changing the environment.
As noted before, PKU syndrome can be avoided by modifying the diet. And it is possible that therapies will be
discovered for women who have the gene for breast cancer that prevent the gene
from doing its destructive work.
Discovering genetic causes can provide insights into the types of
environmental manipulation that would be efficacious.
Another point about question (1) is
that it has to be understood in the right way.
An organism will not develop at all if it has no genes. However, this obvious fact does not mean
that genes automatically
"contribute" to every phenotype we might consider. The reason is that "genetic
contribution" means that genetic differences make a difference
in whether you have a particular phenotype.
For example: an organism cannot develop to the point where it is able to
speak a language if it has no genes.
However, this leaves open whether the genes you have make a difference
in whether you will speak English rather than Chinese. Apparently, your genes make no difference in
this regard:
Language heard as a child
English Chinese
-----------------------------
G1 English
Chinese
Genes you
might have G2 English Chinese
G3 --- ---
-----------------------------
The
genes G1 and G2 each permit normal development, in which case the language you
speak is determined purely by your environment. But suppose that G3 is a genetic configuration that causes a
severe retardation that prevents a person from acquiring any language at
all. If so, your genes affect whether
you will learn a language or not, but they do not affect whether you will learn
English or Chinese. Notice that this is
entirely consistent with the fact that there are genetic differences between
English speakers and speakers of Chinese.
However, these differences do not make a difference; this is correlation
without causation.
Question (2): How much do
genes, as opposed to environment, contribute to the trait?
When
two causes both contribute to an effect, how are we to say how much each
contributed, or which was more important?
Consider an example due to Richard Lewontin (1974). Suppose two bricklayers build a wall. Each brings his own mortar, bricks, and tools
to the site; they start at opposite ends, the one building from the right, the
other from the left. We could determine
which bricklayer contributed more to the resulting wall by counting the number
of bricks in the wall that each had placed there. However, suppose that one bricklayer made the bricks and mortar
and brought all the necessary equipment to the site, while the other used these
items to put up the wall. Now it is
impossible to say which bricklayer contributed more, or to say how much each
contributed in terms of some uniform measure.
The second version of the bricklayer
example resembles the problem we face when we try to say whether genes or
environment contributed more to a given phenotype. If Sally is 5' 8" tall, it will not be true that her genes
built 4' of her and her environment built the rest. Rather, her genes and her environment made different kinds of
contribution, the net result of which was that she grew to a certain height.
Does this mean that question (2) is
meaningless--that it makes no sense to ask whether genes or environment are
more important causes of the resulting phenotype? No. It just means that we
must pose the question in a different way.
Rather than asking about the relative contributions of genes and environment
to the phenotype of a single individual, we change the object of the
preposition. We ask how genetic
differences and environmental differences contribute to the differences in
phenotype found in a population.
To see what this means, consider a simple
experiment designed to show how genetic variation and environmental variation
contribute to variation in height in a population of corn plants. In our experiment, the plants have either
genotype G1 or G2; their environments provide either one unit of
fertilizer (E1) or two units of fertilizer (E2). Thus, there are four "treatment
cells" that a corn plant might occupy; it might be in E1G1, E1G2,
E2G1, or E2G2.
Suppose we plant four plots of corn, each containing a hundred corn
plants, one for each of the four treatment combinations. How will the plants in one treatment cell differ in average height
from the plants in others? Here are
four possible observational outcomes that might be obtained:
G1 G2 G1 G2 G1 G2
G1 G2
--------- --------- --------- ---------
E1 1 1 E1 1 2 E1 1 3 E1 1 4
E2 4 4 E2 3 4 E2 2 4 E2 1 4
--------- --------- --------- ---------
(i) (ii) (iii) (iv)
In outcome (i), the genetic factor
makes no difference; whether the plants have genotype G1 or G2
does not affect their height; it is the environmental factor--the amount of
fertilizer the plants receive--that explains all the observed variation. Outcome (iv) is the mirror image of (i). In (iv), the fertilizer treatment makes no
difference; the genetic variation explains all the variation in height. Outcome (iv) illustrates the idea of genetic
determinism--the general thesis that an individual's phenotype cannot be
modified by changing its environment.
Outcome (i), on the other hand, illustrates the idea of radical
environmentalism--the view that the only factor that influences an individual's
phenotype is its environment. Outcomes
(i) and (iv) thus support monistic explanations of variation in plant height;
each suggests that only one of the factors considered made a difference in the
observed outcome.
Outcomes (ii) and (iii), on the other
hand, would support pluralistic conclusions.
Each suggests that genetic and environmental factors both made a
difference. However, they disagree
about which factor mattered more. In
outcome (ii), changing the fertilizer treatment yields two units of change in
height, whereas changing from one genotype to the other produces only a single
unit of change. In this case, the
environmental factor makes more of a difference than the genetic factor. By the same reasoning, we can see that
outcome (iii) suggests that genetic variation was more important than the
environmental factor considered.
Although the four possible outcomes
described so far differ in various respects, they have something in
common. In each of these data sets, the
change effected by moving from G1 to G2 does not depend on which
environmental condition one considers.
Similarly, changing from E1 to E2 has the same impact on
plant height, regardless of which genotype the plant possesses. Results (i)-(iv) are thus said to be
"additive" (or to show no "gene-environment interaction"). This is not the case for the following
possible results:
G1
G2 G1
G2
--------- --------
E1
1 7 E1 1 1
E2 7 4 E2 1
4
--------- --------
(v) (vi)
In outcome (v), going from one unit of
fertilizer to two increases height for plants with genotype G1, but
reduces height for plants that have genotype G2. In (vi), changing genotype has an effect on
plant height within one fertilizer treatment, but not within the other.
Gene-environment interactions of the
sort depicted in (v) and (vi) occur frequently in nature. Consider for example, the accompanying
figure from an introductory genetics textbook (Griffiths, Miller, Suzuki,
Lewontin, and Gelbart 1993, p. 14). It
depicts the result of taking cuttings from each of seven plants in the species Achillea
millefolium and growing them at high, medium, and low elevations. Notice that different environments have
different effects on plant height; moving from medium to high elevation makes
type 1 cuttings grow taller, but reduces the height of cuttings from type 4;
and even though moving from low to medium elevation reduces plant height in
both types 2 and 3, it does so by different amounts.
Figure
The interaction effect depicted in
(vi) shows that it can be overly simplistic to ask whether a phenotype is
influenced by the environment. Notice
that genotype G2 produces a different phenotype when the environment is
changed, but genotype G1 does not. The
same point holds when we ask whether a phenotype is influenced by genetic
factors. Organisms reared in
environment E2 produce different phenotypes depending on what genotype they
have; organisms reared in environment E1 do not. We can look at the data in (vi) and make the summary statement,
"the phenotype depends on both genotype and environment," but a more
fine-grained analysis shows that genes make a difference in some contexts but
not in others, and that the same is true of the environment considered.
This is not a merely academic fine
point. An important discovery in AIDS
research is that this disease is able to enter host cells by connecting with a
protein found on the surface of CD-4 immune cells. Most human beings produce this protein, and so are vulnerable to
the disease. However, it has recently
been discovered that a small number of individuals possess two copies of a
mutation in the normal gene CKR-5, which causes this protein not to be produced. These individuals are otherwise healthy;
they also seem to be immune to the disease.
Notice what this implies about whether AIDS is an environmental or a
genetic condition. Before this mutation
was discovered, it would have been natural to think that the disease is caused
purely by an environmental insult--the
presence of a virus; the difference between people with the disease and people
without it is completely ascribable to the environment. But this recent discovery complicates the
picture. For some people, not having
AIDS is attributable to their genes, not to their environment. For many others, however, the disease
remains an environmentally induced phenotype.
The simple 2-by-2 experiment we have
described illustrates the basic idea behind the methodology that statisticians call the analysis of
variance (ANOVA). It allows you to
compare how much genes and environment contributed to a phenotypic
outcome. A conclusion might be reached
that "70% of the variation is explained by environmental differences and
30% by genetic differences." ANOVA
quantifies the relative contributions that genes and environment make to
phenotypic variation. It is important
to bear in mind that this type of analysis is highly specific to the range of
genotypes and environments considered.
Even if changing from E1 to E2 has only a negligible effect on plant
height, it is an open question whether changing to a new environment E3 would
make a larger difference. Likewise,
even if genotypes G1 and G2 perform similarly across a given range of
environments, it is quite possible that genotype G3 would behave quite differently in those same environments.
This point is relevant to
understanding how the following two findings are quite compatible: a
significant proportion of the variation in intelligence (as measured by IQ)
found among individuals is attributable to genetic differences (Bouchard et
al. 1990); and intelligence has been increasing steadily in 14 countries,
including the United States, for several decades (Flynn 1987). When quantitative geneticists use ANOVA
techniques, they typically study the range of genes and environments that are
available at the time of their study; the results they obtain say nothing about
whether the range of genes or environments has changed or will do so in the
future, nor do the results predict what will happen should such changes
occur. Even if the variation in height
now found in a population is explained completely by genetic variation, it
remains perfectly possible that the population will have a greater average height
several generations later because nutrition has improved. The fact that genes significantly affect
phenotypic variation does not mean that environmental interventions will be for
naught.
I began my discussion of the 2-by-2
experiments on corn plants by saying that it makes no sense to apportion causal
responsibility between genes and environment with respect to a single
individual (Sally); this was why I shifted focus to the question of explaining
patterns of variation in a population of individuals. However, it might appear that the ANOVA
technique just described does allow one to explain the traits of
individuals. Consider, for example, the
data given in (ii); below I have presented this set of data again, this time
noting in the margins the average heights of individuals sharing the same
environment, the average heights of individuals sharing the same genes, and, in
the lower-right hand corner, the grand mean--the average height of all the
individuals in the experiment:
G1 G2
--------
E1 1
2 1.5
E2 3
4 3.5
--------
2
3 2.5
Consider one of the individuals in the
lower-right hand cell of the 2-by-2 table of data who is 4 units tall. The average height in the whole population
is 2.5. The difference between this
individual's height and the grand mean
(4-2.5=1.5) can be decomposed into a difference between the average
height of individuals with the same genotype as this individual and the grand
mean (3-2.5=0.5) and the difference between the average height of individuals
living in the same environment and the grand mean (3.5-2.5=1.0). Does this show that this individual's being
1.5 units above average in height is explained by her genotype making her 0.5
units above average and her environment making her an additional 1 unit above
average? If so, her genes account for
one third of her overshooting the average and her environment for two thirds.
I do not disagree. However, this is not the same thing as
explaining why the individual is 4 units tall.
Notice that if this individual had the same genes and the same
environment, but had lived in a
population of different composition, her deviation from the mean would have
been different, as would the breakdown between her genetic deviation and her
environmental deviation. Yet the
individual would still be 4 units tall; the genetic and environmental processes
that determine her height would have been the same. ANOVA is an irreducibly population-level analysis; it can be used
to describe how individuals are related to the populations they inhabit, but
this is an entirely different matter from explaining why they possess the
phenotypes they do.
One other conceptual point needs to be
made about the logic of ANOVA studies.
This concerns the relation of within-population differences to
between-population differences. One of
the most controversial subjects in the continuing debate about nature and
nurture is the question of whether the observed difference between white and
black Americans in IQ has a genetic basis.
Murray and Hernnstein's The Bell Curve (19//) is the most recent
attempt to muster evidence for this conclusion; theirs was not the first
effort, nor should we expect it to be the last. The point I want to make here is that their conclusion about
group-level differences would not follow even if variation within the two
groups had a significant genetic component.
Consider the following example, described
by Lewontin (1970). Suppose a
heterogeneous collection of corn seeds is planted in a single environment
E1. Since all the plants experience the
same environment, all the variation in height must be due to genetic
differences. Now suppose that a second
experiment is performed in which the same collection of seeds is planted in a
quite different environment E2; once again, all the phenotypic variation in
this experiment will be due to genetic differences. However, what should we say about the difference between the
average height exhibited in the first experiment and the average height
obtained in the second? This difference
will be due entirely to the environmental difference between E1 and E2, since
the two experiments tested the same range of genotypes. The fact that genetic differences explain
phenotypic variation within two groups does not mean that genetic differences
explain phenotypic variation between those two groups.
I hope this discussion makes clear
what it means to compare the impact of genetic and environmental variation on
variation in some phenotype. However,
it leaves a related question unanswered.
How are we supposed to find out what the contributions of genes and
environment are if we cannot run a controlled experiment of the kind just
described? Manipulations of the type
just described are fine for corn plants, but ethics prevents us from cloning
individuals and rearing them in identical environments. So how is it possible to say anything
meaningful about the relative contributions of genes and environment to human
height, much less to more subtle traits such as intelligence, aggressiveness,
sexual orientation, or risk-taking?
A variety of techniques are used in
the field called quantitative genetics to answer this question--ones that
involve assembling observations about individuals as they are. One approach is to study genetically
identical twins who are reared apart.
If two identical twins differ in height, this must be due to the fact
that their environments were different, since they have the same genes. Suppose pairs of identical twins were more
similar in height than pairs of unrelated individuals are. This would suggest that genes make a
difference in how tall an individual grows.
Such methods are subject to various
pitfalls. For example, in twin studies,
it is important to investigate how much the environment of one twin differs
from the environment of the other.
Suppose that identical twins who are reared in separate households
nonetheless receive the same number of Cheerios, and that this environmental
factor is a powerful influence on how tall an individual grows. It will then turn out that twins
closely resemble each other in height,
but this is not simply because they have the same genes.
Bouchard et al. (1990) make
this point in their report on the Minnesota twin studies, which involved
comparing a set of identical twins who
were reared together with about 100 pairs of identical twins who were reared
apart. These individuals were subjected
to about a week of psychological and physiological tests. Remarkably, the two groups each showed
significant degrees of similarity; even more remarkably, they did not differ
much in terms of how similar they were.
For example, twins reared together are rather similar in how they scored
on tests of "religiosity" (they exhibited a correlation of 0.49);
twins reared apart also were quite similar (they exhibited a correlation of
0.51). Bouchard et al. (p. 227)
point out that the twins reared apart in their study almost never grew up in
extreme poverty and were almost never raised by illiterate parents. This means that these individuals had
environments that were at least somewhat similar, and this fact has to be taken
into account in interpreting the results.
Some of the similarity found in identical twins (whether reared together
or reared apart) will be nongenetic.
There are other caveats that apply to
empirical efforts to estimate the genetic and environmental contributions to
patterns of variation in some phenotype of interest. It is true that a number of studies in the past were sloppy. In addition, it would be naive to think that
quantitative geneticists now do their studies without ever making
mistakes. However, the fact remains
that scientists learn from the errors of their predecessors; scrupulous studies
are now being executed and they will become more numerous with the passage of
time. The mistakes of the past should
not lead us to dismiss twin studies and related inquiries a priori.
Question (3): Which genes
contribute to the trait?
Twin
studies and similar methodologies in quantitative genetics can tell you that
genes make a difference in the chances of having some trait; however, they fail
to tell you which genes matter or how they have this effect. You may find that identical twins resemble
each other in height far more than unrelated individuals do, but which genes on
which chromosomes influence height and how do they do so? An answer to question (2) can leave you
entirely in the dark concerning questions (3) and (4). This is both the strength and the limitation
of quantitative genetics studies. They
can go forward in total ignorance of developmental details; this is why the
field of quantitative genetics developed before the molecular revolution of the
1980s and, indeed, before Watson and Crick discovered the chemical structure of
DNA in the 1950s. Quantitative genetics
is genetics without much attention to genes.
I now want to describe a study that
aimed at providing insights into question (3). It was quite controversial because the scientists were not
studying something innocuous like height in corn plants. They studied sexual orientation in human
beings. This is the study by Dean Hamer
and his associates (1993), in which they claim to have found a region of the
X-chromosome in males that causally contributes to homosexuality. It remains to be seen whether the study will
be replicated and exactly how it should be interpreted. However, the point of interest here is to
understand the logic of Hamer's investigation.
Recall an elementary fact about
human genetics depicted in the diagram
below. Males are XY and females
are XX. This means that males
inherit their X chromosomes from their mothers. Suppose the mother is heterozygous at some
location on her pair of XX chromosomes.
This means that she has one copy of gene A next to a copy of gene
B at that location. Now consider
a population of such heterozygote mothers.
Imagine that each has two sons, who are not identical twins. What is the probability that they will both
have A or both have B on their one and only X
chromosome? The probability that son
#1 has A is 1/2 and the probability that son #2 has A is also
1/2, so the probability that both have A is 1/4; similarly, the
probability that son #1 has B is 1/2, which is also the probability that
son #2 has B, so the probability that both have B is 1/4. This means that the probability of them
matching (i.e., that both have A or that both have B) is
1/4+1/4=1/2:
Mother Father
AB
XX ----------------------- XY
---------------------------
Son
#1 Son #2
? ?
XY XY
Suppose you wanted to know whether the
genes at this locus on the X chromosome, when present in males, affect their
probability of having blue eyes. To
find out, you might assemble 40 pairs of brothers, each of whom has blue eyes,
and each of whom has a mother who is an AB heterozygote at some locus on
her XX chromosomes. If these genes have no bearing on eye color,
you'd expect that 1/4 of the brother pairs will match for A, 1/4 will
match for B, and 1/2 will not match at all. In other words, if these genes do not affect eye color, you'd expect
blue-eyed brothers to match at this locus about half the time. On the other hand, if you found that a very
high proportion of the brother pairs match, this would be evidence that the
locus in question influences eye color.
Hamer assembled 40 pairs of brothers
whose score on a variety of self-report sexual orientation scales placed them
at the homosexuality end of the spectrum, and whose mothers were heterozygotes
for a marker placed at a certain region of their two X chromosomes. Hamer found that 33/40 of the brother pairs
matched for the markers in question.
This is evidence for the claim that genes in this region influence
sexual orientation.
Suppose that these 33 brother pairs
all have gene A. It would not
follow that this gene suffices for homosexuality; there may be individuals, not
in the study, who have the gene, but are not homosexual. Nor would it follow that the gene is
necessary for that phenotype to exist; it may be that this gene is present in only
a small percentage of male homosexuals.
An additional possibility is worth noting; it also is possible, given
Hamer's finding, that the effect of gene A on sexual orientation is
environmentally mediated. Let us
consider a fanciful example to see why.
Suppose that this gene makes boys have a freckle on their forehead and
that this causes their parents to treat them in a certain way. Because of the way their parents treat them,
boys with gene A tend to become gay.
This may lead you to think that homosexuality in this scenario is
environmental, not genetic. However,
geneticists understand the contrast between genes and environment in such a way
that the opposite conclusion is the one
they draw. When genes cause individuals
to be reared in special environments, the resulting phenotype is said to be due
to genes, not to environment.
Christopher Jencks et al.
(1972) made this point in their book Inequality when they discussed the
effects of racism on IQ. They used the
following hypothetical example. Suppose
that red hair is caused by genes, and that the society we live in leads people
to abuse red-headed children. If abuse
lowers IQ, then red-heads who live with their biological parents and red-heads
who live with adoptive parents will suffer the same degree of abuse. The change in environment will not produce a
change in the phenotype, because everyone in the society abuses red-heads. The conclusion will then be drawn that IQ is
genetic; the gene for having red hair is also a gene for lower IQ.
The analysis would be different if
red-headed children were abused by their biological parents, but not by
others. Then an adoption study would
show that a difference in environment makes a difference in the IQ of
red-headed children. Consider the
following two causal pathways:
(a) Genes ---> Red hair ----> Abusive environment --->
Lower IQ
Genes ---> Red
hair
(b) Lower
IQ
Abusive Environment
In
(a), the lower IQ of red-haired children is said to have a genetic cause. In (b), the lower IQ of red-haired children
is said to be caused by their environment, not by their genes. The standard methodology in quantitative
genetics says that the environment makes no difference in (a), but does make a
difference in (b).
The possibility illustrated by this
example is not merely hypothetical. As
noted before, the Minnesota twin study found that identical twins reared apart
are remarkably similar on a variety of measures. Bouchard et al. (1990, p. 227) speculate that this may be
because "their identical genomes make it probable that their effective
environments are similar....Infants with different temperaments elicit
differing parenting responses...children and adolescents seek out environments
that they find congenial." The
suggestion is that genes make an important difference in the phenotypes
measured because different genes lead individuals to experience different
environments. If so, the formula
should not be "nature versus nurture," but "nature via
nurture" (Bouchard et al. 1990, p. 228).
Question (4): How do these
genes contribute to the trait?
Hamer's
study, even if it is replicated, throws no light on the developmental pathway
from a gene to a trait. Question (3)
has been answered, but question (4) has not.
In a sense, question (4) is the hardest of the four. You have to do all the work involved in
answering questions (1)-(3), and then you have to tackle a difficult
developmental question besides. The
reason that question (4) is difficult is that gene/environment pairs do not
directly produce phenotypes like height or sexual orientation or
intelligence. Rather, genes produce
gene products, which are chemicals. How
these gene products interact with other gene products and with the environment
is typically quite complicated.
Somewhere downstream, the observable phenotype results.
There are examples of phenotypes in
which the pathway from gene to phenotype is fairly well understood. Sickle-cell disease is caused by two copies
of a recessive gene. People with two
copies produce abnormal hemoglobin, which is the molecule inside of red blood
cells that carries oxygen from the lungs to the rest of the body. When these individuals are oxygen-deprived,
for example as a result of working hard, their red blood cells become
sickle-shaped, thus blocking blood flow in capillaries. It is worth noting here that this fairly
detailed grasp of developmental details has not yet resulted in the discovery
of a viable gene replacement therapy.
Knowledge and power do not always move exactly in tandem; some diseases
are less well understood than sickle-cell anemia, but more effective therapies
have been obtained nonetheless.
Examples like sickle-cell disease, in
which science has discovered how genes contribute to the production of
phenotypes, should not obscure the fact that when we shift to phenotypes such
as sexual orientation, intelligence, risk-taking, and so on, question (4)
represents a region of vast ignorance.
As we descend from (1) and (2) to (3) and then to (4), the amount of
knowledge we have at each stage vastly shrinks. There are many, many studies that purport to answer questions (1)
and (2). As we have already seen, the
methods of quantitative genetics permit these questions to be addressed even
when science knows nothing about which genes might influence the phenotype
under study and how they do so. However, when we look at questions (3) and
(4), the range of phenotypes studied by science radically contracts. Typically, progress has been made for
phenotypes, like sickle-cell anemia, that are diseases and are influenced by a
small number of genes. It is a task for
future science to try to achieve a more complete grasp of the developmental
pathways that lead to nondiseased phenotypes.
Should we expect genes to be important
in the explanation of normal function, just as they are relevant to the
explanation of some, but not all, diseases?
Let us be clear about what this question means. Genes help explain the difference between
sickle-cell anemia and normal hemoglobin function. Is the same true of the difference between two varieties of
normal hemoglobin function? Is it true
for differences in intelligence, shyness, taste in music, etc., that all are
normal? "Normal" is a vague
term; it encompasses an array of phenotypes that are said to "fall in the
normal range." Will genes be
relevant to explaining differences within the normal range, just as they are
often relevant to explaining differences between normal and abnormal?
It is a striking fact about work in
quantitative genetics that genes are said to make at least some difference in
virtually all phenotypes that have been studied (Bailey 1996). Even when traits like religiosity and
political affiliation are studied by quantitative geneticists, they end up
concluding that genetic differences among individuals matter, at least somewhat
(Bouchard et al. 1990). Their
question concerns how much genes matter, as compared to the environment. Not all these studies have been well
executed, but quantitative geneticists keep getting better and better at
avoiding mistakes. Even after all
fallacies are removed and dubious interpretations are seen for what they are,
we may have to live with the fact that
the genetic contribution to any phenotype of interest is never precisely zero. This does not mean, of course, that genes
make all the difference, or that they are more important than environment. Again, it is crucial to remember that
genetic causality does not rule out environmental causality. Both influences exist. However, if genes contribute to variation in
some phenotype of interest, more detailed questions remain to be addressed
concerning which genes affect the phenotype in question, and how they do so;
these are matters that future science will endeavor to answer.
III. Conclusion
It
is often convenient to save breath or ink by neglecting to make explicit the
relational character of certain claims.
If I say that someone is a good musician, you will know roughly what I
mean. But if you press for precision, I
will have to say what benchmark of comparison I am using. The person in question may be good compared
with the average player, mediocre compared with gifted amateurs, and decidedly
poor when compared with the creme de la creme. This point is not news to anyone, but is part of our ordinary
understanding of what such statements mean.
When we say that X is a genetic
condition, full stop, it is easy to think that a complete statement has been
made. The same conclusion seems
natural when we say that Y is an environmentally acquired phenotype. However, such statements are no less
elliptical than the statement that someone is a good musician. A condition has a significant genetic or
environmental component only relative to a range of genes and a range of
environments. Change the range of genes
or the range of environments, and the conclusion about the condition may change
as well.
In addition to emphasizing this fact
about the relativity of claims concerning genetic causation, I also have tried
to emphasize the difference between quantitative genetics and developmental
genetics. Quantitative genetics studies
have existed for about a hundred years; they long predate the molecular
revolution. These studies can tell us
whether genetic variation helps explain the phenotypic variation found in a
population, but they are utterly silent on the question of which genes affect
the phenotype and how they do so.
Developmental genetics is the science that will make tremendous strides
in coming years because of new techniques that allow scientists to investigate
what genes do.
In fact, these two conclusion are not
unrelated. A large measure of the power
of molecular techniques stems from the fact that they allow scientists to
modify the environments in which genes do their work. In addition, gene replacement therapy holds out the possibility
that individuals can be furnished with new genes. Thus, interventions stemming from developmental genetics will have the effect of revising the range
of environments and the range of genes that are available in human
populations. As a result, it is not a
mere flight of fancy to suspect that quantitative geneticists who now study a
trait will reach conclusions quite different from the ones their successors
will draw in the populations of the future.
Heretofore, geneticists have studied the world of human variation; we
now face a new age in which, for better or worse, they will possess the power
to change it.
Acknowledgments
My thanks to Michael
Bailey, James Crow, and Hill Goldsmith for comments on an earlier draft.
References
Bailey, J. (1996): "Can Behavior Genetics
Contribute to Evolutionary Studies of Behavior?" In Crawford and Krebs
(eds.), Evolution and Human Behavior--Ideas, Issues, and Applications. New York: Erlbaum.
Bouchard, T., Lykken, D., McGue, M., Segal, N.,
Tellegren, A. (1990): "Sources of Human Psychological Differences--The
Minnesota Study of Twins Reared Apart."
Science 250: 223-228.
Flynn, J. (1987): " ." Psychological Bulletin 101: ///-///.
Griffiths, A., Miller, J., Suzuki, D., Lewontin, R., and
Gelbart, W. (1993): An Introduction to Genetic Analysis. New York: W.H. Freeman.
Hamer, D., Hu, S., Magnuson, V., Hu, N., Pattatucci, A.
(1993): "A Linkage Between DNA Markers on the X Chromosome and Male Sexual
Orientation." Science 261:
321-327.
Jencks, C., Smith, M., Acland, H., Bane, M. Cohen, D.,
Gintis, H., Heyns, B., and Michelson, S. (1972): Inequality--A Reassessment
of the Effect of Family and Schooling
in America. New York: Basic Books.
LeVay, S. (1993): The
Sexual Brain.
Lewontin, R. (1970): "Race and Intelligence." Bulletin
of the Atomic Scientists, March, 2-8.
Reprinted in N. Block and G. Dworkin (eds.), The IQ Controversy,
New York: Pantheon, 1976, pp. 78-92.
Lewontin, R. (1974): "The Analysis of Variance and
the Analysis of Causes." American
Journal of Human Genetics 26: 400-411.
Murray and Herrnstein, (19//): The Bell Curve.