Behavior Genes
599
the physical distance between two alleles,
the greater the chance of discordance. RI
strains are ideal for studying linkage and
have a number of advantages. As they are
genetically identical, all people working
on an RI strain are essentially using the
same animal and thus each strain needs
to be genotyped only once. Moreover, the
intensive inbreeding reduces the influence
of environmental effects on a phenotype,
making it possible to study phenotypes
of low and moderate heritability and
complex traits.
3.2
Human Studies
Quantitative genetic approaches to behav-
ior can tell us whether genes are involved
in a particular trait and provide us with
estimates of how much genes contribute.
However, such statistical approaches are
not ends in themselves and molecular
genetic approaches are the next stage al-
lowing us to move on to discover what
genes are involved and how they act in
concert with the environment.
Broadly, there are two approaches to
identifying the genes involved in complex
traits. These are candidate gene studies
and positional cloning. Candidate genes
are those that encode for proteins where
there is a prior hypothesis that they might
be involved in a trait or disorder. Posi-
tional cloning starts out with no prior
hypothesis except that there is a genetic
contribution to the trait. The locations of
genes are then inferred by linkage and
association (Sect. 3.2.1) and then this po-
sitional information is reFned until the
genes are pinpointed and identiFed. Since
at least half of all genes are expressed
in the brain, the potential number of be-
havioral candidate genes is overwhelming
and has to be narrowed down in some
way. The most common approach with
regard to psychiatric disorders has been
to draw up a list of candidates based on
informed guesswork with useful leads be-
ing provided by the mode of action of
drugs. ±or example, all of the standard
drug treatments used in schizophrenia,
the ‘‘typical’’ antipsychotics such as Chlor-
promazine and Haloperidol, are known
to block a class of receptors for the neuro-
transmitter dopamine, called D2 receptors.
The newer ‘‘atypical’’ antipsychotic drugs
(e.g. Clozapine and Olanzapine) block both
dopamine and serotonin receptors in the
brain, most importantly, a type of re-
ceptor designated 5HT2A. Consequently,
researchers have attempted to discover
polymorphisms (variants) in the 5HT2A
receptor gene and in D2 receptor genes,
and compare their frequency in cases af-
fected by schizophrenia and controls who
do not have the disorder. The results over-
all suggest a small but signiFcant effect
of the variant in the 5HT2A receptor gene
and a dopamine receptor gene DRD3, a
member of the D2-like family.
Such investigations are examples of
allelic association studies, to which we
will return to discuss in more detail in
Sect. 3.2.2. A complementary approach
and one that is the starting point for
positional cloning is to carry out genetic
linkage studies. Linkage studies provide
information about the location of genes
involved in traits or disorders where
the causation is unknown. Researchers
c
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e
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ef
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oml
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a
t
i
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nt
og
e
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identiFcation and
then
to
studies
of
structure and sequence and Fnally to
studies of the gene products themselves.
3.2.1
Linkage Analysis
Loci that are on different chromosomes
or that are far apart on the same chromo-
some obey Mendel’s law of independent
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