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Gene 3734 - Qtl mapping summary
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Principles of Behavioral Genetics Chapter 8Quantitative Trait Locus mapping
Overview
Understanding the genetic basis of behaviour requires linking phenotypic variation to variation in the
DNA sequences of genes that contribute to the behaviour. To accomplish this, individuals with
extreme opposite phenotypes can be crossed so that segregation of parental polymorphisms (transfer
from parent to offspring) can be linked to variation in phenotypes (more like mom, or more like dad?).
Statistical methods are used to detect areas of the genome that show similarity between individuals
sharing phenotypes – thus, in which segregation of polymorphic markers correlates with differences
in phenotypic values. Such regions, known as quantitative trait loci (QTLs) typically contain a large
number of genes, and identifying the causal genes within these QTL regions is often a challenge. This
challenge can be overcome by creating large numbers of additional recombinants within the area of
interest (linkage mapping – by using families – recombination but with limited genetic variation), or
by testing whether candidate genes in a QTL region contain polymorphisms that are associated with
phenotypic variation in an outbred population (association mapping – using random / unrelated
population – includes a lot more genetic variation in areas of interest). Additional studies may be
necessary to confirm conclusions drawn on gene identification from linkage and/or association studies
– as discussed in the QTL end game. Linkage and association analyses have been applied to virtually
every behaviour that has been studied to date.
Why do we need to study genetic predisposition to normal / naturally occurring variation in
phenotypes? Knowledge of the QTLs affecting naturally occurring variation in behavioural traits is
important from several perspectives.
1. Understanding the genes and genetic networks affecting variation in behaviour can give
insights about the underlying cellular and neural mechanisms affecting behaviour, which can
lead to novel therapeutic interventions for extreme and pathological behaviours.
2. Performing these analyses in model organisms provides candidate genes for study in humans.
3. We need to know not only the genes, but also the actual molecular polymorphisms affecting
variation in behaviour if we are to understand the evolution of behaviour, and why genetic
variation for behavioural traits is maintained in natural populations.
Mapping QTLs affecting all quantitative traits (complex behaviours) is complicated because we expect
that the genetic variation will be due to multiple QTLs, each with small genotypic effects relative to
the total phenotypic variation, and whose expression is sensitive to the environment. How do we
then go about mapping QTLs? We can, if we can see the DNA sequence and the genetic variation.
With the development of DNA sequencing technologies, sequencing specific regions and even entire
genomes has been made possible. This led to the discovery of so much genetic variation that may be
used in mapping studies. The next question is then, who do we sequence?
There are 2 major methods for mapping QTLs:
- Linkage mapping maps QTLs in families from an outbred population, or in segregating
generations derived from crosses of inbred lines in model organisms. Thus a homogenous
population. This is to reduce the amount of genetic variation included.
- Association mapping maps QTLs in a sample of individuals from an outbred population, or
many inbred lines derived from an outbred population in model organisms. Thus a
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, Principles of Behavioral Genetics Chapter 8
heterogenous population. This is done to include all possible variation to obtain a truly
representative population.
For both methods, we need to obtain measurements of the behavioural phenotype for all individuals
in the mapping population, and determine the marker locus genotypes for all individuals in the
mapping population, at all marker loci. This means that we have to identify individuals who are
phenotypically similar to each other and different from others, then look at where the similar ones
have similar genetic variation, that differs from the phenotypically different group. Then we use a
statistical method to determine whether there are differences in behaviour between marker
genotypes; if so, the QTL is linked to the marker.
Linkage mapping
The simplest linkage mapping experiments involve
crosses between completely inbred lines that differ
genetically for the behaviour in model organisms (e.g.
zebrafish or mice). Such lines are homozygous for all
loci, including marker loci and QTLs affecting the
behaviour. However, many of the loci will be
homozygous for different molecular marker alleles
and QTL alleles; it is these loci that are informative for
mapping. The F1 between two inbred lines is also
genetically uniform: all individuals are heterozygous
for all variable loci. However, F1 progeny derived from
backcrossing to either parent (BC progeny) or by
mating F1 individuals to each other to produce the F2
generation are genetically variable, and can be used
for mapping.
In organisms with short generation times that are
amenable to inbreeding, the F2 population can be subdivided into a large number of lines that are
inbred to a point where they are all homozygous. Such recombinant inbred lines (RILs) are very useful,
and have been used extensively to map QTLs in mice. Although RILs take a long time to construct,
they have the advantage that markers only need to be genotyped once, and the same lines can be
phenotypes in multiple traits and in different environments.
The choice of the experimental design (RILs, BC, F2) often depends on the biology of the species for
which we wish to map QTLs affecting variation in behaviour. BCs and F2 design both permit estimating
homozygous and heterozygous effects. RILs are only feasible in organisms with short generation times
and sufficiently high reproductive rates to be able to tolerate the inevitable loss of lines during
inbreeding. Only homozygous effects of QTLs can be estimated in RIL populations, but crossing in back
to a parental line (BC) can be used to estimate homozygous and heterozygous effects.
In humans, backcrossing is not an option. For human populations, families or geographically isolated
population groups (i.e. homogenous groups) may be used as they will show a reduced amount of
genetic variation. Problems with using humans is finding large families, divorces and remarriages,
illegitimate offspring.
Now that the linkage mapping population have been constructed, the behavioural trait for all
individuals needs to be measured for all individuals within the population, and we determine the
genotype of all individuals for many polymorphic molecular markers covering the entire genome. We
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