Transcript From Genes to Phenotypes

1. From Genes to Phenotypes
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Mendel was fortunate to have chosen some of the most genetically
simple of characters in the garden pea for his seminal experiments
that laid the foundation for the science of genetics.
Differences between traits were determined by single gene
substitutions on different chromosomes, and each trait behaved as
clearly dominant or recessive in this experimental system. This
allowed Mendel to recognize the pattern of inheritance of the
individual genes.
However, the experimental situation devised by Mendel was rather a
particular case, that of unlinked loci with biunivocal correspondence
between homozygous genotypes and dichotomous phenotypes.
Most of the major advances in genetics have come from laboratory
studies on characters having a simple, one-to-one correspondence of
genotype to phenotype. However, in natural populations, phenotypic
variation generally shows a more complex relationship to genotype
and not a one-to-one correspondence.
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a.a. 05-06 prof S. Presciuttini
2. Quantitative variation
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The actual variation between organisms is usually quantitative, not
qualitative. Wheat plants in a cultivated field or wild asters at the side
of the road are not neatly sorted into categories of “tall” and “short”,
any more than humans are neatly sorted into categories of “black” and
“white”. Height, weight, shape, color, metabolic activity, reproductive
rate, and behavior are characteristics that vary more or less
continuously over a range.
Even when the character is intrinsically countable (such as eye facet
or bristle number in Drosophila), the number of distinguishable
classes may be so large that the variation is nearly continuous.
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3. Mendelian traits are the exception rather than the rule
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If we consider extreme individuals - say, a corn plant 8 feet
tall and another one 3 feet tall - a cross between them will
not produce a Mendelian result.
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Such a corn cross will produce plants about 6 feet tall, with some
clear variation among siblings.
The F2 from selfing the F1 will not fall into two or three discrete
height classes in ratios of 3:1 or 1:2:1.
Instead, the F2 will be continuously distributed in height from one
parental extreme to the other.
This behavior of crosses is not an exception; it is the rule for
most characters in most species.
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4. Crosses between pure lines
The inheritance of corolla length in Nicotiana
longiflora. Results are shown as the percentage
frequencies with which individuals fall into
classes, each covering a range of 3 millimeters
in corolla length. This grouping is quite
artificial and the apparent discontinuities are
spurious: corolla length actually varies
continuously. The means of F1 and F2 are
intermediate between those of the parents. The
means of the four F2 families are correlated
with the corolla length of the F2 plants from
which they came, as indicated by the arrows.
Variation in parents and Fl is all nonheritable,
and hence is less than that in F2, which shows
additional variation arising from the segregation
of the genes concerned in the cross. Variation in
F3 is, on the average, less than that of F2 but
greater than that of parents and F1. Its
magnitude varies among the different F2's
according to the number of genes that are
segregating.
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5. Continuity of phenotypic traits under Mendelian
inheritance
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Mendel obtained his simple results because he worked with horticultural varieties of
the garden pea that differed from one another by single allelic differences that had
drastic phenotypic effects. Had Mendel conducted his experiments on the natural
variation of the weeds in his garden, instead of abnormal pea varieties, he would
never have discovered Mendel’s laws. In general, size, shape, color, physiological
activity, and behavior do not assort in a simple way in crosses.
The fact that most phenotypic characters vary continuously does not mean that their
variation is the result of some genetic mechanisms different from the Mendelian
genes with which we have been dealing.
The continuity of phenotype is a result of two phenomena.
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First, each genotype may show such a a wide range of phenotypic values that, as a result,
the phenotypic differences between genotypic classes become blurred, and we are not
able to assign a particular phenotype unambiguously to a particular genotype.
Second, many segregating loci may have alleles that make a difference to the phenotype
being observed.
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6. An apparently insoluble controversy
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Soon after the rediscovery of Mendel’s work, it was debated whether continuously
varying traits were inherited in fundamentally different ways from discrete traits.
Many argued for a form of blending inheritance that did not involve particulate
inheritance (discrete genes).
The claims of the Mendelians, championed by Bateson, were resisted by
biometricians. Biometricians allowed that Mendelian genes might explain a few rare
abnormalities or curious quirks, but pointed out that most of the characters likely to
be important in evolution (body size, build, strength, skill in catching prey or finding
food) were continuous or quantitative characters and not amenable to Mendelian
analysis. You cannot define their inheritance by drawing pedigrees and marking in
the affected people, because we all have these characters, only to different degrees.
Mendelian analysis requires dichotomous characters (characters like extra fingers,
that you either have or don't have).
The controversy ran on, heatedly at times, until 1918. That year saw a seminal paper
by RA Fisher demonstrating that continuous characters governed by a large number
of independent Mendelian factors (polygenic characters) would display precisely the
quantitative variation and family correlations described by the biometricians.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini
7. Two traditions in human genetics
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In principle Fisher's description of polygenic inheritance unified genetics. This was indeed
generally true for the genetics of experimental organisms or farm animals. In human genetics,
however, studies of Mendelian and quantitative characters tended to continue as separate
traditions, and until very recently few investigators felt at home in both worlds.
The spectacular advances of 1970-1990 were entirely in Mendelian genetics, whilst
investigation of nonmendelian characters remained largely limited to statistical studies of
family resemblances. Geneticists from the Mendelian tradition were often reluctant to get
involved in these studies, partly because of the complex statistical methodology and no doubt
also because of a feeling that they were a poor investment of research effort compared to
mapping and cloning genes for mendelian characters.
Recent developments have finally brought together the study of Mendelian and complex
human phenotypes. Automation is allowing genetic analysis and sequencing on a scale
scarcely imagined ten years ago. This has had two consequences. Most human genes are now
identified, so that molecular geneticists are looking for fresh fields to conquer. At the same
time, marker studies can now be done on a scale that is probably large enough to deliver the
statistical power needed to detect individual quantitative trait loci and susceptibility loci.
Given the overwhelming preponderance of non-Mendelian conditions in human disease,
molecular dissection of complex phenotypes is widely seen as the next frontier in human
genetics.
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8. A basic quantitative model
Suppose that five equally important loci affect the number of flowers that will develop
in an annual plant and that each locus has two alleles (call them + and -). For
simplicity, also suppose that there is no dominance and that a + allele adds one flower,
whereas a - allele adds nothing. Thus, there are 35 = 243 different possible genotypes
[three possible genotypes (+ / +, + -, and - / -) at each of five loci], ranging from
but there are only 11 phenotypic classes (10, 9, 8, . . . , 0) because many of the
genotypes will have the same numbers of + and − alleles. For example, although there
is only one genotype with 10 + alleles and therefore an average phenotypic value of
10, there are 51 different genotypes with 5 + alleles and 5 − alleles; for example,
Thus, many different genotypes may have the same average phenotype. At the same
time, because of environmental variation, two individuals of the same genotype may
not have the same phenotype. This lack of a one-to-one correspondence between
genotype and phenotype obscures the underlying Mendelian mechanism.
Genetica per Scienze Naturali
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9. Human skin color as an example of polygenic inheritance
In human, no equivalent may exist of a pure genetic line; however, in the case of skin
color, some populations have been naturally selected for an extreme phenotype, black
or white. This does not guarantee that these “lines” are pure, but it is certainly true that
the differences between the extreme populations are much higher than differences
within populations. Subjects born from parents of the two opposite populations show an
intermediate skin color; the distribution of skin color in the F2 individuals suggests that
three or four loci are involved.
Skin color is measured by
reflectance of light at wavelength
685 nm. F2 distributions are those
expected according to different
hypotheses about the number of
genes involved
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10. Between Mendelian and quantitative genetics
Using the concepts of distribution,
mean, and variance, we can
understand the difference between
quantitative and Mendelian genetic
traits. Suppose that a population of
plants contains three genotypes, each
of which has some differential effect
on growth rate. Furthermore, assume
that there is some environmental
variation from plant to plant. For each
genotype, there will be a separate
distribution of phenotypes with a
mean and a standard deviation that
depend on the genotype and the set of
environments. Suppose that these
distributions look like the following
height distributions:
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11. Mixed distributions
Finally, assume that the population
consists of a mixture of the three
genotypes but in the unequal
proportions 1:2:3 (a/a: A/a: A/A). Then
the phenotypic distribution of
individuals in the population as a whole
will look like the black line in the
following figure:
This is the result of summing the three underlying separate genotypic distributions,
weighted by their frequencies in the population. The mean of the total distribution is the
average of the three genotypic means, again weighted by the frequencies of the
genotypes in the population.
The variance of the total distribution is produced partly by the environmental variation
within each genotype and partly by the slightly different means of the three genotypes.
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12. Distribution of acid phosphatase activity
The human red cell acid posphatase (ACP1) genetic polymorphism
offers a good example of the complementary points of view of
Mendelian and quantitative genetics.
When H. Harris and D. Hopkinson sampled an English population in the
search of genetic polymorphisms, they found that three allelic forms
were present for ACP1, A, B, and C, at different frequencies.
The three alleles combine to
Genotype-specific and population distribution
of red-cell acid phosphatase activity
form six genotypes, and
these show significant
variation in enzyme
activity; however none of
the genotypes can be
unambiguously identified
based on the measured
activity
proportion of individuals
0.12
0.1
0.08
AB
0.06
BB
0.04
AA
0.02
BC
AC
CC
0
50
100
150
200
enzymatic activity
250
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13. Variance of ACP1 activity explained by genetic
differences among individuals
Genotype
A/A
A/B
B/B
A/C
B/C
C/C
Average
Total distribution
Proportion of variance
explained by the ACP locus
Mean
activity
122.4
153.9
188.3
183.8
212.3
240.0
166.0
Variance
of activity
282.4
229.3
380.3
392
533.6
166.0
607.8
Frequency
in population
0.13
0.43
0.36
0.03
0.05
0.002
310.7
(607.8 - 310.7)/
607.8 =
0.49
This Table shows the mean activity, the variance in activity, and the population
frequency of the six genotypes. About half of the variance in activity in the total
distribution (607.8) is explained by the average variance within genotypes (310.7), so
half (607.8 - 310.7 = 297.1) is accounted for by the variance between the means of the
six genotypes. Although much of the variation in activity is explained by the mean
differences between the genotypes, there remains variation within each genotype that
may be the result of environmental influences or of the segregation of other, as yet
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unidentified, genes.
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