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.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini
2. Interactions Between the Alleles of One Gene
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One important generalization of Mendel’s theory concerns the
interactions of the different alleles of a locus in producing a
phenotype
A) Intermediate dominance
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Four-o'clocks are plants native to tropical America. Their name comes
from the fact that their flowers open in the late afternoon. When a
wild-type four-o'clock plant with red petals is crossed with a pure line
with white petals, the F1 has pink petals. If an F2 is produced by
selfing the F1, the result is
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3. Intermediate dominance
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Because of the 1:2:1 ratio in the F2,
we can deduce an inheritance pattern
based on two alleles of a single gene.
However, the heterozygotes (the F1
and half the F2) are intermediate in
phenotype, suggesting an incomplete
type of dominance. Inventing allele
symbols, we can list the genotypes of
the four-o'clocks in this experiment as
c+/c+ (red), c/c (white), and c+/c
(pink).
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4. Incomplete dominance
B) Incomplete dominance
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Incomplete dominance describes the general situation in which the phenotype of a
heterozygote is intermediate between the two homozygotes on some quantitative
scale of measurement.
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This figure gives terms for all the theoretical positions on the scale, but in practice it
is difficult to determine exactly where on such a scale the heterozygote is located. In
cases of full dominance, in the wild-type/mutant heterozygote either half of the
normal amount of transcript and product is adequate for normal cell function (the
gene is haplo-sufficient), or the wild-type allele is "up-regulated" to bring the
concentration of transcript up to normal levels.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini
5. Codominance
C) Codominance
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The human ABO blood groups are determined by three alleles of one gene that show
several types of interaction to produce the four blood types of the ABO system. The
allelic series includes three major alleles, i, IA, and IB, but of course any person can
have only two of the three alleles (or two copies of one of them). There are six
different genotypes, the three homozygotes and three different types of
heterozygotes:
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In this allelic series, the alleles IA and IB each determine a unique antigen, which is
deposited on the surface of the red blood cells. These are two forms of a single
protein. However, the allele i results in no antigenic protein of this type. In the
genotypes IA/i and IB/i, the alleles IA and IB are fully dominant to i. However, in the
genotype IA/IB each of the alleles produces its own antigen, so they are said to be
codominant.
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a.a. 05-06 prof S. Presciuttini
6. Relativity of dominance relationships
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The human disease sickle-cell anemia gives interesting insight into dominance. The
gene concerned affects the molecule hemoglobin, which transports oxygen and is the
major constituent of red blood cells. The three genotypes have different phenotypes,
as follows:
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In regard to the presence or absence of anemia, the HbA allele is obviously
dominant. In regard to blood cell shape, however, there is incomplete dominance.
Finally, in regard to hemoglobin itself there is codominance, as the two hemoglobin
molecules HbA and HbS can be visualized simultaneously by means of
electrophoresis
Sickle-cell anemia illustrates that the terms dominance, incomplete dominance, and
codominance are somewhat arbitrary. The type of dominance inferred depends on the
phenotypic level at which the observations are being made, organismal, cellular, or
molecular. Indeed the same caution can be applied to many of the categories that scientists
use to classify structures and processes; these categories are devised by humans for
convenience of analysis
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7. Sickle cell anemia
The red blood cells of people with sickle cell disease contain
an abnormal type of hemoglobin, the oxygen-carrying
pigment, called hemoglobin S. The deficiency of oxygen in the
blood causes hemoglobin S to crystallize, distorting the red
blood cells into a sickle shape, making them fragile and easily
destroyed, leading to anemia.
Electrophoresis of hemoglobin from an individual
with sickle-cell anemia, a heterozygote (called
sickle-cell trait), and a normal individual. The
smudges show the posi-tions to which the
hemoglobins migrate on the starch gel.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini
8. The complexity of the phenotype
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At one level, geneticists tend to think of genes in isolation. In reality,
genes don't act in isolation. The proteins and RNAs they encode
contribute to specific cellular pathways that also receive input from
the products of many other genes. Furthermore, expression of a single
gene is dependent on many factors, including the specific genetic
backgrounds of the organism and a range of environmental conditions,
temperature, nutritional conditions, population density, and so on.
Gene action is a term that covers a very complex set of events, and
there is probably no case where we understand all the events that
transpire from the level of expression of a single gene to the level of
an organism's phenotype.
Two important generalizations about the complexity of gene action:
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1. There is a one-to-many relationship of genes to phenotypes.
2. There is a one-to-many relationship of phenotypes to genes.
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9. One-to-many relationship of genes to phenotypes
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This relationship is called pleiotropy. Pleiotropy is inferred
from the observation that mutations selected for their effect
on one specific character are often found to affect other
characters of the organism. This might mean that there are
related physiological pathways contributing to a similar
phenotype in several tissues.
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For example, the white eye-color mutation in Drosophila results in
lack of pigmentation not only in compound eyes but also in ocelli
(simple eyes), sheaths of tissue surrounding the male gonad, and
the Malpighian tubules (the fly's kidneys). In all these tissues,
pigment formation requires the uptake of pigment precursors by
the cells. The white allele causes a defect in this uptake, thereby
blocking pigment formation in all these tissues.
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10. Gene mutations may affect apparently unrelated traits
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Often, pleiotropy involves multiple events that are not
obviously physiologically related.
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For example, the dominant Drosophila mutation Dichaete causes
the wings to be held out laterally but also removes certain hairs on
the back of the fly; furthermore, the mutation is inviable when
homozygous. This example shows a real limitation in the way
dominant and recessive mutations are named. The reality is that
a single mutation can be both dominant and recessive, depending
on which aspect of its pleiotropic phenotype is under
consideration. In general, genetic terminology is not up to the task
of representing this level of pleiotropy and complexity in one
symbol, and there is a certain arbitrary or historical aspect as to
how we name alleles.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini
11. Phenylketonuria (PKU)
Another example is human
phenylketonuria, in which loss of an
enzyme involved in the breakdown
of excess phenylalanine causes
pleiotropic effects that include
elevated phenylalanine levels in the
blood plasma, urinary excretion of
intermediate products of
phenylalanine breakdown, severely
reduced IQ, changes in hair color,
and changes in head size.
Figure. Frequency distributions of
phenylketonurics (right) compared with
controls (left). A: d/s = 13, where d is the
difference in the means and s is the average
standard deviation of the two distributions.
B: d/s = 5.5; C: d/s = 2.0; D: d/s = 0.7
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12. The discovery of PKU
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In 1934, Asjbørn Følling, a Swedish physician, recognized that a
certain type of mental retardation was caused by elevated levels of
phenylalanine in body fluids. He identified the disease as an
autosomal recessive condition.
In the 1940s, Lionel Penrose in the UK introduced the idea that PKU
was not randomly distributed in human populations and could be
treatable.
In the mid-1950s, it was demonstrated that individuals with PKU had
a deficiency of hepatic cytosolic phenylalanine hydroxylase (PAH)
enzyme activity. Next it was shown that affected individuals
responded to dietary restriction of the essential nutrient phenylalanine.
During the 1980s, the human PAH gene was mapped and cloned, and
the first mutations identified. In the 1990s, in vitro expression analysis
was being used to study the effects of different PAH alleles on enzyme
function and the crystal structure of PAH was elucidated.
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13. Screening and treatment of PKU
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By the 1960s, a microbial inhibition assay was used for mass
screening of newborns, providing early diagnosis and access to
successful treatment.
In the 1970s, it was discovered that not all cases of hyperphenylalaninemia (HPA) was PKU. Some forms of HPA were caused by
disorders of synthesis and recycling of the cofactor
[tetrahydrobiopterin (BH4)] involved in the phe hydroxylation
reaction (genetic heterogeneity).
HPA is treatable. Affected individuals can lead normal lives.
Continuous efforts are made to improve the taste and convenience of
the current synthetic dietary supplements. Research to improve the
current treatment with restrictive phenylalanine diets, supplemented
by medical formula, is still ongoing.
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14. Distribution of blood phenylalanine concentration
The phenylalanine tolerance test. A short time after administering a measured amount of
phenylalanine to the subject, the concentration of phenylalanine in the blood plasma is
measured. The level is usually substantially higher in people who carry one PKU gene
(even though they show no signs of disease) than in individuals who are homozygous
for the unmutated gene
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15. The complexity of “simple” Mendelian traits
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Phenylalanine hydroxylase deficiency is a 'multifactorial disorder' in
that both environment (dietary intake of phe) and genotype (mutation
of the PAH gene) are necessary causal components of disease.
Because each individual has a personal genome, even those with
similar mutant PAH genotypes may not have similar 'PKU'
phenotypes.
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Variability of metabolic phenotypes in PAH deficiency is caused
primarily by different mutations within the PAH gene. Whereas the
genotype does predict the biochemical phenotype (i.e., by phe loading
tests), it does not always predict the clinical phenotype (i.e.,
occurrence of mental retardation).
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PAH deficiency is therefore a 'complex' disorder at the cognitive and
metabolic levels.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini
16. A single amino acid substitution
The
compounded
consequences
of one amino
acid
substitution in
hemoglobin to
produce sicklecell anemia.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini