Transcript Mendelian inheritance - Center of Statistical Genetics

1. Mendelian inheritance in man
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After rediscovery of Mendel’s principles, an early task was
to show that they were true for animals also, and especially
for humans.
In fact, human families, like the offspring of experimental
organisms, show inheritance patterns both of the type
discovered by Mendel (autosomal inheritance) and of sex
linkage.
In general, what in the hand of an experimental geneticist is
simply a “mutant phenotype”, in the hand of a human
geneticists becomes a disease or a condition of disability
(often a severe disability).
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
2. Mendelian inheritance
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The simplest genetic characters are those whose presence or absence
depends on the genotype at a single locus. That is not to say that the
character itself is programmed by only one pair of genes expression of any human character is likely to require a large
number of genes and environmental factors.
However, sometimes a particular genotype at one locus is both
necessary and sufficient for the character to be expressed, given the
normal genetic and environmental background of the organism.
Such characters are called Mendelian.
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
3. Investigating Mendelian conditions in human
Because controlled experimental crosses cannot be made with humans, geneticists must
resort to scrutinizing records in the hope that informative matings have been made by
chance. Such a scrutiny of records of matings is called pedigree analysis.
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A member of a family who first comes to the
attention of a geneticist is called the proband.
Usually the phenotype of the proband is
exceptional in some way (for example, the
proband might be a dwarf).
The investigator then traces the history of the
phenotype in the proband back through the
history of the family and draws a family tree,
or pedigree, by using standard symbols
Genetica per Scienze Naturali
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4. Dominance and recessiveness
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Dominance and recessiveness are properties of characters, not genes. A
character is dominant if it is manifest in the heterozygote and recessive if
not. Thus alkaptonuria is recessive because only homozygotes for a
defective enzyme manifest it, whereas heterozygotes show the normal
phenotype.
Most human dominant syndromes are known only in heterozygotes.
Sometimes homozygotes have been described, born from matings of two
heterozygous affected people, and often the homozygotes are much more
severely affected. Examples are achondroplasia (short-limbed dwarfism) and
Type 1 Waardenburg syndrome (deafness with pigmentary abnormalities).
Nevertheless we describe achondroplasia and Waardenburg syndrome as
dominant because these terms describe phenotypes seen in heterozygotes.
Males are hemizygous for loci on the X and Y chromosomes, where they
have only a single copy of each gene, so the question of dominance or
recessiveness does not arise in males for X- or Y-linked characters.
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
5. The five basic Mendelian pedigree patterns
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Mendelian characters may be determined by loci on an autosome or on the
X or Y sex chromosomes. Autosomal characters in both sexes and X-linked
characters in females can be dominant or recessive. Thus there are five
archetypal Mendelian pedigree patterns:
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Autosomal dominant
Autosomal recessive
X-linked recessive
X-linked dominant
Y-linked
Only one important gene has been located on the human Y chromosome,
the TDF gene, which codes for a testis-determining factor and plays a
primary role in maleness. Even the X-linked dominant trait are rare.
Therefore, in practice the important mendelian pedigree patterns are
autosomal dominant, autosomal recessive and X-linked.
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
6. Autosomal Dominant Disorders
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In autosomal dominant disorders, the normal allele
is recessive and the abnormal allele is dominant.
An example of an autosomal dominant phenotype
is achondroplasia, a type of dwarfism. In this case,
people with normal stature are genotypically d/d,
and the dwarf phenotype in principle could be D/d
or D/D. However, it is believed that in D/D
individuals the two "doses" of the D allele produce
such a severe effect that this genotype is lethal.
Therefore, all achondroplastics are heterozygotes.
A pedigree showing
autosomal dominant
inheritance
Diego Velásques: The Dwarf
Sebastian de Morra (Museo
del Prado, Madrid)
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
7. Autosomal dominant pedigree pattern
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In pedigree analysis, the main clues for identifying a dominant disorder are
that the phenotype tends to appear in every generation of the pedigree and
that affected fathers and mothers transmit the phenotype to both sons and
daughters.
It has been estimated that 1% of liveborn infants carry a gene for an
autosomal dominant disease; in 20% of these cases (0.2% of livebirths) their
disease is due to a new, or “sporadic” mutation that arose in the reproductive
cells of one of their parents.
More than 1,500 dominant diseases have been described in human
Pedigree of a dominant phenotype
determined by a dominant allele A . In
this pedigree, all the genotypes have
been deduced.
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
8. Autosomal Recessive Disorders
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The phenotype of a recessive disorder is determined by homozygosity for a
recessive allele, and the unaffected phenotype is determined by the
corresponding dominant allele. Although in some instances it may be
misleading, the properties of dominance and recessiveness are thus
transferred from traits to alleles.
In general terms, recessive diseases are determined by alleles that we can
call a, and the normal condition by A. Therefore, sufferers of the diseases are
of genotype a/a, and unaffected people are either A/A or A/a.
About 1,000 recessive diseases have been described in humans.
Pedigree of a rare recessive phenotype determined by a
recessive allele a . Gene symbols are normally not included in
pedigree charts, but genotypes are inserted here for reference.
Note that individuals II-1 and II-5 marry into the family; they
are assumed to be normal because the heritable condition under
scrutiny is rare. Note also that it is not possible to be certain of
the genotype in some persons with normal phenotype; such
persons are indicated by A/–
Genetica per Scienze Naturali
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9. Autosomal recessive pedigree pattern
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Two key points that distinguish pedigrees segregating recessive
conditions are that generally the disease appears in the progeny
of unaffected parents and that the affected progeny include both
males and females equally. When we know that both male and
female phenotypic proportions are equal, we can assume that we
are dealing with autosomal inheritance, not X-linked inheritance.
The following typical pedigree illustrates the key point that
affected children are born to unaffected parents:
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10. Deducing genotypes from phenotypes in pedigrees
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From this pattern we can immediately deduce autosomal inheritance, with the
recessive allele responsible for the rare phenotype (indicated by shading).
Furthermore, we can deduce that the parents must both be heterozygotes, for
example P/p. (Both must have a p allele because each contributed one to each
affected child, and both must have a P allele because the people are phenotypically
normal.) We can identify the genotypes of the children (in the order shown) as P/- ,
p/p, p/p, and P/- (“-” means either P or p). Hence, the pedigree can be rewritten as:
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Notice another interesting feature of pedigree analysis: even though Mendelian rules
are at work, Mendelian ratios are rarely observed in single families because the
sample sizes are too small. In the above example, we see a 1:1 phenotypic ratio in
the progeny of what is clearly a monohybrid cross, in which we might expect a 3:1
ratio. If the couple were to have, say, 20 children, the ratio would undoubtedly be
something like 15 unaffected and 5 affected children), but in a sample of four any
ratio is possible and all ratios are commonly found.
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
11. Classical segregation analysis
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How can an investigator decide if a rare condition, may be showing a certain
level of familial recurrence, can be the consequence of a single mutant gene,
rather than being due to non-genetic causes?
In case of simple dichotomous traits, classical segregation analysis may provide
the answer. Segregation analysis is a statistical method of analyzing family data
that tests whether an observed pattern of phenotypes in families is compatible
with an explicit model of inheritance. In other words, it is the analysis of the
ratios of offspring from a particular parental cross to test for conformity with the
Mendelian theory.
The starting point of segregation analysis is the collection of as may as possible
families with the trait under consideration. Then, considering 1) the frequency
of the mutant gene in the population, 2) the proportion of the marriages of each
possible type in the population and 3) the Mendelian transmission probabilities
in each of the marriage type, an expected number of affected individual can be
calculated and compared with the observed number.
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
12. X-Linked Recessive Disorders
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Phenotypes with X-linked recessive inheritance typically show the
following patterns in pedigrees:
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Many more males than females show the phenotype under study. This is because
a female showing the phenotype can result only from a mating in which both the
mother and the father bear the allele (for example, XA/Xa × Xa/Y), whereas a
male with the phenotype can be produced when only the mother carries the
allele.
None of the offspring of an affected male are affected, but all his daughters must
be heterozygous "carriers" because females must receive one of their X
chromosomes from their fathers. Half the sons born to these carrier daughters
are affected.
Pedigree showing that X-linked recessive alleles expressed
in males are then carried unexpressed by their daughters in
the next generation, to be expressed again in their sons.
Note that III-3 and III-4 cannot be distinguished
phenotypically
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13. Hemophilia
The most famous cases of hemophilia are found in the pedigree of the interrelated royal families
of Europe. The original hemophilia allele in the pedigree arose spontaneously (as a mutation) in
the reproductive cells of Queen Victoria's parents or of Queen Victoria herself. Alexis, the son of
the last czar of Russia, inherited the allele ultimately from Queen Victoria, who was the
grandmother of his mother Alexandra.
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
14. X-linked dominant disorders
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These disorders have the following characteristics:
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1. Affected males pass the condition to all their daughters but to none of their
sons.
2. Affected heterozygous females married to unaffected males pass the condition
to half their sons and daughters.
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There are few examples of X-linked
dominant phenotypes in humans. One
example is hypophosphatemia, a type of
vitamin D-resistant rickets (bones become
bent and distorted).
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
15. Complications to the basic Mendelian patterns
(A) A common recessive, such as
blood group O, can give the
appearance of a dominant pattern.
(B) Autosomal dominant
inheritance with nonpenetrance in
II2. (C) Autosomal dominant
inheritance with variable
expression. (D) Genetic imprinting:
in this family autosomal dominant
glomus tumors manifest only when
the gene is inherited from the
father. (E) Genetic imprinting: in
this family autosomal dominant
Beckwith-Wiedemann syndrome
manifests only when the gene is
inherited from the mother. (F) Xlinked dominant incontinentia
pigmenti. Affected males abort
spontaneously (small squares). (G)
An X-linked recessive pedigree
where inbreeding gives an affected
female and apparent male-to-male
transmission. (H) A new autosomal
dominant mutation, mimicking an
autosomal or X-linked recessive
pattern.
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini
16. Impact of genetic diseases
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With improvements in hygiene and health care during the last century there has been
a decline in the contribution of environmental factors to disease, in particular a
decrease in illness due to infections and nutritional deficiency
Monogenic diseases are responsible for a heavy loss of life. The global prevalence
of all single gene diseases at birth is approximately 10/1000. In Canada, it has been
estimated that taken together, monogenic diseases may account for upto 40% of the
work of hospital based paediatric practice (Scriver, 1995).
This has led to increased relative contribution of genetic disorders to morbidity and
mortality:
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2% of all neonates have a chromosomal abnormality or a single gene disorder.
childhood Mendelian disorders account for 50% of blindness, 50% of deafness, 50% of
all cases of severe mental retardation, 40-50% of childhood deaths
The birth of a “normal” human being is almost a rare occurrence:
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A chromosomal abnormality is present in at least 50% of all recognized first trimester
spontaneous abortions
Genetica per Scienze Naturali
a.a. 04-05 prof S. Presciuttini