Medical Genetics
06疾病的多基因遗传
Monogenic Inheritance
Medical Genetics
Multifactorial inheritance is
responsible for the greatest number
of individuals that will need special
care or hospitalization because of
genetic diseases,
Medical Genetics
Up to 10% of newborn children
will express a multifactorial disease
at some time in their life,Atopic
reactions,diabetes,cancer,spina
bifida/anencephaly,pyloric stenosis,
cleft lip,cleft palate,congenital hip
dysplasia,club foot,and a host of
other diseases all result from
multifactorial inheritance,
Medical Genetics
Some of these diseases occur
more frequently in males,Others
occur more frequently in females,
Environmental factors as well as
genetic factors are involved,
Medical Genetics
1,REGRESSION TO THE MEAN
Multifactorial inheritance was
first studied by Galton,a close
relative of Darwin and a
contemporary of Mendel,Galton
established the principle of what he
termed "regression to mediocrity."
Medical Genetics
Galton studied the inheritance
of continuous characters,height in
humans,intelligence in humans,etc,
Medical Genetics
Galton noticed that extremely tall
fathers tended to have sons shorter than
themselves,and extremely short fathers
tended to have sons taller than
themselves,"Tallness" or "shortness"
didn't breed true like they did in Mendel's
pea experiments,The offspring seemed to
regress to the median,or "mediocrity."
Medical Genetics
Medical Genetics
When comparing height differences
between men and women,women are,on
average,3 inches shorter,A woman with
a certain number of "tall" genes will be,on
average,3 inches shorter than a man with
the same number,When that difference is
taken into account,there is no selective
bias in matings for tallness in human
populations,
Medical Genetics
It is true than men tend to marry
women who are shorter than themselves,
but that is a phenotypic difference,not a
genotypic difference,Since the wives of
taller than average men tend to represent
the general population of women,they will
not have,on the average,as many "tall"
genes to pass on to their offspring as their
husbands,
Medical Genetics
Hence,the son will receive half
of the father's "tall" genes,on
average,and half of the mother's
"tall" genes,on average,but his total
genes for "tallness," on average,will
be less than his father's,
Medical Genetics
Shorter than average males
have fewer "tall" genes than average,
but they are still as tall as an
average female,even though the
average female has more "tall"
genes,
Medical Genetics
Their sons,on average,will be
taller than their fathers because their
mothers have,on average,more
"tall" genes to give to their sons than
their husbands have,On average,
the son will have more "tall" genes
than his father,
Medical Genetics
2,POLYGENIC INHERITANCE
For many years the argument
raged between the "Mendelians" and
the "Galtonians" as to which of the
two paradigms was the correct one
for human inheritance,
Medical Genetics
There was no question that
Mendelian inheritance was correct for
some diseases,but these were rare,
affecting only a small portion of the
population,They were considered
trivial by the Galtonians,
Medical Genetics
On the other hand,the
inheritance of quantitative traits
could not be used to predict
outcomes,only average estimates
measured in large population studies,
Mendelians considered the study of
quantitative traits to be trivial
because they had no predictive value,
Medical Genetics
R,A,Fisher resolved the dispute
by showing that the inheritance of
quantitative traits can be reduced to
Mendelian inheritance at many loci,
Medical Genetics
Consider the following,One locus for
height,with three alleles,Allele h2 adds
2 inches to the average 68-inch
height,Allele h0 neither adds nor
subtracts from the average height of
68 inches,And allele h- subtracts 2
inches from the average height,
Suppose h0 is twice as frequent as
either h2 or h-,
Medical Genetics
The Punnett square for the
population would be as follows,
,
FATHER'S GAMETES
h2 2h0 h-
MOTHER'S
GAMETES
h2 h2,h2 72" 2(h2,h0) 70" h2,h- 68"
2h0 2(h2,h0) 70" 4(h0,h0) 68" 2(h-,h0) 66"
h- h2,h- 68" 2(h-,h0) 66" h-,h- 64"
Medical Genetics
Medical Genetics
If a second locus,called the tall locus,
or t,is also involved in height,with three
alleles as above,one adding two inches,
one neither adding nor subtracting from
the phenotype,and one subtracting 2
inches,with the neutral allele occurring
twice as frequently as the either of the
others,the histogram becomes,
Medical Genetics
Medical Genetics
3,THE MULTIFACTORIAL MODEL
As more loci are included,this
binomial distribution quickly approaches
the Gaussian distribution,or the bell-
shaped normal curve,observed with
human quantitative traits,Three loci,each
with three alleles,are enough to produce
population frequencies indistinguishable
from a normal curve,
Medical Genetics
The multifactorial model is
then,
(1) Several,but not an unlimited number,
loci are involved in the expression of the
trait,
(2) There is no dominance or recessivity at
each of these loci,
(3) The loci act in concert in an additive
fashion,each adding or detracting a small
amount from the phenotype,
(4) The environment interacts with the
genotype to produce the final phenotype,
Medical Genetics
4,THRESHOLD MODEL OF DISEASE
If multifactorial traits are
quantitative traits with continuous
distribution,how can they control
diseases,such as cleft lip or spina
bifida? One either has the disease or
doesn't,There is no intermediate,
Multifactorial diseases are best
explained by the threshold model,
Medical Genetics
The threshold model for multifactorial traits,Below the threshold the trait
is not expressed,Individuals above the threshold have the disease,
Medical Genetics
As the number of multifactorial
genes for the trait increases,the
liability for the disease increases,
When it reaches a threshold,the
liability is so great that abnormality,
what we call disease,results,
Medical Genetics
Medical Genetics
For example,consider the
development of the cleft palate,Early in
embryonic development the palatal arches
are in a vertical position,Through
embryonic and fetal development the
head grows larger,making the arches
farther apart,the tongue increases in size,
making it more difficult to move,and the
arches themselves are growing and
turning horizontal,
Medical Genetics
There is a critical stage in
development by which the two
arches must meet and fuse,Head
growth,tongue growth,and palatal
arch growth are all subject to many
genetic and environmental factors,
Medical Genetics
If the two arches start to grow
in time,grow at the proper rate,and
begin to move soon enough to the
horizontal they will meet and fuse in
spite of head size and tongue growth,
The result is no cleft palate,
Medical Genetics
They may fuse well ahead of the
critical developmental stage or just barely
make it in time,we have no way of telling,
However,if they don't meet by the critical
stage a cleft palate results,If they are
close together at the critical stage,a small
cleft will result,perhaps only a bifurcated
uvula,If they are far apart,a more severe
cleft will result,
Medical Genetics
We call that critical difference in
liability the threshold,Beyond the
threshold,disease results,Below the
threshold,normal development is
observed,
Medical Genetics
Since one is not following a
single locus with dominance or
recessivity but is following several
loci that act in concert,counseling
for multifactorial inheritance diseases
requires a different approach from
that taken for Mendelian inheritance
diseases,
Medical Genetics
One has to calculate the
number of genes in common,The
easiest way to do that is to change
the way we construct pedigrees,
Instead of the familiar sibship
method we use the pathway to
common ancestor method,
Medical Genetics
Pedigree A represents the standard
method of pedigree construction,Pedigree
B represents the pathway system of
pedigree construction,
Medical Genetics
It is much easier to see how genes flow
from generation to generation in Pedigree B,
II-2 and II-3 are brother and sister,They
have two common ancestors,I-1 and I-2,
Medical Genetics
To determine the fraction of genes II-2
and II-3 have in common one simply counts
all of the pathways and their connecting lines
through the common ancestors,There is one
line from II-2 to I-1,and a line from I-1 to II-
3,That is one pathway with two lines of
descent,
Medical Genetics
There is another
line from II-2 to I-2,
and a line from I-2 to
II-3,These are the
only pathways from
II-2 to II-3,The
fraction 1/2 is then
raised to the power of the number of lines of
descent and summed for each possible pathway,
(1/2)2 for the pathway through I-1,and (1/2)2
for the pathway through I-2,making a total of
1/2,Brothers and sisters have,on average,1/2
of their genes in common,
Medical Genetics
A parent and offspring,say I-1
and II-2 also have 1/2 of their genes
in common,There is only one
pathway between them and only one
line in that pathway,(1/2)1,
Medical Genetics
Other relationships follow in the same manner,
III-1 and III-3 are first cousins,There are two
pathways connecting the two individuals,one
through I-1 and the other through I-2,each with
four lines,Their fraction of genes in common is
then (1/2)4 + (1/2)4 or 1/8,First cousins have
1/8 of their genes in common,A grandparent and
grandchild have 1/4 of their genes in common,
There is a single pathway with two lines of
descent,III-1 and IV-1 are first cousins once
removed,Again there are two pathways,one
through I-1 and the other through I-2,each with
5 lines,(1/2)5 + (1/2)5 or 1/16 of their genes in
common,
Medical Genetics
The degree of relationship is often
used rather than the fraction of genes in
common,The degree of relationship is
simply the power to which (1/2) is raised
to reach the fraction of genes in common,
First degree relatives have (1/2) of their
genes in common,Second degree
relatives have 1/4,(1/2)2,of their genes
in common,etc,
Medical Genetics
Method of calculating the recurrence risk of a multifactorial trait to
first degree relatives
Medical Genetics
Recurrence risk to first degree relatives of affected individuals,
Medical Genetics
5,SEVERITY OF DISEASE AND RECURRENCE RISK
Unlike Mendelian traits with
variable expressivity,where the
recurrence risk is the same no
matter how severely the individual is
affected,multifactorial traits have a
higher recurrence risk if the relative
is more severely affected,
Medical Genetics
In multifactorial traits,the more
severely affected the individual,the
more genes he/she has to transmit,
and the higher the recurrence risk,
Medical Genetics
6,MULTIPLE AFFECTED OFFSPRING AND
RECURRENCE RISK
Another difference is the
presence of multiple affected
individuals within a sibship,
Medical Genetics
In Mendelian traits the number of
affected in a family did not change
the recurrence risks,
Medical Genetics
But multiple affected children
does change the recurrence risk for
multifactorial traits,
Medical Genetics
The presence of one affected child
means the parents probably are midway
between the mean for affected and the
mean of the normal population,but the
presence of a second affected child means
they probably are closer to the threshold,
and hence,have a higher recurrence risk
should they choose to have another child,
Medical Genetics
7,CONSANGUINITY
Consanguinity also increases the
probability of an affected child for a
multifactorial trait,but only slightly when
compared to rare autosomal recessive
diseases,First cousin matings may
increase the risk for two normal
individuals to have a child with a
multifactorial disease by about two fold
when compared to the risk for unrelated
individuals,
Medical Genetics
8,HALLMARKS OF MULTIFACTORIAL
INHERITANCE
The hallmarks for multifactorial
inheritance are,
Medical Genetics
(1) Most affected children have normal parents,This is true of
diseases and quantitative traits,Most geniuses come from
normal parents,most mentally challenged come from
normal parents,
(2) Recurrence risk increases with the number of affected
children in a family,
(3) Recurrence risk increases with severity of the defect,A
more severely affected parent is more likely to produce an
affected child,
(4) Consanguinity slightly increases the risk for an affected
child,
(5) Risk of affected relatives falls off very quickly with the
degree of relationship,Contrast this with autosomal
dominant inheritance with incomplete penetrance,where
the recurrence risk falls off proportionately with the
degree of relationship,
(6) If the two sexes have a different probability of being
affected,the least likely sex,if affected,is the most likely
sex to produce an affected offspring,
06疾病的多基因遗传
Monogenic Inheritance
Medical Genetics
Multifactorial inheritance is
responsible for the greatest number
of individuals that will need special
care or hospitalization because of
genetic diseases,
Medical Genetics
Up to 10% of newborn children
will express a multifactorial disease
at some time in their life,Atopic
reactions,diabetes,cancer,spina
bifida/anencephaly,pyloric stenosis,
cleft lip,cleft palate,congenital hip
dysplasia,club foot,and a host of
other diseases all result from
multifactorial inheritance,
Medical Genetics
Some of these diseases occur
more frequently in males,Others
occur more frequently in females,
Environmental factors as well as
genetic factors are involved,
Medical Genetics
1,REGRESSION TO THE MEAN
Multifactorial inheritance was
first studied by Galton,a close
relative of Darwin and a
contemporary of Mendel,Galton
established the principle of what he
termed "regression to mediocrity."
Medical Genetics
Galton studied the inheritance
of continuous characters,height in
humans,intelligence in humans,etc,
Medical Genetics
Galton noticed that extremely tall
fathers tended to have sons shorter than
themselves,and extremely short fathers
tended to have sons taller than
themselves,"Tallness" or "shortness"
didn't breed true like they did in Mendel's
pea experiments,The offspring seemed to
regress to the median,or "mediocrity."
Medical Genetics
Medical Genetics
When comparing height differences
between men and women,women are,on
average,3 inches shorter,A woman with
a certain number of "tall" genes will be,on
average,3 inches shorter than a man with
the same number,When that difference is
taken into account,there is no selective
bias in matings for tallness in human
populations,
Medical Genetics
It is true than men tend to marry
women who are shorter than themselves,
but that is a phenotypic difference,not a
genotypic difference,Since the wives of
taller than average men tend to represent
the general population of women,they will
not have,on the average,as many "tall"
genes to pass on to their offspring as their
husbands,
Medical Genetics
Hence,the son will receive half
of the father's "tall" genes,on
average,and half of the mother's
"tall" genes,on average,but his total
genes for "tallness," on average,will
be less than his father's,
Medical Genetics
Shorter than average males
have fewer "tall" genes than average,
but they are still as tall as an
average female,even though the
average female has more "tall"
genes,
Medical Genetics
Their sons,on average,will be
taller than their fathers because their
mothers have,on average,more
"tall" genes to give to their sons than
their husbands have,On average,
the son will have more "tall" genes
than his father,
Medical Genetics
2,POLYGENIC INHERITANCE
For many years the argument
raged between the "Mendelians" and
the "Galtonians" as to which of the
two paradigms was the correct one
for human inheritance,
Medical Genetics
There was no question that
Mendelian inheritance was correct for
some diseases,but these were rare,
affecting only a small portion of the
population,They were considered
trivial by the Galtonians,
Medical Genetics
On the other hand,the
inheritance of quantitative traits
could not be used to predict
outcomes,only average estimates
measured in large population studies,
Mendelians considered the study of
quantitative traits to be trivial
because they had no predictive value,
Medical Genetics
R,A,Fisher resolved the dispute
by showing that the inheritance of
quantitative traits can be reduced to
Mendelian inheritance at many loci,
Medical Genetics
Consider the following,One locus for
height,with three alleles,Allele h2 adds
2 inches to the average 68-inch
height,Allele h0 neither adds nor
subtracts from the average height of
68 inches,And allele h- subtracts 2
inches from the average height,
Suppose h0 is twice as frequent as
either h2 or h-,
Medical Genetics
The Punnett square for the
population would be as follows,
,
FATHER'S GAMETES
h2 2h0 h-
MOTHER'S
GAMETES
h2 h2,h2 72" 2(h2,h0) 70" h2,h- 68"
2h0 2(h2,h0) 70" 4(h0,h0) 68" 2(h-,h0) 66"
h- h2,h- 68" 2(h-,h0) 66" h-,h- 64"
Medical Genetics
Medical Genetics
If a second locus,called the tall locus,
or t,is also involved in height,with three
alleles as above,one adding two inches,
one neither adding nor subtracting from
the phenotype,and one subtracting 2
inches,with the neutral allele occurring
twice as frequently as the either of the
others,the histogram becomes,
Medical Genetics
Medical Genetics
3,THE MULTIFACTORIAL MODEL
As more loci are included,this
binomial distribution quickly approaches
the Gaussian distribution,or the bell-
shaped normal curve,observed with
human quantitative traits,Three loci,each
with three alleles,are enough to produce
population frequencies indistinguishable
from a normal curve,
Medical Genetics
The multifactorial model is
then,
(1) Several,but not an unlimited number,
loci are involved in the expression of the
trait,
(2) There is no dominance or recessivity at
each of these loci,
(3) The loci act in concert in an additive
fashion,each adding or detracting a small
amount from the phenotype,
(4) The environment interacts with the
genotype to produce the final phenotype,
Medical Genetics
4,THRESHOLD MODEL OF DISEASE
If multifactorial traits are
quantitative traits with continuous
distribution,how can they control
diseases,such as cleft lip or spina
bifida? One either has the disease or
doesn't,There is no intermediate,
Multifactorial diseases are best
explained by the threshold model,
Medical Genetics
The threshold model for multifactorial traits,Below the threshold the trait
is not expressed,Individuals above the threshold have the disease,
Medical Genetics
As the number of multifactorial
genes for the trait increases,the
liability for the disease increases,
When it reaches a threshold,the
liability is so great that abnormality,
what we call disease,results,
Medical Genetics
Medical Genetics
For example,consider the
development of the cleft palate,Early in
embryonic development the palatal arches
are in a vertical position,Through
embryonic and fetal development the
head grows larger,making the arches
farther apart,the tongue increases in size,
making it more difficult to move,and the
arches themselves are growing and
turning horizontal,
Medical Genetics
There is a critical stage in
development by which the two
arches must meet and fuse,Head
growth,tongue growth,and palatal
arch growth are all subject to many
genetic and environmental factors,
Medical Genetics
If the two arches start to grow
in time,grow at the proper rate,and
begin to move soon enough to the
horizontal they will meet and fuse in
spite of head size and tongue growth,
The result is no cleft palate,
Medical Genetics
They may fuse well ahead of the
critical developmental stage or just barely
make it in time,we have no way of telling,
However,if they don't meet by the critical
stage a cleft palate results,If they are
close together at the critical stage,a small
cleft will result,perhaps only a bifurcated
uvula,If they are far apart,a more severe
cleft will result,
Medical Genetics
We call that critical difference in
liability the threshold,Beyond the
threshold,disease results,Below the
threshold,normal development is
observed,
Medical Genetics
Since one is not following a
single locus with dominance or
recessivity but is following several
loci that act in concert,counseling
for multifactorial inheritance diseases
requires a different approach from
that taken for Mendelian inheritance
diseases,
Medical Genetics
One has to calculate the
number of genes in common,The
easiest way to do that is to change
the way we construct pedigrees,
Instead of the familiar sibship
method we use the pathway to
common ancestor method,
Medical Genetics
Pedigree A represents the standard
method of pedigree construction,Pedigree
B represents the pathway system of
pedigree construction,
Medical Genetics
It is much easier to see how genes flow
from generation to generation in Pedigree B,
II-2 and II-3 are brother and sister,They
have two common ancestors,I-1 and I-2,
Medical Genetics
To determine the fraction of genes II-2
and II-3 have in common one simply counts
all of the pathways and their connecting lines
through the common ancestors,There is one
line from II-2 to I-1,and a line from I-1 to II-
3,That is one pathway with two lines of
descent,
Medical Genetics
There is another
line from II-2 to I-2,
and a line from I-2 to
II-3,These are the
only pathways from
II-2 to II-3,The
fraction 1/2 is then
raised to the power of the number of lines of
descent and summed for each possible pathway,
(1/2)2 for the pathway through I-1,and (1/2)2
for the pathway through I-2,making a total of
1/2,Brothers and sisters have,on average,1/2
of their genes in common,
Medical Genetics
A parent and offspring,say I-1
and II-2 also have 1/2 of their genes
in common,There is only one
pathway between them and only one
line in that pathway,(1/2)1,
Medical Genetics
Other relationships follow in the same manner,
III-1 and III-3 are first cousins,There are two
pathways connecting the two individuals,one
through I-1 and the other through I-2,each with
four lines,Their fraction of genes in common is
then (1/2)4 + (1/2)4 or 1/8,First cousins have
1/8 of their genes in common,A grandparent and
grandchild have 1/4 of their genes in common,
There is a single pathway with two lines of
descent,III-1 and IV-1 are first cousins once
removed,Again there are two pathways,one
through I-1 and the other through I-2,each with
5 lines,(1/2)5 + (1/2)5 or 1/16 of their genes in
common,
Medical Genetics
The degree of relationship is often
used rather than the fraction of genes in
common,The degree of relationship is
simply the power to which (1/2) is raised
to reach the fraction of genes in common,
First degree relatives have (1/2) of their
genes in common,Second degree
relatives have 1/4,(1/2)2,of their genes
in common,etc,
Medical Genetics
Method of calculating the recurrence risk of a multifactorial trait to
first degree relatives
Medical Genetics
Recurrence risk to first degree relatives of affected individuals,
Medical Genetics
5,SEVERITY OF DISEASE AND RECURRENCE RISK
Unlike Mendelian traits with
variable expressivity,where the
recurrence risk is the same no
matter how severely the individual is
affected,multifactorial traits have a
higher recurrence risk if the relative
is more severely affected,
Medical Genetics
In multifactorial traits,the more
severely affected the individual,the
more genes he/she has to transmit,
and the higher the recurrence risk,
Medical Genetics
6,MULTIPLE AFFECTED OFFSPRING AND
RECURRENCE RISK
Another difference is the
presence of multiple affected
individuals within a sibship,
Medical Genetics
In Mendelian traits the number of
affected in a family did not change
the recurrence risks,
Medical Genetics
But multiple affected children
does change the recurrence risk for
multifactorial traits,
Medical Genetics
The presence of one affected child
means the parents probably are midway
between the mean for affected and the
mean of the normal population,but the
presence of a second affected child means
they probably are closer to the threshold,
and hence,have a higher recurrence risk
should they choose to have another child,
Medical Genetics
7,CONSANGUINITY
Consanguinity also increases the
probability of an affected child for a
multifactorial trait,but only slightly when
compared to rare autosomal recessive
diseases,First cousin matings may
increase the risk for two normal
individuals to have a child with a
multifactorial disease by about two fold
when compared to the risk for unrelated
individuals,
Medical Genetics
8,HALLMARKS OF MULTIFACTORIAL
INHERITANCE
The hallmarks for multifactorial
inheritance are,
Medical Genetics
(1) Most affected children have normal parents,This is true of
diseases and quantitative traits,Most geniuses come from
normal parents,most mentally challenged come from
normal parents,
(2) Recurrence risk increases with the number of affected
children in a family,
(3) Recurrence risk increases with severity of the defect,A
more severely affected parent is more likely to produce an
affected child,
(4) Consanguinity slightly increases the risk for an affected
child,
(5) Risk of affected relatives falls off very quickly with the
degree of relationship,Contrast this with autosomal
dominant inheritance with incomplete penetrance,where
the recurrence risk falls off proportionately with the
degree of relationship,
(6) If the two sexes have a different probability of being
affected,the least likely sex,if affected,is the most likely
sex to produce an affected offspring,
