MENDELISM IN MAN
=The Mendelian Principles Probably Applicable to Many Characters of
Man.--=We are really just beginning to make the proper observations and
collect the necessary data with reference to the application of Mendelian
principles to the traits of man. Yet brief as has been our study we have
disclosed much significant evidence which makes it seem highly probable
that many of his characters, good and bad, of mind and body are as
subservient to these laws as are the traits and features of lower forms.
Davenport and Plate record over sixty human characters or defects which
are seemingly inherited in Mendelian fashion. Although about fifty of
these are pathological or abnormal conditions, this does not mean that
such conditions are more prone to follow Mendelian inheritance but merely
that being relatively conspicuous or isolated they are easier to follow
and tabulate.
=Difficult to get Correct Data.--=While it must be said that in many cases
no simple form of Mendelian tabulation has been unequivocally established,
yet the general behavior of the various inheritable traits in question is
so obviously related to the conventional Mendelian course that there seems
little reason for doubting that they are at bottom the same. Failure to
obtain exact proportions may be attributable in part to the probability
that what we loosely regard as a character should in reality be analyzed
into more elemental components, and above all to the fact that from the
very nature of the conditions under which human records must be obtained,
there is considerable chance of inaccuracy or error in such accounts. How
many human traits follow Mendelian rules remains largely for future
investigators to establish.
We are handicapped at the outset in man by the many difficulties of
getting correct data from the genealogies on which we must depend, or in
fact of getting any genealogy at all, for in this country at least, most
families keep imperfect records of births and deaths and many of the
institutions for the various kinds of defectives have little in their
records that will help us in following out hereditary conditions. Then in
matters of disease we meet with the fact that many former diagnoses were
erroneous. In yet other cases, and this is particularly true among mental
and moral defectives, we are often not sure of the paternity of a given
child. Furthermore, one is likely to be misled by the proportions which
may occur in the very limited number of children of any given couple.
Still other difficulties exist. Among these is the fact, for example, that
in many cases of defect or susceptibility to disease, a given individual
in the stock may have the trait in an expressible and transmissible form,
yet it never comes to expression because that individual has been
fortunate enough to escape the environmental stimulus which would call it
forth. Thus one highly susceptible to tuberculosis might escape infection,
or persons hovering on the verge of insanity might never receive the
precipitating stimulus which would topple them into actual insanity; yet
each would be wrongfully recorded in a genealogy looking to such traits as
perfectly normal. Or again if it be a question of intellectual brilliancy
as shown by accomplishment in the realm of scholarship, or of worldly
affairs, the ones who although possessing them have had no chance to
display unusual talents would be tabulated as average whereas in fact they
should be recorded as of high rank. That this is particularly likely to
happen in the case of women is evident.
=A Generalized Presence-Absence Formula for Man.--=In man as in lower
forms some characters or traits are due presumably to the presence of
determiners or to their absence. Likewise, dominance and recessiveness are
as much in evidence, for in tracing back pedigrees of various traits we
find the same forms of tabulation that obtain for these conditions in
plants and lower animals hold good. For typical cases in man let us use a
generalized presence-absence formula and the arbitrary symbol A for the
presence of the determiner of the character (double in the individual,
single in the germ) and a for its absence. Thus AA represents a condition
in which similar determiners have been derived from both parents and the
individual is _duplex_ as regards the character in question; each mature
germ-cell will have the determiner. Aa represents a condition in which the
individual has received the determiner from only one parent and is
therefore _simplex_ with regard to the character; half of the gametes of
such an individual will have the determiner and half will lack it. Lastly,
aa represents total absence of the determiner. Such an individual is
_nulliplex_. He or she will not have the determiner represented in any of
the gametes, and can not, of course, transmit a trait represented by the
determiner.
It is evident that six kinds of gametic matings are possible among
individuals representing these various formulae. These matings are as
follows:
Possible
couplings
Matings of gametes Product
1. Nulliplex x Nulliplex (aa x aa) == a------a == all nulliplex
\/
/\
a------a
2. Nulliplex x Simplex (aa x Aa) == a------A == 50 per cent.
\/ with character
/\ nulliplex and
a------a 50 per cent.
with it
simplex.
3. Nulliplex x Duplex (aa x AA) == a------A == all with characters
\/ simplex
/\
a------A
4. Simplex x Simplex (Aa x Aa) == A------A == 25 per cent.
\/ with characters
/\ duplex, 50 per
a------a cent. with it
simplex and 25
per cent. with
it nulliplex.
5. Simplex x Duplex (Aa x AA) == A-------A == 50 per cent.
\/ with character
/\ duplex and 50
a-------A per cent. with
it simplex.
6. Duplex x Duplex (AA x AA) == A-------A == all duplex.
\/
/\
A-------A
=Indications of Incomplete Dominance.--=While in cases of strict Mendelian
dominance it is not possible to distinguish directly the simplex from the
duplex condition, as a matter of fact the individual of simplex
constitution sometimes has the character represented in the single
determiner less perfectly developed than in the corresponding character of
duplex origin. In studying defects in man due to the absence of a
determiner, where theoretically presence of the determiner (normality) is
dominant over its absence in individuals of simplex constitution, one
finds it recorded with increasing frequency that such individuals are more
or less "intermediate" or are "tainted" with the defect; thus showing that
the defect though obscured is not wholly in abeyance. Thus individuals
carrying epilepsy or feeble-mindedness which are regarded as recessive
traits, while not showing specific feeble-mindedness or epilepsy, may
nevertheless apparently show a neuropathic taint in the form of migraine,
alcoholism or other lapse from normality. The condition is seemingly more
akin in some cases to that found in the offspring of certain red flowers
crossbred with white flowers, which though red do not show the same
intensity of color as the original red parent. Just as here the single
determiner or single "dose" of redness is insufficient to produce the
intensity of color that appears when the offspring receive two determiners
for red, one from each parent, so in man a single determiner for normality
of a specific character is inadequate in some cases to make the individual
wholly normal. Or possibly some cases are more of the type of those in
which the character in question, for instance the red color of some wheats
and corn, may be produced by any one of two or three determiners, the
intensity of the characters (red color, e. g.) depending on whether one,
two or three determiners are present.
=Why After the First Generation Only Half the Children May Show the
Dominant Character.--=If the trait is a simple dominant one it is clear
that it will appear in each generation and always spring from an affected
individual. By referring back to our tabulation of possible matings on
page 100 where the dominant character is represented by the letter A, this
can be seen at a glance. If the trait is present in the duplex condition
in one parent and absent from the other, then formula 3 applies; all
children will show the trait, but in the simplex form (Aa). If the trait
is present in the simplex form in one parent and absent in the other,
formula 2 applies. Fifty per cent. of the children will have the character
in the simplex form (Aa) which means also an even chance of transmitting
it to their offspring; fifty per cent. will not inherit it and will be
incapable, furthermore, of transmitting it, since they have become
nulliplex (aa). In human genealogies if an individual having an unusual
trait which is inherited as a dominant marries a normal person and half of
the offspring show the trait (and this is common), this means that the
parent manifesting the trait had it represented only in the simplex
condition, otherwise all of the children would have shown it. Even though
the original ancestor who first developed the condition or structure may
have had it in a duplex form, it would after the first mating, if this
were with an individual lacking the trait, be represented only in the
simplex form (see formula 5) and could never become duplex again unless
two individuals both having the character married, and then only in
twenty-five per cent. of the offspring (see formula 3). If the trait is a
defect all the children showing it, even though marrying normal
(nulliplex) individuals, will pass it on again to half their children, but
those who do not show it may ordinarily marry with impunity since its
non-expression in their make-up means, as far as we know at present, that
their germ-plasm has been purged of the defect and that they are therefore
nulliplex with reference to it.
=Eye-Color in Man.--=Of normal characters in man which follow the
Mendelian formula perhaps eye-color is the best established. Brown or
black eye-color is due to a _melanin_ pigment absent from the blue or gray
eye. That is, a brown eye is practically a blue eye plus an additional
layer of pigment on the outer surface of the iris. The different shades of
brown and the black are due to the relative abundance of this pigment.
Gray color and the shades of blue seem to be a modification of an original
dark blue, due to structural differences in the fibrous tissues of the
iris.
In inheritance brown or black is dominant to blue or gray, or in other
words the _presence_ and _absence_ of a pigment P constitutes a pair of
allelomorphs. Hence two brown-eyed parents, if P is duplex in both (or
duplex in one and simplex in the other) can have only brown-eyed children.
Thus,
1. PP x PP = PP, or all duplex brown.
2. PP x Pp = PP and Pp, half duplex brown and half simplex brown.
If each parent has brown eyes but in simplex condition, then one-fourth
of children will have blue or gray eyes; for example,
Mating Gametic Product
couplings
Pp x Pp = P--P = PP, Pp, pP, and pp, or one-fourth
\/ duplex brown, one-half simplex
/\ brown, and one-fourth blue or
p--p gray.
If both parents have blue or gray eyes they can not have children with
black or brown eyes, since the recessive condition in each parent means
total absence of brown pigment in both.
If one pair is duplex brown and the other blue, then all children will
have brown eyes but of simplex type.
If one parent has simplex brown eyes (type Pp) and one blue (pp) then
one-half of the children will have brown eyes of simplex type and one-half
will have blue eyes.
Occasional objections have been raised against the Mendelian
interpretation of inheritance in eye-color, but the cases cited in
evidence against the theory usually narrow down to those in which the
color is so diluted as to render classification uncertain. For example,
hazel eyes are sometimes called gray; they belong however to the melanic
pigmented type although the brown pigment may be much diluted and occur
mainly around the pupil. So-called green eyes are due to yellow pigment on
a blue background. In the rare cases where in the same individual one eye
is brown and the other blue, the individual should probably be rated as
brown-eyed on the supposition that in the one eye the development of brown
pigment has in some way been suppressed.
=Hair-Color.--=The inheritance of hair-color has also been the subject of
considerable study and while the conditions are not so simple as in the
case of eye-color, there is little doubt that it belongs in the Mendelian
category. In human hair, color has as its foundation apparently two
pigments, black and red. Absence of one or both or various combinations or
dilutions of these seemingly account for the prevailing colors in human
hair. In general dark hair is dominant to light, although because of the
delay sometimes in the darkening of the hair in children this fact is
often obscured. Black is dominant to red. People with glossy black hair,
according to Davenport, are probably simplex for black, the glossiness
being due usually to recessive red. The expectation would be for some of
the children of such a pair to have red hair.
In man occasionally a congenital white lock contrasting strikingly with
the remaining normally pigmented hair occurs. It behaves as a simple
dominant in heredity.
=Hair-Shape.--=Again, straight and curly hair seem to be distinct
inheritable characters. Curly is incompletely dominant to straight, the
simplex condition yielding wavy hair.
Not to enter into details of the matings, statistics gathered by Mr. and
Mrs. Davenport show that, two flaxen-haired parents have flaxen-haired
children; two golden-haired parents have only golden-haired children; two
parents with light brown hair have children with hair of that color or
lighter, but never darker; two parents each with dark brown or black hair
may have children with all the varieties of hair-color. Summing together
a series of recessives Davenport points out that two blue-eyed, flaxen or
golden and straight-haired parents will have only children like
themselves.
[Illustration: FIG. 21
Diagram showing descent of brachydactyly through five generations; black
symbols indicate affected individuals; [male], male; [female], female
(after Farabee).]
=Irregularities.--=If a dominant trait or defect depends on more than a
single factor, as is sometimes the case, or if it is modified by sex or
other conditions, as is true of certain characters, some of which, such as
color-blindness, have already been examined, then we shall find some
apparently non-affected individuals having affected offspring. Certain
diseases, for example, are generally transmitted by affected members of
the family to their children in the expected Mendelian ratio for a
dominant, yet an occasional skip of a generation may appear in which an
apparently perfectly normal individual transmits to his children what,
except for the omission in his own case, appears to be an ordinary
dominant character. This occasional lapse in the appearance of a
character when theoretically it should appear is doubtless due in some
instances to the fact that what is really inherited is a _tendency_, and
although this is present in the apparently normal individual, for some
reason the condition itself has not appeared. This might especially be
true in the case of a disease which does not manifest itself until late in
life. In other cases there are undoubtedly complicating accessory
conditions which modify the behavior of the trait somewhat.
OTHER CASES OF DOMINANCE IN MAN
Among other normal characters in man, as far as available evidence goes,
dark skin is dominant to light skin; normally pigmented condition to
albino; and nervous temperament to phlegmatic.
=Digital Malformations.--=An interesting and easily followed defect is a
condition known as _brachydactylism_, in which the digits are shortened
because of the absence or rudimentary condition of one segment. The
fingers, therefore, appear to be only two-jointed like the thumb. Several
families showing this defect have been charted and it appears to behave as
a typical dominant. In looking over such a chart (Fig. 21, p. 106) one is
struck by the fact that only half of the children from most of the matings
show the defect, but when we recall that the affected parent, after the
first generation, probably carried the condition in only the simplex form
and married a normal individual, such a result is just what would be
expected (see formula 2).
_Polydactylism_ (Figs. 22, 23, pp. 109, 110) is a condition in which there
are extra digits on hands or feet. The character, with apparently slight
exceptions in a few records, behaves as a typical dominant. Among other
digital defects which are inherited as a dominant is a condition known as
_syndactylism_ (Fig. 24, p. 111), in which two or more digits are fused
side by side. For an example of syndactyly which seems to be in the class
of sex-linked characters, see Fig. 15, p. 65.
=Eye Defects.--=_Congenital cataract_ is another not uncommon defect in
man which is transmitted as a dominant (Fig. 25, p. 112) with occasional
irregularities. It is a condition of opacity of the lens of the eye which
produces partial or total blindness. In a paper on _Hereditary Blindness
and Its Prevention_, Clarence Loeb (1909) mentions 304 families of which
pedigrees have been published. Of the 1,012 children in these families
589, or 58 per cent., were affected. It is obvious that this is near the
expected percentage in the case of a dominant trait where matings of
affected with normal individuals prevailed. An unfortunate circumstance
about this malady from the eugenic standpoint is the fact that it is
frequently of the presenile form which comes on late in life so that it is
usually impossible to predict whether an individual of marriageable age is
immune or will later become affected.
[Illustration: FIG. 22
Radiograph (Courtesy of Dr. W. B. Helm) showing polydactyly in a child's
hand. For genealogy of this see Fig. 23, p. 110.]
[Illustration: FIG. 23
Chart showing a history of polydactylism through five generations in the
B---- family. The individual whose hand is pictured in Fig. 22, p. 109, is
of the fifth generation. Squares represent males, circles females.]
Another defect of the eye following the course of a dominant in heredity
is a pigmentary degeneration of the retina known as _retinitis
pigmentosa_. Atrophy of the optic nerve is also involved and the final
result is blindness. Still another example frequently cited is that of
hereditary night blindness (_hemeralopia_), a disease in which the
affected person can not see by any but the brightest light. In most
affected families the final outcome is usually total blindness. One of the
most remarkable pedigrees of defects in man ever collected is one of this
disease published by Nettleship. He succeeded in tracing the defect
through nine generations, back to the seventeenth century. The genealogy
includes 2,116 persons. The character behaves as a single dominant in
males, but frequently, though not always, females may be carriers of the
defect in transmissible form though not exhibiting it themselves. That is,
males in which the condition is simplex (Aa) develop the defect but
females of similar simplex constitution (Aa) frequently do not. It
follows, therefore, that normal males of such strains will have normal
offspring but normal females may have affected children.
[Illustration: FIG. 24
Radiograph (Courtesy of Dr. W. B. Helm) showing a partial syndactyly in
each hand of an individual. Some degree of webbing between the more distal
portions of the affected parts is usual.]
[Illustration: FIG. 25
Pedigree of a family with presenile cataract (black symbols); numbers in
circles indicate unaffected individuals (after Davenport).]
=Other Defects Inherited as Dominants.--=Not to go into details other
defects which behave as dominants or modified dominants in human
inheritance may be mentioned. The following list is not complete and it
must be understood that in some cases the statistics are insufficient to
justify us in making anything but a tentative decision. We may thus
enumerate as dominant over normality: _Achondroplasy_ (abnormally short
limbs with normal head and body); _Keratosis_ (thickening of epidermis);
_Epidermolysis_ (excessive formation of blisters); _Hypotrichosis_
(hairless, toothless condition); _Diabetes insipidus_; _Diabetes
mellitus_; ordinary (not Gower's) _muscular atrophy_; _Glaucoma_ (internal
swelling and pressure of eye-ball); displaced lens; _Coloboma_ (open
suture in iris); spottedness of hair-coat; and corneal opacity.
As a final illustration of a serious malady in man which acts as a
dominant in inheritance, let us take _Huntington's chorea_. Ordinary
_chorea_, or St. Vitus' dance, a disorder characterized by involuntary
muscular movements, is commonly though not always confined to children and
usually ends in recovery, but _Huntington's chorea_ appears typically in
middle life and is a much more dangerous malady. Fig. 26, p. 114,
represents the family history of one of five cases which have been studied
by Doctor Lorenz in the Mendota Hospital for the Insane. All charts which
have been platted of this malady show it to be inherited as a dominant.
This means that half of the children of an individual who carried the
malady in the simplex condition, and all the children of one who carries
it in the duplex condition, are probably marked for this terrible end. And
the true horror of it can only be appreciated by one who has seen the last
stages of the malady. The victim once in its grasp gradually becomes
wrecked in mind and body; the muscular twitchings and disorders of
movement continually increase and dementia progresses until at last death
ensues. Fig. 27, p. 115, is another chart showing inheritance of
_Huntington's chorea_. In still a third case at the Mendota Hospital, the
gravity of the situation can be appreciated when one realizes that the
patient is the father of ten children, ranging in age from one to
seventeen and one-half years. The calamitous fact that this disease does
not manifest itself usually until middle life makes it likely that these
children will all reach maturity, marry and in turn probably produce
offspring before the doomed members of the family realize their fate.
[Illustration: FIG. 26
Chart showing descent of _Huntington's chorea_ in the P---- family
(courtesy of Dr. W. F. Lorenz). Squares represent male, circles female;
shaded figures are choreic members of the family; partially shaded
figures, slightly affected or very "nervous" members. The members of the
last generation are for the most part still too young to show their
condition. The cross indicates the individual in the asylum from whom the
record was traced back.]
CASES OF RECESSIVENESS IN MAN
=Recessive Conditions More Difficult to Deal With Because They Are
Frequently Masked.--=Coming now to the question of recessive conditions in
man, we find that defects are more likely to be of recessive than of
dominant type. Apparently normality usually means the presence of normal
determiners and abnormality, the absence of some essential determiner. In
the latter case, a unit-factor has seemingly been lost out in some way in
the germ-plasm, and the product of such germ-plasm is therefore
incomplete. As long as the loss is counterbalanced by the presence of a
single determiner from the other line of ancestry, that is, as long as the
simplex (Aa) condition prevails, the loss may not be in evidence, except
in cases of incomplete dominance (taints, etc.), but any mating which
permits of the production of the nulliplex condition will bring the defect
to expression again.
[Illustration: FIG. 27
Chart showing inheritance of _Huntington's chorea_ in the R---- family
(courtesy of Dr. W. F. Lorenz); 1, 2 have been patients at Mendota
Hospital for the Insane; 3, died of "paralysis"; the fourth or last
generation indicated by the cross, ranging in age from 6 to 14, are too
young yet to show their condition as regards this malady.]
The obscure nature of recessives makes such conditions more difficult to
deal with than dominant defects. For as regards the latter we have seen
that marriage of unaffected members of the family as far as that
particular trait is concerned, is perfectly safe, even to a cousin, for
once the germ-plasm is purged of such a positive factor, it, in so far as
we know, remains pure. But in the case of a recessive character due to the
absence of some necessary determiner a normal offspring of simplex
constitution (Aa) will probably transmit to half of his children the
capacity for handing on the defect, or if mated to another normal
individual of simplex constitution (Aa) is likely to have the actual
defect revealed again in one-fourth of his children and latent in
two-thirds of the remainder.
=Albinism a Recessive.--=As an easily understood illustration of this type
of case we may take human albinism, a condition which is due to the
absence of a pigment-developing determiner. According to Davenport the
albinic condition is recessive to normal condition. If albino (aa) is
mated with albino (aa) nothing but albino children may be expected. An
albino (aa) mated with a normal individual will have normal offspring
(Aa), but they will have the capacity for transmitting albinism to their
descendants. Thus the normal offspring (Aa) of an albino (aa) and a normal
parent (AA) if mated to another normal individual (Aa) who has also had an
albino parent will probably transmit actual albinism to one-fourth of his
children and the same capacity that he himself has of producing albinos,
to one-half of his children, although the latter will appear to the eye to
be normal.
=Other Recessive Conditions in Man.--=If for albinism we substitute
certain forms of insanity, hereditary feeble-mindedness (Fig. 28, p. 118),
or hereditary epilepsy, all of which apparently follow the same law, we
can readily understand how unfit such matings are where both strains are
affected. Marriage with similarly defective stock will result in the
affection appearing in one-fourth of the progeny, and one-half of them,
though apparently normal themselves, will have the capacity for
transmitting the imperfection. It is in the existence of such hidden
factors that the chief danger in the marriage of cousins, or in fact any
consanguineous marriage lies.
A few of the various defects which seem to be inherited as recessives when
mated with normality are: susceptibility to cancer; _chorea_ (St. Vitus'
dance); true dwarfism (all parts proportionately reduced); _Alkaptonuria_
(urine darkens after passage); alcoholism and criminality, where based on
mental deficiency; hereditary _hysteria_; _multiple sclerosis_ (diffuse
degeneration of nervous tissue); _Friedreich's disease_ (degeneration of
upper part of the spinal cord); _Merriere's disease_ (dizziness and
roaring in ears); _Thomsen's disease_ (lack of muscular tone); hereditary
_ataxia_; possibly the tendency to become hard of hearing with increased
age; and possibly, non-resistance to tuberculosis.
Of non-pathological conditions in man which are inherited as recessives,
apparently either very great or very small intellectual ability are
examples.
[Illustration: FIG. 28
Chart showing descent of feeble-mindedness as a typical recessive (after
Goddard). Squares represent males, circles females; DD, homozygous
dominant; DR, heterozygous dominant (i. e. normal although a carrier); RR,
pure recessive; N, normal; F, feeble-minded; A, alcoholic.]
=Breeding Out Defects.--=Even though recessive defects occur in a stock,
there is the possibility of diluting out the imperfection in successive
generations if care is taken always to marry into a stock wholly free from
it. For example, a normal individual carrying a recessive defect will bear
the abnormality in half of his or her germ-cells. This means that when
such an individual marries a normal, non-carrier, half of their children
will be wholly normal (AA) and half will be carriers; normal but of
simplex constitution (Aa). If now this generation, carriers and
non-carriers, marry only into normal strains of duplex constitution, then
their combined issue will be likewise normal with only one-fourth of them
carriers of the imperfections. This means that even if all of this last
generation were married to persons having the defect only one out of four
would have children showing it although the remaining children would be
carriers. On the other hand if mated to normals only one-eight of the next
generation would be carriers. Thus by continually marrying into strong
strains liability to manifest any recessive defect can be diminished in a
few generations until the descendants are no more likely to have defective
children than are members of our ordinary population.
The proportion in which the recessive defect would appear in successive
generations if all persons in a given generation married only normal
individuals who were non-carriers is indicated in the following table
where AA indicates a normal individual, Aa one who is normal but a
carrier, and aa an individual with the imperfection expressed; to indicate
proportions simply after the first generation, four is arbitrarily chosen
as the number of children which results from each marriage:
Matings Children
Generation 1 aa x AA = Aa
Generation 2 Aa x AA = 2AA + 2Aa
Generation 3 AA x AA = 4AA
AA x AA = 4AA
Aa x AA = 2AA + 2Aa
Aa x AA = 2AA + 2Aa
----------
12AA + 4Aa
=Other Inheritable Conditions in Man.--=While many pedigrees show beyond
dispute that such qualities as musical ability, literary ability, memory,
calculating ability, mechanical skill, longevity, peculiarities of
handwriting, obesity and muscular strength, for example, are inherited,
their modes of inheritance have not yet been sufficiently analyzed to
express them exactly.