Explanation Of Gene Action As Related To Physiological

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Gene Action as Related to Physiological Characteristics
by J. L. Lush
at Fourth Poultry Breeders Eoundtable
Chicago, Illinois 2 June 1955
FROM THE GENEJTO THE CHARACTER
The genes themselves are the units of inheritance, but we know them
only by their effects.
The genes are the things which are transmitted from
parent to offspring, along with enough cytoplasm and other cell machinery
to keep them alive and working as they should.
But between the genes and
their final,effects are many chemical changes, each partly dependent on
the preceding ones and on other genes and o_ the nutrient materials which
are present.
The ways in which the genes do their work are matters of chemistry
and physiology.
These are not matters of inheritance in the narrowest
sense of that word, but they always may and frequently do confuse us in
our attempts to find out about i_theritance.
In a general way the genes act like enzymes or catalysts.
That is,
they promote the chemical processes of growth and development, without
themselves being used up in the process.
However, Lmlike most of the
catalysts or enz_nes which have been studied in test tubes, the genes
are self-duplicating. It seems fair to call them "living catalysts". A
gene acts on one or more substrates transforming or combining_them into
something else.
These substrates or other materials had to come from
somewhere.
Some of them were products of the earlier action of'genes on
prior substrates. Like all other chemical processes, these are affected
also by the presence or absence of nonliving nutrients.
The rates of
many of these chemical changes canbe
modified by changes in temperature,
alkalinity, and other conditions.
The immediate product of a gene may be

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"_ only a substance which can then be changed by other genes or by the products
of other genes. This results in long chains of effects or processes,
whereby the initial fertilized ovum and the surrounding nutrients ultimately
become the adult organism with its many physiological and anatomical
and behavioral characters.
Probably we never will know all the details about all the processes
between the genes and the finished characters which interest us. If we
ever do know, all that, we will also know everything about embryology,
physiology, growth, and all the other life processes_ In our actmal
breeding operations, such as selection, the choice of mates for making
progeny tests, or for perpetuating the line, etc., we necessarily must
work with the end products of the genes, rather than with the genes themselves.
Because the genes may be so remote from the end products and so
many other genes or environmental changes may intervene in the long chain
of events to alter the final results, we may nmke many mistakes in our
breeding operations, expecially if we base our decisions wholly on the
individual's own characters. No complete escape from that seems possible,
although proper use of such things as progeny testing, sib testing, etc.,
will make the errors fewer.
Chemical reactions rarely proceed perfectly linearly, either with time
or with the amount of raw _terial present. A very common type of reaction,
especially where the raw material is limited in amount and the action can
get underway quickly, is that in which the rate of change is proportional
to the amount of untransformed raw material still remaining. This gives
a curve of diminishing returns with time. %_en processes act thus, adding
twice as much catalyst would hasten the change only slightly. T_en genes
act in this way we naturally expect to find complete or nearly complete
dominance in the final character, even though the genes might show: no

dominance in their primary effects if we could measure those directly.
Another common type of chemical reaction, when the activating agent
is very limited in amount and the reactions start slowly, is that the
reaction proceeds in proportion to the amount of product which is already
formed. This would yield a logarithmic or "constant percentage rate"
curve if the relations continued indefinitely without encountering new
obstacles. You are all familiar with this idea from your arithmetic
lessons on compound interest, or from some biology lectures on how many
amoeba you would have at the end of 24 hoursj -- or a week# or a month, --
if you started with one and it and all its successors doubled every hour
and there were no death losses_ Actually no process ever continues long
at such a rate. Instead, it encounters obstacles such as using up the
substrate, competition from other processes or organisms, efficiency
decreasing with size etc. These slow down the process. If a rate starts
like this and then later slows down in proportion to the amount of substrate
still unchanged, we get the very common S-shaped or autocatalytic curves
for the amount of change observed. Most individual growth curves are
this kind, more or less asymmetrical and with much of the earlier part
of the curve having taken place _efore hatching or birth. Populations
expanding in numbers under fixed environmental conditions likewise follow
this S-shaped or logistic curve.
When I consider the wide variety of ways in which these growth and
development process may operate and in which they may help or hinder each
other, or be superposed on each other, I am filled with wonder that the
relations between the genes and their end products are as nearly linear
as they are. I suppose it must be primarily because their very complexity
itself gives them a sort of statistical stability in that the numerous
processes which might cause them to vary cur_i].inearly in one way are

_lOsomewhere
nearly equally balanced by the humerous other processes which,
themselves, would cause an opposite kind of curvilinearity.
Instead of being surprised at dominance or eplstasls and at the many
cases where herltabillty is rather low, I tend to be astonished that
dominance and eplstasls are not more extreme and that herltabilltles as
.._.-.----.---___.
high as i0_o are often found. I suppose natural selection has required
that to be true to a considerable extent, else the specieswould not have
survived. That is, the Mendelian segregation and recombination would have
produced an intolerably large proportion of individuals so defective in
one way or another that they could not survive, if these various growth
processes had combined with each other in extremely irregular ways.
If a species is dependent for survival on having a certain highly _
complex genetic combination, then it can survive only by becoming almost--_
completely homozygous for most of the genes needed in that combination.
This, I am sure, has happenedas concerns differences between major
groupings of the plant or animal world, such as the differences between
Genera, Families and Orders. However, breeders are concerned with
differences such as occur within species and even within breeds. If
these differences are many and if each of them is frequent, then I think
the combinations of their various effects must come somewhere near to
being additive, else the species or breed would have difficulty surviving.
Speculations like these seem to serve no useful purpose, except
that they may help explain how the complicated processes which the genes
initiate or guide can still yield viable individuals most of the time
andhow it happens that the end product can be nearly enough in proportion
to the differences in genes transmitted that we often find
heritabilities of i0 to 20_ or even higher.

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! SUB-DIVISION OR CLASSIFICATION OF THE RESULTS OF GENE ACTION
You are all moderately familiar with outward effects being subdivided
into additive, dominance or epistatic. This classification is
only an operational one. It does not mean that we know exactly what
each gene does or could write the chemical formulas of the reactions
which it causes or controls. We classify the gene effects in this way
because they respond differently to different breeding methods, The
additive effects we can improve by mass selection, reinforced perhaps
with attention to relatives, to sibs, and to progeny tests. The nonadditive
effects are truly hereditary in that they are caused by
differences in the genes which different individuals have; yet they
contribute irregularly or not aZ all to the resemblances between
relatives.
These nonaddltive effects are split into two groups; ..... the
dominance deviations and the epistatlc deviations, .... because the
former can never be transmitted in a single gamete and, therefore,
contribute not a_ all to the likeness Of any relatives except those
who are related through at least two lines of descent which do not
anywhere go through the same gamete. Many of the eplstatic effects do
contribute something (usually not much unless we are concerned with
highlY inbred lines) to the resemblance of individuals related through
only one line of descent.
The additive effect of a gene is the average effect of substituting
it for its allele without any other change. If the substitution actually
has an effect larger than average in some individuals, it must
necessarily have an effect smaller than average in others. These differenceslbetween
the actual effects of the gene, in all sorts of
individuals which interest us, and its average effects are the nonadditive

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ones. The idea of the average affect is, therefore, a clear and simple
one. We have in mind these additive effects when we call a gene ':good"
or "bad",, or when we speak of genes "for:: or genes "against" some character.
We can rarely, if ever, compUte the average effect of a gene
directly because we do not know enough about _its frequency or its actual
effects in all sorts of combinations. Instead, we estimate the amount
of additive variation present by examining the resemblances between
different kinds of relatives. The following table will show for parent
and offspring and for full sibs what fraction of each of these different
kinds of effects would be included in the resemblance between such relatives,
if sire and dam are not related, The fractions become more
complicated where sire and dan are related and some inbreeding, therefore,
has occurred. Of the two numbers describing the kind of effect,
the first is the number of nonallelic genes needed and the second is the
number of pairs of allelic genes. Thus 2, 1 signifies effects such as
those of AbCc or AAbc; while l, 1 signifies joint effects of such combinations
as AaB, aCc, dDd, etc.
Kind of effect Number of genes Amount of this effect which is
needed to produce common to:
the effect Parent & offsprin_ Full sibs
_dditlve i, 0 i 1/2 1/6
Dominance 0ri 2 --- 1/4
EPistatic 2,0 2 I/4 i/4
3,o 3 1/8 1/8
I,i 3 --- i/8
4, 0 4 1/16 1/16
2, i 4 --- 1/16
O, 2 $ --- 1/16
5,0 5 1/32 1/32
3,i 5 --- 1/32
1,2 5 --- 1/32
6, 0 6 1/64 1/64
4,1 6 --- 1/64
2,2 6 --- 1/64
O, 3 6 --- 1/64
_ etc. etc. etc. I etc.

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A glance at this table reveals two things: (i) The more complex the
comblnatlon_ the less it will affect relatives alike_ (2) 0nly when
the second number in the description is zero does such an effect contribute
at all to the likeness between parent and offspring; This latter
fact is merely a consequence of Mendel's law of segregation preventing
two alleiic genes from getting into the same gamete. The former means
that when we estimate heritability, as usual, by comparing the resemblances
between relatives in nearly random bred populations, we vastly
underestimate heritability if most of the hereditary variations are caused
by complex combinations. But these considerations do not of themselves
tell us Whether the complex combinations cause much or only a little of
the total hereditary variation. If they do cause much of it, this would
go far toward explaining why studies of identical twins, or of highly
inbred lines, so often yield surprisingly high estimates of heritability.
The effect of a gene may be large or very small or anywhere between.
0nly the genes with major effects can be identified in a Mendelian manner
and then 0nly if their effects are nearly all additive and if the confusion
by environmental effects is small. Brues says that it is difficult,
if not in_osslble, to identify a single gene in the Mendelian manner
unless that gene pair causes more than half of the total variation in
the character being studied. The epistatic effects are simply what is
left of the actual effects after the additive effects and the effects of
simple dominance have been substracted. That is, eplstasis includes all
the nonadditive effects except simple dominance. Many kinds of eplstatlc
effects were kno_m in some detail before this statistical or operational
definition became common. Examples are complementary genes, inhibitory
genes, multiplicative action, iutermediate preferred, threshold effects,
and many otherS. Complementary genes are those which produce effects

only when both are present. Inhibitory genes prevent other genes from
doing what they would do if the inhibitory genes were absent. Multiplicative
effects are common in differences in growth, especially when
growth is measured as weight or volume. If a gene increases weight 5%
it makes a bigger increase in a bird which weighs 4 lbs. than in one
which weighs 2 lbs. In this way the actual effect of the gene varies,
according to the other genes present. Very often in nature and in animal
breeding the intermediate dimension or quality of the character is
preferred over either extreme. If the character is affected by only one
gene, this becomes overdominance. But if it is affected by many genes,
the intermediates are only a tiny bit more heterozygous than the average
individual in the population and the genetic situation and problem is
very different from that of overdominance. The threshold type of epistasis
is likewise very common. It is usual for characteristics which
can be measured only in two levels, such as mortality, or the breaking
strength of bones. Tkethresholds need not be absolutely sharp. When
they are gradual, the individual differences may be measured on a nearly
continuous scale through a zone just below to just above the threshold
but, when we get far below or far above, further genetic changes make
little or no difference in the outward effect, This leads to a "factor
of safety" type of epistasis which is particularly interesting because
it is the commonest kind in which conducting the progeny test on very
weak or very susceptible special stocks may be worth while.
PLEIOTROPY
The foregoing is phrased as if a gene had only one effect. But
already we know many cases in which a single gene clearly affects several
characters. The usual rule is that the more we study a gene, the more
effects we learn it has. I am inclined to conjecture that nearly all

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genes have manyeffects, although that may be going too far. _en a gene
has more than one effect, the technical term for that is "pleiotropy".
The well-known gene for yellow in the mouse._is one of the earliest
examples found in genetics. This gene has at least three effects; it
makes the mouse yellow and this effect is dominant. Secondly, it makes
him unusually fat and this, likewise, is dominant . Thirdly, it kills him
and this effect is recessive, else we would never have found the gene. It
is not obvious (to me) why yellow color and fatness, which are dominant,
and lethality which is recessive should be caused by a single gene. Perhaps
all three of these effects result from one primary thing which the
gene does and they wouldn't seem so unrelated, to each other if I understood
all the chemistry and physiology of how that gene does its work.
Students of genetics have sometimes distinguished between "primary"
and "secondary" pleiotropy. The primary action occurs if the gene does |
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two or more different things at the very beginning , perhaps produces three\
different catalysts which work on entirely different processes or organs \ \
of the body. "Secondary" pleiotropy occurs if the gene does Just one 1
thing primarily but the product of this action itself affects two or more 1
characters or other actions and these in turn may each affect more than !
one character. This would give a many-branching chain of many final
effects, some of them not obviously related, but all resulting from a
single primary effect. The evidence for secondary plelotropy seems more
convincing but, for practical purposes, it is simply not pertinent whether
plelotropy is primary or secondary. The practical results are the same.
Ofcourse, the distinction is of interest scientifically and finding the
facts in each case would aid our understanding of gene action and might
suggest some therapeutic ways of magnifying some effects while diminishing
others.

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As another example of what
is probably plelotropy, one of you, working
with a dominant gene but back-crosslng to the recessive, found that
this gene had an otherwise unnoticed effect on growth rate.
Because the
gene was dominant and the breeding plan was to backcross
continually to
the recessive, the chickens could be sorted clearly into two groups; those
which had the gene but were heterozygous for it and those which didn't
have the dominant gene at all.
Then it became clear that those which did
not have the dominant gene exceeded the others by a full tenth of a pound
in weight.
Now this difference is big enough to be important practically
but small enough that it would not have been noticed had not the other
effect of the gene been so conspicuous that it was possible to separate
the chickens into a group which had the gene and another group which did
not.
Cases like this make one wonder how many other effects, too small
to be noticed, are exerted by genes which we know by and name for their
major effects only.
Present knowledge of genetics seems (to me) to
indicate that pleiotropy is very common, --- perhaps universal.
One reason for thinking that plelotropy is exceedingly common is the
complex nature of the machine which is the living animal or plant.
In
the much
simpler machines, such as watches and automobiles, the anatomy
and functioning of which we know fairly well, Itls
rare indeed that we
can make a major change in an important part of that machine without having
several different changes results in other aspects of the way that
machine functions.
It seems to me almost certain that this must be true
ofthe
vastly more complicated machines which our living animals are.
Such reasoning seems to me validand
plausible, although it is far less
convincing than actual detailed evidence in each case would be.
The practical consequences of pleiotropy are all in our favor if we
like all of the effects which the gene has. Then if we select for one

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r
effect of the gene, we also get some improvement in the other effects as
a bonus.
Trouble arises when a gene has some effects which we llke and
others which we do not.
Then if we select for one of these effects we
increase the frequency of that gene and improve the flock in that respect
but at the same time we cause the flock to deteriorate in those characters
which the gene affects unfavorably.
In general, the favorable effects of
a gene tend to be at least partiall__dominant_a_e_mthe unfavorable ones.
So far as that is true and most genes have several effects, then overdomlnance__
......for the net effects,_°fthe--g-eneis a hlghly_likely
consequence.
If dominance of the favorable effect were complete in all cases, the heterozygote
would show all of the desired qualities of both homozygotes and
none of the undesired qualities of either.
It is more likely that dominance
of the favored effect is not wholly complete in all cases and that
one homozygote will be better than the other. Hence, overdominance might
be general and yet not often extreme.
That is, the heterozygote might
be only a few percent better
in net merit than the better homozygote,
although far better than the other homozygote.
Most of the variation
in a flock, already improved by years of breeding,
will generally be caused by genes which have some good effects and
some bad ones.
Genes with wholly good effects will have already become
almost homozygous all through the population.
Any gene whose effects were
all inferior to those of its allele will already have been made so scarce
that it causes little variation and makes little trouble.
In these circumstances,
intensifying selection would have the effect of changing the
degree of overdominance and hence the equilibrium frequencies of genes
with some good effects and some bad effects. The population would change
rapidly as the population approached its new equilibrium condition.
Little
or no,genuine fixation of the new condition would occur; if the new selec-

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tlon were then relaxed, the population would soon return to its former
condition.
What can we do about it if overdominance is widespread? There might
be other genes which, in the homozygous condition, would produce the
effect we want. If not, I see nothing better than to breed so that as
large a fraction as possible of the animals in the commercial flocks shall
be heterozygous for these genes whlch sho_ overdomlnance. This means some
kind of a crossbreeding or rotational crossbreeding system patterned some_
what after the hybridcorn plan. The method might even be improved over
the hybrid corn plan if reciprocal recurrent selection actually is effective
in gathering together into contrasting strains the genes which, when
thestrains are crossed together, will produce the maximum amount of
heterosis. This is a vastly different breeding system from the classical
idea of continually improving the relatively pure stock until it becomes
better and better and purer and purer, with the ultimate end of making a
purebred stock which will be perfect. Because this is so different from
those traditional methods, it is of the utmost importance to know whether
overdominance really is abundant enough to justify these more complicated
methods.
TESTS FOR PLEIOTROPY
The test least capable of being interpreted wrongly is to select one
line for largeness in X and the other for smallness in X and then to
observe whether the two lines become different in other characteristics.
Such a change in characters not intentionally selected is often called a
"correlated response". Dr. Falconer, who is here today, Dr. John W.
MacArthur, and many others, have observed such correlated responses.
Experiments involving selecting a high llne and a low line are difficult
to do for more than one or two characters at a time. Also, they need to

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be continued for several generations and on enough lines to exclude the
possibility that the other characters changed purely by accident or
"genetic drift".
Hence, we are not likely to learn about the plelotropy
of many characters in this way, although more experiments of this kind do
seem needed and justified.
A method not requiring one to conduct a selection experiment is to
correlate character X in one individual with Y in a close relative and
also Y in the first individual with X in the second.
Dr. Hazel and others
have used this approach widely in constructing selection indexes.
In
principle it is really a selection experiment covering only one generation.
It may have many degrees of freedom but the sampling errors are high, especially
if heritabillty is low.
One of the things most urgently needed in
shaping breeding plans is a better method for estimating these "genetic
correlations" which are really estimates of the effective amount of
pleiotropy in the population which interests us.
One could estimate pleltropy by correlating flock or line or racial
means for X with the means of the same groups for Y, but this is not at
all sensitive because we never have enou_1 flocks, or lines, or races,
etc., to give us many degrees of freedom.
Also, the environmental differences
are almost certain to be confounded with the genetic differences
between groups.
Moreover, prior selection have been in different directions
or aSdifferent rates in the different populations.
This would give
the appearance of plelotropy even when it didn't really exist.
In short,
relations between the means of such groups for various characters are too
undependable
to furnish useful information about plelotropy.
WHAT IS PRACTICAL TO DO?
So far as the genes interact addltively and with only partial or complete
dominance (i.e. without overdominance or epistasis), the best methods

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of improved breeding seem to bethe
standard ones of selecting on pedigree,
on individuality and On progeny tests. The progeny tests in this case
would normally be conducted on mates from the same stock which was being
improved. Special tester strains for making the progeny test would be
of only a little use.
More accurate selection indexes and more careful
measurements can increase progress considerably under these circumstances.
When overdominance is important and the heterozygous individuals are
superior to both homozyg0tes
(a condition likely to be common if plelotropy
is), progress ought to be maximum if we select mainly On the kind
of individual progeny the animal produces when it is crossed on mates
from the same stock on which its descendants are actually to be used.
This is "reciprocal recurrent selection" if both stocks used in the cross
are being improved simultaneously_
This method promises also to improve
the additive effects and those which are caused by complete or partial
dominance but it lengthens the generation interval in doing so and one
cannot pay much, if any, attention to individualltywhen
making the seiections.
If over-dominance is only a small part of the gene actions, one
might lose more by these two defects than he would gain by the power of
the reciprocal recurrent method to assemble, in the two stocks which are
to be crossed# whatever genes will produce the maximum merit in the
crosses.
Eplstasis of the threshold or "factor of safety" kind may justify the
use of special weak or defective test strains for mates in the progeny
testing. For
instance, if the individuals which are genetically above
the threshold show no further sign of weakness, and if each is bred true
and progeny tested on mates of its own kind, then a strain which if four
units above the threshold and, therefore, has a large genetic factor of
safety, could hardly be distinguished from a strain which is only two
units above the threshold, unless the individual variation within both

• -21-
strains were very large. If_ however, we can find a weak strain which is two
or three units below the threshold and can progeny test the individuals
of the other strains on this weak tester strain, then the progeny averages
will show clearly which strain contained the larger margin of safety.
Breeding for disease resistance may well go in this direction wherever
such a weak strain can be maintained and there is no more economical way
to combat disease.
Breeders of corn have used this method freely in
breeding for stronger stalks and to reduce the percentage of ears dropped
in the field before harvest. The basic reason it is practical in these
threshold cases to use weak or defective strains as special tester
stocks is that we can not measure how far the individual is above the
threshold of breakdown.
Wherever we can find a way to measure the factor
of safety or margin of resistance in each individual, then these threshold
characters can be
treated the same as any character which can be
measured on a continuous scale.
If we know that other kinds of epistatic factor actions are important,
we will, in general, rely more on linebreeding than if we know they
do not exist.
We will do much making of families and subsequent selecting
between those families on the average performance of the family. We
will rely more on the family average than on the individual the surer
we are that we are working with such an epistatic situation.
We will
intercross the very best families and make new lines out of those crosses
which are best.
Incidentally, this is just the exact opposite from what
we would do if we knew that overdominance were important.
That is, if we
know that overdominance is important and we find two families which cross
extremely well, then we know that we ought not try to make new families
from that cross.
Instead, we would make new families out of crosses
among families which all cross well with family Q, for example.
Then we
would test these new families in crosses with family Q.
Similarly, if we

22-
would intercross with each other and with Q the other families which
cross reasonably well with the same families with which Q crosses well.
From
such intercrosses we would make new familes and then would test
these new families by using them, in place of Q, in the crosses Where
Q had beenmoderately successful. This is, after all, only the common
sense method of testing the new families in the very crosses in which
their descendants are to be used.
In summary, special tester stocks on which
to progeny test the stud
candidates can be useful in three genetic situations.
The first is when a prime object is to uncover and discard undesir"
able recesslves.
A current example is in testing beef cattle for whether
they can transmit dwarfness.
At present it is often profitable to maintain
a special tester group of cows known to have produced dwarf calves
an% therefore, to be heterozygous.
Rarely is a recessive important
enough and abundant enough to justify maintaining a special tester stock
for this purpose.
The senond situation is that of threshold effects where one wants to
know how much margin of resistance or factor of safety is in the various
animals or families which are candidates for the stud pens.
For both of these two purposes, the goal is an improved pure stock.
It is rarely possible to keep several different special tester strains,
--- a different one for each important deleterious recessive or threshold
character, perhaps, --- which might be of concern. This can be
overcome in part by testing the males on their own daughters or on
their sisters but the harmful phenotypic effects of inbreeding would make
one count carefully before doing this.
The third case in which progeny testing on special tester stocks is
likely to be worth while is when overdomlnance (or "specific combining

"_3-
ability" in general) is important.
In this case, one is improving the
lines to get still better results when they are used in a continued
outbreeding program, --- not for their own qualities or for commercial
use when bred
pure.
If some kind fairy would promiseto answer for me four questions
about practical animal breeding, my choice of questions would be: 1.
How important is overdominance? 2. How important are interactions
between heredity and environment? 3. How important is eoistasis of
the threshold or "factor of safety" kind? 4. How important are other
epistatic actions?
It is likely that these questions have somewhat
different answers for different species and perhaps even under different
systems of agriculture or different climates.

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Hogsett: In my introduction off.Dr. Lush I failed to state that he has
been the advisor for this group, I believe, ever since its inception and has
done a fine Job in helping the committee plan the program.
Now we will take as much time up to a half hour as you need to ask
Dr. Lush any questions you may desire. Who will be first to ask a question?
Parmenter: Msy I ask a question on this dwarfism in cattle, seeing that
we are chicken breeders. What about the use of this profilometer on bulls,
the accuracy of that?
Lush: The experts on dwarfness in cattle are all meeting in Ames today.
Several of them said they were sorry of the conflict, because they would have
liked robe here. Certainly I would llke to have them here.
Opinions differ on the accuracy of the profilometer. I do not know the
very latest, but I think in general the opinion is that the accuracy is
rather low. A good many people still think it has some accuracy.
The profilometer is a device for running a wheel down the forehead of
the animal, tracing on a piece of paper the profile as seen from a side view.
It was based on the very logical thought that since the dwarfs have very
bulging foreheads, maybe the heterozygotes would have a little bulginess. If
so, you could find who could transmit dwarfness by examining their profiles.
Some of the earlier work convinced Dr. Gregory that he was on the trail of
something very important in this, but there are many statistical pitfalls of
one kind or another in collecting and appraising this kind of evidence.
Others went to work checking it. In the main the checks have not been
very good. It still seems to me natural that the heterozygotes might show
some bulginess. There was a lot of enthusiasm about the profilometer two
or threm years ago but not many people are using it enthusiastically now.
We are still trying it but we have pretty well lost faith in it.
Hogsett: Any further questions?

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Wyatt: I would llke to ask Dr. Lush how you proceed in the case of
mortality in chickens, for example. How do you go about finding one of
these populations that you can use for a tester? How do you know how far
this population is above the threshold and so forth?
Lush: I expect there are some in the room that can answer that better
than I. Maybe some of you think you haven't much difficulty in finding a
population with low vitality!
Seriously, the vitality must be above a certain minimum to keep them
going, does it not? You could not have a tester population in which all
died off before reproduction. They must have a certain amount of vitality
to keep them going.
Incidentally, you do not need a tester strain badly, as long as the
mortality in the stock you are trying to improve is much above thirty per
cent. Then mass selection and progeny testing can give about as much help
as you can use. Even when you get the mortallty below thirty per cent,
progeny testing and family or sib-testlng can help quite a bit until you get
mortality on down toward _wenty or even fifteen. _hen the effectiveness of
these begins to taper out. It does not_go completely to zero, but progeny
tests and slb-tests diminish fast in their effectiveness when your mortality
falls much below twenty per cent. Hence, I would not worry much about finding
a tester stock until the mortality in my own stock was down under fifteen.
If I ever got it under ten, then I would just about have to find a tester
stock with high mortality.
How I would find it, I am not sure. Maybe, if I did not have it in
my own flock, my neighbors might sell me a stock which was low enough in
vitality.
Wyatt: Well, if you are going to measure this tester Just by the incidence
of mortality in the tester, say that that is below the threshold,
_hy can't you just measure the incidence of mortality in the flock you are

-26-
willing to test and say if it is low then I have a high threshold and not
bother to make this cross?
Lush: Well, you might want to make it still higher. If your mortality
is low, say 15 per cent, you mean that you would be content there?
Wyatt: No, not particularly.
Lush: We have to allow for a certain irreducible amount of wholly accidental
death loss. Your ability to push mortality any lower goes almost (hut
not quite) to zero by the time you get the fraction who are dying much under
twenty or fifteen per cent, even with progeny testing on stock of their own
kind.
If you progeny test them then on your own stock, so few would die that
you can hardly tell the difference between those with a little excess vitality
and those with a big reserve of that. But if you had a weaker stock, let us
say a stock in which sixty per cent of them would die, then if you progeny
test your own males on these, you would expect their offspring to be near
enough the threshold, where the test is sensitive, that you could discriminate
between males with a small and males with a large reserve or "factor of safety"
against high mortality.
You might need to allow also for some heterosis if your tester stocks were
distinctly unrelated to your own flock.
Your first approximation in these things is always to suppose that the
offspring will average about halfway between the parental races, plus or minus
whatever heterosis there is in the character concerned.
Warren: May I ask, Dr. Lush, in view of what you have said Just here
then, probably the best thing to do from the practical point of view if you
get mortality below ten is just to forget it_ is that not right, not have
these
tests?
Lush: Well, I suppose if you have other troubles that are more important
practically, I would go along with you. But if that is still the most serious

-27-
! weakness in your stock you would like to remedy it, would you not?
In a Practical way I think it is true of nearly all these things, that
once you get a defect pretty well remedied you are almost sure to find that
some other trouble to which you have not been paying attention is now more
important. Hence, in a good many cases you are not interested in building
up a highreserve over the threshold, but in some cases you are. I would
imagine that those of you who are selling birds for use on farms that have
a higher level of disease incidence than yours might find that often so.
Perhaps you have on your farm a mortality of only five or ten per cent, but
when you put your stock out on the average customer's farm, where the causative
agents of disease are at higher levels, the mortalltymay go up to
thirty per cent or so.
If you found that out you would still like to put more vitality in your
stock so that when your customer got it the mortality would still stay under
five or ten. Since you want to keep your customer coming back next year, I
would not go all the way with you in that view.
Warren: The question that comes to my mind, so often we find that these
people who have breeder strains, take the gene for early feathering, which
is such a simple one that you could make it homozygous, still we find many
people wh0are breeding broiler stock who do not go all the way to make
their flocks completely homozygous for that early feathering gene because
they are interested in so many other things. They get up to about ninety
per cent and then they go along and just tolerate the rest of those. A few
of them have gone all the way, but many of them do not, they do not think it
is worthwhile.
Yohe: I thlnk you hinted at this in one of your answers. This is confined
largely to additive genes. It would not work in a case where you had
dominance or epistasls, would it?

-28-
Lush: You would get some surprises always, yes. The situation in which
the cross averages half way between the two parental stocks would require
complete additive action or some special balance of the plus and minus deviations.
If you had some dominance of favorable genes, then your _cross
would be nearer the better parent.
Warren: On this problem of mortality, would you, before you went to a
test cross, exhaust the possibilities from increased exposure first or would
this be involved?
Lush: I would do whichever were cheaper and in the increased exposure
I would wonder whether the means I used for increasing exposure were the
same as the birds would encounter on the farm.
We had a case one time, I do not know whether it still holds up or not,
on the leucosis thing where the injection of leucosls into the peritoneal
cavity increased the leucosls very greatly, but there was practically no
correlation between the amount of leucosls in the injected half and the uninjected
half of the same family. At the time it looked like the injection
by-passed the natural mechanisms of resistance. In the next trial the
causative agent was just put in the nostrils of the bird. This did increase
!
the incidence in the inoculated birds and it did give a high correlation be-
tween the inoculated and the uninoculated halves of the same family, The
intraperltoneal method did not look as if it were getting us anywhere.
Because of such experiences when one increases the exposure, he needs to ask
himself: Is my method of increasing mortality one which tests more strictly
the natural mechanisms that _might be built up genetically or am I by-passlng
them and not doing any good?
If such a method were cheaper, and I were not by-passlng the natural
mechanisms of resistance, I think that might be cheaper than using special
tester stocks in Progeny tests.

-29-
Hogsett:
Dickerson:
Dr. Dickers0n.
That covers my questions.
Lush:
I would llke to have you answer that.
Dickerson:
I think you did very well.
Lush:
Are there any other questions?
Gorsllne:
Dr. Lush, you intimated the desirability of learning more
in a practical breeding system of the importance of additive effects versus
dominance and esplstasls.
I am wondering if what we may find will apply
equally to all of our classes of animals, whether poultry may be different
from swine or beef cattle, or whether that is of any concern in the approach
that we have in evaluating theimportance of these defects.
Lush:
I would suppose that each species would have to be studied for
itself.
It would not be unreasonable to find that in the breeding of one
species overdominance is the major problem and in another there is enough
additive variance left to keep going another ten generations or so.
The reasoning behind that is that the additive effects yield to the
traditional method of selecting the best, especially if we reinforce that
method a wee bit with pedigree and quite a lot with slb and progeny tests,
They yield enough that, if we have been breeding for many generations toward
the same goal, it would not be surprising if in some species we have used up
most of the additive variance whlchwas there. That left over would be refractory
part that has not yielded yet, that would be the overdomlnant and
eplstatlc effects.
The corn breeders have some pretty good evidence on that.
Dr. Sprague
has studied it. Where you take a whole set of random lines, without selection,
and measure the general and specific combining ability, you find that a large
share of the differences between them are general.
Some are specific but
these are the smaller part.
Now if you take that whole set of lines and
throw away the eighty or ninety per cent which are worst in general ability
and then measure the differences among what you have left, sixty or ninety

-30-
f per cent ofwhat is left in these selected lines is specific.
Now, I do not know whether poultry breeders have been breeding
in the
same direction so long and so diligently that they have nearly used up the
additive effects or not; neither do I know that for pigs, cattle or sheep,
but
it would not be surprising if some of them have gone further in that
direction than others. Again, some evidence would be welcome.
Heisdorf:
Dr. Lush, suppose a poultry breeder has a commercial cross
which
he thinks is fairly good, but in which he knows considerable improvement
can be made.
However, he is afraid that if he continues to select for better
vitality he might actually lose ground in other respects and end up with a
product which is not as desirable as what he has at present. What can he do
to protect himself, whereby he can divide his population and practice additional
selection with one portion, what can he do with the other to hold what he has
already gained so far?
Lush:
Offhand I do not see why he would expect to lose ground unless
the flock Is small enough that the inevitable inbreeding gets out of hand
and he might have some undesirable things happen that way.
Other than that,
I do not see why he should get any worse.
We have run on to one
or two cases in genetics where the correlation
between parent and offspring was negative.
They are very rare and unlikely
conditions.
They involved some prior selection of parents.
If the flock is small enough that the inbreeding is likely to run away
and you fix some things you did not want to, while you were not looking, and
they turn out to be undesirable
later, I do not know any good remedy for that.
Keeping the flock larger might not be financially possible.
It might be better
even to split it in two or three different stocks.
I suppose you have some
other practical reasons for splitting a flock in two or more parts, such as
against disease or disaster wiping
out the flock.

-31°
We used to teach our classes that selection may not do any good, but
at least it would not hurt.
We have modified that a •littlebit noW._ We
say it will not hurt YoU_unless you have a lot of overdominance and some
other special features.
It might hurt you a little bit then.
Shoffner:
Dr. Lush, this is an involved question -- I do not know whether
I can make it clear or not -- but it goes back to this tester stock idea of
using a weak tester.
The thing that has been stressed and I think is in
back of many people's minds is to use a tester for such things as resistance
to certain diseases or certain weaknesses, such as this leucosis complex.
This is partially philosophy, perhaps.
In Minnesota and other places We
thought we had inbred lines that were resistant and we crossed them and found
they were not resistant. Also certain populations -- at Cornell and others
to bespeciflc
-- apparently have resistance and those larger populations,
notinbred flocks, seem to carry some of that resistance through. Some
recent reports indicate that from one population you might get two different
sets of genes or gene complexes that have resistance to the same thing, yet
apparently they are unrelated.
In one recent report, which probably many of you know of, where Drosophila
was subjected to DDT and resistance was obtained in two lines formed from the
very same populatlon,_ the F1 from crossing these two lines was just as resistant
as the parents, but in future generations that resistance broke up.
From
this one population to begin with they were able to separate out two entirely
unrelated sets of genesthat gave resistance, yet they were not thesame genes
or did not complement each other.
How would you take care of a situation like that, which looks llke it
might actually operate in poultry?
How would you separate it from the fact
that we have the possibility of several different viruses or agents to cause
the lymphatic type and all the different types that come•al0ng, so that one
tester might not be adequate?
How would you resolve this problem?

-32-
I am not sure I made this thing clear except to bring up this problem
of possibility
of multiple testers, rather than one single tester, if you
are going to use it for a weakness characteristic.
Lush:
I do not think I can give you an automatic answer that is guaranteed
to give success on that.
There is a danger, theoretically at least, of getting
a line that is genetically so utterly uniform that a pathogen would match it
perfectly and wipe it out before it could recover.
If the resistance were
based
on one gene or two pairs only, the probability of matching or not
matching the genes and the testers _zouldbe greater than if the resistance
were a more
or,less continuous quality affected by several genes.
I suspect
it might be desirable to have two or more weak testers if it
is important enough, but the desirability of that would become high only if
your
stock were closed and had been closed a long time so that it is probably
developing
its own gene complex pretty different from those of other flocks.
Your question stimulates two other comments.
I should have stressed in
an earlier diagram that if the end character is highly important and there
are several genetic steps in making it, then probably other genes might
produce the effect if one of the regular ones failed somewhere along the
llne.
If it is a highly important character, it will probably have built
in some factors of safety so that an individual defective
in one gene will
not be completely wiped out, but that would
take a long time.
The other comment is the point you made very well that the pathogen
may change itself.
Breeding for disease resistance is a matter of increaslng
the resistance of the host.
The pathogen, if it is a living thing, a virus
or a bacterium, may follow and increase its pathogenicity.
Breeding for
disease resistance is a kind of a stern chase of the host trying to run away
from the organism and the pathogen
following the host.
Professor Haldane in England has speculated
-- I think speculation is the
right word
-- that this may have been a rather important factor in evolution,

-3_
that the pathogen, being a virus or bacterium withmany generations for
each generation of the host, could usually evolve faster than the host.
Thus the pathogen would usually not be very far behind the host in catching
up with that new resistance.
The pathogen would adapt itself to whatever
type of host was most common or abundant.
As soon as the pathogen succeeded
in adapting itself to the most abundant type, then selection turns against
that type and the uncommon types are favored.
Such a process would keep
the species forever on the run, keeping it from settling down.
The pathogen
may drive it from this combination to that and to that.
In the process of
being driven endlessly along this planless road, the species may stumble on
to some other importantadaptations.
He speculates that parasites and
diseases may have been a very potent factor in improving all species through
preventing them from resting on their laurels.
Hogsett:
We must adjourn this morning's session, because we must be
back here for a very important part of this program this afternoon at
one-thirty.
Thank you very much, Dr. Lush.