Natural protection of genetic variation


Introduction

Programs to preserve genetic health in dog breeds have been intensively discussed in Sweden in connection with the development
of breed specific genetic strategies. Why have breed specific strategies become a necessity at all in dog breeding? In nature there
are no special breeding programs or strategies to keep species healthy and vital over very long periods of time. The cause of
inherited disorders - observed in so many dog breeds - is that breeders, due to ignorance or extreme breeding forced by various
forms of competition trials, break down the protective barriers against genetic disorders that Nature has built over millions of years
by means of natural selection. What kind of barriers do we need to know about to avoid such mistakes?

The Cell

The body of an animal - even though it is a unit - is composed of billons of cells. The link between generations is however only one
single cell - the fertilized egg cell. Thus everybody involved in breeding ought to know at least a little bit about how the fertilized egg
is protected against genetic disorders.

Genes – protein blueprints

The basic function of a gene is to serve as a blueprint for the cell to use when building a specific protein   There are about 30,000
to 40,000 gene pairs and as many different types of proteins that can be built by the cell. We all need skeletons, muscles, nerve
systems, livers, kidneys and all other internal organs. We also need a large number of hormones, enzymes and signal substances to
make our bodies work properly.

It would all be very simple if there were never any changes in the environment. There would be no need for any changes in the
blueprints to make a specific protein. However, all species have to adapt to continuous change in the environment or live under
threat by predators. In order to adapt to such changes, all animals must themselves be able to change their physical and mental
characteristics. Consequently, there is a need for flexibility of the genetic system.

At the cell level the threat from external enemies is extremely large. Innumerable microorganisms and viruses are continuously
attacking our bodies. Thanks to the very rapid generation turnover these organisms are able to change the way they attack many
times during the normal lifetime of larger organisms such as mammals. To defend oneself against all such attacks each individual
needs a defence system which is as unique as possible. Otherwise a successful attack on one individual would spread rapidly.

The Gene system is subjected to three apparently incompatible demands:

A.Stability to guarantee that all organ systems are working correctly
B.Balanced variation for the entire population to make long term adaptation to a changing environment possible.
C.Individual variation to protect every being against diseases and infections.

During the first 3-4 billion years on Earth there were no more complicated forms of life than single cell organisms. Their normal way
of reproduction was a non-sexual simple cell division.

The DNA molecule, the basic element of genes, is a surprisingly stable chemical compound.   This molecule duplicates itself before
the cell splits itself in two, thus creating two new cells with identical DNA. After such a division both cells have an identical genetic
makeup. But if all cells get identical genomes there can be no genetic adaptation to changes in the environment.  A sudden change
of the DNA molecule, or a single gene, may cause the death of the individual since a vital protein can no longer be produced.
Therefore, a single set of DNA molecules or genes has serious disadvantages both for individuals and for the long term adaptation
of the species. Only very simple organisms can survive such a lack of genetic variation.


Gender and the duplication of the genome

After several billion years, Nature found a solution to the vulnerable system of simple cell division. Cells with identical genomes join
up two by two to create a new cell.  This new type of cell then carries a copy of each single gene. Thus they have an intact copy of
the protein blueprint should the other be damaged for some reason.  Cells of that kind are much less affected by damage to single
genes. Normally, there is a duplicate gene available to guarantee that the right kind of protein will be produced in sufficient amount.

Cells with duplicated genomes can no longer multiply by simple cell division. To make the amount of DNA, and thus the number of
genes, constant over generations, they have to go through two cell stages. At the first stage, they divide into two cells with only half
of the DNA in each of the two new cells. At the next stage two such halved cells meld together in the process of fertilization to
make a new cell which again carries a genome with duplicates of every gene.

Nature’s solution was to create two sexes both having special organs, ovaries and testes, where the reduction of the genome to half
the normal size takes place when creating ova and sperms. The central advantage of two sexes is the duplication of genes to avoid
disastrous results of damage to single genes.

A system with two sexes has another important advantage. At the stage when germs cells (ova and sperm) are created, the DNA
molecules, resembling long strings, wrap around each other. As everybody knows, it may be a complicated matter to untangle
strings. This is also the case for the cells, where the paired chromosomes break and exchange parts with each other. This is called
crossover. Thanks to this crossover, new gene combinations are formed every generation in all individuals, within all species having
two sexes. So we can see that sex has the dual functions of protecting against gene damage and providing an important source of
new genetic variation to facilitate necessary genetic adaptation to changing environmental conditions.

Most, but not all, chromosome changes are harmful. If there is only a minor change in the composition of a protein due to a
mutation (a sudden change in a gene) the new protein may do well in spite of the change. In rare cases the new protein composition
might lead to advantages for the animal. Such advantages will rarely show immediately but might result from later crossing over and
rearrangements of genes along the chromosomes. In cases where such mutated genes cause increased vitality of animals, the
carriers will on average produce more offspring and the favourable gene will be incorporated into the gene pool of the breed or
species. In the opposite case, where gene changes are harmful, the mutated gene will be rapidly erased from the population by
natural selection. The main selection force is again changes in vitality resulting in less progeny produced by affected animals.


Male to female bond affects male reproduction

Evolution throughout millions of years has shown that the division of animals into males and females has been indispensable for the
creation of highly developed animals. However there is a problem connected to the way bisexual mammals reproduce. Although
the reproductive capacity of females is generally restricted to producing progeny in tens rather than in hundreds, males may mate
with a large number of females and thus have many more offspring than females. Such sexual behaviour reintroduces the risk that
two genes with identical origin will come together in succeeding generations.  Male sexual behaviour may thus violate the protective
force of the duplicated gene structure.

Natural selection again found a solution by creating more or less strong bonding between reproducing males and females. It does
not matter if such bonds are for life or only for one reproductive season. The effect will be the same. The upper limit for male
reproduction is set by the number of young an average female may give birth to and rear. The creation of male/female bonds is a
simple and brilliant way in which Nature reinforces the protection caused by the duplicated gene structure in spite of the fact that
males have the capacity of producing a dangerously large number of progeny.

In Sweden an overproducing male with too many offspring is called a “Matador”. Matador was an intensively used bull in the
northerly part of Sweden. He carried a gene for testicular hypoplasia, too small testicles, causing reduced fertility. Due to the
intensive use of the bull, the deleterious gene spread rapidly over the entire local bovine population. It took several decades of
selection against the gene to repair the damage caused by overuse of what once seemed to be a male of exceptionally high quality
as a breeding animal.


MHC – the ID card

The cooperation of billions of cells in a body can only take place if there is a way for all the cells to identify each other as belonging
to the same unit. Otherwise there is no way to identify enemies and defend the body against invasion of other cells causing diseases
or damage to the body. Thus each cell in the body needs an identity card. The identity code of the card should vary as little as
possible among cells belonging to the same animal but at the same time be as unique as possible for each animal.

Nature has solved the problem by creating a special set of genes called MHC, where MHC stands for Major Histocompatibility
Complex. Together the MHC genes form the unique “identity card” carried by all cells of an individual and make it possible for the
cells to cooperate without harming or attacking each other. The MHC genes constitute the basis for our immune system and play an
important role in reproduction.

The genes of the MHC system create special proteins on the surface of each cell. It is the special combination of these proteins that
make up the identity code, which is identical for all cells of an individual. The cells can “read” each others’ identity code and
cooperate with cells carrying the same code as themselves without risk. If cells carrying another code penetrate into the body, they
are attacked by special guard cells called T-cells or murder cells. The T-cells are continuously moving around and looking for cells
with deviating identity codes and they kill such cells immediately when found. Together the combination of MHC proteins and T-
cells make up one of the most important defence mechanisms against invasion of pathogenic cells.

It is now obvious that the more unique the identity code, the better an individual is protected against diseases. Pathogenic cells will
always try to copy the identity code to fool the T-cells that they belong to the body, and may succeed. But to the extent that
individuals carry different identity codes, the pathogenic cells cannot spread easily from one individual to another. They will be
discovered by the T-cells of any individual carrying another identity code.

The basic consequence of inbreeding is to duplicate genes of the same origin. Such duplication will inevitably reduce the number of
genes with different blueprints for protein production and hence also reduce the possible variation of genes in the MHC system.
With fewer proteins as a basis the identity code will be less unique and easier to copy, similar to very short keys in a computer
system. This is why inbred individuals are more susceptible to infectious diseases.


Genetic scent signals

Nature has created a special protection against dangerous reduction of genetic variation in the MHC gene system. Again the
solution is brilliantly simple. The genes of the MHC system take part in the production of the scent substances called pheromones.
The pheromones are important sexual signals which make it possible for animals to “smell” part of the genetic makeup of the MHC
genes carried by a possible mating partner. It has been shown by experiments that all kinds of animals from insects to mammals use
the pheromones to avoid mating with close relatives who carry too many of the same genes in the MHC system. Thus the bond
between the pheromones and the MHC genes protects the genetic variation of the immune system. This kind of protection will be
effective only when there is a free choice of mating partners and the number of possible partners is large enough. If the number of
available partners is low, females may choose to mate with closely related males rather than not mate at all. A less viable progeny
may be better than barrenness.

It is important to accept when the bitches distinctly signal that they do not accept a male. The females know better than the breeder
if the male carries MHC genes which are favourable for her progeny. Forced mating is an effective way to violate one of the most
important protections of genetic variability.



Fertility and inbreeding

Most breeders are well aware of the fact that strong inbreeding has negative effects on viability, health and fertility. But what do the
immune system and reproduction have in common to make them both sensitive to inbreeding?


The fetus is protected from being rejected
Everyone is well aware of the problems in transplantation surgery to ensure that the recipient will not reject the foreign tissue. The
basic reason for the rejection of foreign tissue is that all its cells carry another ID code and hence they will be attacked by the
immune system of the receiver to avoid an unwanted invasion of possibly malignant cells. When transplanting organs from one
individual to another, the process is facilitated if the genetic system of the donor is as similar as possible to the genetic system of the
recipient. But even in cases where donor and recipient are closely related it is necessary to use cytotoxin to avoid rejection of the
transplanted tissue.

The genes of a fertilized egg are 50 % inherited from the mother and 50 % from the father. Hence the genetic system of the
fertilized ova normally deviates to a large extent from that of the mother. As a consequence the fertilized egg ought to be repelled
by the immune defence system of the mother. And in fact, if no other mechanism were at work, pregnancy would not be possible.
But again Nature has found a solution. A very special type of protein is produced in the mother to prepare her for pregnancy. That
protein has the function of guarding the fetuses against attacks by the immune system of the mother. The special protein will guard
the fetuses continuously during pregnancy. It is an interesting fact that the total amount of fetal tissue, including the placenta, shows a
rather similar proportion to the weight of the pregnant female. One of the probable mechanisms that triggers delivery might then be
that the total amount of fetal tissue exceeds the capacity of protection by the special protective protein.

The protection of the fetuses has a negative side effect. After the delivery, the protective protein still remains in the body of the
mother for 2-3 days. During this period she is extremely susceptible to infections since her own immune response is seriously
lowered by the remaining protective protein. It is thus necessary to supply the bitch with a clean and dry environment especially
during the first few days after delivery.

One might think that fetuses with gene systems very like their mothers, i.e., those that are heavily inbred, would benefit from their
genetic likeness to the mother. There should be less tendency to reject such fetuses from the womb. But if there is a very strong
genetic likeness between the mother and her fertilized eggs, another problem arises.   How should the uterus of the mother be able
to identify fertilized eggs as deviating from any other cells of the mother’s body?   One of the prerequisites for the adhesion of the
egg to the uterus wall and the formation of the placenta is the difference in genotype between the fertilized egg and the mother.

Another risk with too much genetic likeness between a mother and her young is that the labour pains during delivery will be
seriously reduced, resulting in  a prolonged delivery.
There is thus a threefold advantage in divergent MHC genotype between the mother and her progeny. The fetus will get a better
start in the mother’s uterus, the delivery process will be shortened and thus less trying, and finally the newborn animal will have a
more unique ID code making it more viable and less prone to infectious diseases.


Number of puppies and size of the mother

One of the fascinating consequences of the fact that total fetal tissue has a rather close relation to the size of the mother is that it
affects litter size in dogs. Normally there is a negative relationship between the size of the mother and the number of progeny in all
litters, i.e. the larger the mother, the fewer her progeny in each litter. Small animals like mice tend to have large litters while large
animals like elephants normally give birth to only one young at a time. In dogs this rather general rule is reversed, as in most breeds
of domesticated pigs. The reason seems to be that our breeding efforts have been much more effective in changing adult size of our
dogs than changing the size of their newborn puppies. Thus with the same proportion of fetal tissue compared to the body weight of
the female, a large female will be able to carry more puppies.


The ova and her selection of sperm

Is there any way in which an unfertilized egg may have any influence upon its genetic variation after fertilization?  Anybody who has
seen pictures of an egg just before fertilization knows that the egg is surrounded by a crowd of sperm. It is not just a coincidence or
an act of Nature’s superabundance that there are millions of sperm produced to fertilize only one or a few eggs. The large amount
of sperm is a guarantee that enough sperm will reach the egg in time for fertilization. The identity code of all cells will then make it
possible for the egg to select a sperm among all available that best matches her own MHS MHCcomplex so as to produce the
most viable progeny possible.

It might sound strange that an unfertilized egg should be able to select the sperm that is allowed to fertilize it. But fertilization is not a
violent process where the sperm forces its way into the egg. The cell wall of the egg has to open up to allow the sperm to pass its
DNA content into the egg cell. Thus the egg cell takes an active, and probably dominant, part in the fertilization.

Similar mechanisms of cross-fertilization in plants have long been well known. If pollen from the flowers of a plant reaches the
stigma of flowers on the same plant the pollen tube will not grow due to blocking chemical reactions. Thus the stigmas of flowers
are able to identify the genotype of pollen and avoid close inbreeding and self-fertilization.

The large number of sperm produced by mammal males has the same function as the large amount of pollen produced by plants. It
gives the female egg the possibility to select a partner producing progeny with the highest possible viability. A large number of
sperm is thus another aspect of Nature’s guarding system to preserve genetic variability in a breed or species. The use of strong
inbreeding will however again break down the protective systems since all the sperm will be too similar in genotype and thus reduce
the possibility for the egg to select a proper sperm.


Artificial reduction of number of sperm

The very large number of sperm normally produced by a male has long been considered just a surplus overflow with no effect
whatsoever in breeding, the argument being that there is need for only one viable sperm to fertilize one egg.  One may wonder why
not try to make fertilization more effective. The number of sperm produced on one occasion would certainly be enough to get many
more females pregnant.  Prominent males could then be used to produce a much larger number of progeny than ever seen in Nature.

When using artificial insemination in cattle breeding, one normally dilutes the ejaculate 1/100, i.e. the number of sperm is reduced to
only one hundredth of the normal number. Although such a reduction may not have any dramatic short term effects it is obvious to
anybody thinking clearly that in the long term perspective, the effect might be deleterious to the genetic variation and thus to the
viability of animals.

With ourselves the experimentation has gone much further. It started with test-tube fertilization. With this method, as with
insemination, the fertilization is quite normal although the number of sperm is often reduced. Today one often uses what is called
microinjection. In that case some scientist or doctor is looking through a microscope trying to find a viable sperm, i.e. one that
swims around and appears alert. Such a sperm is then picked up into a micropipette which is forced through the wall of the
unfertilized egg. When using microinjection to fertilize the egg, the latter is totally depleted of all possibilities to select a sperm that
matches its own genotype to guarantee as viable progeny as possible.

The fact that it might not be possible to immediately, or in a few generations, detect serious negative effects due to such violent
breakdown of the natural security mechanism is not proof  that the technique is not harmful in a long term perspective. Evolution
works through many small steps. Each of those steps may seem to be of minor importance but added over a large number of
generations they may have profound effects on the development of a breed or a species. Therefore one cannot conclude based on
the experiences from just a few generations that it is harmless to bypass all security mechanisms built into the system of fertilization
to preserve vital genetic variation.


Surplus of eggs at each mating

Among multiparous animals there is also another and simpler mechanism to enhance viability among the newborn progeny. The
number of ova shed by the females during the heat period is normally about twice the number born as fully developed young ones.
If the female is mated during a favourable time of heat all the ova will be fertilized. But there is rarely enough room for all the
fertilized eggs in the tubes of the uterus. There will thus be a competition among the eggs for a place where they can adhere to the
uterine wall and start the formation of a placenta. Less viable eggs, for example eggs that have duplicated genes with negative
effects in very early development, will lose the competition. Hence the young ones born have a little less genetic burden to carry.
The actual inbreeding is a little bit less than may be calculated from the pedigrees. This type of selection will never be as strong as
the one based on selection among millions of sperm. But it will guarantee that genes with profound negative effects in early
development cannot easily spread in a population.


Natural selection

Natural selection, or the forces applied by nature to make individuals as viable as possible in their environment, will not preserve
genetic variation in all gene systems. In some cases there is need for genetic stability. As living creatures we all need lungs, hearts,
stomachs, skeletons, nerve systems, brains and so forth. It would be too harmful to the development of our basic organs to have
too much genetic variation in the genetic systems responsible for their development.

What we call natural selection in everyday speech is a force with the purpose to balance the genome in order to give it the best
combined effect on viability. In nature a creature has to find food and protect itself against enemies including microorganisms. It
must also be able to adapt to environmental factors such as heat or cold, rain or lack of continuous supply of water. If an individual
is to have any impact on the genetic future of the species to which it belongs, it has to find itself a mating partner and produce and
rear progeny.  For the females the very complicated process of pregnancy and delivery also has to work without problems. People
tend to overestimate how many animals survive long enough under natural selection to pass all the necessary stages to become
contributors to future generations.

It is of profound importance that all breeders of animals do understand that the basic principle of natural selection is to stabilize the
genetic system to be effective during normal environmental circumstances.  The struggle for life in nature has very little to do with
fights between individuals. The main fights are the fights for survival and reproduction. Only those who produce viable progeny in
the long run are the winners and in nature extreme individuals are not among the winners. The most prolific individuals will win the
race and those are the ones best adapted to the present environment, i.e. the normal individuals closer to the population average. In
a case where changes never take place in the environment, natural selection would probably result in a very extensive genetic
identity between individuals of the same species. But environmental circumstances always change and over long time periods the
changes may be very large. Species that have lost their genetic variation will not be able to adapt to those changes in environment
and hence their destiny is extinction. For this reason Nature will always favour those species that have the power both to preserve
the genetic variation necessary for adaptation and to preserve the genetic stability to form all vital organs of the body.

Normally there is genetic variation in systems responsible for body size and form, colour, length and thickness of the fur and so
forth. It would be advantageous for these kinds of traits to be able to change rather rapidly if environmental conditions undergo
sudden changes. Other gene systems, as for example those are responsible for reproduction, may be more stable. For example,
food supply may vary quite a bit between years and it would not be an advantage if that had an immediate genetic effect to reduce
reproductive capacity.

In wild animals the selective force will under all normal circumstances be directed towards the norm of the population – the average
individual is rewarded. Extreme individuals may have advantages only in cases where the environment changes dramatically. For
example, if the temperature drops heavily, such as it did 65 million years ago, animals with long and protective fur may get a
selective advantage and form the new norm of a population. Should the change be large enough a new species is actually created.
In cases where such environmental changes are very rapid or too large, there might be no animals carrying the necessary genes and
characteristics to survive. Then the entire population or species will become extinct.  That has actually happened to over 98-99 %
of all species ever existing on Earth.

In Nature a stabilizing selection, adapted to small and slow environmental changes is the normal state. The rapid environmental
changes are rare but most of them cause widely spread extinction of living species. The very rapid loss of species today, as a
consequence of our civilization and its effect on the environment, may serve as a commonly known effect of the difficulties species
have in adapting to too sudden changes of their living conditions.


Artificial selection

Artificial selection is the selection of animals by man. When breeding farm animals there is a steadily ongoing selection for faster
growth, more milk or eggs and meatier animals. The most extreme individuals are those who win the race provided they are able to
cope with the burden of rapid change placed upon them. In breeding pet animals such rapid changes should not be necessary.  For
most pet animals however the breeding is governed by show competitions or other trials such as hunting trials and working trials for
dogs. In a contest there is no way to favour the most average individual, as happens in natural selection. In a contest the extreme
individuals are the winners. Too often we reward small differences in characteristics, characteristics which have no impact on
health, or which might even have negative impact on health. As a matter of fact the kind of artificial selection applied to our animals,
including pet animals, is very much like the type of natural selection during environmental catastrophes. Extreme individuals are
primarily the ones selected for breeding. The negative effect of such a selection policy over a long period of time is well known. The
problem in pet and dog breeding is that most people do not plan for more than decades at best, very few for longer periods than
that and none for the effects measured in an evolutionary time perspective.

If we seriously want to breed and rear healthy and vital pet animals we have to learn all the ways Nature preserves viability in wild
animals. We must abandon breeding techniques that invariably violate all the security mechanisms invented by Nature. If we are not
willing to learn how these security systems are built, and how we can use them in favour of our loved animals, breeds of both farm
and pet animals may have a depressing future. Breeding is not primarily a matter of complicated genetic theory. Nature has no
theoretical knowledge of genetics. Successful breeding, with the intention of creating healthy and viable animals, is a matter of
adopting and sticking to a few very simple principles of selection and breeding.


Summary and some practical consequences

At this stage it ought to be evident that the overriding cause of genetic defects and inherited diseases in animals is not just an
unlucky coincidence. It is the direct and unavoidable consequence of lack of knowledge among breeders about some basic rules of
Nature. They have not had knowledge enough to foresee the consequences of the way they have used their animals in breeding.
The driving force most responsible for all the mistakes made is the basically unsound breeding practices and contests and trials
where rapid genetic changes are desired and where these aims have been given higher priority than the health and viability of the
animals. The reward system applied in competitions also stimulates breeders to split breeds into steadily larger number of breeds or
varieties of breeds.  This inevitably produces a large number of populations which are all too small for any kind of proper breeding.
When the number of breeding individuals gets below critical levels the loss of genetic variation is very rapid. Genetic disorders may
be a problem in as short a time as about ten generations or 30-50 years. Most breeds have not existed as pure breeds more than
about 100 years. The steadily growing problem with genetic disorders in our pet breeds is thus exactly what we can expect from
what we know about breeding practices in many breeds.


Those who are looking for advanced breeding programs to correct all the genetic problems we see today are looking in all the
wrong directions. They should try to understand exactly what has gone wrong and start to learn from Nature how animals can be
kept viable over hundreds and thousands of years without any theoretical knowledge at all.


  • 1.The size of a population must be large enough to carry and preserve genetic variation. There is no way to succeed when a  
  •   breeding population has less than about 100-150 breeding animals and twice the number is preferable.

  • 2.Only viable animals in good physical and mental condition and with all natural functions still present should be allowed to  
  •   breed.

  • 3.In highly developed creatures the basic rule is that an individual animal should not be allowed to have more than a restricted
  •   number of progeny during its life.

  • 4.Avoid mating between closely related animals

Those are the four simple basic rules of Nature, rules which when properly applied will keep any population of animals healthy over
very long periods of time. The one and only reason for the genetic disorders in our breeds of dogs and other pet animals is that we
neglect to consider the mechanisms to protect genetic variation created by natural selection during billions of years.


Sprötslinge, July 2006



Per-Erik Sundgren
 Dr. Agric.
"The ISAA thanks Holly Kilpatrick for her willingness to assist with the translation of this article so that it can be
available to our membership in English."