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Compatibility Systems in Nature
M.Tevfik Dorak, MD, PhD
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Self and non-self recognition is a
common requirement for all living organisms. Most taxa
have their own systems to identify self and non-self. Nature makes use of these
systems for several purposes. One common use is to avoid inbreeding by
identifying individuals, cells or gametes as different from self
(self-incompatibility as in mate choice, selective fertilization). Also in
adults, the same discrimination finds its use in co-operation between
individuals or cells (self-compatibility as in kin recognition, colony
formation, nuclear fusion, dual recognition, transplantation). It is not
infrequent that the same system is involved in both levels of recognition in
the same species.
Bacteria, protoctista,
fungi and plants have well studied compatibility systems. In the animal
kingdom, invertebrates have an allorecognition system
which is primarily involved in immunological recognition but also in
fertilization. The other major division in the animal kingdom, the vertebrates,
invariably has the MHC. Recent evidence suggests that inbreeding avoidance is
one of the less appreciated functions of the MHC. Here, a review of the
compatibility systems in nature will be followed by the involvement of the MHC
in reproductive phenomena. The similarities between the MHC and other
compatibility systems will be emphasized with the view that the MHC is
primarily an inbreeding avoidance system and its role in histocompatibility is
a secondary one 1.
The best known compatibility
systems are the protozoan pheromone system 2; 3, the fungal (in)compatibility systems 4-8, angiosperm (flowering
plants) self-incompatibility system 6; 9; 10, and the invertebrate allorecognition systems 11-14. All of these
systems are primarily involved in prevention of matings
between genetically similar individuals to avoid the harmful effects of
inbreeding. As a result of the most polymorphic compatibility system, the
fungus Schizophyllum commune (the edible mushroom)
has the maximal (98.8%) rate of outbreeding in
nature. Even in bacteria in which reproduction is asexual (by binary fission)
as a rule, there are mechanisms to increase genetic diversity via horizontal
gene transfer (conjugation) (see Microbial Genetics). The
green alga Spirogyra and the Zygomycetes phylum of
the fungal kingdom use the mechanism for the same purpose.
Fungal compatibility systems
The fungal incompatibility system
regulates both sexual reproduction and somatic compatibility. The first major
review on this subject was presented by Raper in 1966
15. More recent reviews cover the mating types and pheromone systems
in Basidiomycetes and Ascomycetes
5; 8; 16-20. Between the two phyla, Basidiomycetes
species may have thousands of (tetrapolar) mating
types as well as a pheromone system. The somatic compatibility system which
regulates self/nonself recognition during vegetative
growth in filamentous fungi has also been extensively reviewed 5; 21; 22.
In fungi, both asexual and sexual
reproductions are observed. In sexually reproducing fungi, there is no
distinction between male and female structures but there is a genetically
determined difference among individual fungi. This is due to the mating types.
Individuals of the same mating type cannot mate with one another. The nuclei of
most fungi are haploid except when a zygote is formed in sexual reproduction.
The diploid zygotes undergo meiosis, producing haploid nuclei that will be
integrated into the spores. When haploid fungal spores germinate, their nuclei
divide mitotically to produce hyphae
(the structural unit of a fungus in its vegetative phase or mycelium). These
haploid hyphae in filamentous fungi may be in a dikaryotic stage (n+n) which is
different from haploid (n) or diploid (2n) state. The co-existence of two different
nuclei (heterokaryon or dikaryon)
in the same cell is regulated by the somatic/vegetative/heterokaryon
compatibility system.
The studies on the compatibility
systems in Basidiomycetes 19 include those
on the smut fungus Ustilago maydis
23-26, U.hordei 8 and the
edible members (mushrooms) Schizophyllum commune 7
and Coprinus cinereus 27.
The members of the other phylum Ascomycetes
17; 18 studied are the unicellular yeasts Saccharomyces
cerevisiae 28-30 and Schizosaccharomyces
pombe 17; 19; the filamentous ascomycetes Neurospora crassa 31-34, Podospora
anserina 35; 36 and Cochliobolus
heterostrophus; and Aspergillus
nidulans 37-39. Unique features of
these groups are that Basidiomycetes have more
complex mating type systems consisting of much more polymorphic mating types
and a pheromone/pheromone receptor system, and (filamentous) Ascomycetes have a somatic (heterokaryon)
incompatibility system in addition to the sexual mating types. The heterokaryon compatibility system (het loci) regulates the heterokaryon formation in
filamentous fungi. Filamentous fungi are capable of hyphal
fusion to form dikaryotic heterokaryons
during their vegetative growth but the formation of this new composite mycelium
is under the control of het loci as well as one of the mating type loci 5;
21; 40-42. The coexpression of the antagonistic
het alleles triggers a lethal reaction and prevents the formation of viable heterokaryons. In Neurospora crassa, allelic differences at any one of at least 11 het
loci trigger an incompatibility response (thus, the heterokaryon
is homozygous at all het loci). The number of the het loci in other Ascomycetes is 17 in P.anserina,
eight in A.nidulans and at least five in Cryphonectria parasitica (the
chestnut blight ascomycete) 5; 21. The heterokaryon formation and the role of similarity in this
process is very similar to the control of colony formation and fusion in
invertebrates 13, kin recognition in mice 43; 44, and
transplant acceptance in the animal kingdom 45-49. Heterokaryosis is the first step in sexual reproduction of
non-filamentous fungi such as Basidiomycetes, but
here diversity is favored and this is regulated by the mating types 19.
Allelic incompatibility in the het loci does not generally affect sexual
function; strains with numerous het differences can mate.
In N.crassa,
which is heterothallic (self-incompatible), strains of opposite mating type, A and a, must interact to give the series of events
resulting in sexual reproduction: fruiting body formation, meiosis, and the
generation of dormant ascospores. While the mating
type sequences must be of the opposite kind for mating to occur in the sexual
cycle, two strains of opposite mating type cannot form a stable heterokaryon during vegetative growth. In haploid
heterothallic species, the genome only contains one of the A or a mating type loci. The genus Neurospora
also includes homothallic (self-compatible) species. Those carry a single
haploid nucleus and are able to form fruiting bodies, undergo meiosis, and
produce new haploid spores. One such species, N. terricola,
contains one copy each of the A and the a sequences
within each haploid genome 34. Homothallism
in these species is not due to mating-type switching, as it is in Saccharomyces cerevisiae 32.
In S.cerevisiae, the genome contains both mating type
loci and switching between them is possible 8. Each haploid genome
contains both the a and a genes and
normally one of them is transcribed with its interaction with the MAT locus
while the other one is silent. Sometimes, a new copy of the silence mating type
gene is made, the other one is removed from the MAT locus and the new type is
transcribed.
During (sexual) conjugation in S.cerevisiae, two cells of opposite mating type (MATa and MAT a) fuse to form a diploid
zygote. Conjugation requires that each cell locates an appropriate mating
partner. This is achieved by pheromones and pheromone receptors. In MAT-a cells, both production of a-pheromone and response to a-pheromone
are necessary for successful 'courtship' 50. Unlike the pheromone
system of Basidiomycetes, in the yeast, the pheromone
system is under the control of the mating types (not independent).
The function of the mating types
is obviously avoidance of inbreeding with no homozygosity is allowed and
consequently, absolute heterozygote advantage. This helps to increase genetic
diversity of survival chances of the species. On the other hand, the function
of the heterokaryon compatibility system is not
clear. While having two nuclei offers the advantages of diploidy
(for example, masking recessive deleterious genes), why they have to be the
same genetic type is not known. One of the hypotheses is that the horizontal
transfer of cytoplasmic genetic elements is reduced
between incompatible strains and this protects strains of natural populations
against invasion by harmful cytoplasmic genetic
elements (stable RNA, mitochondria and plasmids). The prevention of horizontal
gene transfer, however, is not absolute and the het loci differ in their
efficiency in this process 38; 40; 51.
Mating
types in fungi:
BIPOLAR
MATING TYPES:
Zygomycetes: (+) and
(-)
All heterothallic ascomycetes have single-locus, two-allele mating systems:
S.cerevisiae: a (a1,
a2) and a (a1, a2) [type switching is possible]
N.crassa: A
(mtA-1) and a (mta-1) [idiomorphic]
U.hordei: a and b
(linked)
TETRAPOLAR MATING TYPES:
U.maydis: biallelic pheromone system a (a1, a2) and multiallelic b locus (homeodomain transcription factor)
S.commune and C.cinereus: multiallelic A (transcription factor) and multiallelic
B (pheromone and pheromone receptor)
Plant self-incompatibility system
Mechanisms that prevent
self-pollination are of crucial importance for maintaining genetic diversity
within flowering plant (angiosperm) populations. This is because the flowers
often have male and female organs within close proximity on the same plant and
not infrequently on the same flower. Self-incompatibility,
is a genetically controlled mechanism to reject its own pollen. For a classical
treatment of this subject, the reader is referred to the monograph by de Nettancourt 52. More recent reviews have dealt
with the nature, molecular and population genetics of this system 9; 10;
20; 53-57. See also Plant Genetics.
Some flowers have developed
mechanical barriers for their own pollen to prevent them from reaching the
female organ (pistil) in the same flower or plant. Some plants have timing
differences between their male and female flowerings. The self-incompatibility
systems creating a topological barrier (due to different morphologies of their
flowers) are called heteromorphic
self-incompatibility systems 10; 52; 53. The homomorphic
self-incompatibility (SI) involves the rejection of self-pollen and was first
recognized by Darwin. Over half of the flowering plants have flowers with
similar shape and this type of self-incompatibility 52; 58. The homomorphic type is further classified into gametophytic and sporophytic
types. In the former pollen's own SI type is perceived by the stigma and should
not match either of the plants SI alleles for successful fertilization. In the
more interesting sporophytic type, the two alleles of
pollen's parent are recognized by the stigma and there should be no matching
combination between the two alleles of the stigma and two alleles of the plant
from which the pollen has derived to avoid self-rejection. The gametophytic type is more common (found in 60 families of
angiosperms) than the sporophytic type (found in six
families) 10. The two types are not related and evolved
independently. The gametophytic type has been studied
in Papaveracea (poppies), Poaceae,
Rosaceae, Scruphulariaceae,
and Solaneceae (including tobacco, potato and
tomato). The sporophytic type has only been studies
in Brassicaceae (including cabbage and mustard, for
example Arabidopsis thaliana). Despite being very common among angiosperms, the
SI system in different families have different origins, in other words, they
evolved independently several times 56; 59.
Self-incompatible (heterothallic)
plants necessarily produce offspring that are heterozygous at the S locus which
in general, contains 30-50 alleles 53; 60. The alleles of the S
locus confer genetic identity (S haplotype specificity) on the pollen and
stigma of self-incompatible plants. The S locus of the sporophytic
type has two genes encoding two proteins expressed on the stigma surface. These
are a transmembrane S receptor protein kinase (SRK) and S locus glycoprotein
(SLG) which has RNAse activity 61. It is
the SRK gene product which determines the S haplotype specificity of the stigma
but the SI response is stronger if SLG of the same haplotype is also expressed.57.
The corresponding protein on the pollen surface has recently been identified as
a member of the pollen coat protein family (SCR) 62; 63. When a self pollen reaches the stigma on the same flower or
plant, a self-rejection reaction takes place. The biochemical mechanism of
self-rejection involves the cytotoxic action of the RNase
activity 64; 65. The end result is the prevention of pollen tube
growth. In the gametophytic type, the same is
achieved by a single glycoprotein with an RNAse
activity 66.
Just like the fungal mating types,
the plant self-incompatibility system provides an example of balancing
selection in the maintenance of their alleles 22; 60; 67. It is easy
to imagine how this works. Any new allele would have selective advantage since a pollen with this allele will always be accepted by the
stigma until this allele reaches a remarkable frequency in the population. Once
it has been established, the frequency will still be maintained through
heterozygote advantage. Since this occurs for any new allele created as a
result of mutations, balancing selection results in extreme polymorphism
detected in these compatibility systems including the vertebrate MHC 8;
60; 68; 69. The resulting highly diverged alleles will also have very
long evolutionary life times and their existence will cover the life times of
several successive species (transspecies
polymorphism). The evidence suggesting this pattern of polymorphism is greater
sequence similarity of alleles between species than similarities within
species. This is again typical of all these compatibility systems 22; 67;
70-76. Another piece of evidence for the action of balancing selection on
the self-incompatibility alleles is the clustering of non-synonymous mutations
in hypervariable regions (HVRs)
rather than a homogeneous distribution 67. Under a strictly neutral
model, there would be no such heterogeneity in the distribution of substitution
rates. The continuous stretches of non-polymorphic sequences in different
alleles suggest that these segments are functionally constrained and any
non-synonymous substitution in these parts would be deleterious and subject to
purifying selection. These segments may still have a rate of high synonymous
base substitutions. On the other hand, if new alleles are favored as in
heterozygote advantage, non-synonymous substitutions will be concentrated on
the segments encoding the allelic specificity (HVRs).
This is exactly what happens in the fungal het loci 22, plant SI 67;
72 and vertebrate MHC alleles 77-81.
Invertebrate compatibility systems
Although the MHC multigene family is restricted to vertebrates,
histocompatibility loci are also found in invertebrates where they appear to
have an analogous role in the regulation of mating systems 11; 82. A
histocompatibility system of immunorecognition is
postulated to have originated in multicellular
invertebrates probably beginning with coelenterates (corals) 45; 46; 83.
The best studied invertebrate compatibility system is that of the colonial
tunicates 11; 13; 14; 84; 85. The best known species in this group
is Bottryllus schlosseri
and its compatibility system is called fusion/histocompatibility (Fu/HC). Allorecognition in Botryllus is
principally controlled by this single Mendelian locus, with a large number of codominantly expressed alleles 85. The number of
alleles is estimated to be 30-200 13.
Colonial tunicates are complex
marine invertebrates (in fact protochordates) that
undergo a variety of histocompatibility reactions in their intraspecific
competition for feeding surfaces. By means of these reactions colonies fuse
with kin, extend domination over a feeding surface, while isolating unrelated conspecifics. A Botryllus colony
is composed of numerous units which are embedded within the
translucent-gelatinous matrix, the tunic. Each hermaphroditic member possesses
male and female gonads. Following fusion with nonidentical
kin sharing 1 or more Fu/HC allele(s), the fused pair expands both chimeric partners via an asexual budding process, further
extending domination over a feeding surface. However, at some later time point
an intense set of histoincompatibility reactions
occurs between fused kin, resulting in the destruction of all individuals of
one of the genotypes, ending the chimeric state 13.
Apart from prevention of fusion
with non-kin 11; 84, the Fu/HC also affects self-fertilization by
sperm-egg incompatibility. Eggs resist fertilization by sperm from the same
colony represented by its Fu/HC allele. This interaction
results in selective fertilization by sperm bearing a different Fu/HC allele 11;
82. This situation in hermaphroditic invertebrates is very similar
to what happens in fungi and plants.
Similar to the situation with the
other compatibility systems and the MHC, there is yet no evidence for a common
ancestor for the invertebrate compatibility systems and the vertebrate MHC 13;
14. This shows that the widespread existence of these systems is not a
co-incidence due to a common ancestor but suggests a biological requirement to
have a system to promote outbreeding. The best
evidence for that is that in plants, the self-incompatibility system arose
independently more than one times. It appears, however, that the main function
of all these systems is to enforce heterozygosity by acting at the earliest
phase of sexual reproduction. There is still a possibility that the vertebrate
histocompatibility genes evolved from gametic self-nonself recognition systems which prevent
self-fertilization in hermaphroditic organisms 11. This idea was first
put forward by the Nobel Laureate immunologists FM Burnet 86.
Vertebrate MHC and compatibility
The MHC also prevents inbreeding through its influence on mate choice in mice 87; 88 and humans 89; 90; and on reproductive processes in rats 91, mice 92; 93 and humans 94; 95. The reproductive mechanisms are varied and range from selective fertilization to selective abortion. A major common feature of the compatibility systems is that they favor genetic dissimilarity between mates and the gametes (mate choice, selective fertilization); but similarity in co-operation (kin recognition, dual recognition, transplant matching) 1; 96. All these functions are based on the provision of a phenotype for the genetic identity of the individual by the MHC: either cell surface molecules or chemosensory signals. See also Non-Pathogen-Based Selection in Origin of the MHC and Its Polymorphism.
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