Compatibility Systems in Nature [MT Dorak]

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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 Major Histocompatibility System (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 mating type loci 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 mating type 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 allowed and consequently, heterozygote advantage. This helps to increase genetic diversity and 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 for rejection of 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 studied in Brassicaceae (including cabbage and mustard, for example Arabidopsis thaliana). Despite being very common among angiosperms, the SI systems 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 (frequency-dependent selection). 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 lifetimes 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 Botryllus schlosseri and its compatibility system is called fusion/histocompatibility (Fu/HC) (see the link below to De Tomaso Lab). 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(see a recent review on the allorecognition systems in Botryllus by McKitrick et al, 2011; and the report on selection operating on the fester histocompatibility system in Botryllus: Nydam & De Tomaso, 2012).

The ability to discriminate between self and nonself (i.e., allorecognition), is ubiquitous among colonial metazoans. The genetics of allorecognition has also been studied in another invertebrate, the colonial cnidarian Hydractinia (Buss, 1990; Cadavid et al, 2004 & 2005). Two allorecognition loci, alr1 and alr2, have been isolated in the same chromosomal region, which is called the allorecognition complex (ARC) (Rosa et al, 2010 & Rosengarten, 2011).

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 one 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.

As 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 due to a common ancestor but suggests a biological requirement to have a system to promote outbreeding for different taxa. The best evidence for that is that in plants, the self-incompatibility system arose independently more than once. 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 Frank Macfarlane 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 and Kempenaers B (2007): Mate Choice & Genetic Quality.

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