Power, Sex, Suicide: Mitochondria and the Meaning of Life (43 page)

The search for a fundamental difference between the sexes takes us back to primitive eukaryotic organisms, such as algae and fungi, some of which have two sexes despite there being no obvious distinctions between their gametes (sex cells). They are said to be
isogamous
, meaning that their sex cells are equally sized. In fact, the two sexes appear to be identical in every way. Because they are basically the same, it makes more sense to refer to them as mating types rather than sexes. But the very lack of differences between the two mating types highlights the fact that there are still two of them. Individuals are restricted to mating with only half the population. As the pioneers of this field, Laurence Hurst and William Hamilton, pointed out, if finding a mate presents a problem then halving the population size ought to be a serious constraint. Imagine that a mutant mating type appeared in the population, which was able to mate with both the existing mating types. This third type ought to spread swiftly, as it has twice the choice of mates. Any subsequent mutants that could mate with all three types would have a similar advantage. The number of mating types should therefore tend towards infinity; and indeed the widespread ‘split gill’
mushroom
Schizophyllum commune
has 28 000. Short of having no sexes at all (all are the same sex) then it makes sense to have as many as possible. Two is the worst of all possible worlds.

So why do many isogamous species still have two mating types? If there really is a deep asymmetry between the sexes, a grain of inequality from which all other inequalities grow, then the algae and fungi are the place to look.

The answer betrays a fundamental intolerance that makes our own battle of the sexes look like a love-in. Take the primitive alga
Vulva
, for example, also known as the sea lettuce. It is a multicellular alga, which forms into sheets of cells only two cells thick but up to a metre long, giving the appearance of leaves. Sea lettuces produce identical gametes, or isogametes, which contain both chloroplasts and mitochondria. The two gametes, and their nuclei, fuse together in a perfectly normal fashion, but after cell fusion the organelles attack each other with savage ferocity. Within a couple of hours of fusion, the chloroplasts and mitochondria deriving from one of the gametes have been pulped to a swollen mass, and soon afterwards disintegrate altogether.

This is an extreme example of a general trend. The common denominator is an intolerance of the organelles from one of the two parents, but the method of extermination varies widely. Perhaps the most illuminating example is the single-celled alga
Chlamydomonas rheinhardtii
, which at first sight appears to buck the trend. Instead of destroying half its chloroplasts in a wanton display of violence, the chloroplasts fuse together peaceably. But biochemical scrutiny shows this alga is no more tolerant than its cousins; rather, it is more refined in its intolerance, like a cultivated Nazi. To use the correct, rather chilling euphemism,
Chlamydomonas
practices ‘selective silencing’: it eliminates the DNA in the organelles rather than the whole organelles, leaving the infrastructure intact. The organelle DNA from each parent attacks the other with lethal DNA-digesting enzymes. According to some reports, 95 per cent of all the organelle DNA is dissolved, but the speed of destruction is slightly faster on one side than the other. The surviving DNA, by definition, derives from the ‘maternal’ parent.

The upshot is that nuclear fusion and recombination are fine, but the organelles—the chloroplasts and mitochondria—are almost invariably inherited from only one parent. The problem is not with the organelles, but with their DNA. There’s something about this DNA that fate abhors. Two cells fuse, but only one of them passes on the organelle DNA.

Here lies the deepest difference between the sexes: the female sex passes on organelles, the male sex does not. The result is
uniparental inheritance
, which means that organelles, such as mitochondria, are normally inherited only down the maternal line, like Judaism. The realization that mitochondria are inherited only from the mother is not age-old knowledge: it was first reported
in 1974, in horse-donkey hybrids, by the geneticist and jazz pianist Clyde Hutchison III and his colleagues at the University of North Carolina.

Is this really the deepest difference between sexes? The best place to look for a reality check is at any apparent exceptions to the rule. We already noted, for example, that the mushroom
S. commune
has 28 000 mating types. These are encoded by two ‘incompatibility’ genes on different chromosomes, each of which comes in many possible versions (alleles). An individual inherits one out of more than 300 possible alleles on one chromosome, and one out of more than 90 on the other, giving a total of 28 000 possible combinations. If two cells share the same allele on either chromosome, they cannot mate. This is likely to be the case among siblings, which encourages out-breeding. However, if the gametes have different alleles at both loci, they are free to mate, and this allows them to mate with more than 99 per cent of the population, rather than a feeble 50 per cent like the rest of us.

But with all these sexes, how on earth do the fungi keep track of their organelles? Can they, too, ensure that organelles are inherited from only one of two parents? If so, with 28 000 sexes, how do they know which is the ‘mother’? In fact they solve the problem by engaging in a fastidious form of sex, a loveless fungal missionary position, and are zealous never to mix bodily fluids. Sex, for
S. commune
, is all about getting two nuclei into the same cell, and the cytoplasm never conjoins in blissful union: cell fusion does not take place. In other words, these fungi get around the sex problem altogether by evading the issue. While it can be said that they have 28 000 different sexes, it is better to say they don’t have any at all: they have incompatibility types instead.

Intriguingly, incompatibility types can coexist with sexes in the same individual, implying that these adaptations really do serve different functions. The best examples come from the flowering plants, or angiosperms, many of which, as we have seen, are hermaphrodites (the individuals are both male and female). In principle, this means that plants can fertilize themselves or their closest relations—and in practice, given the difficulties of dispersal faced by the sessile plants, this would be the most likely scenario. The trouble is that local fertilization favours in-breeding, thereby losing the benefits of sex altogether. Many angiosperms get around the problem by having incompatibility types as well as two sexes, ensuring that out-breeding takes place.

In principle, it’s possible to have more than two sexes, while maintaining uniparental inheritance. There are examples of this among primitive eukaryotes, notably the slime moulds, which fuse cells together into a matrix with numerous nuclei sharing the same vast cell. Slime moulds look similar to fungi, overgrowing woody mulch or grass as an amorphous mass; some bright yellow moulds have been likened to dog vomit. From our point of view, the most important aspect is that some of them have more than two sexes, even though
the whole gametes fuse together, not just the nuclei. The best known example is
Physarum polycephalum
, which has at least 13 sexes, encoded by different alleles of a gene known as
matA
. While looking the same, however, these sexes are not equal—their mitochondrial DNA is ranked in a pecking order. Upon fusion of the gametes, the mitochondrial DNA of the more dominant strain persists, while that of the subordinate strain is digested, and disappears completely within a couple of hours; the vacant sheaths are eliminated within three days of fusion. So uniparental inheritance is preserved despite the occurrence of multiple sexes. Presumably there is a limit to how high a pecking order can rise; it’s hard to imagine a hierarchy accommodating all 28 000 sexes of
S. commune
, for example. And in practice, more than two sexes is rare.

To draw a general conclusion, we can say that the act of
sex
involves nuclear fusion (and out-breeding can be enforced by having incompatibility types), but proper
sexes
can only be distinguished when cytoplasm is shared. In other words,
sexes
develop when the cells as well as their nuclei fuse. Then the female passes on some of her organelles, and the male must accept the untimely demise of all of his. Even when there are multiple sexes, uniparental inheritance of the mitochondria is the rule.

Why is uniparental inheritance so important? And why are multiple sexes so uncommon, given that they expand the mating opportunities and are technically feasible? The most widely accepted reason was developed as a forceful hypothesis by Leda Cosmides and John Tooby, at Harvard, in 1981. They argued that mixing the cytoplasm from two different cells creates an opportunity for conflict between different cytoplasmic genomes. These include both mitochondrial and chloroplast genomes, but also any other cytoplasmic ‘passengers’ such as viruses, bacteria, endosymbionts, and so on. If these passengers are genetically identical, there can be no competition between them; but as soon as they begin to differ, there is scope for competition to gain entrance to the gametes.

Consider, for example, two different populations of mitochondria, one of which replicates faster than the other. If one population becomes more numerous, it gains preferential entry to the gametes. The other population will be eliminated unless it speeds up its own replication, and to do so almost certainly means that it will fail to do its proper job, generating energy, as effectively. This is because the easiest way to speed up replication is to jettison ‘unnecessary’ genes, as we saw in
Part 3
; and the genes that are unnecessary for mitochondrial replication are of course exactly the genes that the cell as a whole needs for energy production. So competition between mitochondrial genomes leads to
an evolutionary arms race, in which selfish interests take precedence over the interests of the host cell.

The host cell inevitably suffers from competition between mitochondrial genomes, and this in turn generates a strong selective pressure on the genes in the nucleus to ensure that all the mitochondria are identical, thereby preventing such conflict. This can be achieved by the ‘selective silencing’ of one population, as in
Chlamydomonas
, but in general it is safest to preclude their entrance altogether; this simultaneously precludes competition between other cytoplasmic elements, such as bacteria and viruses. Thus, in this selfish theory, the reason that two sexes develop is because this is the most effective means of preventing conflict between selfish cytoplasmic genomes.

The male mitochondria don’t take their purging lying down. Any attempt to exclude them is met with stiff resistance. The angiosperms attest eloquently to the reality of selfish mitochondrial behaviour. In these hermaphrodite flowering plants the mitochondria strive to avoid being caged in the male part of the plant, a dead end for them because they are not passed on in pollen. They avoid ending up in pollen by sterilizing the male sex organs, usually by bringing about the abortion of pollen development. Not surprisingly, this is an important trait in agriculture, discussed at length by Darwin himself, and known rather forbiddingly as
male cytoplasmic sterility
. By sterilizing the male sex organs, the mitochondria convert a hermaphrodite into a female, thereby helping safeguard their own transmission. However, because this upsets the sex balance of the population as a whole, which now comprises females and hermaphrodites, various nuclear genes that counteract the selfish mitochondrial actions have been selected over evolution, restoring full fertility. The battle is still being waged. A trail of selfish mitochondrial mutants and nuclear suppressor genes shows that female conversion took place repeatedly, only to be suppressed each time. In Europe today, 7.5 per cent of angiosperm species are gynodioecious, to use the term Darwin coined—their population comprises both females and hermaphrodites.

Hermaphrodites are particularly vulnerable to male sterilization, because the female organs leave open the possibility of mitochondrial transmission in the same individual. But even when the male and female sex organs are housed in separate individuals, there are indications that mitochondria attempt to distort the sex balance by harming males. Some diseases, notably Leigh’s hereditary optic neuropathy, are caused by mutations in the mitochondrial DNA, and are more prevalent in men than women. This situation is similar to the action of
Wolbachia
in arthropods, which we noted earlier. In crustaceans, infection with
Wolbachia
converts males into females, but in many insects the effect is even more drastic: males are simply killed. The ‘objective’ of the bacteria, which are passed on from one generation to the next only in the egg, is to
convert the entire population into females, thereby improving their own chances of transmission. Mitochondria, too, can help safeguard their own transmission in the egg by eliminating males. Unlike
Wolbachia
, however, their success seems to be very limited. Presumably, this is because there has been a stronger counter-selection against selfish mitochondria. Fully functional mitochondria are essential to our survival and health, and selfish mutants are less likely to be effective at respiring. They are therefore likely to be heavily selected against.
Wolbachia
, in contrast, distorts the sex ratio but doesn’t necessarily cause much damage otherwise; accordingly, there is a lower selective pressure against it.

All these various attempts to subvert the sex ratio come about because mitochondria, along with other cytoplasmic elements such as chloroplasts and
Wolbachia
, are passed on only in the egg. The pressure to bend the rules has almost certainly polarized the existing differences between the sperm and eggs even further. For example, the pressure exerted by selfish mitochondria probably contributed to the extreme size difference between sperm and eggs. The simplest way to tip the scales against the selfish mitochondria is to stack the odds against them. There are some 100 000 mitochondria in human egg cells, but fewer than 100 in sperm. If the male mitochondria get into the egg at all (they do in many species, including ourselves), they are simply diluted out. But even dilution is not enough. Numerous tricks have evolved to exclude male mitochondria from the fertilized egg altogether, or to ensure the permanent silencing of the few that do get in. In mice and humans, for example, the male mitochondria are tagged with a protein called ubiquitin, which marks them up for destruction in the egg. In most cases, the male mitochondria are degraded within a few days of entry to the egg. In other species the male mitochondria are excluded from the egg altogether, or even from the sperm, as in crayfish and some plants.