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http://eprints.utas.edu.au/12671/

CHAPTER 10

RECENT INFORMATION ON THE MOLECULAR BIOLOGY OF DNA

The aim of science is to acquire not just information, but understanding - of what things are and why they happen.’ Thomas Nagel1

INTRODUCTION

No modern day theory of evolution could be complete without taking into account the data from

the recent discoveries in molecular biology, namely:

1. Repetitive DNA.

It transpires that there is a most unusual organization to eukaryotic DNA. Not only is there a

staggering large amount of apparently non-informational DNA present in eukaryotes, but much of it is

now known to be highly repetitive,2 often consisting of extremely small sequences repeated up to

millions of time.3 This repetitive DNA has been widely studied in the past few years, and certain

aspects of its organization and distribution within the genome are gradually becoming clearer, but its

function remains totally obscure. Some regard it as mere genetic ‘junk,’4,5 but there is increasing

evidence that at least part of it can be transcribed, and this may turn out to be important in relation to

the regulation of gene expression.6,7 its origins are even more obscure, and this is the major aspect

we will address in the present chapter, particularly the possible relationship to viruses

2. Non-coding DNA.

Genes in higher organisms are divided into exons separated by many segments of intervening

non-coding DNA. Both are transcribed, and the exons joined to form the final gene, with the

intervening mRNA being clipped out. Translated genes, which code for functional cell proteins and

enzymes, constitute a very small proportion of the total genome (less than 1.5% in humans.8 The

emphasis here will be mostly in the intervening sequences (Introns), and their possible origin as

viruses or other mobile genetic elements.

3. Non-coding mRNA regulation of gene expression.

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relate to viral influences on evolution, and whether it can be seen in any way as being truly

‘epigenetic.’

1. REPETITIVE DNA

A great deal of DNA in eukaryotes consists of repetitive nucleotide sequences. Some is

transcribed into RNA, but very little is translated into protein. Repetitive DNA can contribute up to half

of total genomic DNA.9 In general, is restricted to eukaryotes.2 Two broad categories have been

defined, termed interspersed repetitive DNA and highly repetitive DNA respectively.

Interspersed Repetitive DNA

Background

This class of repetitive DNA consists of multiple copies of variable length nucleotide sequences is

widely dispersed throughout the genome, largely outside genetic sequences,10 and constitutes up to

as three quarters of total repetitive DNA.11 Its periodicity, sequence length, and pattern of dispersal

vary between different species and with different repetitive sequence types, but the amount and copy

number of any particular family usually remains fairly constant within any one species. It is organized

largely as single copies of the repeat sequence spaced at fairly regular intervals between coding

stretches of genetic DNA,10 but may occur in long tandem arrays of repeats clustered at particular

genomic sites,10,12 similar to the organization of highly repetitive DNA discussed below. Different

species, of drosophila for example, contain different copy numbers of repeat ‘families’ or consensus

sequences, and even different strains among the same species can have different members of these

repeats located in quite different chromosomal positions, as if they wander about in an almost

‘nomadic’ way.13 Nonetheless, if we take this ‘consensus’ view of these repeats, the number of

different families within species reduces to the relative few, for example eight in drosophila,13 and

one dominant family in both rodent and primate species viz., the Alu 1 family.10 It is also possible to

discern similarities between the consensus sequence families of different species, as in the close

homology between the dispersed Alu 1 repeats of rodents and primates.10

Despite the above, it has to be said that this grouping of dispersed repetitive DNA into families of

common consensus sequence often hides an enormous amount of sequence variability within any

‘family’ unit. This even includes a variability between different individuals of the same species.10

Moreover, much of this variation is of a non-random type, with some sections of the Alu 1 consensus

sequence in man, for example, apparently being much freer to vary than others over its different

genomic locations.10

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In the first edition of this book, I spent much time and space discussing this, and concluded that it

could be explained as being of viral origin. This arose partly from the finding that differences between

sequences, for example the Alu 1 consensus sequences of primates and rodents, seemed often

related more to insertional events than random point-mutational change.10 It also became

increasingly clear that a good deal this repeat DNA was very mobile within the genome,10,13 in

keeping with a ‘viral’ view.

It is now evident that most interspersed repeat DNA is indeed derived from viruses or viral

elements. The most prominent among these is the retroviral group of viruses and their subunit mobile

elements. The human integrated endogenous retrovirus group is the classic case, with integration

being either of complete sequences as so-called HERVs (mostly replication-defective), or of their

subunits - the LTR retrotransposons, the non-LTR retrotransposons (L1 elements), and the short

Alu1 elements. Kazazian14 has summarized these in detail, not only in regard to their ability for

internal retrotransposition and mobility around individual genomes, but also the prospect they hold for

horizontal transfer as potential ‘drivers of genome evolution’. Accepting this latter point, others have

taken the necessary further step of attempting to explain the means by which such horizontal genetic

transfer from one individual or species to another might be realized. Gilbert and colleagues have

proposed that parasites might be the vehicle of transmission,15 and Schaack and colleagues16 have

extended this further by suggesting that transposon DNA could be directly transferred by parasites

via exchanges of blood and saliva during feeding.16 However, it is one thing to transfer DNA in

secretions, and quite another to have it taken up and dispersed around the entire cellular DNA of a

new host, including the germ line. A common salt lick hardly seems adequate to such a task.

My own view, already discussed in chapter 9, is that viruses mediate such horizontal transfer. In

the case of subunits of retroviral elements, this might well be done by the parent retrovirus itself, but

when these eventually become replication-defective other viruses can carry out the task equally well

– for example, the adenoviruses.17

Highly Repetitive DNA

In contradistinction to interspersed repetitive DNA, this repeat DNA class is highly clustered at

localized sites within the genome, in long tandem arrays.18 Highly repetitive DNA represents a large

proportion of the total,11 sometimes over 50%.19 The basic repeating sequence is often extremely

simple,3 sometimes only a few base pairs long. But within each clustered array there is usually a

longer-range periodicity, sometimes extending over several thousand base pairs, and consisting of

many different versions of the same fundamental short repeating ‘consensus’ unit.20 One surprising

finding in this respect is that there is often a much closer degree of hybridization matching between

these longer-period repeats than between the different versions of the short unit of which they are

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units are themselves usually ordered within longer-periodicity repeats in a very precise and highly

non-random way.20-22

Satellite DNA

This consists of very large arrays of short base pair nucleotides arranged as thousands, even

millions, of tandemly repeating, non-coding DNA. It is the main component of centromeres, and the

main structural constituent of heterochromatin. Satellite DNA is extremely variable, not only in

nucleotide sequence, but also in the repetition number and location of family members within the

genome - even within individual species.23,24 If we accept a ‘consensus’ concept of the resulting

tandem arrays as sequence variation on a common theme, the number of satellite ‘families’ within

any one species can usually be reduced to a relative few. However, as with interspersed repeat

DNA, this should not be allowed to obscure the fact that within each family there are characteristically

many different sequence versions both within and between species.23,25,26 Moreover, as with other

highly repetitive DNA, these different versions are not infrequently organized in the longer units in a

rather precise and characteristically nonrandom way.20,27

Satellite DNA distribution within and between species is complex. Even closely related species

can show enormous differences in their satellite DNA. An extreme case exists in the kangaroo rat

species, where D. deserti appears to carry none of the three satellites which make up more than 50%

of the closely related D. ordii species.28 On the other hand, consensus sequences can be very similar

in the satellites of distant species - even as far apart as (kangaroo rat and guinea pig,28 or drosophila

and man.23,28,29 Importantly, many such sequences often seem to disappear at some stages of

evolution only to reappear later at others as the species lines are followed over evolutionary time.28

Even more perplexing is that different versions of the same consensus sequence within the tandem

arrays of any one satellite can show enormous variation in the repeat sequence, and with a variation

that can be highly non-random. I will now look at the generation of these sequences a little more

closely.

In an attempt to explain the variation of sequence type, as well as amount, within satellite DNA

between species,28 put forward the suggestion that related species, whilst often appearing to carry

entirely different satellites, each actually contain all of the different satellites characteristic of the

species group, as if sharing them all from a common ‘library’ of sequences, but in vastly differing

amounts. According to this view, differences in satellites between related species would be more

quantitative than qualitative, and be due to particular sequences being ‘amplified’ to abundance in

some species and ‘contacted’ to below the limit of detection in others. Dover and Coen30 have

suggested a similar ‘spring-cleaning’ process for amplification and contraction, drawing parallels from

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‘conversion’ where new sequences were exchanged for old. Drawing on parallels between

interspersed repeats and transposable elements, they postulated further, that repeated transposition

of new sequences led to its subsequent spread throughout the genome, in a process they termed

‘concerted evolution.’30

Dover and colleagues’ concept of the mechanism of change in repetitive DNA between species

has also been useful, particularly as it incorporates the (retro-) transposon nature32 of many

interspersed repeats. However, it is inadequate alone to account for all aspects of variation within

interspersed repeat DNA for several reasons. First, though it may give an explanation of how new

sequences might be amplified and spread throughout the genome, it does not explain at all how

pre-existing sequences are removed in the way they imply. Second, transposition would normally be

expected to produce identical copies of the transposed units at each of the different genomic sites or,

at the very most, randomly varying ones. And though such uniformity may be seen among, say, the

non-transcriber repeats (NTS) of ribosomal spacer DNA,30 it is not the case for most satellite DNA.

Third, the NTS sequences themselves are interrupted by multiple insertion elements that seem to be

totally impervious to the proposed conversion process.30

Despite all this, there is no doubt that the analogy Dover and Coen30 have drawn between the

‘concerted’ nature of the evolutionary processes which lead to the replacement of interspersed

repetitive DNA, and ‘spring-cleaning’, does capture the essence of the dramatic genomic change

underlying the variation in this repetitive DNA class. In addition, something akin to transposition

would undoubtedly be a good explanation for how the pattern of dispersal of any given consensus

sequence family may vary markedly both between related species, and between different strains

among the same species — almost, in the case of some long-period interspersed repetitive DNA, as

if they were indeed ‘nomadic.’13 What is needed is to find a process that would yield similar

transposition events between individuals and species, so that library sequences could be borrowed

across a larger scale. If we could understand that, it might even be possible to develop a unifying

concept for repetitive DNA in general, because the two repetitive DNA classes are often closely

intermingled.30,33,34

AViral Theory of repetitive DNA Origin and Change

I suggest here that most of the puzzles of satellite and other repetitive DNA could be explained if

they arose and evolved by viral DNA sequence uptake and interchange between viruses and host.

Larger partial sequences in repetitive DNA could arise either from viral transduction35 — where

imprecise excision allows sequences from the viral integration site to be exchanged between virus

and host — or from internal viral sequence exchange, either by direct transfer of sub-unit mobile

elements from viruses, or by double crossover recombinational exchange between corresponding

segments on viral mobile element and host. This could explain how longer repetitive units such as

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repetitive DNA.33,34,36,37 It would account also for the non-random ‘patchwork’ nature of much satellite

and other DNA build-up.21,38-42 Sometimes such accumulation appears in ‘transposition bursts’ as an

extremely rapid process in evolutionary terms.43-45

The heterochromatin location of satellites may mean that any mobile element insertion there

could be relatively innocuous. This has two consequences. First is could be a convenient launching

ground for genetic experimentation, in that transferred sequences could subsequently be moved

elsewhere in the genome ‘on approval’ and even amplified in the process. Second, mobile element

insertion and excision generates short base pair repeats46-48 and, in recurrent bouts, this could

account for much of the short highly repetitive base pair sequences that constitute most satellite

DNA. Different mobile elements can have different sites of preferred DNA insertion and excision, as

in ‘transposition memory,’44 and this could lead to variations in short base pair repeats with each new

episode and hence to the apparently non-random consensus sequence build-up of much satellite

and other repetitive DNA.49,50

Such a theory could account for a great deal of the behavior of repetitive DNA in general. The

existence of the various sequences of repetitive DNA in multiple copy number could now be related

to the recurrence of viral infection with each new host generation over the long evolutionary

time-period the virus remained in an infective relationship with the host species. Differences in repetitive

DNA location from one individual to another among a species could be explained by the occurrence

of different viral integration sites with each new host-infection. In addition, variability of repetitive

DNA, including satellite consensus sequence type, might well be due to molecular evolution within

the virus itself, and as such it would not be surprising if, being determined by selective mechanisms,

it were of a non-random nature. On the other hand, the absence of particular repeat sequences from

one of a group of related species could now be explained by the failure of a particular virus to interact

with the species concerned, either because of the lack of an appropriate receptor for the virus, or

because that species was not exposed to the virus by virtue of its being located in some different

geographic ecosphere distribution. Occasionally, the absent sequences might have been deleted by

homologous recombination via direct repeats at the ends of some satellite sequence block. This

might occur, for example, when two insertion sequences, known to exist in at least some satellites,37

happened to become incorporated into satellite DNA in such a way as to flank a stretch of its

oligonucleotide tandem arrays. The whole block of intervening satellite could then be removed, either

by its transposition into some virus resident at the time, or by the formation of (circular)

extra-chromosomal DNA with subsequent gradual deletion from the progeny line of descent.

Generally speaking, we would expect that related species, particularly those evolving within the

same geographic area, would interact with similar viruses, so it would not be surprising if the build-up

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‘library,’ as Fry and Salser proposed.28 But, according to the present viral view, it would no longer be

necessary to postulate that all members of any related group of species contained all of the library

sequences because interactions with different viral forms might well produce different types of

repeatedly-integrated sequences. In addition, whilst the sharing of similar sequences between

distantly related species might sometimes indeed be due to a long evolutionary history of sequence

conservation through traditional evolutionary mechanisms, on the present basis it might also reflect

the two species merely having belonged to the same general host/virus ecosphere at some stage of

their evolution, and not necessarily a distant one in evolutionary time. Even in the case where the

original sequence did arise remotely in time, subsequent and very real conservation over long

evolutionary periods need not reflect any importance that sequence had for the host species itself,

because it could relate to the continuance of some important viral function, or to a function in some other host species with which the virus was in separate genetic contact. Because this would mean

that sequence conservation might often be due to an existence that sequence had entirely outside

the species under consideration, it could also explain the paradox of how some repeated DNA

sequences come to be deleted after long evolutionary conservation with relative impunity.

Most of the longer sequences incriminated here in the development and evolution of

repetitive DNA are segments of retroviruses. Apart from HIV viruses, these are no longer as active as

they once were. “So”, it might be asked, “Where are the vehicles for continuing repeat sequence

mobile element transfer and interchange between individuals and species in the manner proposed?” In this respect, a number of DNA viruses have been shown capable of taking up into host repetitive

DNA elements. This includes the Epstein-Barr virus,51 the papovavirus,52 a mutant adenovirus SV40

virus,53 and the SV40 virus.54,55 Indeed, Rosenberg and colleagues55 have observed that when SV40

is grown on monkey kidney cells, there is repeated incorporation of primate alpha satellite DNA

sequences into the virus such that viral variants eventually arise consisting mostly of satellite DNA.54 Of course, these are examples of incorporation of host sequences into virus rather than the reverse,

but there is evidence for the opposite process as well. Thus, primate repetitive DNA has now been

found that contains sequences of close homology with the replication origins of the SV40 virus56 and

the paparvoviruses.52 Even replication-defective adenoviruses can be a vehicle for the integration of

retroviruses into human cell lines,17 so that the process for continuing foreign mobile element uptake

and integration as repetitive DNA might sometimes hinge on something as simple as a common cold.

Come to that, it seems that simple RNA viruses can occasionally be reverse transcribed by cellular

reverse transcriptases,57 so broadening the potential range of intercommunication between viruses

and higher life forms

.

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The second surprise in the field of molecular biology during modern times has been the finding

that individual genes are broken up into pieces called ‘exons’, each of which codes for a particular

domain or segment of the total protein molecule, and each one of which is separated from the next

by non-translated intervening sequences called introns. The process of intron removal is referred to

as ‘gene-splicing,’ where the sub-unit gene ‘exons’ are joined together to form the final messenger

RNA. Introns are located in a wide range of genes, including those generating proteins, ribosomal

RNA (rRNA), and transfer RNA (tRNA), and moreover even in species as primitive as

bacteriophages.58 At the time of their discovery,59,60 none of this made any sense. Many aspects

have since become clearer.

The mechanism of gene-splicing differs with different introns, and interestingly RNA enzyme

catalysis plays a role in them all.

The most primitive are the group I self-splicing ribozymal introns - i.e. with RNA enzymes rather

than protein - that catalyze their own excision (as simple circular RNA) from mRNA, tRNA and rRNA

of relatively simple organisms such as bacteria, protozoa, and lower eukaryotes.61 The intron ends

are brought together preparatory to splicing by base pairing of internal guide RNA sequences with

the downstream exon.

Group II introns occur in somewhat higher life forms. The yeast mitochrondion provides the

classic example.62 Here, the intron is excised in two stages, the first being formation of an internal

loop, and the second the excision of the whole intron, but now as a lariat structure.62 Catalysis is

again directed by RNA ribozymes. A conserved sequence UACAACC box within the intron specifies

the branch point for lariat formation via U2 complementary base pairing binding. (Reviewed by

Robertson63)

Pre-messenger nuclear RNA excision extends this mechanism. Here, the intron is again first

folded into a lariat structure using sequence complementarity, but the actual splicing is done by a

more complex ribonucleoprotein or ‘spliceosome.’ Lariat removal involves U1, U2, U4, U5 and U6

short RNA sequences. U1 binds at the U5 junction and U2 binds at a consensus sequence of about

30 nucleotides from the 3’ junction where ‘U2AF’ binds. In the second step, U1 and U2 come

together with U4, 5 and 6 and the free lariat is generated, with U6 being particularly important for final

intron excision.64 This has all been reviewed well elsewhere63,65

A Viral Theory of Intron Origin

I suggest that the whole process of gene-splicing and intron origin could be explained if it reflects a

long history of life evolving as the gradual build up of viruses, as I envisaged at the outset, even

before introns were described.66 In an extension of this initial view, such introns would be seen as

being established on the basis of RNA viroid/viral inserts into host in earliest RNA world,67 followed

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transcription and the retroviruses. On this basis, the finding of ‘genes in pieces’68 would reflect the

essence of the way life has evolved over the eons - by the ad hoc ‘experimental’ shuffling of genetic

modules, but a shuffling now based on non-random genetic change due to prior evolution within the

viral modules themselves. And the increasing evidence is that introns exist even in the most primitive

life forms, including bacteria,69-71 viruses,59 and even simple phages,58,72 so this kind of basis for

evolutionary progress is well established.

In respect to early life forms, some of the nucleotide sequences in simple viroids bear a striking

resemblance to primitive group I introns,73,74 particularly at intron ends.75,76 These group I introns are

removed as circular structures very reminiscent of viroids, and often behave as mobile genetic

elements.77,78 They encode sequence specific DNA endonucleases, and so are quite capable of

transposing to other genomic sites via direct DNA transfer.77,79

Higher level (group II) introns are able to reverse RNA-splice themselves into other RNA,80,81 and

they display a remarkable similarity to retroviral reverse transcriptases,82,83 even to the extent that

they can be regarded as ‘infectious.’84

Things get rather more complicated higher up the evolutionary scale, but there are strong

indications here, too, that introns retain a capacity for mobility. It is clear, for example, that many

nuclear messenger RNA introns contain sequences of close homology with DNA repetitive

transposable elements85 such asAlu1,86,87 and even retroviruses.88

Evolutionary origin of introns

There are two opposing views on this: ‘Introns early’, and ‘introns late.’(See Sharp89) Needless to

say, the present thesis is more closely aligned with the ‘introns early’ view. And there is increasing

evidence this is the case.70,72,78,90

Particularly because they can be so mobile, introns might be seen as being

potentially disruptive to the genome, and therefore to the species. However there are probably ways

of limiting this,14,91 and on the other hand they offer important evolutionary advantages because of

being ‘silent’ host genetic areas into which foreign DNA can harmlessly be inserted via transposition

and retrotransposition. And after such incorporation, that DNA could itself subsequently be

transposed, almost ‘on approval,’ to other sites on the host genome without overwhelming it

randomly with new DNA information at any one time.

Such a process could also facilitate the entry and incorporation of sophisticated genetic material

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experimental inserts, and the genetic shuffling arising from them, might well be disadvantageous,

and because of this many would no doubt be deleted, or suppressed,92 over evolutionary time. But as

I see it, this would be more than offset in evolutionary terms by the continuingly offering an

evolutionary advantage to both virus and host species.

Nature seems to me to be essentially opportunistic, and as such, it would be surprising indeed if

the various species did not take full advantage of any genetic information available to them from

other individuals and species, particularly that which had already been ‘processed’ in some host/virus

ecosphere elsewhere. Genetic ‘shuffling’ along these lines could offer enormous mutual benefit to

both host and viral species. In recent years, it has become increasingly recognized that DNA within

the eukaryotic genome has a high degree of mobility, and in some ways all I am suggesting here is

that this mobility may extend far beyond the individual.

It will be noted that the present view puts a marked emphasis on a co-operative aspect to Nature

during evolution. This is not to say, however, that the struggle for survival does not occur at the level

of the individual in the way Darwin envisaged. Indeed, it clearly does, but that does not deny, either,

the importance the present mechanism offers to the evolution of species as a whole, by the

interchange of pre-processed genetic material ‘on approval,’ as the basis for non-random mutational

change. In this context, co-operation between organisms in evolution seems to me to have been

given far too little credence in evolutionary mechanisms till now.

3. NON-CODING RNA REGULATION OF GENE EXPRESSION

The final aspect of recent interest concerning non-coding DNA is its importance in the regulation

of gene expression

Although some introns are now known to be translated into enzymes important in the

processing of other introns within the same or different genes,93 the function of the vast bulk of

intervening sequences and repetitive DNA remains obscure. In this respect, it is interesting that

Britten and Davidson94 suggested many years ago that dispersed repetitive DNA sequences within

the eukaryotic genome might well be important in gene regulation and, compatible with their view,

they subsequently showed that the initial mRNA transcripts arising from these DNA repeats were

often expressed in different ways, not only at different times during evolution, but during different

stages of individual development, even within different tissues from the same individual.6 Now, that

finding has turned out to be most perceptive. Since that time, many discoveries about non-coding

RNA have been made,95 and is now clear that it has a vital role in regulation of gene expression, 96-99

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Epigenetics

Finally, a word on epigenetics.

Because non-coding DNA is now known to have important functions in regulating DNA

expression, there is a tendency refer to it as epigenetic. Now, the influence of non-coding DNA/RNA

is certainly outside the exome (exon component of the genome), but it is still part of the DNA we

inherit. The problem is that term epigenetic means different things to different investigators,100 and it

sometimes carries more than a hint of neo-Lamarckism. Now, that may sometimes be the case,43,101

in the way Steele originally envisaged.102 But there is no reason to think, de novo, that the

environment is any more likely to influence non-coding RNA than the exomic coding DNA. Even

when it does,7 we should not assume that such influence will be transmitted through the germ line.8

Despite clear examples of epigenetic inheritance,103-105 we need to be careful not to extend this

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UNIFIED THEORY OF MECHANISMS IN STRESS, DISEASE AND EVOLUTION

Our discussion on evolutionary mechanisms in the latter chapters of this book has emphasized

the importance of viral infection, virus/host genetic exchange, and genomic DNA mobility in general,

as a driving force for evolution. However, I have alluded several times to the fact that the genomes of

most species, includes their integrated viral material, are normally fairly stable, unless and until the

cell DNA is damaged or disrupted in some way. Then, these viral elements can become activated to

promote genetic immobility and disseminate overt viral disease. In lower organisms, the stress

leading to this activated state is normally thought to be in the nature of physical damage. However, in

higher organisms, endowed with a vascular system, there is also the possibility that cell damage may

be induced by ischemia, and from our earlier theory we can recognize that this could, in turn, be

readily brought about by stress-induced activation of the sympathetic nervous system.

This extended view therefore allows us to complete the circle to a unified hypothesis of the

importance of stress-induced ischemia, namely that it may not only cause disease but, by activating

(germ-line) endogenous viral material, may provide a strong driving force underlying evolution itself.

So although individuals may be the worse for endogenous viral activation, the species to which

they belong may be the better for it in terms of their evolution. The situation may perhaps be likened

to battle, where the invaders, under the provocation of stress, may conquer and defeat individuals.

Then, though initially hostile as prisoners, they may eventually become reconciled with, and

integrated into, the new community to add their own strengths and talents. In the same way, it may

well be that despite their propensity to maim and kill individuals, endogenous viral materials,

activated from their genomic reservoirs by stress of whatever sort, may eventually offer long term

evolutionary advantage to species concerned. Perhaps, therefore, immunologists may not be the

only ones to have their Generators Of Diversity, and that just as no man is thoroughly bad, even the

Damaging Effects of Viral Infection on Life can on occasions be Generators Of Orderly Diversity.

Finally, if viruses are part of our being, we cannot, and perhaps for the sake of our evolution,

should not, hope to prevent all viral infection and viral-related disease. But we should at least be able

to limit their adverse effects by preventing that cell damage from stress and other causes which

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