[Paleopsych] is evolutionary change stockpiled?
HowlBloom at aol.com
HowlBloom at aol.com
Tue Nov 23 07:27:45 UTC 2004
There's a lot of material to back Greg up on "cryptic evolution"--evolution
of the genome that takes place in hiding, not revealing itself in changes of
the body of a creature. There's also a lot to back him up in his notion of
endogenous retroviruses--retroviruses packaged as part of the genome, then used by
the genome as domesticated transport animals when the time is ripe.
And there's quite a bit to back up Joel's suspicion that the genetic shuttles
of endogenous retroviruses and the hidden products of genetic research and
development are tucked away in that horribly mislabeled stuff called junk dna.
Here's more than you ever wanted to read on the topic. Howard
http://news.bmn.com/news/story?day=010705&story=1, downloaded 7/6/01
- 5 July 2001 Today's News Stories News Archive When three steps forward
is one step back 4 July 2001 17:00 GMT by Henry Nicholls, BioMedNet News
Research published tomorrow further enhances Lewis Carroll's reputation as a
closet evolutionary biologist by revealing, in an exceptional analysis according
to some specialists, how genetic evolution can fail to keep up with a changing
environment. Such "cryptic evolution", so called because the evolving
genotype is masked by an apparently unresponsive phenotype, could be widespread in
nature, says the Finnish researcher who led the work. The analysis focuses on
a 20-year study of an isolated bird population, reports Juha Merilä, senior
researcher in the department of ecology and systematics at the University of
Helsinki. Collared flycatchers, Ficedula albicollis, on the Swedish island
of Gotland have evolved genes to increase their body mass as the birds'
environment has deteriorated, but they are losing weight. "Quantitative genetic
theory predicts that the relative body mass of flycatcher offspring, which is a
heritable trait under positive directional selection, should increase over
time, but the relative mass at fledging has actually decreased," Merilä told
BioMedNet News. "Our results suggest that if today's flycatcher chicks were to
experience a similar environment as the ones that lived in the early 1980s,
they would be much fatter than they are today," he said. "I would not be
surprised if this [cryptic evolution] turned out to be common," he added. "We
should realize ... that similarity in character state in time or space does not
mean that evolution has not occurred. A lot of evolution might be of this
cryptic nature and we will keep on overlooking it unless we focus more on
similarities, rather than exclusively on dissimilarities in character state,"
warned Merilä. "To my knowledge, this is the first time we have managed to
demonstrate occurrence of cryptic genetic evolution over a relatively short period
of time in the wild," he said. The work impresses Peter Boag, professor of
biology at Queen's University in Ontario. "The really unique feature of this
study is that rarely has anyone collected sufficient data from a real world,
wild vertebrate population to allow a believable dissection of this complex web
of interactions," noted Boag. Merilä readily drew a parallel between his
findings and the Red Queen Hypothesis, which originates from Carroll's Through
the Looking Glass. "To my mind, the Red Queen metaphor is a fascinating and
an intuitive way of thinking about evolution," he acknowledged. Leigh Van
Valen, now professor of ecology and evolution at the University of Chicago,
famously drew on Carroll's fantasy tale, and in particular the Red Queen's advice
to Alice that "it takes all the running you can do to keep in the same
place", as a metaphor for evolution. In 1973, he proposed that in a changing
environment, organisms must evolve just to maintain their fitness. The hypothesis
is most commonly cast in terms of two organisms, such as the co-evolution
between a parasite and its host. As the parasite evolves novel ways of
exploiting its host, selection favours the host that evolves novel ways of defending
itself against the parasite. Over an evolutionary timescale, both parasite
and host will have evolved and yet their relationship might not have changed -
neither will appear to be any more successful at outwitting the other.
However, in an interview with BioMedNet News, Van Valen pointed out that "the Red
Queen's Hypothesis can easily apply to abiotically caused deterioration, which
isn't usually realized," and he agreed that Merilä's flycatchers seem to be
subject to the paradox of the Red Queen. "The [flycatchers'] response to
selection isn't enough to prevent the population from deteriorating," he noted.
"All the running [the flycatchers] can do isn't enough to keep [them] in the
same place... It's pretty persuasive and fascinating [research]," he said.
Merilä speculates that a large-scale climatic trend could underlie the
worsening environment that the flycatchers are experiencing. "Increased spring
temperatures have led to increasingly poor synchronization between the hatching
date of caterpillars and the date of bud-burst of the oak trees on which they
feed," he writes in this week's issue of Nature, published tomorrow. This is
bad news for the flycatchers, notes Merilä, because caterpillars are the main
source of food for growing nestlings. And it raises the evolutionarily
interesting question of "how far can [the flycatchers] lag behind before they have
to give up the race?" Merilä concluded: "This strengthens my belief that
long-term population studies can be immensely valuable for both evolutionary and
environmental biologists, especially now that we seem to be entering into an
era of rapid environmental changes caused by anthropogenic activities...
These studies can be a valuable resource in the future." Send us your feedback.
Printer ready version E-mail article to a friend See also: Warmer
springs disrupt the synchrony of oak and winter moth phenology. [MEDLINE]
Visser ME, Holleman LJ Proc R Soc Lond B Biol Sci 2001 Feb 7 268:1464
289-94 Parasites, predators and the Red Queen [News and Comment] Koen
Martens and Isa Schön Trends in Ecology & Evolution, 2000, 15:10:392-393 In
Search of the Red Queen [Comment] M.E.J. Woolhouse and J.P. Webster
Parasitology Today, 2000, 16:12:506-508 In Search of the Red Queen: A Response
[Letters] Curtis M. Lively and Mark F. Dybdahl Parasitology Today,
2000, 16:12:508 Heritable variation and evolution under favourable and
unfavourable conditions [Review] Ary A. Hoffmann and Juha Merilä Trends in
Ecology & Evolution, 1999, 14:3:96-101 Related links on other sites: The
Red Queen: Sex and the Evolution of Human Nature by Matt Ridley
Paperback - June 1995) Amazon.com Printer ready version E-mail article to a
friend Today's News Stories News Archive
05 July 2001 Nature 412, 76 - 79 (2001) © Macmillan
Publishers Ltd. Cryptic evolution in a wild bird population J. MERILÄ*, L. E. B.
KRUUK† & B. C. SHELDON‡§ * Department of Population Biology, Evolutionary
Biology Centre, Uppsala University, Norbyvägen 18d, SE-752 36 Uppsala, Sweden †
Institute of Cell, Animal and Population Biology, University of Edinburgh,
Edinburgh EH9 3JT, UK ‡ Department of Zoology, University of Oxford, South Parks
Road, Oxford OX1 3PS, UK § Department of Animal Ecology, Evolutionary Biology
Centre, Uppsala University, Norbyvägen 18d, SE-752 36 Uppsala, Sweden
Correspondence and requests for materials should be addressed to J.M. (e-mail:
juha.merila at ebc.uu.se). Microevolution is expected to be commonplace, yet there are few
thoroughly documented cases of microevolution in wild populations1, 2. In
contrast, it is often observed that apparently heritable traits under strong and
consistent directional selection fail to show the expected evolutionary
response3, 4. One explanation proposed for this paradox is that a genetic response
to selection may be masked by opposing changes in the environment5, 6. We used
data from a 20-year study of collared flycatchers (Ficedula albicollis) to
explore selection on, and evolution of, a heritable trait: relative body weight
at fledging ('condition'). Despite consistent positive directional selection,
on both the phenotypic and the additive genetic component (breeding values,
estimated from an animal model) of condition, the mean phenotypic value of this
trait in the population has declined, rather than increased, over time. Here we
show that, despite this decline, the mean breeding value for condition has
increased over time. The mismatch between response to selection at the levels of
genotype and phenotype can be explained by environmental deterioration,
concealing underlying evolution. This form of cryptic evolution may be common in
natural environments. If selection acts consistently on a heritable trait in a
population, it should, all else being equal, induce a permanent change in the
distribution of that trait7. The frequent lack of expected evolutionary change
in heritable traits under directional selection in the wild has therefore
puzzled evolutionary biologists for some time. Explanations proposed to account
for this paradox include: inflated estimates of heritability owing to
environmental covariance between relatives7, spatially and temporally varying selection
pressures8, negative genetic correlations between different components of
fitness8, and selection restricted to the environmental component of the
phenotype3, 4. Another possibility is that a genetic response to selection does in
fact occur, but is masked by opposing changes in the environment5, 6. However, to
date, these alternatives have been subjected to very little empirical
scrutiny8. In many passerine bird species, relative body mass (the condition index)
is an important predictor of the survival of fledglings: relatively heavier
nestlings are more likely to survive to become breeding adults9-11. This is also
true for juvenile survival in other taxa, such as reptiles12 and mammals13.
In the collared flycatcher, quantitative genetic analyses using traditional
methods suggest a significant additive genetic component to variation in the body
condition index14. Mixed model analysis of variance using data for 17,717
offspring in 3,836 breeding attempts, from a long-term study of this species on
the island of Gotland, Sweden, confirms this finding, revealing a narrow-sense
heritability of 0.30 (standard error, s.e. = 0.03; ref. 15). Analyses of
survival selection show that there is significant positive directional selection on
condition, such that the survivors are, on average, 0.23 (s.e. = 0.02; P <
0.001) standard deviations above the population mean (Fig. 1a; ref. 15). In some
years (6 out of 17), there is also significant stabilizing selection acting
on condition, but this is both weaker and less consistent than the directional
selection (Fig. 1b). Given that the condition index is heritable and under
positive directional selection, we would expect the mean in this population to be
evolving towards higher values. However, in contrast to this expectation, the
mean condition in the population decreased significantly between 1981 and
1999 (linear regression of annual means: b = -0.036, s.e. = 0.015, t15 = 2.35, P
= 0.032; Fig. 2a; generalized linear mixed model (GLMM) of individual values,
controlling for family structure and non-independence of observations from the
same year: b = -0.035, s.e. = 0.003, t16,057 = 10.25, P < 0.001). Figure 1
Patterns of natural selection on condition index of nestling collared
flycatchers from 1981 to 1998. Full legend High resolution image and legend (46k)
Figure 2 Changes in condition index over time in the collared flycatcher
population from 1981 to 1999. Full legend High resolution image and legend (46k)
One plausible explanation for the lack of response to selection is that it is
predominantly the non-heritable, or environmental, component of the condition
index that determines survival3, 4, such that natural selection does not act
on the genetic component of variation in condition. A role for environmental
variation in natural selection is suggested by the observation that selection
tends to be strongest in years when the mean condition is lowest (linear
regression: b = -0.315, s.e. = 0.079, t15 = 4.24; P < 0.001; Fig. 1c). However, a
direct test is to calculate selection on estimated breeding values, or the
expected effect of the genes that an individual passes on to its offspring, which
can be derived from pedigree information7. This analysis shows that selection
acts directly on breeding values (standardized selection differential, S = 0.14,
s.e. = 0.02, P < 0.001), not only on environmental deviations15. Furthermore,
there is no evidence that a response to selection on condition would be
constrained by negative genetic correlations with other fitness components. Both
individual life-span (LSP) and lifetime reproductive success (LRS) are
positively correlated with the breeding values for condition (GLMM: LSP, 2(1) = 9.88, P
= 0.002; LRS, 2(1) = 21.42, P < 0.001; Fig. 3), and the genetic correlations
between condition and LSP and between condition and LRS were 0.009 (s.e. =
0.151) and -0.066 (s.e. =" 0.265), respectively: neither of these correlations
was significantly different from zero. Figure 3 Associations between key life
history traits and estimated breeding values (EBVs) for condition. Full legend
High resolution image and legend (58k) An alternative explanation for the
apparent paradox "the absence of any evolutionary change despite significant
directional selection on a heritable trait—lies in the possibility of change in
environmental conditions over the study period5, 6. This explanation runs
parallel to that suggested to account for the apparent lack of genetic
differentiation across environmental gradients when such differentiation is expected—a
phenomenon referred to as countergradient variation16 (Fig. 4a).
Countergradient variation is defined as a negative covariance between the environmental and
genetic influences on a given trait across some environmental gradient, and it
can effectively conceal genetic differentiation when the environmental
influence is sufficiently strong16. In the context of the current study the
countergradient hypothesis would predict that, at the genotypic level, there should be
a positive correlation between year of the study and condition index. Using
estimated breeding values we found that the mean estimated breeding value had
indeed increased over the course of the study (linear regression of annual
means: b = 0.0022, s.e. = 0.0009, t15 = 2.38, P = 0.030; GLMM of individual
values: b = 0.0023, s.e. = 0.0008, t16,057 = 2.70, P = 0.007; Fig. 2b). Hence,
despite the negative trend at the phenotypic level (Fig. 2a), at the level of the
genotype the population mean condition index has increased over time. Figure 4
Environmental deterioration over time. Full legend High resolution image
and legend (41k) The estimated microevolutionary change has presumably been
concealed by an increasingly negative influence of environmental conditions on
the condition index (Fig. 4a), which has caused the phenotypic decline. The
intensity of selection on the condition has increased with time (linear
regression: b = 0.015, s.e. = 0.007, t17 = 1.99, P = 0.06; Fig. 1d), and fledging
success has decreased with time (Fig. 4b; linear regression: b = -0.011, s.e. =
0.003, t18 = 3.19, P < 0.005). Both relationships are indicative of environmental
deterioration. A plausible agent explaining this deterioration is the
large-scale climatic trend that has reduced the caterpillar food supplys" "the main
food of growing nestlings—over the last few decades17. Increased spring
temperatures have led to increasingly poor synchronization between the hatching date
of caterpillars and the date of bud-burst of the oak trees on which they feed.
Estimates of the lag between caterpillar hatching date and oak bud-burst date
from a Dutch study17 were positively correlated with the annual mean
condition index (coefficient of correlation r = 0.613, test statistic z17 = 2.76, P =
0.0057; Fig. 4c), tarsus length (r = 0.621, z17 = 2.89, P = 0.0021) and
fledging success (r = 0.531, z17 = 2.82, P = 0.0049; Fig. 4d) of collared
flycatchers on Gotland. Because the degree of synchrony between caterpillar emergence
and bud-burst dates is driven by large-scale climatic phenomena17, such
correlations can be expected to occur across continental scales. Increased intra- and
interspecific competition, both of which lower condition in this18, 19 and
other bird populations20 are other potential, but perhaps less likely,
explanations for the decline in reproductive success and condition observed in this
study. In conclusion, in accordance with data from studies of spatial genetic
differentiation16, our results show that microevolutionary transitions at the
genotypic level need not necessarily be manifested at the phenotypic level16, and
that an apparent lack of evolutionary response in a heritable trait subject
to directional natural selection can be understood in terms of the environment
masking genotypic evolution, rather than selection on environmental deviations
only3. Alternative explanations for the lack of selection response (that is,
biased heritability estimates, negative genetic correlations between the focal
trait and other components of fitness, reversed direction of selection on
later life stages) could be excluded on the basis of detailed analysis using new
methods. To this end, our results concur with the view21, 22 that many
evolutionary transitions may consist of changes not visible at the level of the
phenotype. Methods The data The material for this study was collected between 1980
and 1999 from a nest-box-breeding collared flycatcher population inhabiting
the island of Gotland, off the Swedish east coast in the Baltic sea. All
breeding attempts were monitored from the date of egg-laying until all nestlings had
fledged. When 12 days old, nestlings were measured for tarsus length with
digital calipers (to nearest 0.1 mm), weighed with a Pesola spring balance (to
nearest 0.1 g) and marked with individually numbered aluminium rings. At the
same time, their parents were captured and their identity was checked (see refs
14 and 15 for more information on collection procedures). Condition index was
estimated as the residuals from a linear regression of body mass at fledging on
tarsus length (see refs 10 and 14 for details and analysis of linearity of
this relationship). Data were available for 4,888 breeding attempts involving
23,336 individuals. Because the sexes do not differ in growth patterns or
condition at fledging23, data on both sexes were analysed together (with one
exception: see below). Breeding attempts subject to manipulative experiments were
excluded from the analyses. Quantitative genetic analyses Heritability of
condition and individual breeding values were estimated through a mixed model
restricted maximum likelihood (REML) estimation procedure using the software
packages VCE24 and PEST25. An individual 'animal model' was fitted, in which an
individual's phenotypic value of condition was broken down into components of
additive genetic value and other random and fixed effects7, 26. The area of the
study site and the year were included as random effects to account for spatial
and temporal heterogeneity in environmental effects on phenotype. Nest-box
identity was also fitted as a random effect to account for further
common-environment effects specific to the individual brood; this term will incorporate any
non-genetic maternal effects. The only fixed effect in the model was a
population mean. The narrow-sense heritability (h2) was estimated as the ratio of the
additive genetic variance (VA) to the total phenotypic variance (VP): h2 =
VA/VP. Best linear unbiased predictors (BLUP) of individual breeding values were
quantified from pedigree information using REML estimates of variance
components, with the software package PEST25. BLUP estimates of breeding values (EBVs)
are unbiased even in populations under selection, or exhibiting assortative
mating, and estimates from different generations will reflect changes in
additive genetic effects resulting from selection, genetic drift or inbreeding7. With
an annual breeding population size in excess of 1,500 pairs, the occurrence
of genetic drift in this population is unlikely. Calculation of inbreeding
coefficients (IBCs) revealed that only 0.5% of pairings resulted in individuals
with an IBC greater than 0, and there was no evidence for between-year
heterogeneity in IBCs (Kruskal–Wallis H18 = 15.15, P = 0.65; estimated using Pedigree
Viewer, available from http://www-personal.une.edu.au/~bkinghor/pedigree.htm).
Changes in EBVs across generations can therefore be taken as evidence of a
response to selection, or 'genetic trend'27, 28. Genetic correlations were
estimated from a multivariate animal model analysis of fledgling condition,
life-span (LSP; in years) and lifetime reproductive success (LRS; defined as the
number of offspring recruited into the breeding population). Genetic correlation
analyses were necessarily restricted to individuals surviving to adulthood; area
and year were included as random effects, and sex (known for individuals
recaptured as adults) as a fixed effect. Selection analyses Estimates of survival
selection on phenotypic and estimated breeding values of condition index were
based on recapture data under the assumption that nestlings not returning to
the study area in subsequent years had died. As many of the individuals
recruit to the population at the age of two years, the survival analyses were
restricted to the period of 1981–1998. Standardized directional (S) and quadratic
(c2) selection differentials were estimated by linear regression of relative
fitness on standardized (zero mean, unit variance) phenotypic or breeding values
of the condition index using standard methods29. Statistical significance of
the selection differentials was estimated with logistic regression29.
Associations between individual LSP or LRS and EBVs for condition were tested using
GLMMs with negative binomial error structure, using the procedure IRREML in
Genstat30. Nest of origin, year and area were included as random effects in the
model, to account for repeated measures. The significance of the fixed effect of
condition breeding value as a predictor of LSP or LRS was assessed by the Wald
statistic, distributed as 2(1) (ref. 30). Received 26 February 2001;accepted
14 May 2001 References 1. Grant, P. R. & Grant, B. R. Predicting
microevolutionary responses to directional selection on heritable variation. Evolution
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F., Taylor, P. D., Frances, C. M. & Rockwell, R. F. Directional selection and
clutch size in birds. Am. Nat. 136, 261-267 (1990). 6. Frank, S. A. &
Slatkin, M. Fisher's fundamental theorem of natural selection. Trends Ecol. Evol. 7,
92-95 (1992). 7. Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative
Traits (Sinauer, Sunderland, Massachusetts, 1998). 8. Roff, D. A.
Evolutionary Quantitative Genetics (Chapman & Hall, New York, 1997). 9. Hochachka, W.
& Smith, J. N. Determinants and consequences of nestling condition in song
sparrows. J. Anim. Ecol. 60, 995-1008 (1991). 10. Lindén, M., Gustafsson, L. &
Pärt, T. Selection of fledging mass in the collared flycatcher and the great
tit. Ecology 73, 336-343 (1992). 11. Both, C., Visser, M. E. & Verboven, N.
Density-dependent recruitment rates in great tits: the importance of being
heavier. Proc. R. Soc. Lond. B 266, 465-469 (1999). | Article | 12. Sorci,
G. & Clobert, J. Natural selection on hatching body size and mass in two
environments in the common lizard (Lacerta vivipara). Evol. Ecol. Res. 1, 303-316
(1999). 13. Boltnev, A. I., York, A. E. & Antonelis, G. A. Northern fur seal
young: interrelationships among birth size, growth, and survival. Can. J.
Zool. 76, 843-854 (1998). | Article | 14. Merilä, J. Genetic variation in
offspring condition--an experiment. Funct. Ecol. 10, 465-474 (1996). 15.
Merilä, J., Kruuk, L. E. B. & Sheldon, B. C. Natural selection on the genetical
component of body condition in a wild bird population. J. Evol. Biol.
(submitted). 16. Conover, D. O. & Schultz, E. T. Phenotypic similarity and the
evolutionary significance of countergradient variation. Trends Ecol. Evol. 10,
248-252 (1995). 17. Visser, M. E. & Holleman, L. J. M. Warmer springs disrupt the
synchrony of oak and winter moth phenology. Proc. R. Soc. Lond. B 268,
289-294 (2001). | Article | PubMed | 18. Gustafsson, L. Inter- and intraspecific
competition for nest holes in a population of the collared flycatcher Ficedula
albicollis. Ibis 130, 11-16 (1988). 19. Doligez, B., Danchin, E., Clobert,
J. & Gustafsson, L. The use of conspecific reproductive success for breeding
habitat selection in a non-colonial, hole-nesting species, the collared
flycatcher. J. Anim. Ecol. 68, 1193-1206 (2000). | Article | 20. Alatalo, R. V. &
Lundberg, A. Density-dependence in breeding success of the pied flycatcher
(Ficedula hypoleuca). J. Anim. Ecol. 53, 969-978 (1984). 21. Lewontin, R. C.
Adaptation. Sci. Am. 239, 212-230 (1978). | PubMed | 22. Gilchrist, A. S. &
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three parallel body size clines of Drosophila melanogaster. Genetics 153,
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Ellegren, H. Gender and environmental sensitivity in nestling collared
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Multi-Model Restricted Maximum Likelihood (Co)Variance Component Estimation
Package, Version 3.2 User's Guide. (Institute of Animal Husbandry and Animal
Behaviour, Federal Research Center of Agriculture (FAL), Mariensee, Germany,
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algorithms in a general purpose BLUP package for multivariate prediction and
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maximum-likelihood to estimate variance components for animal models with several
random effects using a derivative-free algorithm. Genet. Selection Evol. 21,
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W. Genetic and environmental trends for litter size in swine. J. Anim. Sci.
69, 3177-3182 (1991). | PubMed | 29. Merilä, J., Sheldon, B. C. & Ellegren,
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Genstat, 1998. Genstat 5, Release 4.1 (Lawes Agricultural Trust, IACR, Rothamsted,
1998). Acknowledgements. We thank I. P. F. Owens, A. J. van Noordwijk, B. Walsh
and D. A. Roff for comments on the manuscript, M. Visser for data on
caterpillars and oaks, and the numerous people who have helped in collecting the data
in the course of the study, in particular L. Gustafsson. Our research was
supported by the Swedish Natural Science Research Council, the Nordic Academy for
the Advanced Study (J.M.) and by Royal Society University Research Fellowships
to B.C.S. and L.E.B.K. Nature © Macmillan Publishers Ltd 2001 Registered No.
_Retrieved from the World Wide WebJune 13, 2003
Not Junk After All Wojciech Makalowski Science 2003 May 23; 300:
1246-1247. (in Perspectives)
Not Junk After All Wojciech Makalowski* From bacteria to mammals, the DNA
content of genomes has increased by about three orders of magnitude in just 3
billion years of evolution (1). Early DNA association studies showed that the
human genome is full of repeated segments, such as Alu elements, that are
repeated hundreds of thousands of times (2). The vast majority of a mammalian genome
does not code for proteins. So, the question is, "Why do we need so much
DNA?" Most researchers have assumed that repetitive DNA elements do not have any
function: They are simply useless, selfish DNA sequences that proliferate in
our genome, making as many copies as possible. The late Sozumu Ohno coined the
term "junk DNA" to describe these repetitive elements. On page 1288 of this
issue, Lev-Maor and colleagues (3) take junk DNA to new heights with their
analysis of how Alu elements in the introns of human genes end up in the coding
exons, and in so doing influence evolution. Although catchy, the term "junk DNA"
for many years repelled mainstream researchers from studying noncoding DNA.
Who, except a small number of genomic clochards, would like to dig through
genomic garbage? However, in science as in normal life, there are some clochards
who, at the risk of being ridiculed, explore unpopular territories. Because of
them, the view of junk DNA, especially repetitive elements, began to change in
the early 1990s. Now, more and more biologists regard repetitive elements as a
genomic treasure (4, 5). Genomes are dynamic entities: New functional
elements appear and old ones become extinct. It appears that transposable elements
are not useless DNA. They interact with the surrounding genomic environment and
increase the ability of the organism to evolve. They do this by serving as
recombination hotspots, and providing a mechanism for genomic shuffling and a
source of "ready-to-use" motifs for new transcriptional regulatory elements,
polyadenylation signals, and protein-coding sequences. The last of these is
especially exciting because it has a direct influence on protein evolution. More
than a decade ago, Mitchell et al. showed that a point mutation in an Alu
element residing in the third intron of the ornithine aminotransferase gene
activated a cryptic splice site, and consequently led to the introduction of a partial
Alu element into an open reading frame (6). The in-frame stop codon carried
by the Alu element resulted in a truncated protein and ornithine
aminotransferase deficiency. This discovery led to the hypothesis that a similar mechanism
may result in fast evolutionary changes in protein structure and increased
protein variability (7). Several genome-wide investigations have shown that all
types of mobile elements in all vertebrate genomes can be used in this way. The
unsolved mystery is how a genome adapts to the drastic changes conferred on a
protein by the insertion of a mobile element into the coding region of its
gene. Lev-Maor and co-workers and a second group now demonstrate how this process
takes place without disturbing the function of the original protein (see the
figure) (3, 8). Figure 1 Junk DNA caught in the act. Two ways in which a
repetitive DNA element, such as an Alu element, can be incorporated into the
coding region of a gene without destroying the gene's function. (Top) A TE-cassette
is inserted into the mRNA as an alternative exon. (Bottom) Insertion of a
TE-cassette is preceded by a gene duplication. In both cases, the genome gains
two forms of the mRNA transcript--one with and one without the TE-cassette.
Last year, Sorek et al. (9) noticed that about 5% of alternatively spliced
internal exons in the human genome originate in an Alu sequence. Interestingly,
because Alu elements are primate specific, these exons must be primate or human
specific as well as much younger than other exons in a gene. Additionally, they
noticed that the vast majority of "Alu exons" are alternatively spliced (that
is, there is always another messenger RNA without the Alu element in the
coding region). They concluded that "Alu elements have the evolutionary potential
to enhance the coding capacity and regulatory versatility of the genome without
compromising its integrity" (9). In their new work, this group now shows how
alternative splicing of Alu exons is regulated (3). It is well established
that the precise selection of the 3' splice site depends on the distance between
the branch point site (BPS) and the AG dinucleotide downstream of the BPS.
The optimal distance between the BPS and the AG dinucleotide is relatively
narrow (19 to 23 nucleotides). Interestingly, if there is another AG dinucleotide
closer to the BPS, it will be recognized by a spliceosome even if a second AG
located more optimally is used in the transesterification reaction (10). A
splicing factor, hSlu7, is required to facilitate recognition of the correct AG.
Thus, the correct selection of the 3' splice site is an interplay between AG
dinucleotides and certain splicing factors. It is even more tricky to maintain
the delicate balance of signals that cause an exon to be spliced
alternatively--you make one mistake (a point mutation) and either a splicing signal becomes
too strong and an exon is spliced constitutively, or the signal becomes too
weak and an exon is skipped. Lev-Maor and colleagues (3) performed a series of
experiments to identify an ideal sequence signal surrounding the 3' splice
site within the Alu element that kept the Alu element alternatively spliced. It
appears that in addition to the distance between two AG dinucleotides, a
nucleotide immediately upstream of proximal AG is also important. Hence, a proximal
GAG sequence serves as a signal weak enough to create an alternatively spliced
Alu exon. Any mutation of a proximal GAG in the first position results in a
constitutive Alu exon. This is an important observation because most of the
more than 1 million Alu elements populating the human genome contain such a
potential 3' splice site. Of these, 238,000 are located within introns of
protein-coding genes, and each one can become an exon. Unfortunately, most mutations
will lead to abnormal proteins and are likely to result in disease. Yet a small
number may create an evolutionary novelty, and nature's "alternative splicing
approach" guarantees that such a novelty may be tested while the original
protein stays intact. Another way to exploit an evolutionary novelty without
disturbing the function of the original protein is gene duplication (see the
figure). Gene duplication is one of the major ways in which organisms can generate
new genes (11). After a gene duplication, one copy maintains its original
function whereas the other is free to evolve and can be used for "nature's
experiments." Usually, this is accomplished through point mutations and the whole
process is very slow. However, recycling some modules that already exist in a
genome (for example, in transposons) can speed up the natural mutagenesis process
tremendously. Several years ago, Iwashita and colleagues discovered a bovine
gene containing a piece of a transposable element (called a TE-cassette) in
the middle of its open reading frame (12). This cassette contributes a whole new
domain to the bovine BCNT protein, namely an endonuclease domain native to
the ruminant retrotransposable element-1 (RTE-1). Interestingly, the human and
mouse homologs of bovine BCNT lack the endonuclease domain but instead contain
a different one at their carboxyl terminus. This raised two questions: When
did the BCNT protein acquire the endonuclease domain, and how did the bovine
genome manage such a drastic rearrangement of BCNT without losing its fitness?
Iwashita et al. give the answers to both questions in their new study (8). They
discovered another copy of the bovine bcnt gene that resembles mammalian bcnt
homologs (also called CFDP1) just six kilobases downstream of the gene with
the TE-cassette. Both copies of the gene are apparently expressed and both
proteins are functional. Phylogenetic analysis suggests that shortly after gene
duplication in the ruminant lineage, one of the copies acquired an endonuclease
domain from an RTE-1 retrotransposon. Not surprisingly, this gene undergoes
accelerated evolution. The reports by Lev-Maor et al. and Iwashita and
colleagues describe different ways in which genes can be rapidly rearranged and acquire
evolutionary novelty through the use of so-called junk DNA. These discoveries
wouldn't be so exciting if they didn't show how genomes achieve this without
disturbing an original protein. To quote an old Polish proverb: "A wolf is
sated and a lamb survived." These two papers demonstrate that repetitive elements
are not useless junk DNA but rather are important, integral components of
eukaryotic genomes. Risking personification of biological processes, we can say
that evolution is too wise to waste this valuable information. Therefore,
repetitive DNA should be called not junk DNA but a genomic scrapyard, because it is
a reservoir of ready-to-use segments for nature's evolutionary experiments
(13). References 1. M. Nei, Nature 221, 40 (1969) [Medline]. 2. R. Britten, D.
Kohne, Science 161, 529 (1968) [Medline]. 3. G. Lev-Maor, R. Sorek, N.
Shomron, G. Ast, Science 300, 1288 (2003). 4. J. Brosius, Science 251, 753 (1991)
[Medline]. 5. R. Nowak, Science 263, 608 (1994) [Medline]. 6. G. A. Mitchell
et al., Proc. Natl. Acad. Sci. U.S.A. 88, 815 (1991) [Medline]. 7. W.
Makalowski, G. A. Mitchell, D. Labuda, Trends Genet. 10, 188 (1994) [Medline]. 8.
S. Iwashita et al., Mol. Biol. Evol., in press. 9. R. Sorek, G. Ast, D. Graur,
Genome Res. 12, 1060 (2002) [Medline]. 10. K. Chua, R. Reed, Mol. Cell. Biol.
21, 1509 (2001) [Medline]. 11. S. Ohno, Evolution by Gene Duplication
(Springer-Verlag, New York, 1970). 12. T. Nobukuni et al., J. Biol. Chem. 272, 2801
(1997) [Medline]. 13. W. Makalowski, Gene 259, 61 (2000) [Medline]. The author
is at the Institute of Molecular Evolutionary Genetics and Department of
Biology, Pennsylvania State University, PA 16802, USA. E-mail: wojtek at psu.edu
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Collections: Genetics Related articles in Science: The Birth of an Alternatively
Spliced Exon: 3' Splice-Site Selection in Alu Exons Galit Lev-Maor, Rotem Sorek,
Noam Shomron, and Gil Ast Science 2003 300: 1288-1291. (in Reports) [Abstract]
[Full Text] Volume 300, Number 5623, Issue of 23 May 2003, pp. 1246-1247.
Copyright © 2003 by The American Association for the Advancement of Science. All
Science. All rights reserved.
Retrieved December 16, 2002, from the World Wide Web
The following is a detailed and referenced document. The Viruses That Make
Us: A Role For Endogenous Retrovirus In The Evolution Of Placental Species by
Luis P. Villarreal Chromosome evolution, higher order and parasitic elements.
With the accumulation of genomic sequence data, certain unexplained patterns
of genome evolution have begun to emerge. One striking observation is the
general tendency of genomes of higher organisms to evolve an ever decreasing gene
density with higher order. For example, E. Coli has a gene density of about 2
Kb per gene, Drosophila 4 Kb per gene and mammalian about 30 Kb per gene. Much
of the decreased density is due to the increase in the accumulation of
non-coding or 'parasitic DNA' elements, such as type one and two transposons.
Current evolutionary theory does not adequately account for this observation (81).
In addition mammals appear to have retained the presence of at least some
copies of non-defective 'genomic retroviruses', such as intercysternal A-type
particles (IAP's) or endogenous retroviruses (ERVs), (51,85). It is currently
difficult to account for the selective pressure that retains these genomic viruses,
since they often lack similarity to existing free autonomous retroviruses. It
is widely accepted that viral agents act a negative selecting force on their
host. However, viral agents have very high mutation and adaption rates. This
character led Salvador Luria to speculate early on that perhaps viruses
contribute to host evolution (52). There is now sufficient evidence to suggest that
horizontally transmitted agents and gene sets allow the rapid adaption of
various living systems, including bacteria, yeast, drosophila and hymenoptera.
'Pathogenic islands' are contiguous regions of DNA that contain gene sets in
bacteria that appear to be horizontally acquired and can exist as either prophage,
episomes or genomic sequences (21). These pathogenic islands appear to account
for much of the rapid adaptability in bacteria. Transposons of Drosophila
appear to require horizontal transmission in order to be maintained during
evolution and appear to have been the underlying mechanism of hybrid dysgenesis
(10). The parasitioid wasp species (hymenoptera) maintain genomic polydnaviruses
in most species which are highly produced into non-replicating viral forms
during egg development and subsequently suppress host larval immunity making them
essential for egg survival (47,74). Thus horizontally transmitted genetic
elements are common in the genomes of all species. The mammalian chromosome
presents an especially interesting case of accumulation of 'parasitic' DNA. All
placental species have unique LINE elements present at very high abundance as well
as other related and even more abundant elements, such as the SINES or
primate specific alu elements (see (70) for references). Yet there appears to be no
common progenitor to these elements. All these elements appear to be products
of reverse transcription of cellular RNA's however, there is no explanation
for the conservation to RT activity in mammals. Although endogenous retroviruses
are found in most organisms prior to mammalian radiation, the levels of these
genomic agents is relatively low in non-mammals and the nature of retroposons
seems distinct form that in mammalian. Mammalian LINES, for example lack a
precise 5' end, have no poly-A 3' end, and lack RT coding regions that are
characteristic of all LINE elements as opposed to avian or other retroposon
elements of vertebrates that do not have these features. Why are mammalian
(eutherian) chromosomes especially so full of these RT derived agents? What selects for
their generation or retention? A genomic retrovirus: essential for placentals?
In a proposal published in 1997, I raised the issue of endogenous retrovirus
and proposed that these viruses are essential to the biology of Eutherians.
Viviparous mammals confront an immunological dilemma in that mammals which have
highly adaptive immune systems fail to recognize their own allogenic embryos
(58). The relationship of mammalian mother to her fetus resembles that of a
parasite and host in that the fetus 'parasite' must be able to suppress the
immune response of the 'host' mother in order to survive. As viviparous mammals are
also noteworthy for having genomes that are highly infected with endogenous
retroviruses and as retroviruses are generally immunosuppressive, the possible
participation of endogenous retroviruses in the immunosuppression by the
embryo was then considered. In addition, it was considered if such endogenous
viruses might be more broadly involved in the evolution of their host and the
resulting host genome that now appear to have many derivatives (such
retrotransposons and as LINE elements) of such genomic viruses. This grant application seeks
support to do an experimental evaluation in a mouse model of the proposed
involvement of endogenous retroviruses in the immunologically escape by the
embryo in the mother. I argue that endogenous retrovirus is hence essential for the
biology of non-egg laying placental mammals. This study could provide
evidence of the biological function of endogenous retroviruses and also address the
broader issues concerning the possible contribution of genomic virus to host
genome evolution. The dilemma of viviparous mammals and their allogeneic
embryos. This mammalian dilemma was clearly stated by Medawar in the early 1950's,
see (31,50). Since then, this dilemma has remained one of the most vexing and
persisting problems in immunology. An array of models have since been proposed
attempting to explain this situation. These include a limited embryonic
expression and presentation of MHC class I or class II antigen ((88) or expression of
alternative MHC, HLA I-G, (40), or a high hydrocortisone hormonal suppression
of immunity, and more recently the possible role of Fas L embryonic
expression in ablating T-cell recognition of the embryo (66). All of these models,
though with some support, have significant problems. Inflammatory reactions, which
appear to be involved in embryo rejection (see below) would not be checked by
low MHC expression. Lowered MHC I expression would also be expected to elicit
a natural killer cell response, which appears to be important in embryo
implantation (41), although the human embryo specific alternative MHC gene, HLA-IG,
could substitute for MHC I to negatively regulate NK activity. Up regulated
expression of Class I MHC by interferon does not allow CTL killing of
trophoblasts suggesting that trophoblast actively inhibit CTL killing (for references,
see (26)). Also, humans with deficient beta-2 microglobulin do not express
HLA-IG yet the fetus comes to term indicating HLA-IG is not essential for
implantation (James Cross, personal communication). In addition, other species, such
as mouse have no analogue of the HLA-IG antigen, which suggest this antigen
cannot be a general solution to the immunological dilemma of viviparous species.
Fas null mice, although displaying defects in peripheral clonal immune
selection, allow implantation of embryos (1). General immune suppression, such as
hydrocortisone cannot explain the relatively normal immune response in pregnant
mothers to many agents or elevated level of TH2 reactive cells (which are
important for mucosal macroparasite elimination) seen in pregnant woman, see T.
Mossman, (49). Also, the glucocorticoid effect may be mediated via the p15E-like
gene of endogenous retrovirus (20). In addition, it is interesting to note
that autoimmunity, such as rheumatoid arthritis can often abate during pregnancy
suggesting an altered immunity that appears not mediated via hormones
(Fackelman, Science News 144:260). Most effective immune reactions appear to be of a
rather local nature. Therefore local suppression seems a likely way to
regulate embryo immune recognition. Although TH1 reactivity in pregnancy is weak, the
TH2 response, which is important for inflammatory like reactions, is not
decreased and is possibly enhanced (T. Mossman). Neither the MHC model, nor the
Fas-Fas ligand model can account to the failure to initiate an inflammatory
reaction or NK activity against the embryo (activated NK cells can reject
xenografts (41)) The Role of Mucosal Uterine Macrophages or NK cells Embryo
implantation occurs in the mucosal epithelial tissues of the uterus. Like most mucosal
surfaces, the uterus has a high abundance of macrophages (37,70) and NK cells
(41). Once activated, these cells should respond vigorously to parasites or
allogeneic tissues and reject xenografts. The regulation of these cells and their
subsequent inflammatory reaction and induction of the adaptive immune
response involves IL-1 beta, IL-6, TGF beta-1, TNF-alpha, CSF-1 (26,88). The uterus
appears to present an immunologically tolerant site as grafts into the uterus
of pregnant rats have prolonged survival relative to other locations, see (5)
for review. Macrophages are central to the initiation of innate and subsequent
adaptive immune responses (18). Although most macrophages can act as
immunostimulatory cells, evidence suggest that uterine macrophages can make
immunosuppressive molecules. For example, despite MHC II display, uterine macrophages
don't present antigens to T-cells (44). Other results suggest that uterine
macrophages can contribute to embryo loss. Preterm mouse delivery is associated with
high levels of macrophage derived IL-1-beta, IL-6, TNF- a . High rates of
early embryo loss can be associated with the specific mouse strains that are
mated in that low rates of embryo loss can sometimes be seen with inbred
crossings, whereas some outbred crossings can show higher embryo loss rates. For
example, crosses between CBA/J X DBA/2 are prone to early embryo loss relative to
inbred crosses which is enhanced by IFN induction (27). This breeding associated
embryo loss is also linked with inflammation and iNO production by local
decidual macrophages (27) as inhibition of macrophage iNO enhanced litter size.
Macrophage iNO inactivates nearby macrophages and mediates immunosuppression in
inflammation via bystander lymphocyte autocytotoxicity, suggesting a way to
elicit immunosuppression. The Importance of Trophoblast Role in implantation. In
the implanting embryo, trophoblasts are the first cells of the egg to
differentiate. Following the loss of the zona pellucida shell, trophoblast
differentiate into cytotrophoblast the finally into the fused syncytiotrophoblast that
forms the cell layer that directly contacts the uterus and the mothers blood
system. These trophoblasts are considered a part of uterine macrophage-cytokine
network (26,88). Trophoblast resemble macrophages in many of the genes that
they express. Uterine macrophage produced IL-1 which may play critical role
during implantation (28). Trophoblasts protect inner cell mass from macrophage
destruction (69). Trophoblast can be transplanted across mouse strain barriers
without being rejected suggesting they have immunosuppressive activities (38).
Also, trophoblasts have a very unique pattern of gene expression in that
expression is restricted to paternal (androgenic) genes while inner cell mass
express maternal genes (79). This is in stark contrast to other somatic tissues
where mosaic expression is observed. With trophoblast gene expression being
androgenic (79,80), it seems curious that X chromosome inactivation is also paternal
in trophoblast, see Renfree (61) for references. It is interesting therefore
to note that female mice are less able to kill tumors bearing paternal
antigens then tumors bearing maternal antigens (T. Mossman, personal communication).
Trophoblasts are intriguing in an evolutionary sense as well. Other
non-viviparous mammals (marsupials, monotremes) completely lack the
trophoblast-syncytiotrophoblast layer, see (59) for review. Unlike viviparous mammals, marsupial
gestation is short (averaging several to 12 days), their eggs are yolk-filled
resembling those of reptiles and marsupial eggs are surrounded by a maternal
derived shell membrane which once lost allows only minimal maternal-fetal
contact for a period of only several days. Most of marsupial egg incubation is
outside of mothers body and birth is associated with local inflammatory events.
Marsupials also lack hormonal control of uterus or other tissues (61). Given that
the trophectoderm is the first mammalian egg cell type to differentiate and
the relatively recent evolutionary development of this layer in mammals, early
embryos of the viviparous mammal do not seem to recapitulate evolutionary
history with respect to this first cell type. Thus the trophoblastic cells appear
to be centrally involved in implantation and embryo immunomodulation.
Trophoblast produced ERV's. Another rather unique feature of syncytiotrophoblasts is
in their ability to produce a high quantity of endogenous retroviruses , see
(85). This also appears to be a general characteristic of all placental mammals.
The production of endogenous retroviruses in early mammalian embryos is a
long standing and often repeated observation. Multiple detections of particles in
normal human embryonic cells, especially basal surface of human placental
syncytiotrophoblast tissue have been frequently reported as have similar particle
production in old and new world primates placentas (for early review see
(84)). Normal human placentas have measurable RT activity (56) and appear to
express HERV env gene (45). Primary trophoblasts of rhesus monkeys also produce
ERV's (77). Furthermore, the levels of mouse virus particle production can be as
high as 105 per cell (60), which exceeds by far the capacity of most
permissive cell culture systems for retrovirus production. In addition, these
endogenous retrovirus particles are frequently made following induction in testicular
teratocarcinoma which constitute a HERV (Human Endogenous Retrovirus) group,
similar to C-type particle (85). In addition, antibody studies have established
that CTL reactive to ERV proteins can be found in most pregnant woman as can
immuno-precipitation reactivity to p28, p15 and p15E (for references see (85),
p. 86-87). Interestingly, RD114 cross-reactive antibodies were significantly
correlated with complications during pregnancy and with prior abortions and
stillbirths (78). In humans, these trophectoderm expressed HERV's represent two
large diverse multi copy families HERV-R and HERV-K., the latter is capable of
expressing the env and p15E gene products in vaccinia vectors (83). Thus,
endogenous retrovirus are mainly isolated from reproductive embryonic tissues but
to a lesser extent from circulating lymphocytes or monocytes of some mouse
strains (42). These viruses are highly suppressed in most somatic tissues
probably due to DNA methylation, (see below). However, these viruses do not seem
transmissible in usual sense of leading to productive infections. Nondefective
endogenous retroviruses are conserved and expressed in trophoblast HERVs
constitute about 0.6% of the human genome and appear more related to rodent viruses
than any known human viruses. The great majority of these endogenous viruses are
defective and deleted of various gene products, especially the env gene but
also gag/pol. For an early review of the human endogenous retroviruses see
(46). Initially, it was felt that there all copies of HERV's in the genome were
defective, but it subsequently became clear that highly conserved non-defective
copies also exist at low levels (see Urnovitz (85) table 6 , p.93 for refs.).
For example, the HERV-K sequence of the human teratocarcinoma derived virus
type (HTDV), is reported to be able to make retrovirus like particle and can
express gag, pol and env genes via vectors (83). Also, ERV 3 can express env gene
in embryonic placental tissues (45). Such reports may now explain the
numerous early observations of being able to find viral particles in human tissues
(13), (see (33) for early references). Although some HERV's are expressed in
mammary tumors, the feline RD114, ERV-3, and HERV K10+ are all expressed in
placental tissues. What then is the significance of nondefective ERVs and why is
expression so common in embryos? There has developed a confusing system of
nomenclature and corresponding phylogenetics of ERVs due to multiple names for
similar viral sequences. In addition, sequences from several ERV's appear to be
made up of mosaic elements such that different relationship will be apparent
when different parts (e.g. gag/pol vs env) are analyzed as seen with HERV-K10+,
which can add to confusion (85). A relatively clear system of nomenclature has
been presented by Urnovitz and Murphy (85). They propose HERV's can be
classified according to established non-defective endogenous viruses. For example,
both the ERV-1 (with a deleted env region) and the single copy ERV-3 (which can p
lacentally express an intact env gene) are also called HERV-R (45) can be
classified as ERV-3 derivatives. Accordingly, the defective HERV-K10 with deleted
env, or the non-defective full length HERV-K10+ and the HERV K(C4), are thus
related to HERV-K10+. In addition, RTLV-H, in which most copies are pol
defective but is also expressed in embryonic tissues and also has an env gene (32),
is present as a low copy nondefective copy; RTLV-Hp. Interestingly, this
RTLV-Hp sequence appears to have been conserved phylogenetically (via neutral codon
substitutions) and implies that it belongs to a functional and selected
subclass of highly retained ERV's (89). This classification method allows clearer
identification of highly conserved and intact ERVs. What could an ERV function
be for the host cell? I (68) and Venables et al. in the Boyd group (8,86) have
proposed that some of these HERV's may function during embryo implantation to
help prevent immune recognition by the mother's immune system. Immunological
activity of ERV (IAP) genes Most retroviruses appear to be generally
immunosuppressive of the host immune system (for review see (25)). The
immunosuppressive nature of retroviruses was first investigated in detail with feline leukemia
virus of domestic cats (FeLV) and led to the identification of the CKS-17
hydrophobic transmembrane domain of the env gene as an important immune
modulator. This domain is present in the highly conserved p15E peptide which maintains
the immunosuppressive character, for review see (30). A main effect of p15E is
to inhibit T-cells via cytokine (TNF and IFN ) mediated processes (29) and
can be elicited by synthetic or recombinant p15E (65,67). p15E also inhibits
mononuclear phagocyte chemotaxis (85). Thus the env gene is a primary candidate
of an ERV gene product that could modulate the mother's immune recognition,
which fits well with its proposed role in syncytiotrophoblast expression. In
addition, the ERV gag gene product may also be immuno-modulatory. The p70 (gag) of
mouse IAP has been cloned and expressed and shown to be identical to IgE
binding factor (IgE-BF) which is a regulator of B-cell ability to produce IgH
(43,54). More recently, it has been reported that endogenous gag is Fv-1,
an-Herv.L like endogenous virus which confers resistance to MLV tumors (7). Although
some researchers disagree with the immunomodulatory role of p15E, an immune
suppressing activity in culture assays has been clearly established. These
supporting results seem sufficiently clear to warrant a serious investigation that
both the env and gag gene products of ERV's may modulate immunity. ERV's and
placental macrophages If non-defective ERV gene (env) products are indeed
immuno-modulatory, we can now offer explanations for various other observations. For
one, env expression should be highly selected for in the early embryo (hence
the conserved single intact copy), but strongly counter selected for
expression in ectopic sites which would render these genes inappropriately
immunosuppressive. Therefore most transposed copies of ERV's would be expected to be under
selection to lose the env gene, as is observed. Also, ERV expression is
somatic tissue is generally highly repressed, also as expected from this model. In
addition, it can be expected that the main target of ERV action would be the
local immune cells of the uterus. A likely cell type to affect would be the
uterine macrophages. Given the central role of innate immune modulators (18) and
macrophages (2) in the induction of the acquired immune response, uterine
macrophages and the cytokines they effect seems a likely candidate to target for
embryo immune regulation. However, there is no evidence that ERV's are
transmitted in a productive manner. We therefore might expect the trophectoderm
derived ERV's act more like a replication defective recombinant retrovirus that is
able to effect locally exposed cells, but not replicate and transmit to other
cells (see (87). This would mean that these ERV's are essentially local acting
agents. Thus a central unanswered question is what effect IAP producing
trophoblasts have on nearby macrophages, especially with respect to a macrophage's
role in innate and acquired immune function. Of some relevance to this issue
are reports glucocorticoid mediates increased Mtv env (p15E) expression in
P388D1 macrophage and T-like mouse line (20). Such cell systems could be used
experimentally to examine possible role of env in immune modulation. One seemingly
contradictory observation concerning the above proposal is that normal embryo
development appears to occur in the presence of inhibitors of reverse
transcriptase, AZT, such as in AZT treated HIV infected mothers which generally
produce normal offspring. If the embryo produced ERV's are needed for immune
modulation, it seems likely that embryo's would be immunologically rejected if RT
inhibitors prevent the production of ERV's. However, early embryo development is
severely affected by AZT, see (82). AZT will efficiently inhibit normal
embryo's at post fertilization but preimplantation stages. AZT is toxic to early
embryos at before blastocyst stage however, but it is not toxic at post
blastocyst implantation stage (82). The possibility that embryos were being rejected by
the mother's immune system was not examined in these studies. An additional
consideration concerning the possible use of RT inhibitors is that because the
ERV's are being produced in the trophectoderm from genomic copies of virus, RT
inhibitors are not expected to inhibit trophectoderm produced ERV's as viral
genomes are already integrated as DNA (88). Support for this comes from HIV
studies showing that AZT did not inhibit HIV gene expression in infected
placental trophoblasts. However, it might be predicted that local immune cells, such
as uterine monocytes or macrophages, might not be properly 'reprogrammed' to
immune nonrecognition by ERV's infection as the integration step in these cells
would be inhibited. Once these macrophages were reprogrammed by ERV
infection, their 'anergic' state could persist rendering them resistant to further RT
inhibitors as long as the cells live, which is seldom known for these cell
types. Clearly, this issue should be examined experimentally. IAPs and cancer IAP
expression, although normally highly repressed, is often observed in various
tumor tissues (14,15,90). If these ERVs are a normal host system of immune
modulation as I have proposed, it could be expected that tumors would select for
the expression of immuno-modulatory ERV or ERV gene products (such as p15E) in
order to avoid immuno-surveillance. Early reports presented evidence that p15E
is made in many human breast cancers (73). This suggest that tumor cells
might also be used as an experimental system in which to examine this issue. In
some tumors, there appears to be interesting converse links between IAP
expression and tumor recognition. BL6 melanoma normally make high levels of IAP and do
not express H-2kLd . IAP production can affect IgE production and is
conversely is lost when MHC-I H-2kLd ,and H-2kLb but not H-2Dd H-2Ld is transfected
into BL6 cells (48). Also, P15E-like proteins in serum, urine and tumor
effusions of cancer patients suppress immune responses that can be reversed by
anti-p15E antibody (71,73). ERV (IAP) genetics and implications for the functional
subsets. Because human and mouse ERV's are present at about 900 copies per
haploid genome, a genetic analysis would appear to present a daunting if not
impossible task. For example, gene knockout experiments in mice, which have been so
valuable at elucidating gene function, would seem not possible in the context
of IAPs. However, intact env genes are sometimes present at much lower levels,
and in some cases as single copies (ERV-3). It seems likely that this limited
subset is the functional set that might be important. ERV-3 seems like a very
good candidate that could provide immunosuppressive barrier between human
mother and fetus as it has highly expressed env in syncytiotrophoblasts,
expresses antigens that react to antibodies specific to the transmembrane domain
(p15E-like), and is present as a complete, single copy sequence on chromosome 7,
(Larsson, '97 NEED THIS) (86). Other good candidate human ERV's are the
HERV-K(C4) and HERV-K which are also highly expressed in the placenta. Interestingly,
Y human chromosome has lots (20) of different ERV's related to ERV3 (Kjellman,
Sjogren, Widegren, '95, NEED THIS) which may code for potential HY antigens.
However, what is really needed for experimental analysis is the mouse
homologue to the human ERV-3. One possible functional homologue is the IAPE virus
which like ERV-3, has an intact env sequence (62). In addition, this IAP env
sequence appears to be expressed as a protein in NH15-CA2 cell lines suggesting a
functional gene (62). The IAPE sequences, however, are complicated by the
existence of about 200 copies/cell in mus musculus (63). But the IAPE-A locus seems
complete and intact relative to the other IAPE's which lack gag or pol
sequences and IAPE-A is present at lower levels. IAPE's are found in all lab strains
(mostly Mus musculus domesticus derived) in variable and genetically unique
levels that identify the strain (12), suggesting an unexplained link of
inbreeding to IAPE variation. Some outbred strains, such as CE/J, had much lower
levels of IAPE sequences, but maintain IAPE-A (75). These CE/J mice might offer a
simpler genetic system to investigate the possible function of IAPs. Yet,
mouse strains do not seem to vary much with respect to the very massive RNA levels
(105 copies per cell) of early embryo expressed IAP (60). As IAPE-A is
complete and it also codes for intact env sequence, this seems like a logical but
untested candidate for possible trophectoderm expression. IAPE-Y is an IAPE-A so
named because it has amplified on Y-chromosome. However, the Y-amplified head
to tail copies are not found in all musculus species indicating that this
amplification appears to be a recent evolutionary change (19). The repetitive
head to tail Y-copies of IAPE are limited to only male Mus musculus domesticus
and the asian Mus musculus molossinus and M. Musculus castaneus. The more
distant Spanish Mus spretus lacked the repetitive copies on the Y chromosome, but
conserved IAPE-A. MuRVY is genetically associated but distinct from IAPE, is
also on Y and could represent a second class of trophectoderm expressed IAPs
(17,19). Y condensation in most tissue (except testes Sertoli cells) probably
limits expression of these IAP-Ys. However, IAPE-A expression, (also related to
Hamster H-18 IAP (3)), although usually highly repressed in most tissues, may at
times be expressed in some somatic (thymus) tissues of some mouse strains
(42). Phylogenetic studies suggest that this env gene was under functional
constrains not to evolve quickly, although the defective copies are evolving very
rapidly. Thus IAPE-A seems like a good candidate for an ERV env gene involved in
mouse embryo implantation. However, it has not previously been established
that this env sequence is expressed in trophoblasts (see preliminary results
below). The possible relevance of ES and EC cells. It has long been established
that some testicular derived teratocarcinoma cells can differentiate from
embryonal stem cells into several cell types (76). Of particular interest is the
capacity of some EC lines to differentiate into trophectoderm. Treatment with
10-3 M retinoic acid will differentiate some of these cells into parietal
trophectoderm-like cells which will eventually develop structures resembling a 3.5
day blastocyst. Thus this tissue resembles the extra-embryonic trophectoderm
that is the proposed source of immunosuppressive ERV's. Along these lines, it
has also long been established that differentiated (but not undifferentiated)
mouse EC cells induces high levels of two distinct populations of IAPs (36).
Thus at least by this parameter, EC cells my accurately model trophectoderm gene
specific control. Other reports show IAP production in differentiated EC cells
can be significantly reduced without affecting the ability of these cells to
differentiate into trophectoderm. F9-EC cells containing integrated SV40
sequences (F912-1 cells), resulted in IAP production that was significantly reduced
after differentiation. In these cells, it appears that IAP expression is
tightly linked to DNA methylation and that SV40 has affected methylation without
affecting cell specific expression (34). EC cell differentiation has been well
characterized and many expressed sequence tags have been catalogued (57). It
should therefore be possible to accurately determine if the EC differentiation
program is otherwise affected by SV40 T-Ag or other regulatory proteins.
Historically, EC cells were also used to study cell specific replication by
polyomavirus. This led to the development of enhancer variants of polyomavirus that
had increased capacity to replicate in undifferentiated EC cells. Using the
enhancer/origin from Py (PyF101), Gassmann et al. with P. Berg constructed a Py
T-Ag expressing plasmid (PMGD20neo) that allowed for episomal selection in ES
cells (9,24). This plasmid had the interesting capacity to be stably maintained
as an episome in ES cells without integration. Some of the resulting ES cell
lines could then be used to make mosaic mice that also maintained the Py
plasmid. Thus it seems clear that the presence of Py T-Ag expressing DNA was not
detrimental to the development of most normal mouse tissues. This plasmid could
offer a very useful experimental tool for the genetic analysis of ES and EC
cell function (see below). Another interesting use of EC and ES cells concerns
their ability to grow into masses (tumor-like) in the more immunologically
privileged site of the brain. Both ES and EC cells can be differentiated into
trophectoderm containing embryoid bodies. These embryos will generally grow in
various transplanted sites only with immunosuppression. However, following brain
implantation of embryoid bodies, ES cells will grow rapidly into large masses
(91). Implantation of 2-4 cell embryos, which lack trophectoderm, however, do
not grow. It seems possible that the capacity of the embryoid tissues to grow
in the brain might be related to the presence of trophectoderm. If so, this
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page, please contact Einstein at uci.edu Last Updated 7/14/1999
In a message dated 11/22/2004 8:43:11 PM Eastern Standard Time,
ursus at earthlink.net writes:
It's a provocative idea, isn't it? Invisible mutations, occurring at the
metabolic level, in the "infrastructure," so to speak, but not manifesting
in large-scale phenotypic changes.
However, I think it's also apparent that all organisms today have a set of
"grammatically correct" bauplan variations that can be called upon in
incremental (but not gradual) stages in response to environmental challenges
over perhaps hundreds or thousands of years in larger animals, and tens of
years in insects, and days or weeks in bacteria.
The best recent example is the reoccurrence of wings in stick insects...
From: paleopsych-bounces at paleopsych.org
[mailto:paleopsych-bounces at paleopsych.org] On Behalf Of Geraldine Reinhardt
Sent: Monday, November 22, 2004 5:32 PM
To: The new improved paleopsych list
Subject: Re: [Paleopsych] is evolutionary change stockpiled?
Could be. Check with Greg Bear.
----- Original Message -----
From: "Steve Hovland" <shovland at mindspring.com>
To: "'The new improved paleopsych list'"
<paleopsych at paleopsych.org>
Sent: Monday, November 22, 2004 4:15 PM
Subject: RE: [Paleopsych] is evolutionary change
> Is it possible that there are incremental changes
> in the environment that don't require an immediate
> outward response, but which do cause a series of
> "invisible" mutations which suddenly manifest when
> the environmental changes reach some triggering
> Steve Hovland
> -----Original Message-----
> From: HowlBloom at aol.com [SMTP:HowlBloom at aol.com]
> Sent: Monday, November 22, 2004 3:42 PM
> To: paleopsych at paleopsych.org
> Subject: [Paleopsych] is evolutionary change
> << File: ATT00005.txt; charset = UTF-8 >> << File:
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> ATT00007.txt >>
> paleopsych mailing list
> paleopsych at paleopsych.org
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Author of The Lucifer Principle: A Scientific Expedition Into the Forces of
History and Global Brain: The Evolution of Mass Mind From The Big Bang to the
Visiting Scholar-Graduate Psychology Department, New York University; Core
Faculty Member, The Graduate Institute
Founder: International Paleopsychology Project; founding board member: Epic
of Evolution Society; founding board member, The Darwin Project; founder: The
Big Bang Tango Media Lab; member: New York Academy of Sciences, American
Association for the Advancement of Science, American Psychological Society, Academy
of Political Science, Human Behavior and Evolution Society, International
Society for Human Ethology; advisory board member: Youthactivism.org; executive
editor -- New Paradigm book series.
For information on The International Paleopsychology Project, see:
for two chapters from
The Lucifer Principle: A Scientific Expedition Into the Forces of History,
For information on Global Brain: The Evolution of Mass Mind from the Big Bang
to the 21st Century, see www.howardbloom.net
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