trans

102 ANTIGENIC VARIATION
‘silent’ ES promoters. This became strikingly
apparent when ESAG6 was deleted from the
active ES. That this was not lethal was attributed
to the demonstrable transcription from
‘silent’ ESs. This trickle transcription of many
transferrin receptors could also contribute to
the parasite’s flexibility in different hosts, but
it could also be used as an argument against
receptor–host specificity being the reason for
the existence of multiple ESs. Furthermore,
because many copies of ESAG6 and ESAG7 are
being simultaneously transcribed, a large number
of heterodimeric receptor combinations
may be present, greatly extending the range of
transferrin receptor properties.
Duplicative transposition of silent telomeric
VSGs into the active ES seems likely to be the
more quantitatively important mechanism for
activating VSG genes, because telomeres appear
to cluster together at several stages in the life
cycle. The abundant minichromosomes of
T. brucei appear to be a major reservoir of VSGs.
The trypanosome may be forced into selecting
less accessible (therefore activated at a lower
frequency) ‘chromosome-internal’ silent VSGs
at later stages of an infection. This is a time
where mosaic VSGs have been described, arising
from conversion of partial VSG sequences
through recombination within the coding
region of the active VSG.
Dynamics of antigenic variation:
switching rates and modeling studies
Switching frequencies have been measured in
different ways and, whichever methods were
used, a wide range of frequencies has been
reported. Switch frequency has been proposed
to be a function of the trypanosome line, with
more recently isolated or tsetse-transmitted
lines having the highest switching rates, perhaps
as high as one switch per 100 cells per generation.
On the other hand, the switching rate
of laboratory strains that routinely show very
low switching rates (1 switch per 10 6 cells per
generation) can be dramatically increased by
certain ES manipulations. There are some fairly
obvious ES features that might influence switching
rates, but few of these, including telomere
length, have been experimentally manipulated.
Early serological data suggested that the
sequence of VSG expression, in different experiments,
is neither totally predictable nor random.
This semi-predictability may be due to
the telomeric VSG repertoire being more accessible.
Although that hypothesis has not been
tested extensively and quantitatively, the trend
is apparent in several recent studies.
Being largely controlled by the antibody arm
of the immune system, antigenic variation is a
seductive target for mathematical modelers,
although the outcome of attempts to model the
process have remained controversial. As one
suspects is often the case, a model can be manipulated
to mimic known features of a real infection,
but the strength or weakness of any model
ultimately depend upon knowing all the biological
parameters that must be included, and
on the quality of the real-world data that are
selected to seed the models.
Evolution of VSG genes
T. brucei is diploid and contains 11 chromosome
pairs, ranging from 1 to 5 Mb, which
appear to contain the entire complement of
essential genes, and about 100 ‘minichromosomes’,
ranging from 25–150 kb. The (haploid
equivalent) informational content of the T. brucei
genome, after discounting major repetitive
sequences, is about 25 Mb, similar to S. cerevisiae.
By the time this book reaches the reader,
the genomic sequencing of T. brucei should
be close to completion. Even now, sequences
representing the entire gene complement are
available in the public databases, in the form
MOLECULAR BIOLOGY