Professional Documents
Culture Documents
Gene Families Brenner
Gene Families Brenner
selection) and thus, they are subject to genetic drift, genetic material actually occurs in a subsequent gen-
inherited by some offspring but not others derived eration after the transposed region has segregated into
from parents that carry the duplication unit. By the same genome as the originally positioned region
chance, most neutral genetic elements will succumb from a nondeleted homolog. In theory, there is no
to extinction within a matter of generations. But upper limit to the size of a genomic region that can
even when a duplicated region survives for a sig- be duplicated in this way.
nificant period of time, random mutations in what A much more common mode of transposition
were once-functional genes will almost always lead occurs by means of an intermediate RNA transcript
to nonfunctionality. At this point, the gene becomes a that is reverse-transcribed into DNA and then
pseudogene. Pseudogenes will be subject to continu- inserted randomly into the genome. This process is
ous genetic drift with the accumulation of new muta- referred to as retrotransposition. The size of the retro-
tions at a pace that is so predictable (~0.5% divergence transposition unit ± called a retroposon ± cannot be
per million years) as to be likened to a `molecular larger than the size of the intermediate RNA tran-
clock.' Eventually, nearly all pseudogene sequences script. Retrotransposition has been exploited by vari-
will tend to drift past a boundary where it is no longer ous families of selfish genetic elements, some of
possible to identify the functional genes from which which have been copied into 100 000 or more locations
they derived. Continued drift will act to turn a once- dispersed throughout the genome with a self-encoded
functional sequence into a sequence of essentially ran- reverse transcriptase. But, examples of functional,
dom DNA. intronless retroposons ± such as Pgk2 and Pdha2 ±
Miraculously, every so often, the accumulation of a have also been identified. In such cases, functionality
set of random mutations in a spare copy of a gene can is absolutely dependent upon novel regulatory ele-
lead to the emergence of a new functional unit ± or ments either present at the site of insertion or created
gene ± that provides benefit and, as a consequence, by subsequent mutations in these sequences.
selective advantage to the organism in which it resides.
Usually, the new gene has a function that is related to
the original gene function. However, it is often the
Duplication by Unequal Crossing-Over
case that the new gene will have a novel expression The second broad class of duplication events result
pattern ± spatially, temporally, or both ± which must from unequal crossing-over. Normal crossing-over,
result from alterations in cis-regulatory sequences that or recombination, can occur between equivalent
occur along with codon changes. A new function can sequences on homologous chromatids present in a
emerge directly from a previously functional gene or synaptonemal complex that forms during the pachy-
even from a pseudogene. In the latter case, a gene can tene stage of meiosis in both male and female mam-
go through a period of nonfunctionality during which mals. Unequal crossing-over ± also referred to as
there may be multiple alterations before the gene illegitimate recombination ± refers to crossover events
comes back to life. Molecular events of this class can that occur between nonequivalent sequences. Unequal
play a role in `punctuated evolution' where, according crossing-over can be initiated by the presence of re-
to the fossil or phylogenetic record, an organism or lated sequences ± such as highly repeated retroposon-
evolutionary line appears to have taken a `quantum dispersed selfish elements ± located nearby in the
leap' forward to a new phenotypic state. genome. Although the event is unequal, in this case,
it is still mediated by the homology that exists at the
two nonequivalent sites.
Duplication by Transposition So-called nonhomologous unequal crossovers can
With duplication acting as such an important force in also occur, although they are much rarer than homo-
evolution, it is critical to understand the mechanisms logous events. They are ``so-called'' because even these
by which it occurs. These fall into two broad cat- events may be dependent on at least a short stretch of
egories: (1) transposition is responsible for the disper- sequence homology at the two sites at which the event
sion of related sequences; (2) unequal crossing-over is is initiated. The initial duplication event that produces
responsible for the generation of gene clusters. Trans- a two-gene cluster may be either homologous or non-
position refers to a process in which one region of the homologous, but once two units of related sequence
genome relocates to a new chromosomal location. are present in tandem, further rounds of homologous
Transposition can occur either through the direct unequal crossing-over can be easily initiated between
movement of original sequences from one site to nonequivalent members of the pair as illustrated in the
another or through an RNA intermediate that leaves Figure 1. Thus, it is easy to see how clusters can
the original site intact. When the genomic region itself expand to contain three, four, and many more copies
(rather than its proxy) has moved, the `duplication' of of an original DNA sequence.
668 E vo l u ti o n o f G e n e F a m i l i e s
Initial duplication of single copy region Further expansion from a two repeat cluster
A B' B C
A B C genetic
exchange B′ B C
sites region of crossover
A' B' pairing site
A B' B/B' B C
reciprocal products
divergence
deleted chromosome
A C'
A B1 B2 B3 C
A' B' B C
three-member gene family cluster
duplicated segments
Figure 1 Unequal crossing-over generates gene families. The left side illustrates an unequal crossing-over event and
the two products that are generated. One product is deleted and the other is duplicated for the same region. In this
example, the duplicated region contains a second complete copy of a single gene (B). The right side illustrates a
second round of unequal crossing-over that can occur in a genome that is homozygous for the original duplicated
chromosome. In this case, the crossover event has occurred between the two copies of the original gene. Only the
duplicated product generated by this event is shown. Over time, the three copies of the B gene can diverge into three
distinct functional units of a gene family cluster.
In all cases, unequal crossing-over between homo- same exact process that is responsible for unequal
logs results in two reciprocal chromosomal products: crossing-over. This alternative outcome is known as
one will have a duplication of the region located be- intergenic gene conversion. Gene conversion was ori-
tween the two sites and the other will have a deletion ginally defined in yeast through the observation of
that covers the same exact region (Figure 1). It is im- altered ratios of segregation from individual loci that
portant to remember that, unlike retrotransposition, were followed in tetrad analyses. These observations
unequal crossing-over operates on genomic regions were fully explained within the context of the Holli-
without regard to functional boundaries. The size of day model of DNA recombination which states that
the duplicated region can vary from a few base pairs to homologous DNA duplexes first exchange single
tens or even hundreds of kilobases and it can contain strands that hybridize to their complements and
no genes, a portion of a gene, a few genes, or many. migrate for hundreds or thousands of bases. Resolu-
tion of this `Holliday intermediate' can lead with
equal frequency to crossing-over between flanking
Genetic Exchange between Related markers or back to the status quo without crossing-
DNA Elements over. In the latter case, a short single strand stretch
There are many examples in the genome where genetic from the invading molecule will be left behind within
information appears to flow from one DNA element the DNA that was invaded. If an invading strand
to other related ± but nonallelic ± elements located carries nucleotides that differ at any site from the
nearby or even on different chromosomes. In some strand that was replaced, these will lead to the produc-
special cases, the flow of information is so extreme as tion of heteroduplexes with base pair mismatches.
to allow all members of a gene family to coevolve with Mismatches can be repaired (in either direction) by
near-identity as in the case of ribosomal RNA genes. In specialized `repair enzymes' or they can remain as-is
at least one case ± that of the class I genes of the major to produce non-identical daughter DNAs through the
histocompatibility complex (MHC or H2) ± informa- next round of replication.
tion flow is unidirectionally selected, going from a By extrapolation, it is easy to see how the Holliday
series of 25 to 38 nonfunctional pseudogenes into two model can be applied to the case of an unequal cross-
or three functional genes. In this case, intergenic infor- over intermediate which can be resolved in one of two
mation transfer serves to increase dramatically the directions with equal probability. With one resolution,
level of polymorphism that is present at the small unequal crossing-over will result; with the alternative
number of functional gene members of this family. resolution, gene conversion can be initiated between
Information flow between related DNA sequences nonallelic sequences. Remarkably, information trans-
occurs as a result of an alternative outcome from the fer ± presumably by means of gene conversion ± can
E vo l u t i o n a r i l y S ta b l e S t r a t e g i e s 669
also occur across related DNA sequences that are even ESS attempts to define conditions under which blind
distributed to different chromosomes. There have evolution will return to the strategy in question, rather
been numerous modifications of the Holliday model than requiring rational foresight to dissuade the ex-
± including those proposed by Meselson and Rading ± ploration of alternatives.
that allow a better fit to the actual data, and there is An ESS is a strategy that cannot be beaten by any
still lack of consensus on the some of the details other strategy. An individual adopting it outperforms
involved. However, the central feature of the Holliday any individual adopting any alternative tactic. No
model ± single-strand invasion, branch migration, and other strategy can outperform an ESS. Individuals
duplex resolution ± is still considered to provide the adopting an ESS tactic have a higher reproductive
molecular basis for gene conversion. success than individuals adopting other tactics. Such
an unbeatable tactic can go to fixation (100%) in a
population and such a population cannot be invaded
See also: Gene Conversion; Holliday's Model;
by any other tactic. Inevitably, an ESS ends up
Major Histocompatibility Complex (MHC);
encountering itself more often than it confronts any
Molecular Clock; Unequal Crossing Over
other strategy, and it must therefore perform better
against itself than any other strategy can perform
against it.
Evolutionarily Stable Game theory involves conflicts of interest in which
Strategies the value of a given action by a decision maker
depends both on its own choices as well as on those
E Pianka of others. A `payoff' matrix of values of outcomes is
Copyright ß 2001 Academic Press postulated based on the respective behaviors of two or
doi: 10.1006/rwgn.2001.0431 more contestants under all possible situations. Payoffs
are frequency dependent. Decision rules that repre-
sent an evolutionarily stable solution to such an
When natural selection acts on several different alter- evolutionary game constitute an ESS (Axelrod and
native behaviors, the most optimal should be favored. Hamilton, 1981).
If costs and benefits of alternatives depend on choices As an example, consider a well-known game theor-
made by other individuals, optimal solutions are not etical model called the `prisoner's dilemma.' In this
always as obvious as they are in simpler situations. An hypothetical situation, two partners in crime have
evolutionarily stable strategy, or ESS, is a mathemat- been arrested. The police interrogate each person
ical definition for an optimal choice of strategy under alone. Each party could cooperate with the other and
such conditions. steadfastly refuse to squeal on their friend. If both
Interactions between two individuals can be de- cooperate and remain silent, the authorities cannot
picted as a mathematical game between two players. establish guilt and both get off scott free (loyalty
A branch of mathematics, called game theory, seeks to pays off). Alternatively, each could betray their part-
find the best strategy to play in any given carefully ner and confess. Now consider respective rewards and
defined game. The central problem of game theory is punishments received by each partner for making each
to find the best strategy to take in a game that depends decision. If only one party confesses while the other
on what other players are expected to do. remains quiet, this betrayal is rewarded by giving the
Originally used in studies of economics and human confessor a light sentence for providing `state's evi-
conflicts of interest, game theoretical thinking was dence' and testifying as to the guilt of their loyal silent
first used in biology by Hamilton (1967) to study evo- partner, who is then found guilty and receives a much
lution of sex ratios. Later, game theory was explicitly longer prison term (he gets the `sucker's payoff').
applied to behavioral biology by Maynard Smith (1972) However, if both partners tell, the authorities put
and Maynard Smith and Price (1973). Maynard Smith both on trial and both receive moderate, but not
coined the term ESS for a refinement of the Nash long, sentences of imprisonment. In a `zero sum'
equilibrium used by economists to define a solution game, all losses add up to equal all gains. Not so in
to a game. this game, where each partner can gain considerably
The notion of a Nash equilibrium makes some tacit without as much loss to the other (indeed, by working
assumptions about rational foresight on the part of the together, both could escape conviction altogether).
player. An ESS must meet a stricter set of require- But they are not allowed to work together and neither
ments than Nash equilibria; the mathematical differ- knows what the other will do.
ence boils down to whether a tie between strategies Here then, is the classic `prisoner's dilemma': each
leads to a new strategy being considered better. An prisoner must decide what to do without knowing