cis versus trans effects - senecio7の日記

Carroll SB 2005 Evolution at two levels: on genes and form. PLoS Biol 3:e245.

in their classic paper "Evolution at Two Levels in Humans and Chimpanzees," published exactly 30 years ago, Mary-Claire King and Allan Wilson described the great similarity between many proteins of chimpanzees and humans
it extrapolated from molecular data to make inferences about the evolution of form
it may also be considered a pioneering study in evolutionary developmental biology

one critical parameter that affects the relative contribution of different genetic mechanisms to anatomical variation is the pleiotropy of mutations [20]
mutations with greater pleiotropic effects will have more deleterious effects on organismal fitness and will be a less common source of variation in form than mutations with less widespread effects
a mutation in the coding region of a transcription factor that functions in multiple tissues may directly affect all of the genes the protein regulates
a mutation in a single cis-regulatory element will affect gene expression only in the domain governed by that element
John Gerhart and Marc Kirschner [21,22] have discussed in depth how certain features of animal genetic regulatory systems influence "evolvability"
the capacity to generate tolerable, heritable variation
redundancy reduces constraint on change by circumventing or minimizing the potentially deleterious effects of some mutations
compartmentation also facilitates change
by uncoupling variation in one process from variation in another, pleiotropy is decreased

changes in the expression of an individual gene may evolve through alterations in cis-regulatory sequences
or in the deployment and activity of the transcription factors that control gene expression
or both

a handful of studies have genetically demonstrated that evolution at particular loci has affected the gain [32], loss [26,27,33], or modification of morphological traits [25]
these studies—highlighted below—have firmly eliminated coding sequences as a possible cause and thereby implicated regulatory sequence evolution at loci encoding pleiotropic transcription factors
in a few cases, direct evidence of functional changes in cis-regulatory elements has been obtained

there are several salient general features of the evolution of pigment patterns in fruit flies
many or all of the structural genes involved are pleiotropic
they have roles in multiple parts of the body and in other physiological processes
for example, neurotransmitter synthesis and behavior
they are regulated, at least in part, by widely deployed, highly conserved pleiotropic regulatory proteins
some of which are themselves regulated by deeply conserved and evolutionarily stable global regulators of body pattern formation
the coding sequences of the structural and regulatory proteins are constrained by pleiotropy
modular cis-regulatory regions enable a great diversity of patterns to arise from alterations in regulatory circuits through the evolution of novel combinations of sites for regulatory proteins in cis-regulatory elements

functional mutations in a coding region are usually poorly tolerated and eliminated by purifying selection
even complete loss-of-function mutations in regulatory elements are possible
because the compartmentation created by the modularity of cis-regulatory elements limits the effects of mutations to individual body parts
does this mean that coding sequences cannot contribute to morphological evolution?
not at all
there are several clear examples of functional sequence changes in proteins that affect form

while the agnostic, "wait and see" position would appear safer, that would not at all be in keeping with the bold spirit of the pioneers who first wrestled with the question
I argue that a trend is evident
that trend should, of course, inform ongoing and future work

I have argued elsewhere [60] that the evolution of complex traits such as brain size, craniofacial morphology, cortical speech and language areas, hand and digit form, dentition, and body skeletal morphology must have a highly polygenic and largely regulatory basis