interpreting the functional significance of genetic polymorphisms in natural populations poses a major challenge . here i review recent work in yeast , flies , mice and primates that examines the influences of naturally occurring sequence variation , chromosomal order and speciation on genome - wide expression profiles of both rna and protein . a synthetic view from these experiments would suggest that gene expression is not randomly distributed along chromosomes , that variations in mrna and protein expression within a single species result from a surprising balance between polymorphisms acting in cis and polymorphisms acting in trans to the regulated gene , and consequently that relatively few adaptive changes could have major impacts in remodeling gene expression patterns over the course of evolution . sequence polymorphism and genome - wide haplotype maps have begun to catalog the extent and structure of genetic variation present in human populations   and to a lesser extent inbred strains of model organisms . an emerging theme from such maps is that linked polymorphisms tend to travel through a population together , creating haplotype blocks , by virtue of either recombination hotspots or population expansions of chromosomes carrying ancestral recombination events . recent reports have also documented variation in gene expression profiles between individuals and , more importantly , reproducible variations between inbred strains . however , assigning functional significance to individual polymorphisms at the level of either sequence or expression is a different problem . a series of recent papers has taken a complementary approach by examining the sources of variation in expression profiles between strains of model organisms . the availability of nearly complete genome sequences and large sets of gene expression data has led several groups to consider whether gene expression profiles are structured by chromosomal order . individual gene clusters have been observed and analyzed since almost the beginnings of molecular genetics , and genome sequences have demonstrated that genomes are not randomly organized . but how prevalent is chromosomal organization by gene expression ? new comparisons of transcript maps and expression profiles with genome sequence have indicated nonrandom clustering of genes into chromosomal expression domains in flies , nematodes , and humans . have shown that housekeeping genes cluster more readily than do other gene classes ( as measured by breadth of representation in serial analysis of gene expression ( sage ) experiments ) , but clustering patterns that are more specific have also been reported . report in bmc genomics that sage tags found in normal brain or brain tumor samples cluster along chromosomes more than would be expected by chance , and that the normal and tumor clusters are distinct from each other . although more work to understand the underlying reasons for these statistical clusters is warranted , such clustering would make a ready substrate for evolutionary remodeling of gene expression patterns . one intriguing question is to what extent variation in gene expression within a population is controlled by sequence variation within the gene itself ( in cis ) compared with variations in unlinked regulatory genes ( in trans ) . multiple layers of control of gene expression have been selected in evolution ( transcription , processing , export and stability of rna ; and translation , folding , modification , trafficking and degradation of protein ) , and variation in genes that act in any layer could produce systematic variation in gene expression among individuals in a population . this raises an interesting question about the genetic architecture of gene expression differences among individuals in natural populations , between inbred strains of laboratory organisms , and between evolving species . starting with a relatively simple case , kruglyak and colleagues   have mapped sources of mrna expression differences between a laboratory strain and a wild isolate of saccharomyces cerevisiae . among 6,215 rnas monitored , 1,528 showed highly significant expression differences between the two parental strains ( p < 0.005 and < 2% expected false - positive rate by permutation testing ) . by examining both expression profiles and genetic markers in the same cross progeny , brem et al .   were able to estimate the heritability of expression variations and map the loci that control the variation . the heritability estimates indicated that 84% of the expression difference was genetic ; surprisingly , however , only 308 of the 1,528 expression differences showed significant genetic linkage among 40 haploid segregants . a power calculation puts this in perspective : a cross of this size and marker density should detect nearly all loci that control all of an expression difference and nearly 30% of loci that control as much as a third of the variation for an expression difference . as brem et al . found linkage for only about 20% of the expression differences - and only a third of those map back to the structural gene - this suggests that interstrain expression differences ( and therefore inter - individual differences in a broader population ) in even a ' simple ' eukaryote can be genetically complex and that the majority can not be accounted for simply by changes in cis - acting sequences . similarly , klose and colleagues   have taken a genetic approach for an initial look at a more complex question : protein expression in the mouse brain . identified 8,767 distinct two - dimensional gel spots , representing isoforms of an estimated 2,770 proteins ( based on mass spectrometry of identified spots ) from soluble extracts . of these , 1,324 spots ( an estimated 936 proteins ) were polymorphic between species . clearly , a large number of mechanisms can operate on both abundance and electrophoretic mobility of proteins compared to rna , but which of them is most prevalent between recently diverged species ? about half of the polymorphic spots ( 40% of the proteins ) varied primarily in a qualitative manner , having altered migration patterns , with the remainder being primarily quantitative . not surprisingly , qualitative differences proved easier to follow than purely quantitative differences in backcross progeny ( one limitation of this experimental design is that only one sex of the f1 hybrid is fertile and only one of the possible backcrosses was examined , and thus about 343 protein spots for which the backcross parent has a dominant allele could not be scored ) . .   followed linkage of 409 polymorphic spots ( 273 qualitative , 176 quantitative ) in 200 backcross ( f1  m. spretus ) progeny from the previously genotyped panel . consistent with the yeast rna experiments , several of the protein spots appeared to be affected by more than one gene , and some by as many as three . among 150 polymorphic proteins identified by mass spectrometry , 42 mapped to the known location of the structural gene , suggesting either amino - acid substitutions or cis - regulatory changes , and 41 polymorphisms mapped to sites other than the structural gene . as with yeast rna expression , this again points to a high degree of unlinked regulatory polymorphism in the control of proteome expression . nor does this analysis exhaust the approach ; klose et al . focused on the soluble fraction of their extracts , leaving membrane and chromatin fractions for later consideration . it will be of interest to see whether proteins with additional constraints on their trafficking and localization have any significant difference in the kind or number of linkages for protein polymorphisms . one wonders about other patterns of change that may be observed at the edge of speciation . several reproductively isolated but interfertile subspecies of mice have been inbred , including mus musculus castaneus and mus musculus molossinus . polymorphism rates between these strains and canonical lab mice are not quite as high as for m. spretus but still average about one amino - acid change per protein , and both sexes of the hybrid progeny are fertile , allowing an intercross design . comparisons among multiple sibling species ( or subspecies ) may provide an additional layer of functional annotation by highlighting proteins that are either highly constrained or highly plastic in their two - dimensional gel profiles . how the balance of cis versus trans effects might change over different evolutionary distances would also be of interest . the nature and distribution of polymorphisms in humans and experimental animals is important for disease and modifier gene hunts , but also for understanding mechanisms of selection and adaptation in evolution . the distributions of amino - acid substitutions and gene expression changes are particularly interesting in view of the changes in global patterns of gene expression recently observed in primate speciation . to the human eye , by contrast , humans and chimpanzees , which differ by roughly the same level of nucleotide changes , seem quite different . the protein expression analysis of enard et al .   would suggest otherwise . while brain protein differences between mouse species are about evenly split between quantitative and qualitative changes , a similar analysis of humans and chimps , even after accounting for inter - individual differences , shows a several - fold increase in the rate of quantitative differences . it will be of great interest to see how these changes distribute between cis - acting regulatory changes and changes in trans - acting regulatory factors ; and whether this index differs with morphological divergence . robust performance in a noisy environment is a hallmark of well - engineered systems , from telecommunications networks to the human brain . biological populations require variation among individuals for adaptation to changing environments and to take advantage of new niche opportunities . a multi - pronged approach that includes global analysis of sequence variants , expression variants and genetic mapping promises to provide a new understanding of how the population structure of the genome - wide response to genetic variants influence biological traits .
how do naturally occurring polymorphisms in dna sequence relate to variation in gene expression ? 
 recent work to map genetic sources of expression variation has shown a surprising balance between cis and trans effects . 
 other work suggests some chromosomal clustering of genes by expression pattern .