in bisexual organisms with chromosomal sex determination , sex - linked genes occur in 
                 different dosages in the two sexes , and this dosage difference in genes not directly 
                 related to sex determination is compensated by a variety mechanisms , such as 
                 deactivation of one of x chromosomes in mammalian females ( lyon 1988 ; straub and 
                     becker 2007 ) or higher expression of x - linked genes in drosophila males 
                     ( baker et al .
gene - specific data indicate 
                 that autosomal dosage compensation may be a common phenomenon in drosophila and that 
                 it is likely to occur on the transcriptional level ( devlin et al .
broader evidence that a broad spectrum of autosomal genes are 
                 under transcriptional regulation compensating for aneuploidy comes from 
                 transcriptome analysis of trisomies ( fitzpatrick 
                     et al .
2002 ) and cancer - associated aneuploidies ( tsafrir et al . 2006 ; williams et al .
2008 ) in human and mice and a variety of aneuploid 
                 genotypes in yeast ( torres et al .
although transcriptional level , as detected by microarrays , generally followed the 
                 dna dosage trend in these studies , two important trends became apparent : at least 
                 some genes in aneuploid regions are , in fact , transcribed at a nearly normal diploid 
                 level and many misregulated genes are not located in aneuploid regions ( fitzpatrick et al .
in contrast to 
                 mammalian and yeast data , two recent studies ( gupta et al .
2009 ) indicated that autosomal dosage compensation is 
                 a rule rather than exception in drosophila ( see below ) .
if autosomal transcriptional dosage compensation is indeed common in at least some 
                 organisms , three important questions can be asked .
first , do these mechanisms act on 
                 gene - specific level or on the level of larger chromosomal segments ?
second , are 
                 these mechanisms capable of fine - tuned regulation of transcription level 
                 compensating for both deficiencies and duplications or do they operate on a more 
                 coarse scale , that is , assuring that genes with high - demand products are expressed 
                 at a sufficiently high level ? finally , can autosomal dosage compensation be the 
                 fundamental basis of dominance ?
there are two 
                 aspects of dominance that require explanation : 1 ) why do most genes exhibit complete 
                 dominance of one of the alleles rather than additivity of the action of two alleles 
                 ( i.e. , why is codominance a relatively rare phenomenon ) , and 2 ) why is it the 
                 wild - type allele that is usually dominant .
possible explanation of these factors has 
                 been the subject of perhaps the fiercest debate between the founding fathers of 
                 modern synthesis .
fisher ( 1928 ) proposed 
                 that dominance of the wild - type alleles is the result of selection on modifier 
                 genes , which epistatically mask the action of the mutant allele in a heterozygote . 
                 by necessity such evolution
this 
                 idea was met with criticism by cofounders of the modern synthesis ( wright 1934 ; haldane 1939 ) . instead , wright suggested that dominance is an 
                 inherent property of the physiological systems , perhaps evolved through selection to 
                 provide a safety margin in the action of a single functional copy of a gene , which 
                 would allow to accommodate for environmental fluctuations and for the lack of 
                 activity of the other gene .
such selection would act on the entire population , not 
                 on heterozygotes only , and is therefore much more powerful .
a variety of studies during last 30 years provided strong evidence in favor of the 
                 physiological theory of dominance .
in particular , the metabolic control theory 
                     ( kacser and burns 1981 ) implies that 
                 enzymes functioning in metabolic pathways are bound to exhibit a diminishing return 
                 relationship between activity of an individual enzyme and the flux of metabolites 
                 through the whole pathway , which ultimately determines the phenotype .
thus , 2-fold 
                 change in protein titer ( as in a heterozygote for a loss - of - function mutation ) is 
                 usually negligible in terms of the resulting phenotype .
this idea was supported by 
                 negative correlation between the strength of a mutant allele and its dominance 
                     ( charlesworth 1979 ; crow 1979 ; crow and simmons 1983 ; phadnis and fry 
                     2005 ) .
further support to the physiological dominance theory came from 
                 the observation that dominance is prevalent in organisms , which spend much of their 
                 life cycle in haploid phase , such as in chlamydomonas ( orr 1991 ) or fission yeast ( baek et al .
finally , loss - of - function 
                 mutations are more likely to be fully recessive in enzyme - coding genes than in genes 
                 coding for structural or regulatory proteins ( fisher and scambler 1994 ; veitia 
                 2002 ; kondrashov and koonin 2004 ) 
                 and for proteins that are less likely to form protein complexes ( papp et al .
the physiological mechanisms behind dosage compensations are 
                 thought to be acting primarily on the protein level . on the other hand , dosage compensation may as well occur at the lever of 
                 transcription , resulting in a mechanism of dominance independent from the protein 
                 function .
eukaryotic transcriptional machinery is equipped with a stunning variety 
                 of mechanisms enabling fine - tuned regulation of transcription ( lee et al .
such mechanisms often incorporate negative 
                 feedbacks allowing adjustment of transcription level to match the environmental 
                 fluctuations or tissue - specific developmental needs ; these feedbacks may as well 
                 provide compensation for a loss - of - function mutation in one of the alleles . on the 
                 other hand , one can hypothesize that , in many genes , the regulation of gene 
                 expression may be a lot less sophisticated and lacking fine - tuned gene - specific 
                 homeostasis mechanisms .
in fact , the number of transcription factors present in the 
                 genome is constrained by the limits set by coding theory : unlimited increase of the 
                 number of transcription factors capable of recognizing specific nucleotide sequences 
                 would lead to the increase of misrecognition errors ( itzkovitz et al .
, there may be genes coding 
                 for high demand proteins , which are constitutively transcribed at a high rate , and 
                 genes coding for low demand proteins , whose transcription is maintained at low 
                 level . if this is true , one would expect that transcriptional dosage compensation to 
                 be widespread and to correlate with the overall gene expression level .
indeed , the 
                 pervasive nature of autosomal transcriptional compensation has been recently 
                 demonstrated in drosophila ( gupta et al . 
                
2009 ) report 
                 that the degree of compensation is different in genes with different degree of 
                 tissue specificity of expression : ubiquitously expressed genes are stronger 
                 compensated for deficiencies and less effectively for a duplication than 
                 tissue - specific ones .
( 2009 ) also suggest that there is no correlation between the degree of 
                 compensation and overall expression level . here , we test these results using three 
                 sets of drosophila genes .
we measured the level of gene expression in two isogenic 
                 deletional lines using oligonucleotide microarrays and compared our results with 
                 published data on transcriptional compensation in heterozygotes for a duplication 
                     ( gupta et al .
two drosdel ( ryder et al . 2007 ) 
                     drosophila melanogaster isogenic lines , df(3l)ed4475 and 
                 df(3l)ed4543 , heterozygous for long deletions on 3l chromosomal branch both 
                 maintained against the tm6c balancer , were used for microarray experiment . 
                
twenty - five adult flies 25 days after eclosion were frozen in liquid 
                 nitrogen and used for rna extraction by trizol method ( invitrogen ) in 12 replicates 
                 from each line .
samples were reverse transcribed , labeled , and hybridized to 
                 two - color 14k oligonucleotide microarrays by canadian drosophila microarray centre 
                 ( missassauga , ontario , canada ; neal et al . 
                
the two lines , which serve as controls for each other , were alternated 
                 between cy3 and cy5 dyes to minimize possible channel bias .
fluorescence intensity 
                 data ( background intensity subtracted ) were analyzed by jmp genomics 3.0 ( sas institute 2007 ) .
the data are available 
                 at gene expression omnibus ( geo ) ( edgar et al . 
                    
data were anova - normalized to eliminate the effects of arrays and channels , mean 
                 intensity of fluorescence for hemizygous and diploid line calculated for each gene 
                 and the ratio of the intensity in the line with the deletion to that in the control 
                 line ( r ) analyzed . for a comparison with gupta et 
                     al .
( 2006 ) , in which raw data are available and to avoid possible 
                 expression level - dependent bias in expression ratios , the correlation between 
                 expression ratio and mean expression level was also analyzed without any 
                 normalization ; the results are virtually identical .
line ed4475 had slightly but 
                 statistically significantly higher fluorescence across the genome ( ed4475 : ed4543 
                 = 1.017 for diploid genes ) , and therefore , the ratio was adjusted by this 
                 factor . this adjustment had no effect on any of the findings reported . presence or 
                 absence of expression for each gene was evaluated by comparison of average 
                 fluorescence across all arrays with the internal blank ( autoblank ) intensities and 
                 genes with intensities significantly ( p < 0.05 ) above the 
                 autoblank level were considered detectable .
the distribution of r in hemizygous 
                 genes was analyzed by maximum likelihood as a superposition of two normal 
                 distributions one with the mean of 0.5 ( uncompensated genes ) , the other ( partially 
                 compensated genes ) with unknown mean ; this unknown mean , standard deviations of both 
                 distributions and the frequency of uncompensated genes were simultaneously 
                 optimized . in order to verify that the observed expression ratios in deletion lines are not an 
                 artifact of inherent microarray noise
, we performed a neural network - based analysis 
                 of the distribution of expression ratios along the chromosome .
a neural network 
                 consisting of three nodes in one hidden layer and implemented within jmp genomics 
                 package ( sas institute 2007 ) was provided 
                 the input data in the form of expression ratio for each gene with detectable 
                 expression along with the expression ratios of this gene s five nearest 
                 neighbors on each side ( again , using only gene with detectable expression ) .
the 
                 network was then trained to recognize each deletion using the data on the other 
                 deletion as the training set .
the network recognized genes within deletions with 
                 4.4% of false negatives ( almost all on the deletion breakpoints ) and 9.75% false 
                 positives ( fig .
more than half of the 
                 false positives were present in runs of more than three adjacent genes and may 
                 represent actual unknown short deletions present in the drosdel lines we used .
we 
                 conclude , therefore , that our data contain a sufficiently strong signal to allow us 
                 the comparison of expression ratios between hemizygous and diploid genes . sliding average ( 5 genes ) of expression ratio along 3l chromosome 
                         branch .
gray line : diploid genes ( wild type : wild type ) ; red line : genes in 
                         deletions ( deletion : wild type ) .
thick red bars at 
                         log2r = 0.5 indicate genes 
                         identified as hemizygous by a neural network prediction .
( 2009 ) approach , 
                 to compare ubiquitously expressed genes to tissue - specific genes , genes were 
                 classified as  ubiquitous  if they had expression value of at 
                 least 6 in all 26 adult and larval tissues present in the flyatlas database ( chintapalli et al .
2002 ) , accession numbers 
                 gsm37444 , gsm37445 , gsm37447 , gsm37448 , gsm77751 , and gsm77752 .
these data contain 
                 expression levels in heterozygotes for a long duplication dp(2;2)cam3 relative to 
                 heterozygotes for a deletion df(2l)jh located within the duplication .
thus , genes 
                 located within the duplication but outside of the deletion are compared with the 
                 diploid wild type ( 1.5-fold dosage ) , whereas genes located within the deletion are 
                 compared in lines with 3-fold gene dosage .
there are 289 genes ( 2.1% of the genome ) 
                 in the dp(2;2)cam3 duplication , 59 of which ( 0.4% of the genome ) lay within the 
                 deletion df(2l)jh .
( 2006 ) 
                 for rna extraction , microarray hybridization and scanning , and data handling 
                 details .
deletions ed4475 and ed4543 contain 119 and 65 genes , respectively , comprising about 
                 1.3% of the genome . of these 184 genes all
184 demonstrated transcription level 
                 resulting in higher than background fluorescence , however , in only 69 ( 0.5% of the 
                 genome ) the average fluorescence across all arrays was significantly 
                 ( p < 0.05 ) above the autoblank level .
the distribution of 
                 expression ratios in genes with detectable expression along the chromosomal branch 
                 3l , along with the neural network identification of hemizygous regions is presented 
                 on figure 1 .
the distribution of ratio of mean fluorescence intensities 
                 ( log2r ) of hemizygous genes ( i.e. , genes within the 
                 deletions ) is significantly different from that of the genes outside of the 
                 deletions ( p < 10 , fig .
it is shifted to the 
                 left ( lower expression of hemizygous genes ) with the modal class at 
                     log2r = 0.1 
                 ( r = 0.93 ) and with a distinct shoulder at 
                     log2r = 1 ( the value expected 
                 in case of no transcriptional compensation ) .
the frequency of observations within 
                 1.32 to 0.74 range ( corresponding to the range of ratios 
                 0.40.6 ) among hemizygous is significantly higher than among diploid genes 
                     (  = 20.9 , p < 0.0001 ) . 
                
the distribution of log2r differed somewhat between the 
                 two deletion lines ( p < 0.05 ) with the secondary mode around 
                 1 more pronounced in line ed4543 ( fig . 
                 1 ) , indicating that the frequency of noncompensated genes may differ across 
                 chromosomal regions .
the distribution of log2r 
                 significantly deviated from normal in both deletion lines ( shapiro  wilk 
                 test , p < 0.004 ) . assuming a contaminated normal 
                 distribution ( i.e. , a distribution , in which the majority of observations is from a 
                 specified normal distribution , but a small proportion is from a normal distribution 
                 with a different mean and/or variance ) and optimizing all parameters ( both means , 
                 both variances , and the degree of contamination ) ,
the maximal likelihood estimate of 
                 the frequency of uncompensated genes f0.5 was 0.05 . 
                
values of f0.5 exceeding 0.25 and 0.35 can be excluded 
                 with significance level of 0.05 and 0.01 , respectively .
thus , majority of genes 
                 within the two deletions exhibit at least partial compensation at the stage of 
                 transcription .
deletion : wild type ( red ) and wild type : wild type ( green ) . 
                        
duplication : wild type ( red ) , duplication : deletion 
                         ( gray ) , and wild type : wild type ( green ) .
the distribution of the ratio of expression 
                 intensity in heterozygotes for duplication relative to wild type and heterozygotes 
                 for duplication relative to heterozygotes for a deletion are significantly higher 
                 than the control ( expression ratios of genes outside of the aberrations ; 
                 p < 10 ) but with modes close to 0 , 
                 indicating nearly complete dosage compensation in many genes and relatively few 
                 genes with no dosage compensation at all . in both studies ,
the degree of dosage 
                 compensation appears to be independent from the molecular function category to which 
                 genes belong ( fig .
expression ratio in heterozygotes for deficiencies relative to wild type 
                         ( dark bars , this study ) , heterozygotes for a duplication relative to wild 
                         type ( white bars , gupta et al . 
                        
2006 ) , and in heterozygotes for duplication relative to heterozygotes 
                         for a deficiency ( gray bars , gupta et al . 
                            
error bars are standard errors 
                         reflecting variation among genes within molecular function category . one - way 
                         analysis of variance results for the three data sets were : 
                         f = 0.64 ; p > 0.69 ; 
                             f = 0.48 , p > 0.87 , 
                         and f = 1.06 , p > 0.4034 
                         for this study , gupta et al . 
                        
there was , as predicted , a positive correlation between expression ratio 
                     ( log2r ) and overall expression level 
                     ( log2 m ) . for heterozygotes , for deletions ,
4a ; 
                     log2r = 0.77 + 0.077 
                  log2 m ; p < 0.007 ; 
                     p < 0.02 with the uppermost outlier point removed ) 
                 suggests that genes with barely detectable expression are nearly noncompensated 
                     ( log2r = 1 ) , whereas genes 
                 with highest observed expression level approach full compensation 
                     ( log2r = 0 ) . for heterozygotes , for a 
                 duplication versus diploid wild type ,
the regression ( fig . 4b ; log2r 
                 = 0.77 + 0.14  
                 log2 m ; p <
0.0001 ) suggests that 
                 there is a nearly complete compensation of low expression genes 
                     ( log2r = 0 ) , whereas highly expressed 
                 genes demonstrate little dosage compensation ( log2r 
                 = log2(1.5 ) = 0.58 ) .
the regression of expression 
                 ratio in heterozygotes for a duplication to that is heterozygotes for a deletion 
                 ( 3-fold dosage difference ) over overall expression level is also positive ( fig .
4b ; 
                     log2r = 1.41 + 0.25 
                  log2 m ; p < 0.0008 ) . 
                
the corresponding regression for genes outside of the aberrations is nearly 
                 horizontal for both data sets , suggesting that the observed correlations are not a 
                 product of a bias in the expression data .
it should be noted that this result is 
                 identical for both normalized and nonnormalized data .
the observed correlations are 
                 also not artifacts of data fanning . for example , for deletions ,
expression ratios 
                 for genes with lower expression are expected tend to be located below the 
                     log2r = 0 line simply for the reason of 
                 being underexpressed in hemizygous state , whereas expression ratios for highly 
                 expressed genes , if not affected by mean expression , would be expected to cluster 
                 around log2r = 1 , not 
                     log2r = 0 as are points corresponding to 
                 diploid genes .
correlation between logarithm of mean expression level and logarithm of 
                         aberration : wild type expression ratio .
( a ) : this study 
                         ( red circles : deletion : wild type ) .
( 2006 ) data ( orange 
                         circles : duplication : wild type ; green circles : duplication : deletion ) .
small 
                         circles are control ( diploid ) genes on both a and 
                         b. log2r = 0 
                         corresponds to full dosage compensation .
figure 5 shows the relationship between the 
                 degree of tissue specificity of expression and degree of compensation in two 
                 deletions in this study ( a ) and in a duplication ( gupta et al .
2009 ) , ubiquitously expressed 
                 genes are less strongly compensated than tissue - specific genes ( p 
                 <
0.003 ) , but in the other deletion , ed4542 , the difference is not 
                 significant . likewise , for the duplication , transcriptional compensation of 
                 ubiquitously expressed genes is weaker than that of tissue - specific genes , in a 
                 reversal of the pattern observed on figure 
                         3b in stenberg et 
                     al .
strength of transcriptional compensation in tissue - specific and ubiquitously 
                         expressed genes in two deletions ( a , this study ) and in a 
                         duplication ( b , gupta et 
                             al . 2006 ) .
our data confirm the recently observed phenomenon of widespread transcriptional 
                 compensation of genes located in haploid and triploid areas in drosophila lines with 
                 chromosomal aberrations , in a striking contrast to data recently reported in mammals 
                     ( williams et al .
this conclusion is based on the comparison of aberration : wild 
                 type expression ratios to diploid expression ratios and is , therefore , dependent on 
                 the assumption that chromosomal aberrations as such have no effect on the expression 
                 of diploid genes . with that caveat in mind
, we also demonstrate that the degree of 
                 such compensation does not depend on the molecular function of the coded protein . 
                    
( 2009 ) reported that 
                 aberration : wild type expression ratios are distributed normally , indicating a 
                 universal ( or at least chromosome wide or segment wide ) rather than gene - specific 
                 compensatory mechanism . here
we demonstrate that for in both deletions studied the 
                 distribution of deletion : wild type ratios was significantly deviant from normal , 
                 with a strong suggestion of a shoulder around log2r 
                 = 1 , which suggest that some genes are stronger compensated 
                 than others , perhaps through the action of at least some gene - specific regulatory 
                 mechanisms .
on the other hand , higher level of transcriptional compensation in 
                 tissue - specific genes than in ubiquitously expressed genes ( see below ) was observed 
                 for one deletion but not for the other , suggesting that some chromosomal 
                 segment - specific regulation may be taking place .
( 2009 ) , we observe a correlation between the degree of compensation and the 
                 overall expression level of a gene .
genes with higher expression level are more 
                 likely to be compensated for a deletion but less likely to be compensated for a 
                 duplication . a positive correlation between transcriptional compensation of a 
                 deletion and overall expression level ( fig . 
                        
4a ) can be explained by the existence of genes , 
                 which are constantly expressed at the highest possible level , limited by 
                 gene - unspecific factor such as the availability of rna polymerase complexes or 
                 individual transcription factors .
however , this explanation is incompatible with the 
                 observed positive correlation between compensation for duplication and expression 
                 level ( fig .
4b ) : 
                 transcriptional limitation of highly expressed genes would result in this 
                 correlation having a negative not positive sign .
we hypothesize that this finding 
                 indicates that highly expressed genes are equipped with a regulatory feedback 
                 mechanism more efficient in preventing underexpression than in preventing 
                 overexpression .
in contrast , genes with low overall expression are more efficiently 
                 regulated to prevent overexpression in case of an overdose than to prevent 
                 underexpression in case of half the normal dosage .
we hypothesize that the relationship between the degree of transcriptional dosage 
                 compensation and overall gene expression may be widespread .
although stenberg et al . ( 2009 ) reported such 
                 relationship for only 1 comparison out of 4 , a careful examination of their figure 
                     s4a , suggests that at least one other comparison may be 
                 approaching significance , demonstrating the same pattern we observed in this study : 
                 highly expressed genes are strongly compensated for the deficiency , perhaps with a 
                 hint of a nonmonotonic relationship ( see also fig .
( 2009 ) did not 
                 observe this correlation , despite using very similar deletion lines , is that in this 
                 study we used a more stringent criterion to exclude genes with expression rate near 
                 or below detection level ( and , therefore , meaningless expression ratios ) by 
                 excluding genes with transcript signal not statistically different from the 
                 autoblank signal across arrays .
( 2009 ) study , an arbitrary cutoff was used , possibly 
                 leaving in some genes with low signal - to - noise ratio .
this would account both for 
                 the lack of a significant correlation with the expression level and for the apparent 
                 nonmonotonic relationship between expression ratio in deficiencies and expression 
                 level ( fig . 4a and 
                     c in stenberg et al . 
                    
( 2009 ) that ubiquitous genes are less effectively compensated for the 
                 dosage deficiency .
the fact that this relationship is observed in one deletion but 
                 not the other , corroborates stenberg et al . 
                
( 2009 ) idea that such compensatory mechanisms may be chromosome region 
                 specific or chromosomal region specific .
observe that the correlation with gene 
                 expression level is not confounded with this result : ubiquitously expressed genes 
                 tend to have a higher expression level ( simply due to the way they are defined for 
                 this analysis ) , so if the correlations with expression level were artifacts of 
                 confounding with the ubiquitousness of gene expression , it would have been expected 
                 to the opposite of what is actually observed .
( 2009 ) suggest that transcription of ubiquitously 
                 expressed genes tend to be limited by copy number . although consistent with the 
                 patterns observed for deletions in this study and by stenberg et al .
( 2009 ) , this explanation is inconsistent with 
                 higher degree of compensation of ubiquitously expressed genes : if these genes were 
                 universally copy number limited , one would expect the transcription level to be 
                 directly proportional to the number of copies of the gene .
rather , we hypothesize that the observed patterns can be explained by the existence 
                 of a continuum of genes with respect to most general types of regulatory mechanisms , 
                 genes on one end of the distribution being compensated more efficiently for 
                 underexpression than for overexpression and with the pattern reversed on the 
                 opposite end of the continuum .
the former types of genes tend to : 1 ) have high 
                 overall expression or be expressed in a tissue - specific manner , 2 ) demonstrate a 
                 stronger dosage compensation for a deficiency , and 3 ) demonstrate little dosage 
                 compensation for duplication .
genes of the second type tend to have low overall 
                 expression or be expressed ubiquitously , demonstrate little compensation for 
                 deficiency and greater compensation for duplication . at present
it is impossible to 
                 differentiate between two possibilities : 1 ) highly expressed genes are equipped with 
                 a regulatory mechanism more efficiently preventing underexpression in order to 
                 maintain the required high level of expression and 2 ) a regulatory mechanism more 
                 efficient in preventing underexpression than overexpression causes the cognate gene 
                 to have a higher than average baseline expression level .
one consideration speaks in 
                 favor of the former hypothesis : highly expressed genes are known to evolve slower 
                     ( pl et al .
2001 ; drummond and wilke 2008 ) , which indicates 
                 that essential or household genes are overrepresented among genes with high 
                 expression level .
one might speculate that household genes are more likely than 
                 nonessential genes to evolve a regulatory mechanism maintaining a necessary minimal 
                 level of transcription but more permitting of overexpression .
likewise , it remains unknown whether the observed compensation patterns are a 
                 manifestation of some generalregulatory mechanisms ( whether gene - specific or 
                 chromosome - wide ) capable of detecting copy number imbalance and predating the 
                 individual aberrations , or the result of a recent and fast adaptation to compensate 
                 for the aberration , which occurred in these particular lines since the introduction 
                 of the chromosomal abnormality .
some of the lines used in these studies ( such as 
                 df(2l)jh in gupta et al .
2006 ; stenberg et al . 2009 ) are fairly old and had 
                 an ample opportunity to evolve ; others , as drosdel lines in stenberg et al .
( 2009 ) and this study are younger but have 
                 also been maintained in a balanced hemizygous state for some time .
one observation , namely the comparison of expression rate in heterozygotes for a 
                 duplication to that in heterozygotes for a deletion in gupta et al .
if 
                 transcriptional compensation of genes in deletion df(2l)jh is characterized by the 
                 same patters observed deletions in our experiment , then the expected correlation 
                 between expression ratio duplication : deletion and overall gene expression should be 
                 negative . yet , this regression has a positive slope , in fact , higher than the 
                 regression of duplication : wild type ratios .
either the pattern observed in our data 
                 is region or chromosome specific , or the deletion df(2l)jh ( which contains only 59 
                 genes ) happens to be enriched with genes fully compensated despite their low 
                 expression level
. high degree of transcriptional compensation in heterozygotes for a deletion suggests 
                 that recessivity of most loss - of - function mutations in drosophila can be explained 
                 by transcriptional compensation .
this implies that relatively rare dominant mutant 
                 alleles either are not compensated at transcription or are gain - of - function 
                 mutations .
there are only three genes with known dominant mutant alleles located 
                 within studied deletions ( dichaete , frizzled , 
                     and breathless ) , and none of them show detectable expression , 
                 so we can not test the hypothesis that these genes are less likely to be compensated 
                 than genes with fully recessive mutations .
it might be noted , however , that the line 
                 ed4543 , which is hemizygous for dichaete , does not exhibit the 
                 dominant phenotype of classic dichaete alleles ( extended and 
                 elevated wings ) , indicating that the classic alleles may be of gain - of - function 
                 type .
we hypothesize that dominance of the wild - type allele caused by transcription - level 
                 compensation is a by - product of the regulatory mechanisms whose purpose is to 
                 maintain the expression level to meet changing environmental or developmental 
                 conditions rather than a direct result of selection to compensate for mutant 
                 alleles .
this hypothesis is consistent with the theoretical prediction that 
                 selection to compensate for mutations is weak , whereas selection to maintain the 
                 optimal gene expression is strong ( hurst and 
                     randerson 2000 ) and with the observation that mammalian genes possess 
                 abundant variation for such optimization ( rockman 
                     and wray 2002 ) .
it is also consistent with the increased frequency of 
                 codominance of deleterious alleles observed in genes whose products are involved in 
                 protein  protein interactions ( papp et 
                     al .
such interactions require a balance between expression levels 
                 of all genes in a group of interacting genes , which imposes constraints on the 
                 evolution of regulation of individual genes , resulting in lower opportunity for 
                 transcriptional compensation . because highly expressed genes demonstrate a more complete compensation for 
                 deletions ,
we predict that transcriptional compensation - based dominance of the 
                 wild - type alleles should be more common in highly expressed genes , whereas dominant 
                 mutations are more likely in genes with low overall expression .
moreover , we can 
                 hypothesize that transcriptional - level dominance can be of two types : in genes with 
                 high expression loss - of - function mutations are compensated at transcription , whereas 
                 in genes with low expression high levels of gene products are simply not necessary , 
                 that is , haploinsufficiency is unlikely .
we also found that , unlike compensation on the protein level , transcriptional 
                 compensation appears to be independent of protein function .
we do not see any 
                 evidence of greater transcriptional compensation of enzyme - coding genes than 
                 regulatory genes coding for transcription factors and nucleic acid - binding proteins . 
                
it is hard to imagine that all genes for transcription factors are regulated at 
                 transcription , because it implies an endless pyramid of transcription factors for 
                 transcription factors and leads to low fidelity of regulation ( itzkovitz et al .
in addition , not every transcription 
                 regulation mechanism will automatically compensate for mutant alleles . for this to 
                 occur
, the regulatory mechanism must be based on a negative feedback detecting 
                 abundance or activity or of the gene product .
positive regulatory mechanisms , for 
                 example those , which detect a particular environmental variable , independent from 
                 the gene product will not result in transcriptional compensation of mutations .
it 
                 should be therefore possible to test the hypothesis that transcriptional 
                 compensation is a by - product of evolution of negative feedback regulation of 
                 transcription by measuring transcription level in genes known to respond to 
                 environmental cues and in genes known to respond to abundance or activity of their 
                 own products .
we predict that the first group will demonstrate lower transcriptional 
                 compensation of mutations than the second one .
 little is known about dosage compensation in autosomal genes . 
 transcription - level 
                     compensation of deletions and other loss - of - function mutations may be a 
                     mechanism of dominance of wild - type alleles , a ubiquitous phenomenon whose 
                     nature has been a subject of a long debate . 
 we measured gene expression in two 
                     isogenic drosophila lines heterozygous for long deletions and compared our 
                     results with previously published gene expression data in a line heterozygous 
                     for a long duplication . 
 we find that a majority of genes are at least partially 
                     compensated at transcription , both for -fold dosage ( in 
                     heterozygotes for deletions ) and for 1.5-fold dosage ( in heterozygotes for a 
                     duplication ) . 
 the degree of compensation does not vary among functional classes 
                     of genes . 
 compensation for deletions is stronger for highly expressed genes . in 
                     contrast , the degree of compensation for duplications is stronger for weakly 
                     expressed genes . 
 thus , partial transcriptional compensation appears to be based 
                     on regulatory mechanisms that insure high transcription levels of some genes and 
                     low transcription levels of other genes , instead of precise maintenance of a 
                     particular homeostatic expression level . 
 given the ubiquity of transcriptional 
                     compensation , dominance of wild - type alleles may be at least partially caused by 
                     of the regulation at transcription level . 
Introduction
Materials and Methods
Results
Discussion