The regulatory content of intergenic DNA shapes genome architecture

BackgroundFactors affecting the organization and spacing of functionally unrelated genes in metazoan genomes are not well understood. Because of the vast size of a typical metazoan genome compared to known regulatory and protein-coding regions, functional DNA is generally considered to have a negligible impact on gene spacing and genome organization. In particular, it has been impossible to estimate the global impact, if any, of regulatory elements on genome architecture.ResultsTo investigate this, we examined the relationship between regulatory complexity and gene spacing in Caenorhabditis elegans and Drosophila melanogaster. We found that gene density directly reflects local regulatory complexity, such that the amount of noncoding DNA between a gene and its nearest neighbors correlates positively with that gene's regulatory complexity. Genes with complex functions are flanked by significantly more noncoding DNA than genes with simple or housekeeping functions. Genes of low regulatory complexity are associated with approximately the same amount of noncoding DNA in D. melanogaster and C. elegans, while loci of high regulatory complexity are significantly larger in the more complex animal. Complex genes in C. elegans have larger 5' than 3' noncoding intervals, whereas those in D. melanogaster have roughly equivalent 5' and 3' noncoding intervals.ConclusionsIntergenic distance, and hence genome architecture, is highly nonrandom. Rather, it is shaped by regulatory information contained in noncoding DNA. Our findings suggest that in compact genomes, the species-specific loss of nonfunctional DNA reveals a landscape of regulatory information by leaving a profile of functional DNA in its wake.

[1]  F. Hoffmann,et al.  Pattern-specific expression of the Drosophila decapentaplegic gene in imaginal disks is regulated by 3' cis-regulatory elements. , 1990, Genes & development.

[2]  Yuri Y. Shevelyov,et al.  Large clusters of co-expressed genes in the Drosophila genome , 2002, Nature.

[3]  Dmitri A Petrov,et al.  Mutational equilibrium model of genome size evolution. , 2002, Theoretical population biology.

[4]  Stephen S. Gisselbrecht,et al.  Ras Pathway Specificity Is Determined by the Integration of Multiple Signal-Activated and Tissue-Restricted Transcription Factors , 2000, Cell.

[5]  T. Gregory.  Genome size and developmental complexity , 2002, Genetica.

[6]  J. Warrington,et al.  Comparison of human adult and fetal expression and identification of 535 housekeeping/maintenance genes. , 2000, Physiological genomics.

[7]  Jean Thierry-Mieg,et al.  A global analysis of Caenorhabditis elegans operons , 2002, Nature.

[8]  D. Petrov,et al.  High rate of DNA loss in the Drosophila melanogaster and Drosophila virilis species groups. , 1998, Molecular biology and evolution.

[9]  R. Carthew,et al.  Overlapping Activators and Repressors Delimit Transcriptional Response to Receptor Tyrosine Kinase Signals in the Drosophila Eye , 2000, Cell.

[10]  Juancarlos Chan,et al.  WormBase: a cross-species database for comparative genomics , 2003, Nucleic Acids Res..

[11]  D. Moazed,et al.  Heterochromatin and Epigenetic Control of Gene Expression , 2003, Science.

[12]  N. Gostling,et al.  From DNA to Diversity: Molecular Genetics and the Evolution of Animal Design , 2002, Heredity.

[13]  D. Petrov,et al.  Genome size as a mutation-selection-drift process. , 1999, Genes & genetic systems.

[14]  D. Kingsley,et al.  An extensive 3' regulatory region controls expression of Bmp5 in specific anatomical structures of the mouse embryo. , 1998, Genetics.

[15]  Tom Maniatis,et al.  Early and late periodic patterns of even skipped expression are controlled by distinct regulatory elements that respond to different spatial cues , 1989, Cell.

[16]  Walter J. Gehring,et al.  Regulation and function of the Drosophila segmentation gene fushi tarazu , 1987, Cell.

[17]  G. Ruvkun,et al.  Lineage-specific regulators couple cell lineage asymmetry to the transcription of the Caenorhabditis elegans POU gene unc-86 during neurogenesis. , 1996, Genes & development.

[18]  H. Duan,et al.  shaven and sparkling are mutations in separate enhancers of the Drosophila Pax2 homolog. , 1998, Development.

[19]  G Bernardi,et al.  The distribution of genes in the human genome. , 1991, Gene.

[20]  M. G. Kidwell,et al.  Transposable elements and the evolution of genome size in eukaryotes , 2002, Genetica.

[21]  Martin J. Lercher,et al.  Clustering of housekeeping genes provides a unified model of gene order in the human genome , 2002, Nature Genetics.

[22]  M. Laubichler.  Review of: Carroll, Sean B., Jennifer K. Grenier and Scott D. Weatherbee: From DNA to diversity : molecular genetics and the evolution of animal design. Malden, Mass [u.a.]: Blackwell Science 2001 , 2003 .

[23]  A. West,et al.  Insulators and boundaries: versatile regulatory elements in the eukaryotic genome. , 2001, Science.

[24]  D. Petrov,et al.  Evidence for DNA loss as a determinant of genome size. , 2000, Science.

[25]  Michael Levine,et al.  Promoter-proximal tethering elements regulate enhancer-promoter specificity in the Drosophila Antennapedia complex , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Gerhart,et al.  Cells, Embryos and Evolution , 1997 .

[27]  W. Gelbart,et al.  An extensive 3' cis-regulatory region directs the imaginal disk expression of decapentaplegic, a member of the TGF-beta family in Drosophila. , 1991, Development.

[28]  H. Robertson,et al.  The large srh family of chemoreceptor genes in Caenorhabditis nematodes reveals processes of genome evolution involving large duplications and deletions and intron gains and losses. , 2000, Genome research.

[29]  W. McGinnis,et al.  Shaping animal body plans in development and evolution by modulation of Hox expression patterns , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[30]  G. Bernardi,et al.  The human genome: organization and evolutionary history. , 1995, Annual review of genetics.

[31]  G. D’Onofrio.  Expression patterns and gene distribution in the human genome. , 2002, Gene.

[32]  E. Davidson.  Genomic Regulatory Systems: Development and Evolution , 2005 .

[33]  R. Jackson.  Genomic regulatory systems , 2001 .

[34]  Michael Ashburner,et al.  Annotation of the Drosophila melanogaster euchromatic genome: a systematic review , 2002, Genome Biology.

[35]  M. Kreitman,et al.  Population, evolutionary and genomic consequences of interference selection. , 2002, Genetics.

[36]  Y Sun,et al.  Transcriptional regulation of atonal during development of the Drosophila peripheral nervous system. , 1998, Development.

[37]  D. Petrov,et al.  How intron splicing affects the deletion and insertion profile in Drosophila melanogaster. , 2002, Genetics.

[38]  M. Ashburner,et al.  Systematic determination of patterns of gene expression during Drosophila embryogenesis , 2002, Genome Biology.

[39]  D. Petrov,et al.  Trash DNA is what gets thrown away: high rate of DNA loss in Drosophila. , 1997, Gene.

[40]  C. D. Darlington,et al.  Evolution Of Genetic Systems , 1942 .

[41]  J. M. Comeron,et al.  What controls the length of noncoding DNA? , 2001, Current opinion in genetics & development.

[42]  Joshua M. Stuart,et al.  Chromosomal clustering of muscle-expressed genes in Caenorhabditis elegans , 2002, Nature.

[43]  T. Gregory.  The bigger the C-value, the larger the cell: genome size and red blood cell size in vertebrates. , 2001, Blood cells, molecules & diseases.

[44]  H. Bussemaker,et al.  The human transcriptome map reveals extremes in gene density, intron length, GC content, and repeat pattern for domains of highly and weakly expressed genes. , 2003, Genome research.

[45]  Naoto Endo,et al.  Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[46]  E. Davidson,et al.  Cis-regulation downstream of cell type specification: a single compact element controls the complex expression of the CyIIa gene in sea urchin embryos. , 1998, Development.

[47]  P. Okkema,et al.  Multiple enhancers contribute to expression of the NK‐2 homeobox gene ceh‐22 in C. elegans pharyngeal muscle , 2001, Genesis.

[48]  D. Hartl.  Molecular melodies in high and low C , 2000, Nature Reviews Genetics.

[49]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[50]  S. Ohno,et al.  So much "junk" DNA in our genome. , 1972, Brookhaven symposia in biology.

[51]  E. Levanon,et al.  Human housekeeping genes are compact. , 2003, Trends in genetics : TIG.

[52]  Martin Vingron,et al.  New evidence for genome-wide duplications at the origin of vertebrates using an amphioxus gene set and completed animal genomes. , 2003, Genome research.

[53]  Sean B. Carroll,et al.  Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene , 1996, Nature.

[54]  J. McGhee,et al.  Transcription Factors and Transcriptional Regulation , 1997 .

[55]  Alistair G. Rust,et al.  Ensembl 2002: accommodating comparative genomics , 2003, Nucleic Acids Res..

[56]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[57]  Gerald M Rubin,et al.  Evidence for large domains of similarly expressed genes in the Drosophila genome , 2002, Journal of biology.

[58]  R. Schwartz,et al.  Building the heart piece by piece: modularity of cis-elements regulating Nkx2-5 transcription. , 1999, Development.

[59]  A. Gnirke,et al.  Assessing the impact of comparative genomic sequence data on the functional annotation of the Drosophila genome , 2002, Genome Biology.

[60]  E. Davidson,et al.  Cis-regulatory logic in the endo16 gene: switching from a specification to a differentiation mode of control. , 2001, Development.

[61]  Darren A. Natale,et al.  The COG database: an updated version includes eukaryotes , 2003, BMC Bioinformatics.

[62]  M. Kreitman,et al.  Analysis of conserved noncoding DNA in Drosophila reveals similar constraints in intergenic and intronic sequences. , 2001, Genome research.

[63]  M. Fujioka,et al.  The even-skipped locus is contained in a 16-kb chromatin domain. , 1999, Developmental biology.

[64]  G. Stephanopoulos,et al.  A compendium of gene expression in normal human tissues. , 2001, Physiological genomics.

[65]  U. Banerjee,et al.  Combinatorial Signaling in the Specification of Unique Cell Fates , 2000, Cell.

[66]  Sudhir Kumar,et al.  Comparative Genomics in Eukaryotes , 2005 .

[67]  M. Noll,et al.  The Drosophila Pox neuro gene: control of male courtship behavior and fertility as revealed by a complete dissection of all enhancers , 2002, Development.