Systematic Analysis of Head-to-Head Gene Organization: Evolutionary Conservation and Potential Biological Relevance

Li, Yuanyuan; Yu, Hui; Guo, Zong-Ming; Guo, Ting-Qing; Tu, Kang; Li, Yixue

doi:10.1371/journal.pcbi.0020074

Cited by 132 publications

(148 citation statements)

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“…Some genomic regions encompass genes that share regulatory sequences or genes separated from their regulatory regions by functionally and phylogenetically unrelated genes (Gould et al 1997;Trowsdale 2002;Spitz et al 2003;Li et al 2006). The complex architecture of these regulatory landscapes could contribute significantly to the conservation of their integrity (Spitz et al 2003(Spitz et al , 2005Mackenzie et al 2004), as has been shown among vertebrate species (Goode et al 2005;Kikuta et al 2007).…”

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confidence: 99%

Fragile regions and not functional constraints predominate in shaping gene organization in the genus Drosophila

Grotthuss¹,

Ashburner²,

Ranz³

2010

Genome Res.

135

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During evolution, gene repatterning across eukaryotic genomes is not uniform. Some genomic regions exhibit a gene organization conserved phylogenetically, while others are recurrently involved in chromosomal rearrangement, resulting in breakpoint reuse. Both gene order conservation and breakpoint reuse can result from the existence of functional constraints on where chromosomal breakpoints occur or from the existence of regions that are susceptible to breakage. The balance between these two mechanisms is still poorly understood. Drosophila species have very dynamic genomes and, therefore, can be very informative. We compared the gene organization of the main five chromosomal elements (Muller's elements A-E) of nine Drosophila species. Under a parsimonious evolutionary scenario, we estimate that 6116 breakpoints differentiate the gene orders of the species and that breakpoint reuse is associated with~80% of the orthologous landmarks. The comparison of the observed patterns of change in gene organization with those predicted under different simulated modes of evolution shows that fragile regions alone can explain the observed key patterns of Muller's element A (X chromosome) more often than for any other Muller's element. High levels of fragility plus constraints operating oñ 15% of the genome are sufficient to explain the observed patterns of change and conservation across species. The orthologous landmarks more likely to be under constraint exhibit both a remarkable internal functional heterogeneity and a lack of common functional themes with the exception of the presence of highly conserved noncoding elements. Fragile regions rather than functional constraints have been the main determinant of the evolution of the Drosophila chromosomes.

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confidence: 99%

Fragile regions and not functional constraints predominate in shaping gene organization in the genus Drosophila

Grotthuss¹,

Ashburner²,

Ranz³

2010

Genome Res.

135

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“…The importance of the three components is best illustrated by head-to-head clustering: two adjacent genes separated by a short intergenic distance and oriented in divergent (−+) transcription configuration. Head-to-head clusters are prevalent and conserved in many eukaryotes, including yeasts, plants, invertebrates, and vertebrates (2)(3)(4)(5). Protein-coding genes also can form head-to-head clusters with noncoding genes (6).…”

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confidence: 99%

Gene clustering pattern, promoter architecture, and gene expression stability in eukaryotic genomes

Woo

2011

Proc. Natl. Acad. Sci. U.S.A.

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A balance between gene expression stability and evolvability is essential for the long-term maintenance of a living system. In this paper, we studied whether the genetic and epigenetic properties of the promoter affect gene expression variability. We hypothesized that upstream distance and orientation (head-to-head or head-to-tail) are important for the promoter architecture and gene expression variability. We found that in budding yeast genes with a short upstream distance tend to have low gene expression variability, and their promoter is flanked by strongly positioned nucleosomes and tends to have low nucleosome occupancy. These observations suggest that in vivo positioning of the flanking nucleosomes facilitates stable nucleosome depletion at the core promoter region and enhances gene expression stability. Head-to-head genes have, on average, lower gene expression variability, greater nucleosome depletion at the core promoter region, and more strongly positioned nucleosomes that flank the core promoter than do head-to-tail genes. These observations hold for diverse eukaryotes. In complex organisms such as mammals, only a small fraction of head-to-tail genes have retained a short upstream distance, probably because the promoter may not be flanked by a strongly positioned nucleosome on the upstream side.

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“…Accordingly, the CYP1A1 and CYP1A2 genes are located at human chromosome 15q24.1, in head-to-head orientation, 23,306 bases from one transcription initiation start-site to the other [5]. Of three mammalian genomes studied, estimates are that about 10% of gene duplication pairs share bidirectional promoters [6]. The latest data from the UCSC browser assembled by NCBI and the Mouse Genome Sequencing Consortium puts the Cyp1a1 and Cyp1a2 genes on mouse chromosome 9 at cM 31.0, also in a head-to-head orientation, 13,954 bases from one transcription start-site to the other.…”

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confidence: 99%

Generation of ‘humanized’ hCYP1A1_1A2_Cyp1a1/1a2(−/−) mouse line

Dragin

Uno

Wang

et al. 2007

Biochemical and Biophysical Research Communications

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Human/rodent CYP1A1 and CYP1A2 orthologs are well known to exhibit species-specific differences in substrate preferences and rates of metabolism. This lab previously characterized a BAC-transgenic mouse carrying the human CYP1A1_CYP1A2 locus; in this line, human dioxininducible CYP1A1 and basal vs dioxin-inducible CYP1A2 have been shown to be expressed normally (with regard to mRNAs, proteins and three enzyme activities) in every one of nine mouse tissues studied. The mouse Cyp1a1 and Cyp1a2 genes are oriented head-to-head and share a bidirectional promoter region of 13,954 bp. Using Cre recombinase and loxP sites inserted 3′ of the stop codons of both genes, we show here a successful interchromosomal excision of 26,173 bp that ablated both genes on the same allele. The Cyp1a1/1a2(−) double-knockout allele was bred with the "humanized" line; the final product is the hCYP1A1_1A2_Cyp1a1/1a2(−/−) line on a theoretically >99.8% C57BL/6J genetic background-having both human genes replacing the mouse orthologs. This line will be valuable for human risk assessment studies involving any environmental toxicant or drug that is a substrate for CYP1A1 or CYP1A2. KeywordsHumanized mouse line; Human CYP1A1_1A2 locus; Mouse Cyp1a1_1a2 locus; loxP; Cre recombinase; Interchromosomal excision; Benzo [a]pyrene; DioxinThe human and mouse cytochrome P450 (CYP) gene superfamilies contain 57 and 102 proteincoding genes, respectively; one of the 18 mammalian CYP families is CYP1, having three members in both human and mouse-CYP1A1, CYP1A2, and CYP1B1 [1][2][3]. The CYP1A and CYP1B subfamily ancestors diverged from one another probably more than 500 million years ago; CYP1A2 arose as a gene duplication event from CYP1A1 about 450 million years ago. Thus, land animals (including fowl) carry both CYP1A1 and CYP1A2; sea animals do not have the CYP1A2 gene [4]. Accordingly, the CYP1A1 and CYP1A2 genes are located at human chromosome 15q24.1, in head-to-head orientation, 23,306 bases from one transcription initiation start-site to the other [5]. Of three mammalian genomes studied, estimates are that about 10% of gene duplication pairs share bidirectional promoters [6]. The latest data from the UCSC browser assembled by NCBI and the Mouse Genome Sequencing Consortium puts the Cyp1a1 and Cyp1a2 genes on mouse chromosome 9 at cM 31.0, also in a head-to-head orientation, 13,954 bases from one transcription start-site to the other. In contrast, CYP1B1 is located on human chromosome 2p22.2, and Cyp1b1 (syntenic with human CYP1B1) is located on mouse chromosome 17. Using bacterial artificial chromosomes (BACs), we and others have been able to generate "humanized" hCYP1A1_1A2 BAC-transgenic lines [5,14]. Studies have been carried out with the hCYP1A1_1A2_Cyp1a1(−/−) line vs the hCYP1A1_1A2_Cyp1a2(−/−) line; for example, these lines were used both for theophylline [15] and for the food mutagen 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) [14]. In both cases, human CYP1A2 was shown to be responsible for the "human metabolite profile...

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Systematic Analysis of Head-to-Head Gene Organization: Evolutionary Conservation and Potential Biological Relevance

Cited by 132 publications

References 35 publications

Fragile regions and not functional constraints predominate in shaping gene organization in the genus Drosophila

Fragile regions and not functional constraints predominate in shaping gene organization in the genus Drosophila

Gene clustering pattern, promoter architecture, and gene expression stability in eukaryotic genomes

Generation of ‘humanized’ hCYP1A1_1A2_Cyp1a1/1a2(−/−) mouse line

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