Clusters of Co-expressed Genes in Mammalian Genomes Are Conserved by Natural Selection

Singer, Gregory A. C.; Lloyd, Andrew T.; Huminiecki, Łukasz; Wolfe, Kenneth H.

doi:10.1093/molbev/msi062

Cited by 144 publications

(123 citation statements)

References 29 publications

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“…It is also worth pointing out that the synteny of many of the COBRA1-regulated gene clusters is conserved between mouse and human. For example, the order of the neighboring genes at the TFF-encompassing cluster (Figure 6) is maintained between chromosome 21 in human and chromosome 17 in mouse, consistent with the notion that the co-expressed gene clusters are conserved owing to functional selection (Singer et al, 2005).…”

Section: Discussionsupporting

confidence: 75%

“…Likewise, a large number of housekeeping genes and highly expressed genes in the human genome are clustered (Caron et al, 2001;Lercher et al, 2002). Co-expression of most gene clusters is unlikely owing to a 'bystander effect' wherein genes might be activated simply because they are adjacent to other actively transcribed genes, as syntenic analyses of mouse and human genomes indicate that the order of co-expressed genes in a cluster is conserved by natural selection (Singer et al, 2005). Therefore, clustering of coexpressed genes may have a functional advantage in coordinating gene expression during cell proliferation, differentiation and development.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of clustered gene expression by cofactor of BRCA1 (COBRA1) in breast cancer cells

et al. 2006

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Regulation of clustered gene expression by cofactor of BRCA1 (COBRA1) in breast cancer cells

et al. 2006

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“…Although both coordination of gene expression (5,6,(11)(12)(13)(14)(15)(16) and genetic linkage (7, 17) have been offered as genetic mechanisms underlying these metabolic gene clusters, unlike the butterfly example above, the phenotype(s) that drives their formation and maintenance in fungi is not known. We noted that the cause of several human metabolic disorders is the accumulation of toxic intermediate compounds (ICs).…”

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confidence: 99%

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

McGary

Slot

Rokas

2013

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

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Genomic analyses have proliferated without being tied to tangible phenotypes. For example, although coordination of both gene expression and genetic linkage have been offered as genetic mechanisms for the frequently observed clustering of genes participating in fungal metabolic pathways, elucidation of the phenotype(s) favored by selection, resulting in cluster formation and maintenance, has not been forthcoming. We noted that the cause of certain well-studied human metabolic disorders is the accumulation of toxic intermediate compounds (ICs), which occurs when the product of an enzyme is not used as a substrate by a downstream neighbor in the metabolic network. This raises the hypothesis that the phenotype favored by selection to drive gene clustering is the mitigation of IC toxicity. To test this, we examined 100 diverse fungal genomes for the simplest type of cluster, gene pairs that are both metabolic neighbors and chromosomal neighbors immediately adjacent to each other, which we refer to as "double neighbor gene pairs" (DNGPs). Examination of the toxicity of their corresponding ICs shows that, compared with chromosomally nonadjacent metabolic neighbors, DNGPs are enriched for ICs that have acutely toxic LD 50 doses or reactive functional groups. Furthermore, DNGPs are significantly more likely to be divergently oriented on the chromosome; remarkably, ∼40% of these DNGPs have ICs known to be toxic. We submit that the structure of synteny in metabolic pathways of fungi is a signature of selection for protection against the accumulation of toxic metabolic intermediates.gene cluster | gene orientation | inborn error of metabolism | secondary metabolism | specialized metabolism T here is a critical distinction between selection for a trait, which occurs at the phenotypic level, and selection of the underlying molecular genetic mechanisms that generate the trait (1). For example, some butterfly species avoid predation by mimicking the wing-pattern morphs of other butterflies that are toxic to birds (2, 3). In this case, predation avoidance selects for specific wing-pattern morphs, resulting in the selection of specific allelic combinations of genes in a supergene locus (4).The rise of molecular biology and subsequent abundance of genomic data have shifted the focus from phenotypes to genotypes, blurring the distinction between selection for and selection of. For example, many studies indicate that selection has sculpted the order and orientation of genes in eukaryotic genomes (5-13); although these analyses convincingly argue that specific genetic mechanisms are important in fine-tuning the structure of synteny on chromosomes, they implicitly assume that it is the genetic mechanisms themselves, rather than organismal phenotypes, that selection targets.One of the most conspicuous characteristics of fungal genomes is that the genes participating in a metabolic pathway are often physically linked, or clustered. Although both coordination of gene expression (5,6,(11)(12)(13)(14)(15)(16) and genetic linkage (7, 17) h...

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“…For example, between human and mouse only 3%-5% of the genome was found to be organized as co-expressed clusters of two to three genes (Semon and Duret 2006). Mixed results were obtained when the integrity of clusters of co-expressed genes in humans was examined in mouse (Singer et al 2005;Liao and Zhang 2008). Large-scale remodeling of chromatin structure due to actively transcribed genes, or the participation of these genes in transcription factories, could expose neighboring genes to the transcriptional machinery, and this alone could lead to a degree of basal transcription in the absence of specific repressive or tethering elements (Spitz and Duboule 2008).…”

mentioning

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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Clusters of Co-expressed Genes in Mammalian Genomes Are Conserved by Natural Selection

Cited by 144 publications

References 29 publications

Regulation of clustered gene expression by cofactor of BRCA1 (COBRA1) in breast cancer cells

Regulation of clustered gene expression by cofactor of BRCA1 (COBRA1) in breast cancer cells

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

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

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