A quantitative model for characterizing the evolutionary history of mammalian gene expression

Chen, Jenny; Swofford, Ross; Johnson, Jeremy; Cummings, Beryl B.; Rogel, Noga; Lindblad‐Toh, Kerstin; Haerty, Wilfried; Palma, Federica Di; Regev, Aviv

doi:10.1101/229096

Cited by 9 publications

(9 citation statements)

References 84 publications

(77 reference statements)

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“…Gene expression profiles have long plays fundamental role in evolution 65 and gene’s expression across tissue could help to reveal the function and important role of those genes 66 . We used the expression profile of candidate epistatic genes across different floral tissues and found majority of them expressed in panicle and other floral tissues (Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of epistasis loci underlying rice flowering time by controlling population stratification and polygenic effect

et al. 2018

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Flowering time is an important agronomic trait, attributed by multiple genes, gene–gene interactions and environmental factors. Population stratification and polygenic effects might confound genetic effects of the causal loci underlying this complex trait. We proposed a two-step approach for detecting epistasis interactions underlying rice flowering time by accounting population structure and polygenic effects. Simulation studies showed that the approach used in this study performs better than classical and PC-linear approaches in terms of powers and false discovery rates in the case of population stratification and polygenic effects. Whole genome epistasis analyses identified 589 putative genetic interactions for flowering time. Eighteen of these interactions are located within 10 kilobases of regions of known protein–protein interactions. Thirty-seven SNPs near to twenty-five genes involve in rice or/and Arabidopsis (orthologue) flowering pathway. Bioinformatics analysis showed that 66.55% pairwise genes of the identified interactions (392 out of the 589 interactions) have similarity in various genomic features. Moreover, significant numbers of detected epistatic genes have high expression in different floral tissues. Our findings highlight the importance of epistasis analysis by controlling population stratification and polygenic effect and provided novel insights into the genetic architecture of rice flowering which could assist breeding programmes.

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Section: Discussionmentioning

confidence: 99%

Identification of epistasis loci underlying rice flowering time by controlling population stratification and polygenic effect

et al. 2018

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“…Gene regulatory network divergence can serve as a substrate for the evolution of phenotypic diversity and adaptation. In both unicellular and multicellular organisms, various mechanisms of regulatory and gene expression divergence underlying phenotypic diversity have been elucidated: horizontal gene transfer and regulatory reorganization in bacteria 33 ; gene duplication in fungi 34 ; cis-regulatory expression divergence in flies 35 ; variable gene co-expression in worms 36 ; dynamic rewiring of TFs in plant leaf shape 9 ; cis-regulatory mutations in stickleback fish 37 ; alternative splicing 38 and differential rate of gene expression evolution shaped by various selective pressures 39,40 in mammals. Despite these changes to genomic and regulatory architecture, some of these groups have remained virtually unvaried for millions of years of evolution, whereas certain organisms, like the near 1,500 species of East African cichlid fish, have rapidly radiated and diversified in an explosive manner.…”

Section: Discussionmentioning

confidence: 99%

“…However, very little is known about the evolution of regulatory networks (genotype) and their potential phenotypic effect across ecologically-diverse cichlid species (ecotype) 41 . To study the various mechanisms of regulatory divergence towards phenotypic diversity as shown in other organisms 9,[33][34][35][36][37][38][39][40]42 and cichlids 17,41 , we developed a novel framework to 1) identify ancestral and extant species co-expression modules and 2) integrate associated regulators (cis-regulatory elements, transcription factors and miRNAs) to dissect gene expression and regulatory contribution to cichlid phenotypic diversity.…”

Section: Eastmentioning

confidence: 99%

Evolution of regulatory networks associated with traits under selection in cichlids

Mehta

Koch

Nash

et al. 2018

Preprint

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Seminal studies in vertebrate protein evolution concluded that gene regulatory changes likely drive anatomical innovations. Even in the unparalleled East African cichlid fish radiation, we demonstrate cis-regulatory divergence as a contributor to phenotypic diversity. To further investigate this mechanism, we extended the Arboretum algorithm, initially designed for yeast adaptation to study the evolution of regulatory expression divergence in complex vertebrate species. For the first time, we reconstruct tissuespecific gene regulatory networks underpinning evolutionary adaptations from multiple vertebrate species in a phylogeny. Our framework consists of identifying ancestral reconstructed and extant species gene co-expression modules and integrating their associated regulators to investigate gene regulatory network evolution contributing to traits of phenotypic diversity in the East African cichlids. Along the phylogeny, we identify tissue-specific co-expression patterns across six tissues of five cichlids species that were predicted to be regulated by divergent suites of regulators. We report striking cases of rapid network rewiring for adaptive trait genes, such as the visual system. In regulatory regions of visual opsin genes e.g. sws1, in vitro assays confirm that single nucleotide polymorphisms (SNPs) in transcription factor binding sites (TFBSs) have driven network rewiring between species sharing the same visual palette. SNPs overlapping TFBSs segregate according to phylogeny and ecology suggesting ecotype-associated network rewiring in East African cichlid radiations. Our unique integrative approach inferring multispecies regulatory networks allowed us to identify regulatory changes associated with traits of phenotypic diversity in radiating cichlids.These species occupy a large diversity of ecological niches and differ dramatically in phenotypic traits, including skeletal morphology, dentition, color patterning, and a range of behavioral traits. Such explosive phenotypic diversification of East African cichlids is unparalleled among vertebrates making cichlid fishes an ideal model to investigate the evolution of gene regulatory networks associated with phenotypes under selection.Sequencing and analyses of representative East African cichlid genomes and transcriptomes suggested that bursts of gene duplication events combined with the rapid evolution of regulatory elements and selected protein coding genes contributed to evolutionary innovations 17 . This, coupled with low levels of nucleotide diversity between cichlid species pairs (Lake Malawi cichlids, 0.1-0.25%) 18 , implies high impact of low level regulatory sequence divergence to gene expression diversity. This likely fuels GRN rewiring, serving as a substrate for the evolution of phenotypic diversity in cichlids.To investigate the functional implications of changes in gene regulation on phenotypic and ecotypic diversity in cichlids, we developed a framework to characterize changes in gene regulation at the sequence, regulatory edge, expression and...

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“…complex disease) may therefore be reflected in selection on gene expression. Across species, gene expression levels have been shown to evolve more slowly than would be expected under a neutral model (8)(9)(10)(11)). An analysis of mammalian gene duplications also showed that the total expression of gene pairs in species that experienced a duplication event is similar to the expression of the corresponding single gene copy in species without duplication (12).…”

Section: Introductionmentioning

confidence: 99%

Measurement of selective constraint on human gene expression

Glassberg

Gao

Harpak

et al. 2018

Preprint

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Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression levels. Here, we explore the effects of stabilizing selection on cisregulatory genetic variation in humans. We analyze patterns of expression variation at copy number variants and find evidence for selection against large increases in gene expression. Using allele-specific expression (ASE) data, we further show evidence of selection against smaller-effect variants. We estimate that, across all genes, singletons in a sample of 122 individuals have approximately 2.5× greater effects on expression variance than common variants. Despite their increased effect sizes relative to common variants, we estimate that singletons in the sample studied explain, on average, only 5% of the heritability of gene expression from cis-regulatory variants. Finally, we show that genes depleted for loss-of-function variants are also depleted for cis-eQTLs and have low levels of allelic imbalance, confirming tighter constraint on the expression levels of these genes. We conclude that constraint on gene expression is present, but has relatively weak effects on most cis-regulatory variants, thus permitting high levels of gene-regulatory genetic variation. Gene expression|Allele-specific expression|Stabilizing selection|Heritability IntroductionVariation in human complex traits is connected to variation in gene expression levels (1-7). Selection on complex traits (i.e. complex disease) may therefore be reflected in selection on gene expression. Across species, gene expression levels have been shown to evolve more slowly than would be expected under a neutral model (8)(9)(10)(11)). An analysis of mammalian gene duplications also showed that the total expression of gene pairs in species that experienced a duplication event is similar to the expression of the corresponding single gene copy in species without duplication (12). As a duplication event would be expected to dramatically increase gene expression, this observation suggests that stabilizing selection on gene expression may act to return the total expression of duplicate gene pairs to an optimal expression level. Constraint on gene expression levels has also been shown to influence patterns of genetic variation within humans. First, 1 Correspondence: pritch@stanford.edu 2 ECG and ZG contributed equally to this work. some genes are unusually depleted for loss-of-function and copy number variants (13,14). These genes are thought to be particularly constrained with respect to their expression. Further, individuals with extreme expression levels for a particular gene are more likely to have rare variants in cis than individuals with average expression levels (15-18), suggesting that large gene expression changes are associated with rare genetic variation. As detailed below, this observation is consistent with stabilizing selection on expression levels selecting against large-effect regulatory variants. Des...

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A quantitative model for characterizing the evolutionary history of mammalian gene expression

Cited by 9 publications

References 84 publications

Identification of epistasis loci underlying rice flowering time by controlling population stratification and polygenic effect

Identification of epistasis loci underlying rice flowering time by controlling population stratification and polygenic effect

Evolution of regulatory networks associated with traits under selection in cichlids

Measurement of selective constraint on human gene expression

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