Using Reporter Gene Assays to Identify<i>cis</i>Regulatory Differences Between Humans and Chimpanzees

Chabot, Adrien E.; Shrit, Ralla A.; Blekhman, Ran; Gilad, Yoav

doi:10.1534/genetics.107.073429

Cited by 17 publications

(12 citation statements)

References 51 publications

(68 reference statements)

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“…In a number of cases, these studies also pointed to possible connections between interspecies differences in gene regulation and differences in ultimate physiological or morphological phenotypes (Rockman et al 2005;Loisel et al 2006;Pollard et al 2006;Prabhakar et al 2008;Warner et al 2009;Babbitt et al 2010b). However, we still know little about the relative importance of different regulatory mechanisms to interspecies differences in gene expression levels (Chabot et al 2007;Blekhman et al 2009). In particular, little is known about the relative contribution of changes in epigenetic modifications to regulatory variation in primates.…”

Section: Omparative Studies Of Gene Expression Havementioning

confidence: 99%

Gene Expression Differences Among Primates Are Associated With Changes in a Histone Epigenetic Modification

et al. 2011

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Changes in gene regulation are thought to play an important role in speciation and adaptation, especially in primates. However, we still know relatively little about the mechanisms underlying regulatory evolution. In particular, the extent to which epigenetic modifications underlie gene expression differences between primates is not yet known. Our study focuses on an epigenetic histone modification, H3K4me3, which is thought to promote transcription. To investigate the contribution of H3K4me3 to regulatory differences between species, we collected gene expression data and identified H3K4me3-associated genomic regions in lymphoblastoid cell lines (LCLs) from humans, chimpanzees, and rhesus macaques, using three cell lines from each species. We found strong evidence for conservation of H3K4me3 localization in primates. Moreover, regardless of species, H3K4me3 is consistently enriched near annotated transcription start sites (TSS), and highly expressed genes are more likely than lowly expressed genes to have the histone modification near their TSS. Interestingly, we observed an enrichment of interspecies differences in H3K4me3 at the TSS of genes that are differentially expressed between species. We estimate that as much as 7% of gene expression differences between the LCLs of humans, chimpanzees, and rhesus macaques may be explained, at least in part, by changes in the status of H3K4me3 histone modifications. Our results suggest a modest, yet important role for epigenetic changes in gene expression differences between primates.

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Section: Omparative Studies Of Gene Expression Havementioning

confidence: 99%

Gene Expression Differences Among Primates Are Associated With Changes in a Histone Epigenetic Modification

et al. 2011

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“…The two genes in this category with smallest P-values are MYOM1, a structural protein defining the M-Band of the sarcomere, and MYH1, which encodes a myosin heavy chain of skeletal muscle, and variants are associated with risk of colorectal cancer (Jenkins et al 2006). Two further musclerelated genes are among the 15 most extreme genes: MYBPHL, which contains functional promoter differences between humans and chimpanzees (Chabot et al 2007), and PAMR1 (also known as DKFZP586H2123), a regeneration associated muscle protease.…”

Section: Excess Of High Frequency-derived Alleles (Mwu-high)mentioning

confidence: 99%

Darwinian and demographic forces affecting human protein coding genes

Nielsen¹,

Hubisz²,

Hellmann³

et al. 2009

Genome Res.

144

158

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Past demographic changes can produce distortions in patterns of genetic variation that can mimic the appearance of natural selection unless the demographic effects are explicitly removed. Here we fit a detailed model of human demography that incorporates divergence, migration, admixture, and changes in population size to directly sequenced data from 13,400 protein coding genes from 20 European-American and 19 African-American individuals. Based on this demographic model, we use several new and established statistical methods for identifying genes with extreme patterns of polymorphism likely to be caused by Darwinian selection, providing the first genome-wide analysis of allele frequency distributions in humans based on directly sequenced data. The tests are based on observations of excesses of high frequency-derived alleles, excesses of low frequency-derived alleles, and excesses of differences in allele frequencies between populations. We detect numerous new genes with strong evidence of selection, including a number of genes related to psychiatric and other diseases. We also show that microRNA controlled genes evolve under extremely high constraints and are more likely to undergo negative selection than other genes. Furthermore, we show that genes involved in muscle development have been subject to positive selection during recent human history. In accordance with previous studies, we find evidence for negative selection against mutations in genes associated with Mendelian disease and positive selection acting on genes associated with several complex diseases.

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“…Moreover, a number of studies have shown that evolutionary turnover of regulatory elements is a common feature of eukaryotic genomes with examples in yeast (Tanay et al 2005;Borneman et al 2007;Tuch et al 2008), Drosophila , zebrafish (McGaughey et al 2008), and mammals (Dermitzakis and Clark 2002;Birney et al 2007;Chabot et al 2007;Odom et al 2007;Jegga et al 2008).…”

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confidence: 99%

Evolution of the mammalian transcription factor binding repertoire via transposable elements

Bourque

Leong²,

Vega³

et al. 2008

Genome Res.

521

515

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Identification of lineage-specific innovations in genomic control elements is critical for understanding transcriptional regulatory networks and phenotypic heterogeneity. We analyzed, from an evolutionary perspective, the binding regions of seven mammalian transcription factors (ESR1, TP53, MYC, RELA, POU5F1, SOX2, and CTCF) identified on a genome-wide scale by different chromatin immunoprecipitation approaches and found that only a minority of sites appear to be conserved at the sequence level. Instead, we uncovered a pervasive association with genomic repeats by showing that a large fraction of the bona fide binding sites for five of the seven transcription factors (ESR1, TP53, POU5F1, SOX2, and CTCF) are embedded in distinctive families of transposable elements. Using the age of the repeats, we established that these repeat-associated binding sites (RABS) have been associated with significant regulatory expansions throughout the mammalian phylogeny. We validated the functional significance of these RABS by showing that they are over-represented in proximity of regulated genes and that the binding motifs within these repeats have undergone evolutionary selection. Our results demonstrate that transcriptional regulatory networks are highly dynamic in eukaryotic genomes and that transposable elements play an important role in expanding the repertoire of binding sites.

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Using Reporter Gene Assays to IdentifycisRegulatory Differences Between Humans and Chimpanzees

Cited by 17 publications

References 51 publications

Gene Expression Differences Among Primates Are Associated With Changes in a Histone Epigenetic Modification

Gene Expression Differences Among Primates Are Associated With Changes in a Histone Epigenetic Modification

Darwinian and demographic forces affecting human protein coding genes

Evolution of the mammalian transcription factor binding repertoire via transposable elements

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