Functional Analysis of the Chimpanzee and Humanapo(a) Promoter Sequences

Huby, Thierry; Dachet, C.; Lawn, Richard M.; Wickings, Jean; Chapman, M. John; Thillet, Joëlle

doi:10.1074/jbc.m102204200

Cited by 25 publications

(2 citation statements)

References 41 publications

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“…While divergence in gene complement [1–4] and amino acid sequence [5–9] are discernable from genome sequences, functional divergence in cis -regulatory regions is largely invisible in sequence data. Consequently, while we now know of many uniquely human aspects of gene complement and protein sequence, we possess only a few documented examples of human-specific cis -regulation [10,11]. Moreover, while statistical tests for discerning the signature of positive selection in protein-coding sequences are well developed, and genomic surveys have identified many human genes showing evidence of positive selection [12,13] or diminished negative selection [14], in only a single instance has positive selection been implicated in cis -regulatory divergence between humans and other apes [15].…”

Section: Introductionmentioning

confidence: 99%

Ancient and Recent Positive Selection Transformed Opioid cis-Regulation in Humans

et al. 2005

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Changes in the cis-regulation of neural genes likely contributed to the evolution of our species' unique attributes, but evidence of a role for natural selection has been lacking. We found that positive natural selection altered the cis-regulation of human prodynorphin, the precursor molecule for a suite of endogenous opioids and neuropeptides with critical roles in regulating perception, behavior, and memory. Independent lines of phylogenetic and population genetic evidence support a history of selective sweeps driving the evolution of the human prodynorphin promoter. In experimental assays of chimpanzee–human hybrid promoters, the selected sequence increases transcriptional inducibility. The evidence for a change in the response of the brain's natural opioids to inductive stimuli points to potential human-specific characteristics favored during evolution. In addition, the pattern of linked nucleotide and microsatellite variation among and within modern human populations suggests that recent selection, subsequent to the fixation of the human-specific mutations and the peopling of the globe, has favored different prodynorphin cis-regulatory alleles in different parts of the world.

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Section: Introductionmentioning

confidence: 99%

Ancient and Recent Positive Selection Transformed Opioid cis-Regulation in Humans

et al. 2005

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“…Previous studies aiming at identifying species-specific cis -regulatory sites were driven by the interest in a particular gene ( Huby et al 2001 ; Rockman et al 2005 ; Romanelli et al 2009 ), or based on genome-wide bioinformatics approaches, for instance, the search for certain substitution patterns in multiple species alignments ( Haygood et al 2007 ; Taylor et al 2008 ; Molineris et al 2011 ). However, experimentally supported examples for species-specific cis -regulatory sites are still sparse.…”

Section: Introductionmentioning

confidence: 99%

Human Lineage-Specific Transcriptional Regulation through GA-Binding Protein Transcription Factor Alpha (GABPa)

et al. 2016

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A substantial fraction of phenotypic differences between closely related species are likely caused by differences in gene regulation. While this has already been postulated over 30 years ago, only few examples of evolutionary changes in gene regulation have been verified. Here, we identified and investigated binding sites of the transcription factor GA-binding protein alpha (GABPa) aiming to discover cis-regulatory adaptations on the human lineage. By performing chromatin immunoprecipitation-sequencing experiments in a human cell line, we found 11,619 putative GABPa binding sites. Through sequence comparisons of the human GABPa binding regions with orthologous sequences from 34 mammals, we identified substitutions that have resulted in 224 putative human-specific GABPa binding sites. To experimentally assess the transcriptional impact of those substitutions, we selected four promoters for promoter-reporter gene assays using human and African green monkey cells. We compared the activities of wild-type promoters to mutated forms, where we have introduced one or more substitutions to mimic the ancestral state devoid of the GABPa consensus binding sequence. Similarly, we introduced the human-specific substitutions into chimpanzee and macaque promoter backgrounds. Our results demonstrate that the identified substitutions are functional, both in human and nonhuman promoters. In addition, we performed GABPa knock-down experiments and found 1,215 genes as strong candidates for primary targets. Further analyses of our data sets link GABPa to cognitive disorders, diabetes, KRAB zinc finger (KRAB-ZNF), and human-specific genes. Thus, we propose that differences in GABPa binding sites played important roles in the evolution of human-specific phenotypes.

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Significant differentiation in the apolipoprotein(a)/lipoprotein(a) trait between chimpanzees from Western and Central Africa

Noureen

Ronke

Khalifa

et al. 2017

American J Primatol

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Elevated Lipoprotein(a) (Lp(a)) plasma concentrations are a risk factor for cardiovascular disease in humans, largely controlled by the LPA gene encoding apolipoprotein(a) (apo(a)). Lp(a) is composed of low-density lipoprotein (LDL) and apo(a) and restricted to Catarrhini. A variable number of kringle IV (KIV) domains in LPA lead to a size polymorphism of apo(a) that is inversely correlated with Lp(a) concentrations. Smaller apo(a) isoforms and higher Lp(a) levels in central chimpanzees (Pan troglodytes troglodytes [PTT]) compared to humans from Europe had been reported. We studied apo(a) isoforms and Lp(a) concentrations in 75 western (Pan troglodytes verus [PTV]) and 112 central chimpanzees, and 12 bonobos (Pan paniscus [PPA]), all wild born and living in sanctuaries in Sierra Leone, Republic of the Congo, and DR Congo, respectively, and 116 humans from Gabon. Lp(a) levels were severalfold higher in western than in central chimpanzees (181.0 ± 6.7 mg/dl vs. 56.5 ± 4.3 mg/dl), whereas bonobos showed intermediate levels (134.8 ± 33.4 mg/dl). Apo(a) isoform sizes differed significantly between subspecies (means 20.9 ± 2.2, 22.9 ± 4.4, and 23.8 ± 3.8 KIV repeats in PTV, PTT, and PPA, respectively). However, far higher isoform-associated Lp(a) concentrations for all isoform sizes in western chimpanzees offered the main explanation for the higher overall Lp(a) levels in this subspecies. Human Lp(a) concentrations (mean 47.9 ± 2.8 mg/dl) were similar to those in central chimpanzees despite larger isoforms (mean 27.1 ± 4.9 KIV). Lp(a) and LDL, apoB-100, and total cholesterol levels only correlated in PTV. This remarkable differentiation between chimpanzees from different African habitats and the trait's similarity in humans and chimpanzees from Central Africa poses the question of a possible impact of an environmental factor that has shaped the genetic architecture of LPA. Overall, studies on the cholesterol-containing particles of Lp(a) and LDL in chimpanzees should consider differentiation between subspecies.

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Functional Analysis of the Chimpanzee and Humanapo(a) Promoter Sequences

Cited by 25 publications

References 41 publications

Ancient and Recent Positive Selection Transformed Opioid cis-Regulation in Humans

Ancient and Recent Positive Selection Transformed Opioid cis-Regulation in Humans

Human Lineage-Specific Transcriptional Regulation through GA-Binding Protein Transcription Factor Alpha (GABPa)

Significant differentiation in the apolipoprotein(a)/lipoprotein(a) trait between chimpanzees from Western and Central Africa

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