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Christian Dorofeev
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The Chimp Paradox Pdf.37 ((HOT))

Another study was focused on sequences conserved in chimpanzees and other primates but underrepresented in humans (termed hCONDELs) [19]. Comparison of human, chimpanzee and macaque genomes revealed 510 conserved regions deleted in humans, all of them representing non-coding sequences except CMAHP gene, see below. The hCONDELs identified were enriched near genes involved in steroid hormone signaling and neuronal functioning. One hCONDEL was a sensory vibrissae and penile spines-specific enhancer of androgen receptor (AR) gene. Its absence caused the loss of vibrissae and spines in humans. Another deletion involved enhancer of a tumor suppressor gene GADD45G, which activated expression of this gene in the subventricular zone of the forebrain. It could relate to the specific pattern of expansion of brain regions in humans. In turn, the chimpanzee genome also lacks several conserved sequences. Among 344 such regions identified, significant enrichment was found for the localizations near genes related to synapse formation and functioning of glutamate receptors [19].

the chimp paradox pdf.37

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Finally, substantial differences in copy numbers were reported for transposable elements (TEs). According to various estimates, the number of human-specific TE insertions varied from eight [26] to 15,000 copies [27]. It was estimated that humans have approximately twice as many unique TE copies as the chimpanzees [8, 26]. Since human-chimpanzee ancestral divergence, the most active TE groups were Alu, LINE1 and SVA which accounted for nearly 95% of all species-specific insertions [26]. The most numerous group was Alu, which made over 5 thousand human-specific insertions and proliferated approx. Three times more intensely in humans than in chimpanzees [26, 27]. Most of chimpanzee-specific Alu copies are represented by subfamilies Alu Y and AluYc1, while human-specific insertions are predominantly the members of AluYa5 and AluYb8 subfamilies [8, 26]. However, both species also have specific inserts of AluS and AluYg6 family members.

The new copies of transposable elements can appear in the genome not only through insertions but also due to duplications of genomic DNA. For example, several hundred copies of recently integrated HERV-K (HML-2) family provirus К111 were found in centromeres of 15 different human chromosomes. They amplified and spread due to recombinations of the enclosing progenitor locus. In contrast, there is only one copy of К111 in the chimpanzee genome and no copies in the other primates [35, 36]. Similarly, several dozen copies of a more ancient provirus K222 of the same family arose due to chromosomal recombination in pericentromeric regions of nine human chromosomes, versus only one copy in the chimpanzees and other higher primates [36].

TE inserts also could play an important role in the speciation. TEs contain various regulatory elements such as promoters, enhancers, splice-sites and signals of transcriptional termination, which they use for their own expression and spread. Approximately 34% of all species-specific TEs in humans and chimpanzees are located close to known genes [26]. Species-specific TE inserts, therefore, can strongly influence regulatory landscape of the host genome [79, 80]. In addition, TEs can disrupt gene structures by inserting themselves or through recombinations between their copies [21, 23]. These events could influence gene functioning and might cause the respective phenotypic differences [81, 82].

There is also a particular fraction of non-coding sequences that was accelerated in humans but relatively conserved in the other species called HACNs (human accelerated conserved noncoding sequences) [49]. They can overlap with the abovementioned HARs [50]. HACNs are enriched near genes related to neuronal functioning, such as neuronal cell adhesion [49] and brain development [100]. Based on structural analyses of HACNs, HARs and their genomic contexts, around one third of them was predicted to be developmental enhancers [50]. By functional role, they contribute in approximately equal proportions to brain and limb development and to a lesser extent - to heart development. Among 29 pairs of HARs and their chimpanzee orthologous regions tested in mouse embryos, 24 showed enhancer activity in vivo. Moreover, five of them demonstrated differential enhancer activities between human and chimpanzee sequences [50].

It has been postulated few decades ago that differences between humans and chimpanzees are mostly caused by gene regulation changes rather than by alterations in their protein-coding sequences, and that these changes must affect embryo development [6]. For example, evolutional acquisitions such as enlarged brain or modified arm emerged as a result of developmental changes during embryogenesis [102, 103]. Such changes include when, where and how genes are expressed. A plethora of genes involved in embryogenesis have pleiotropic effects [104] and mutations within their coding sequence may cause complex, mostly negative, consequences for an organism. On the other hand, changes in gene regulation could be limited to a certain tissue or time frame that can enable fine tuning of a gene activity [105]. Indeed, the fast-evolving sequences (HARs or HACNs) are often found close to the genes active during embryo- and neurogenesis [48,49,50, 100]. For example, HACNS1 (HAR2) demonstrates greater enhancer activity in limb buds of transgenic mice compared to orthologous sequences from chimpanzee or rhesus macaque [106]. A similar pattern was observed for the aforementioned HARs related to genes NPAS3 and FZD8 that are active during CNS development in embryogenesis [51, 98].

Epigenetic regulation is another factor that should be considered when looking at interspecies differences in gene expression. High throughput analysis of differentially methylated DNA in human and chimpanzee brains showed that human promoters had lower degree of methylation. A fraction of genes related to neurologic/psychiatric disorders and cancer was enriched among the differentially methylated entries [118]. The analysis of H3K4me3 (trimethylated histone H3 is a marker of transcriptionally active chromatin) distribution in the neurons of prefrontal lobe revealed 471 human-specific regions, 33 of them were neuron-specific. Some of these regions were proximate to genes associated with neurologic and mental disorders, such as ADCYAP1, CACNA1C, CHL1, CNTN4, DGCR6, DPP10, FOXP2, LMX1B, NOTCH4, PDE4DIP, SLC2A3, SORCS1, TRIB3, TUBB2B and ZNF423 [119, 120]. Another active chromatin biomarker is the distribution of DNase I hypersensitivity sites (DHSs), that often indicate gene regulatory elements. It was found that 542 DHSs overlapped with HARs, thus being so-called human accelerated DHSs, haDHSs [121]. Using chromatin immunoprecipitation assay, a number of haDHSs interacting genes were identified, many of which were connected with early development and neurogenesis [3, 121]. In a later study [122], about 3,5 thousand haDHSs were found, that were enriched near the genes related to neuronal functioning [122].

The chimpanzees also demonstrate substantial genome diversity with many population-specific traits: the central chimpanzees retain the highest diversity in the chimpanzee lineage, whereas the other subspecies show multiple signs of population bottlenecks [125].

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