approximately what percentage of the human genome is identical to that of a chimpanzee?

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• Published: x September 2020

Differences between human and chimpanzee genomes and their implications in factor expression, protein functions and biochemical backdrop of the two species

BMC Genomics volume 21, Article number:535 (2020) Cite this article

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Abstract

Chimpanzees are the closest living relatives of humans. The divergence between homo and chimpanzee ancestors dates to approximately 6,5–7,five meg years ago. Genetic features distinguishing us from chimpanzees and making us humans are notwithstanding of a great involvement. After divergence of their ancestor lineages, human and chimpanzee genomes underwent multiple changes including single nucleotide substitutions, deletions and duplications of Dna fragments of different size, insertion of transposable elements and chromosomal rearrangements. Human-specific single nucleotide alterations constituted 1.23% of man Deoxyribonucleic acid, whereas more than extended deletions and insertions embrace ~ 3% of our genome. Moreover, much higher proportion is made by differential chromosomal inversions and translocations comprising several megabase-long regions or even whole chromosomes. However, despite of extensive knowledge of structural genomic changes accompanying man evolution we nonetheless cannot identify with certainty the causative genes of human identity. Most structural factor-influential changes happened at the level of expression regulation, which in turn provoked larger alterations of interactome gene regulation networks. In this review, we summarized the available information about genetic differences between humans and chimpanzees and their potential functional impacts on differential molecular, anatomical, physiological and cognitive peculiarities of these species.

Groundwork

The divergence of human being and chimpanzee ancestors dates back to approximately half dozen,5–7,5 million years ago [ane] or even earlier [2]. It is still of a great interest to identify genetic elements that distinguish humans from chimpanzees and encode features of human physiological and mental identities [3,4,v]. Information technology's a difficult job to quantitate the exact percentage of differences between human and chimpanzee genomes. In early works, divergence of human and chimpanzee genomes was estimated as roughly 1% [6]. This guess was based on the comparing of poly peptide-coding sequences and didn't consider not-coding (major) part of Deoxyribonucleic acid. However, the idea of ~ 99% similarity of genomes persisted for a long time, until 2005 when nearly complete initial sequencing results of both human being [seven] and chimpanzee (Pan troglodytes) [8] genomes became bachelor. It was found that genome differences represented by single nucleotide alterations formed 1.23% of human being Dna, whereas larger deletions and insertions constituted ~ iii% of our genome [8]. Moreover, fifty-fifty college proportion was shaped by chromosomal inversions and translocations comprising several megabase-long chromosomal regions or even entire chromosomes, every bit for the chromosomal fusion that took identify when the human chromosome 2 was formed [9]. Here we tried to review the major known structural and regulatory genetic alterations that had or might accept a functional impact on the man and chimpanzee speciation (Tabular array 1).

Table ane Molecular genetic differences between humans and chimpanzees

Full size table

Karyotype

Human karyotype is represented past 46 chromosomes, whereas chimpanzees have 48 chromosomes [ix]. In general, both karyotypes are very similar. However, in that location is a major departure corresponding to the human chromosome 2. Information technology has originated due to a fusion of 2 ancestral acrocentric chromosomes corresponding to chromosomes 2a and 2b in chimpanzee. Likewise, significant pericentric inversions were institute in nine other chromosomes [nine]. Two out of 9 are thought to occur in human chromosomes 1 and 18, and the other seven – in chimpanzee chromosomes 4, 5, 9, 12, xv, 16 and 17 [10,11,12]. In addition, there are numerous differences in the chromosomal organization of pericentric, paracentric, intercalary and Y blazon heterochromatin; for case, the chimpanzees have large additional telomeric heterochromatin region on chromosome xviii [nine]. Additionally, the majority of chimpanzee'south chromosomes incorporate subterminal constitutive heterochromatin (C-band) blocks (SCBs) that are absent-minded in human chromosomes. SCBs predominantly consist of the subterminal satellite (StSat) repeats, they are institute in African nifty apes but not in humans [53]. The presence of such SCBs affects chimpanzees' chromosomes behavior during meiosis causing persistent subtelomeric associations between homologous and non-homologous chromosomes. As a result of homologous and ectopic recombinations chimpanzees demonstrate greater chromatin variability in their subtelomeric regions [54].

Studying sexual practice chromosomes also revealed several peculiar traits. At that place are several regions of homology between Ten and Y chromosomes, so-called pseudoautosomal regions (PARs) almost probably arisen due to translocation of Deoxyribonucleic acid from X to Y chromosome [xiii]. The term "pseudoautosomal" ways that they can human action every bit autosomes being involved in recombination between X and Y chromosomes. PAR1 is a 2,vi Mb long region located at the terminate of Y chromosome short arm. It is homologous to the last region of the short arm on X chromosome. PAR2 is a 330 kb-long sequence located on the termini of long artillery of Ten and Y chromosomes. In contrast to PAR1 presenting in many mammalian genomes, PAR2 is human-specific [14]. It includes four genes: SPRY3, SYBL1, IL9R and CXYorf1. The first two genes (SPRY3, SYBL1) are silent on the Y chromosome (SPRY3, SYBL1) and are subjects of X-inactivation-like mechanism. On the other hand, the genes IL9R and CXYorf1 are active in both sex chromosomes [55, 56]. Moreover, the brusque arm of Y contains a iv Mb-long translocated region from the long arm of X chromosome, called 10-translocated region (XTR) [14, 57]. A part of the XTR has undergone inversion due to recombination between the two mobile elements of LINE-1 family. Both translocation and inversion took place already later separation of human and chimpanzee ancestors [fourteen, 58]. Finally, this region also includes genes PCDH11Y and TGIF2LY which correspond to X chromosome genes PCDH11X and TGIF2LX [15]. Effectually 2% of man population take signs of recombination between 10 and Y chromosomes at the XTR. Information technology should be considered, therefore, as an boosted homo-specific pseudoautosomal region PAR3 [15].

Insertions, deletions and copy number variations

Enzymatic machinery of LINE1 retrotransposons non only reverse transcribes its own RNA molecules, merely also frequently produces cDNA copies of other cellular transcripts, eastward.g. host genes or non-coding RNAs [59, 60] Sometimes a template switch can occur due to opposite transcription, thus resulting in double or even triple chimeric retrotranscripts [61]. Opposite-transcribed copies of the host genes are called processed pseudogenes [62]. Immediately afterward master associates of the human being and chimpanzee genomes, near 200 human- and 300 – chimpanzee-specific processed pseudogenes were identified. Near of them were copies of ribosomal protein genes which accounted for ~ 20% of species-specific pseudogenes [viii]. Nevertheless, these numbers were significantly underestimated. For example, another study revealed already ~ 1800 and 1500 processed pseudogenes of ribosomal protein in the human and chimpanzee genomes, respectively, of which ~ 1300 were common [16].

In addition to genome sequencing, DNA hybridization arrays were widely used for copy number variation studies [63, 64]. In human, microarray assay revealed a relatively increased copy number of 134 and decreased - of vi genes compared to the genomes of other groovy apes such as chimpanzee (Pan troglodytes), bonobo (Pan paniscus), gorilla (Gorilla gorilla) and orangutan (Pongo pygmaeus) [17]. However, the figure of six genes with decreased re-create numbers was certainly an underestimation because hybridization was performed using the probes for man genes. This assay besides couldn't distinguish functional genes and pseudogenes. Anyway, the human-amplified group was found to be enriched in genes involved in key nervous organization (CNS) functioning. These were NAIP (neuronal apoptosis inhibitory protein), SLC6A13 (gamma-aminobutyric acid (GABA) transporter), KIAAA0738 (zinc-finger transcription factor, expressed in encephalon), CHRFAM7A (fusion of acetylcholine receptor gene and FAM7), ARHGEF5 (guanine exchange cistron), ROCK1 (Rho-dependent protein kinase), and also members of the gene families: ARHGEF, PAK, RhoGAP and USP10 (ubiquitin-specific protease) associated with various forms of mental retardation. Relatively to humans, chimpanzees had increased copy numbers of 37 and decreased copy numbers of 15 genes [17].

The same report besides revealed increased re-create number of Rho GTPase-activating protein SRGAP2 cistron in human genome [17]. There were also two truncated man-specific homologs of this gene: SRGAP2B and SRGAP2C. The experiments with mouse embryos showed that SRGAP2 could facilitate maturation and limit density of dendrite spines in the developing neurons in neocortex. Truncated poly peptide SRGAP2C forms a dimeric complex with the normal SRGAP2 and inhibits it. Apparently, physiological expression of SRGAP2C and SRGAP2B could impact human brain development by causing specific increase of spine density and extension of maturation of pyramidal neurons in human neocortex [18].

Some other study was focused on sequences conserved in chimpanzees and other primates simply underrepresented in humans (termed hCONDELs) [19]. Comparison of human being, chimpanzee and macaque genomes revealed 510 conserved regions deleted in humans, all of them representing non-coding sequences except CMAHP factor, see below. The hCONDELs identified were enriched well-nigh genes involved in steroid hormone signaling and neuronal operation. 1 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 cistron 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 plow, the chimpanzee genome as well lacks several conserved sequences. Among 344 such regions identified, pregnant enrichment was found for the localizations near genes related to synapse formation and functioning of glutamate receptors [nineteen].

Finally, substantial differences in re-create numbers were reported for transposable elements (TEs). According to various estimates, the number of human-specific TE insertions varied from viii [26] to 15,000 copies [27]. It was estimated that humans take approximately twice as many unique TE copies every bit the chimpanzees [eight, 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 grouping was Alu, which made over five k human-specific insertions and proliferated approx. Three times more intensely in humans than in chimpanzees [26, 27]. Nearly of chimpanzee-specific Alu copies are represented by subfamilies Alu Y and AluYc1, while homo-specific insertions are predominantly the members of AluYa5 and AluYb8 subfamilies [viii, 26]. Nevertheless, both species too have specific inserts of AluS and AluYg6 family members.

Besides insertional polymorphism, Alu as well impacted divergence of the 2 genomes through homologous recombination. At to the lowest degree 492 human-specific deletions emerged because of recombinations between the different Alu copies that made ~ 400 kb of excised Dna. Of them, 295 deletions covered known or predicted genes [21]. For example, the aforementioned CMAHP gene lost its 6th exon due to recombination event between the two Alu elements [20]. Another example is tropoelastin cistron. In nigh vertebrates, it has 36 exons. During the evolution, primate ancestors have lost the 35th exon, so human being ancestors additionally lost the exon 34, also near probably due to recombination between the Alu elements [65]. On the other mitt, Alu-Alu recombinations had significant touch as well for the chimpanzee genome: at least 663 such chimpanzee-specific deletions lead to 771 kb Dna loss, and roughly a half of them took place inside factor regions [25].

The activities of LINE-i transposable elements were comparable in humans and chimpanzees and resulted in over 2000 species-specific integrations [28]. LINE-i is ~ six kb-long TE harboring two open up reading frames. The bulk of LINE-1 inserts are 5′-truncated, nearly probably due to apparently abortive reverse transcription [66]. Interestingly, among the man-specific TEs in that location were several times more full-length LINE-1 elements with intact open reading frames. The species-specific insertions were made by the members of the LINE-1 subfamilies L1-Hs and L1-PA2 [26, 28, 67]. In add-on, LINE-one elements were responsible for at least 73 man-specific deletions collectively resulting in a loss of nearly 450 kb of genomic Dna [22, 23].

Some other family termed SVA (SINE-VNTR-Alu) elements is represented in the human being genome by about k species-specific genomic copies, which is approximately twice higher than in the chimpanzee [26, 27]. Noteworthy, the human genome contains at least 84 insertions of a new, exclusively human being-specific type of transposable elements called CpG-SVA or SVAF1, formed past CpG-island of human gene MAST2 fused with 5′-truncated fragment of SVA. This group about probable emerged through insertion of an SVA chemical element into the first exon of MAST2 gene containing a CpG-island. Because of MAST2 promoter action, a chimeric transcript was formed, candy and and so reverse transcribed past LINE-1 enzymatic mechanism followed by insertions into a plethora of new genomic positions. For these new copies of a hybrid element, MAST2 CpG island enabled male germ line-specific expression, thus facilitating fixation in the genome [29, xxx]. Finally, similar the other major groups of TEs SVA elements also mediated loss of human genomic DNA. At least 26 cases of SVA-associated human-specific deletions were mentioned in the literature, which totally resulted in ~ 46 kb of deleted DNA [24].

After split of human and chimpanzee ancestors, there was also a HERV-K (HML-2) family of endogenous retroviruses that was proliferating in both genomes [31, 32, 68, 69]. Its insertional activity resulted in ~ 140 human-specific copies that formed ~ 330 kb of man DNA [31,32,33,34], some of them beingness polymorphic in human being populations [69,lxx,71,72,73,74]. In plough, the chimpanzee genome has at to the lowest degree 45 species-specific insertions of these elements [37, 38]. In addition, 2 new specific retroviral families – PtERV1 and PtERV2 with 250 totally chimpanzee-specific copies, arose already in the chimpanzee genome [viii, 39].

The new copies of transposable elements can appear in the genome non only through insertions but likewise due to duplications of genomic Deoxyribonucleic acid. For case, several hundred copies of recently integrated HERV-K (HML-2) family provirus К111 were establish in centromeres of 15 dissimilar human being chromosomes. They amplified and spread due to recombinations of the enclosing progenitor locus. In contrast, in that location 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 ix human being chromosomes, versus only 1 re-create in the chimpanzees and other higher primates [36].

Furthermore, a homo-specific endogenous retroviral (ERV) insert was demonstrated to serve as the tissue-specific enhancer driving hippocampal expression of PRODH factor responsible for proline degradation and metabolism of neuromediators in CNS [75]. Finally, the ERVs can provide their promoters for expression of non-coding RNAs from the downstream genomic loci [76]. About all ERV inserts in introns of human genes were fixed in the antisense orientation relative to gene transcriptional management [77], near probably because of the interference of gene expression with their polyadenylation signals. Withal, it has a functional upshot of ERV-driven antisense transcripts overlapping with human genes. For two genes, SLC4A8 (for sodium bicarbonate cotransporter) and IFT172 (for intraflagellar transport protein 172), these human-specific antisense transcripts overlap with the exons and regulate their expression by specifically decreasing their mRNA levels [78].

TE inserts also could play an important role in the speciation. TEs contain diverse 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, tin 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 performance and might cause the corresponding phenotypic differences [81, 82].

Information technology is worth to annotation that the main complication of the before studies was connected with the quality of non-human genomes assembly. Start of all, in that location were persisting several thousand gaps in the chimpanzee genome, which made a substantial fraction of Deoxyribonucleic acid inaccessible for comparisons. Second, the final stages of apes genomes assemblies and annotations were performed using the human genome as a template [8]. This manifestly bias results by "humanizing" great ape genomes thereby concealing some human-specific structural variations. The combination of long-read sequence assembly and full-length cDNA sequencing for de novo chimpanzee genome associates without guidance from the homo genome immune to overcome this trouble [83]. Comparing of de novo sequenced and independently assembled human and great ape genomes revealed 17,789 fixed homo-specific structural variants (fhSVs), including 11,897 fixed man-specific insertions and 5892 fixed human-specific deletions. Among fhSVs, a loss of 13 start codons, 16 stop codons, and 61 exonic deletions in the human lineage were detected. Also, fhSVs affected 643 regulatory regions near 479 genes. Totally, 46 fhSVs deletions were detected that were expected to disrupt human genes, 41 of them were new. The affected genes included for example caspase recruitment domain family member viii (CARD8), genes FADS1 and FADS2 involved in fatty acids biosynthesis, and two jail cell wheel genes WEE1 and CDC25C [83].

Single nucleotide alterations

Man specific single nucleotide alterations constitute ~ 1.23% of our genome. This value was found past directly comparing human with chimpanzee genomes. It was very close to the previous theoretical estimate of 1.two% calculated using average divergence charge per unit for autosomes, for the time of man and chimpanzee ancestor's divergence [84]. In the homo populations, ~ 86% of all human being specific single nucleotide alterations is fixed and the balance 14% is polymorphic [8]. Remarkably, the everyman and the highest human being-chimpanzee nucleotide sequence divergences, 1.0 and 1.9%, respectively, were detected in the chromosomes X and Y. Outstandingly, every bit much every bit 15% of all bequeathed CG-dinucleotides underwent mutations either in the human or in the chimpanzee lineage [85].

Poly peptide-coding sequences

Protein coding sequences are 99.1% identical between the 2 species [86], and in two-thirds of the proteins amino acid sequences are absolutely the aforementioned [8]. Generally, in comparison with the model of the latest common ancestor genome, the chimpanzee has more genes that underwent positive selection than human. This tin can be explained by the different effective sizes of bequeathed populations of the two species [87]. However, after departure, transcription factors (TFs) were the fastest evolving group of genes, and human TFs had ~ one,5 times college amino acids exchange rate [8]. 2d, genes linked with neuronal operation also evolved faster in the human lineage [88].

There is a connectedness identified between mutations in the transcription cistron FOXP2 gene and speech disorders, and an assumption was made that FOXP2 is responsible for speech and language development in humans. Indeed, the sequence analysis revealed that FOXP2 has signs of positive selection during human evolution [43] having two human-specific amino acrid substitutions: Thr303Asn and Asn325Ser, where the latter led to a new potential phosphorylation site [44]. In vivo experiments showed that these substitutions may have important functional significance. Transgenic mice with humanized version of their FoxP2 gene demonstrated faster learning when both declarative and procedural mechanisms were involved. Besides, they had peculiar dopamine levels and higher neuronal plasticity in the striatum [45].

The microcephalin cistron MCPH1 is involved in the regulation of brain development. Its mutations are linked with astringent genetic disorders similar microcephaly. During homo speciation, this cistron evolved under potent positive selection, which is still going on in the modern human being population [46]. Another gene continued with the encephalon size regulation, ASPM (abnormal spindle-similar microcephaly associated, MCPH5), also evolved faster in hominids than in the other primates, having the highest charge per unit of non-synonymous to synonymous substitutions in the human lineage [47].

Several sexual reproduction genes were also among the well-nigh speedily evolving and positively selected hits [44, 89], such as protamine genes PRM1 and PRM2 encoding histone analogs in sperm cells. Remarkably, human protamines evolve oppositely to histones, whose structures are highly conservative [89].

Another grouping of highly diverged genes relates to immunity and cell recognition [viii]. A betoken mutation in the variable domain of T-prison cell gamma-receptor TCRGV10 destroyed a donor splice-site, which prevented splicing of the leader intron. Chimpanzees don't have this mutation and their gene remains functional [41].

Both species take many specific mutations in the genes involved in sialic acids metabolism - ST6GAL1, ST6GALNAC3, ST6GALNAC4, ST8SIA2 and HF1 [viii]. Sialic acids, or N-acetyl neuraminic (Neu5Ac) and N-glycolyl neuraminic acid (Neu5Gc), are mutual components of the carbohydrate cell surface complexes in mammals. Humans are exceptional because they completely lack Neu5Gc on their prison cell surfaces [xc] because their cistron CMAHP coding an enzyme – cytidine monophosphate-N-acetylneuraminic acid hydroxylase – responsible for the conversion of CMP-Neu5Ac into CMP-Neu5Gc, has lost its activity. Information technology happened because of the loss of a 92-nucleotide exon corresponding to the 6th ancestral exon, caused past insertion of an AluY chemical element followed by recombination [20, 91].

Moreover, the mechanism of sialic acids recognition was as well affected in the man lineage. Human factor SIGLEC11 for sialic acid receptor underwent a conversion with the pseudogene SIGLEC16 that significantly compromised its ability to bind sialic acids. However, it still can bind oligosialic acids (Neu5Acα2–eight)_two–three, that are highly abundant in the brain. Moreover, SIGLEC11 demonstrates human-specific expression in microglia [92]. Similarly, the protein SIGLEC12 lost its sialic acrid-bounden activity due to human-specific exchange R122C. All the same, SIGLEC12 gene is nonetheless expressed in macrophages and in several epithelial prison cell types [93].

Another major affected group of genes is for the olfactory receptors. Humans and chimpanzees have a comparable number of olfactory receptor genes, around 800, and 689 of them are orthologous in the two species [40]. Nonetheless, in both species about half of them have lost their activities and became pseudogenes. Even though the last numbers of active genes are equal in human and chimpanzee, their repertoire is strikingly different – as much equally 25% of the active olfactory receptor genes are species-specific. This has led to an assumption that the most contempo common ancestor had more active olfactory receptor genes than modern humans and chimpanzees [40].

Other examples include caspase 12, mannose-binding lectin gene MBL1P and keratin isoform KRTHAP1 that lost their activities due to human-specific mutations [8, 42, 94].

Non-coding sequences

Non-coding sequences play crucial roles in gene regulation [95, 96]. Assay of species-specific polymorphisms revealed that 96% of regions with the highest density of alterations (HAR, human accelerated region) map on non-coding Dna. The genes located well-nigh HARs are predominantly related to interaction with Deoxyribonucleic acid, transcriptional regulation and neuronal development [48, 97].

The biggest number of HARs was observed for the NPAS3 (neuronal PAS domain-containing protein) gene. It codes for a transcription gene involved in brain evolution. The 14 HARs _NPAS3 are located in non-coding regions and most of them may have regulatory functions, equally confirmed by enhancer activities demonstrated in prison cell culture assay [98].

Chop-chop evolving homo genome region HAR1 was found in the overlap of two non-coding RNA genes: HAR1F and HAR1R. The former is expressed at 7–19 weeks of embryonic development in the Cajal-Retzius cells of the emerging neocortex. At the later gestation period and in adulthood HAR1F is expressed also in the other parts of the brain. This expression pattern is conserved in all higher primates, but homo-specific nucleotide alterations afflicted the secondary structure of this RNA [48, 99]. Some other accelerated region HARE5 (HAR enhancer five) is ~ i,ii kb long enhancer of FZD8 gene. After human being and chimpanzee ancestral divergence, their orthologous loci accumulated 10 and 6 nucleotide substitutions, respectively. FZD8 encodes a receptor protein in the WNT signaling pathway, which is involved in the regulation of encephalon evolution and size. In mouse, endogenous HARE5 homolog physically interacts with Fzd8 core promoter in the neocortex. In transgenic mice with Fzd8 nether control of either human or chimpanzee enhancer, both demonstrated their activities in the developing neocortex, but the human enhancer became active at the before stages of development and its result was more pronounced. Embryos with the human HARE5, therefore, showed a marked acceleration of neural progenitor cell cycle and increased brain size [51].

At that place is too a detail fraction of non-coding sequences that was accelerated in humans but relatively conserved in the other species chosen HACNs (human accelerated conserved noncoding sequences) [49]. They tin overlap with the abovementioned HARs [50]. HACNs are enriched near genes related to neuronal functioning, such every bit neuronal jail cell adhesion [49] and brain development [100]. Based on structural analyses of HACNs, HARs and their genomic contexts, around 1 3rd of them was predicted to be developmental enhancers [50]. By functional function, 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 betwixt man and chimpanzee sequences [fifty].

In some other study, all human enhancers predicted by the FANTOM projection [101] were aligned with the primate genomes in order to obtain human being-specific fraction [52]. Notably, the fastest evolving human enhancers predominantly regulated genes activated in neurons and neuronal stem cells. Totally, nigh 100 human-specific neuronal enhancers were identified, and 1 of them located on the 8q23.1 region was presumably related to Alzheimer's illness development. Information technology was assumed by the authors that recent homo-specific enhancers, adaptive, on the one paw, may also touch age-related diseases [52].

Transcriptional regulation

It has been postulated few decades ago that differences betwixt humans and chimpanzees are more often than not caused by gene regulation changes rather than past alterations in their poly peptide-coding sequences, and that these changes must affect embryo evolution [6]. For example, evolutional acquisitions such equally enlarged encephalon 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 fourth dimension frame that can enable fine tuning of a gene activity [105]. Indeed, the fast-evolving sequences (HARs or HACNs) are oft constitute close to the genes agile during embryo- and neurogenesis [48,49,50, 100]. For example, HACNS1 (HAR2) demonstrates greater enhancer activeness in limb buds of transgenic mice compared to orthologous sequences from chimpanzee or rhesus macaque [106]. A like pattern was observed for the aforementioned HARs related to genes NPAS3 and FZD8 that are agile during CNS development in embryogenesis [51, 98].

Many studies were focused on finding differences between humans, chimpanzees and other mammals at the level of gene transcription [107,108,109]. Importantly, tissue-specific differences within the same species significantly exceeded in amplitude all species-specific differences in whatsoever tissue. The most transcriptionally divergent organs between humans and chimpanzees were liver and testis, and to a lesser extent – kidney and heart [107, 108]. A transcriptional stardom of liver may exist a consequence of dissimilar nutritional adaptations in the two species. The major differences in testes are largely unexplained but may exist related to predominantly monogamous beliefs in humans. Surprisingly, the brain was the least divergent organ betwixt humans and chimpanzees at the transcriptional level. In this regard, information technology is suggested that tighter regulation of signaling pathways in the brain underlies behavioral and cerebral differences [109, 110]. Withal, it was found that during evolution in the human cerebral cortex there were more transcriptional changes than in the chimpanzee [109]. Among them, the prevailed difference was increased transcriptional activity [110, 111]. In addition, many differences were identified in the alternative splicing patterns including 6–8% of gene exons, thus supporting a concept that the differentially spliced transcripts have pronounced functional consequences for the speciation [112].

Another study of transcriptional action in the forebrain evidenced the higher difference between human and chimpanzee in the frontal lobe [113]. The functions of frontal lobe-specific groups of co-expressed genes dealt mostly with neurogenesis and cell adhesion [113]. Furthermore, the analysis of 230 genes associated with communication showed that most a quarter of them was differentially expressed in the brains of humans and other primates [110]. KRAB-zinc finger (KRAB-ZNF) genes were overrepresented among the genes differentially expressed in the brain [114]. Remarkably, the KRAB-ZNF cistron family unit is known for its rapid development in primates, especially for its human- or chimpanzee-specific members [115]. The studies of transcriptional timing in the postnatal brain development besides revealed a number of human-specific features. A specific set of genes was found whose expression was delayed in humans compared to the other primates. For case, the maximum expression of synaptic genes in the human prefrontal cortex was shifted from 1 yr of age as for the chimpanzees and macaques, to 5 years. It is congruent with the prolonged brain evolution menstruation in humans relative to other primates [116, 117]. The results recently published by Pollen and colleagues allowed to expect deeper into the developing man and chimpanzee brains past applying the organoid model [118]. Cerebral organoids were generated from induced pluripotent stem cells (iPSCs) of humans and chimpanzees. Transcriptome analyses revealed 261 genes deferentially expressed in human versus chimpanzee cerebral organoids and macaque cortex. The PI3K/AKT/mTOR signaling axis appeared to be stronger activated in homo, especially in radial glia [118].

Epigenetic regulation is another factor that should exist considered when looking at interspecies differences in gene expression. High throughput assay of differentially methylated DNA in man 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 amidst the differentially methylated entries [118]. The analysis of H3K4me3 (trimethylated histone H3 is a marking of transcriptionally active chromatin) distribution in the neurons of prefrontal lobe revealed 471 homo-specific regions, 33 of them were neuron-specific. Some of these regions were proximate to genes associated with neurologic and mental disorders, such equally ADCYAP1, CACNA1C, CHL1, CNTN4, DGCR6, DPP10, FOXP2, LMX1B, NOTCH4, PDE4DIP, SLC2A3, SORCS1, TRIB3, TUBB2B and ZNF423 [119, 120]. Another agile chromatin biomarker is the distribution of DNase I hypersensitivity sites (DHSs), that often bespeak gene regulatory elements. It was found that 542 DHSs overlapped with HARs, thus being so-called homo accelerated DHSs, haDHSs [121]. Using chromatin immunoprecipitation assay, a number of haDHSs interacting genes were identified, many of which were connected with early on evolution and neurogenesis [three, 121]. In a after report [122], about 3,5 grand haDHSs were found, that were enriched near the genes related to neuronal functioning [122].

Conclusions

It is now generally accepted that both changes in factor regulation and alterations of poly peptide coding sequences might take played a major role in shaping the phenotypic differences between humans and chimpanzees. In this context, complex bioinformatic approaches combining diverse OMICS information analyses, are becoming the central for finding genetic elements that contributed to homo development. It is as well extremely important to have relevant experimental models to validate the candidate species-specific genomic alterations. The currently developing experimental methods such as obtaining pluripotent stem cells and target genome modifications, similar CRISPR-CAS [105], open up exciting perspectives for finding a "needle in haystack" that was truly important for human functional evolution, or probably many such needles. However, at least for now using these experimental approaches for millions of species specific potentially impactful features reviewed hither is impossible due to high costs and labor intensity. In plow, an alternative approach could be combining the refined data in a realistic model of human-specific development using a new generation systems biology approach trained on a functional genomic Big Data of humans and other primates. Such an approach could integrate knowledge of protein-protein interactions, biochemical pathways, spatio-temporal epigenetic, transcriptomic and proteomic patterns as well as high throughput simulation of functional changes caused by altered protein structures. The differences revealed could be as well analyzed in the context of mammalian and primate-specific evolutionary trends, due east.g. by using dN/dS approach to measure evolutionary rates of structural changes in proteins [115] and enrichment past transposable elements in functional genomic loci to estimate regulatory development of genes [116]. Apart from the single-factor level of data analysis, this information could exist aggregated to wait at the whole organismic, developmental or intracellular processes e.g. by using Gene Ontology terms enrichment analysis [117] and quantitative assay of molecular pathways [118].

And finally, most of the results described hither were obtained for the human being and chimpanzee reference genomes, which were built each using DNAs of several individuals. Nowadays the greater availability of whole-genome sequencing highlighted the next challenge in human and chimpanzee comparison – populational genome diverseness. For example, the recent study [123] of 910 native African genomes was focused on the fraction of sequences absent from the reference Hg38 genome associates. As many as 125,715 insertions missing in the Hg38 was identified with the average number of 859 insertions per individual, making upwards a total of 296,v Mb. These findings conspicuously propose that the electric current version of the human genome assembly tin can lack nearly ten% of the genome data. Furthermore, it likewise reflects the high degree of genome heterogeneity of the African population [123]. Similar studies were performed for other populations as well. For example, in the Chinese population a total of 29,5 Mb new DNA and 167 predicted novel genes missing in the reference genome assembly was discovered [124].

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

And so far there were not so many studies published on the topic of non-reference man and chimpanzee genome comparison. However, some estimates can be made. In the recent report of 1000 genomes from the Swedish population [126] there were identified totally 61,044 clusters totally making ~ 46 Mb of man DNA that were absent-minded from the reference Hg38 human being genome associates. These clusters were chosen past the authors "new sequences" (NSs). As expected, NSs were enriched in simple repeats and satellites and varied greatly among the individuals. The most office of NSs (32,794) aligned confidently to the non-reference sequences from the aforementioned study of 910 African genomes [123]. Finally, as many every bit 18,773 NSs were nowadays also in the chimpanzee PT4 genome assembly. In terms of protein coding sequences, 143 orthologous chimpanzee genes contained a total of 2807 NSs, where four genes were strongly enriched: EPPK1, OR8U1, NINL, and METTL21C. Positioning of NS insertions in the human genome revealed that 2195 of them located within 2384 genes, where 85 NS insertion events were found within the exons of 82 genes [126].

Another research consortium studied not-repetitive non-reference sequences (NRNR) in the genomes of 15,219 Icelanders [127]. A total of 326,596 bp of NRNR Deoxyribonucleic acid was plant, where ~ 84% was formed by only 244 insertions longer than 200 bp. Notably, comparing with the chimpanzee genome revealed that over 95% of the NRNRs longer than 200 bp were nowadays also in the chimpanzee genome associates, thus indicating that they were ancestral [127]. Thus, the lack of information on genome populational diversity could bear on the full extent of human and chimpanzee interspecies divergence by misinterpretation of polymorphic sequences. However, it doesn't abrogate most of the hypotheses and facts mentioned in this review. Still, these findings inevitably lead to the thought of the need, firstly, to create, and secondly, to compare human being and chimpanzee pan-genomes.

Availability of data and materials

Not applicable.

Abbreviations

Mya:

Meg years agone

Mb:

Megabase (million base pairs)

kb:

Kilobase (thousand base of operations pairs)

HAR:

Human accelerated region

HERV:

Human endogenous retrovirus

LINE:

Long interspersed nuclear element

PAR:

Pseudoautosomal region

TE:

Transposable chemical element

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Acknowledgements

We give thanks Dr. Alexander Markov (Moscow State University, Russia) for insightful discussion.

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This article has been published every bit function of BMC Genomics Volume 21 Supplement 7, 2020: Selected Topics in "Systems Biology and Bioinformatics" - 2019: genomics. The full contents of the supplement are available online at https://bmcgenomics.biomedcentral.com/articles/supplements/volume-21-supplement-7.

Funding

This report was supported by the Russian Foundation for Basic Inquiry Grant 19–29-01108. Publication costs were funded past Moscow Institute of Physics and Technology (National Research University). The funding bodies played no role in the design of this report and collection, analysis, and estimation of data and in writing of the manuscript.

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Affiliations

1. Constitute for personalized medicine, I.One thousand. Sechenov First Moscow State Medical University, Trubetskaya viii, Moscow, Russia

   Maria V. Suntsova & Anton A. Buzdin

2. Shemyakin-Ovchinnikov Found of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya, 16/10, Moscow, Russia

   Anton A. Buzdin

3. Omicsway Corp, Walnut, CA, The states

   Anton A. Buzdin

4. Moscow Institute of Physics and Technology (National Research University), 141700, Moscow, Russia

   Anton A. Buzdin

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AB and MS systematically analyzed the literature, interpreted the information, read and edited the manuscript. All authors read and approved the last manuscript.

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Correspondence to Anton A. Buzdin.

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Suntsova, Chiliad.V., Buzdin, A.A. Differences betwixt man and chimpanzee genomes and their implications in gene expression, protein functions and biochemical backdrop of the two species. BMC Genomics 21, 535 (2020). https://doi.org/10.1186/s12864-020-06962-8

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• Received: xvi July 2020

• Accepted: 29 July 2020

• Published: ten September 2020

• DOI : https://doi.org/10.1186/s12864-020-06962-8

Keywords

• Human-specific
• Chimpanzee
• Genome alterations
• Genetic differences
• Molecular development

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Source: https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-020-06962-8

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