Which Organisms Dna Will Differ From the Chimpanzee the Most

Which Organisms Dna Will Differ From the Chimpanzee the Most.

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Differences betwixt human and chimpanzee genomes and their implications in gene expression, protein functions and biochemical properties of the two species

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Abstract

Chimpanzees are the closest living relatives of humans. The divergence between homo and chimpanzee ancestors dates to approximately half dozen,5–7,five million years ago. Genetic features distinguishing u.s. from chimpanzees and making us humans are withal of a great involvement. Afterwards divergence of their ancestor lineages, homo and chimpanzee genomes underwent multiple changes including single nucleotide substitutions, deletions and duplications of DNA fragments of dissimilar size, insertion of transposable elements and chromosomal rearrangements. Human being-specific single nucleotide alterations constituted 1.23% of human DNA, whereas more extended deletions and insertions embrace ~ 3% of our genome. Moreover, much college proportion is made past differential chromosomal inversions and translocations comprising several megabase-long regions or fifty-fifty whole chromosomes. However, despite of extensive knowledge of structural genomic changes accompanying human evolution we still cannot identify with certainty the causative genes of human identity. Well-nigh structural gene-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.

Background

The difference of human and chimpanzee ancestors dates back to approximately 6,v–7,5 one thousand thousand years ago [i] or even earlier [2]. It is still of a great interest to identify genetic elements that distinguish humans from chimpanzees and encode features of man physiological and mental identities [3,4,5]. It’south a difficult task to quantitate the exact per centum of differences between human and chimpanzee genomes. In early works, divergence of human and chimpanzee genomes was estimated as roughly 1% [6]. This estimate was based on the comparison of protein-coding sequences and didn’t consider non-coding (major) function of Dna. However, the idea of ~ 99% similarity of genomes persisted for a long fourth dimension, until 2005 when nigh complete initial sequencing results of both human [vii] and chimpanzee (Pan troglodytes) [8] genomes became available. It was found that genome differences represented by single nucleotide alterations formed 1.23% of human DNA, whereas larger deletions and insertions constituted ~ 3% of our genome [viii]. Moreover, fifty-fifty higher proportion was shaped past chromosomal inversions and translocations comprising several megabase-long chromosomal regions or even unabridged chromosomes, equally for the chromosomal fusion that took place when the man
chromosome 2
was formed [9]. Here we tried to review the major known structural and regulatory genetic alterations that had or might take a functional touch on the homo and chimpanzee speciation (Table 1).

Table 1 Molecular genetic differences between humans and chimpanzees

Total size table

Karyotype

Human karyotype is represented by 46 chromosomes, whereas chimpanzees accept 48 chromosomes [9]. In full general, both karyotypes are very similar. However, there is a major divergence corresponding to the human
chromosome 2. It has originated due to a fusion of two ancestral acrocentric chromosomes corresponding to
chromosomes 2a
and
2b
in chimpanzee. Also, significant pericentric inversions were found in 9 other chromosomes [nine]. Ii out of nine are thought to occur in human
chromosomes 1
and
xviii, and the other seven – in chimpanzee
chromosomes four, 5, 9, 12, 15, xvi
and
17
[10,xi,12]. In add-on, in that location are numerous differences in the chromosomal organization of pericentric, paracentric, intercalary and Y type heterochromatin; for instance, the chimpanzees take large additional telomeric heterochromatin region on
chromosome 18
[ix]. Additionally, the bulk of chimpanzee’s chromosomes contain subterminal constitutive heterochromatin (C-band) blocks (SCBs) that are absent in human being chromosomes. SCBs predominantly consist of the subterminal satellite (StSat) repeats, they are establish in African keen apes but not in humans [53]. The presence of such SCBs affects chimpanzees’ chromosomes behavior during meiosis causing persistent subtelomeric associations between homologous and not-homologous chromosomes. As a outcome of homologous and ectopic recombinations chimpanzees demonstrate greater chromatin variability in their subtelomeric regions [54].

Studying sex chromosomes also revealed several peculiar traits. There are several regions of homology betwixt
X
and
Y chromosomes, so-called pseudoautosomal regions (PARs) near probably arisen due to translocation of DNA from
10
to
Y chromosome
[13]. The term “pseudoautosomal” ways that they tin act as autosomes being involved in recombination betwixt
X
and
Y chromosomes. PAR1 is a ii,half-dozen Mb long region located at the finish of
Y chromosome
brusque arm. It is homologous to the final region of the curt arm on
X chromosome. PAR2 is a 330 kb-long sequence located on the termini of long arms of
10
and
Y chromosomes. In dissimilarity to PAR1 presenting in many mammalian genomes, PAR2 is human being-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 short arm of
Y
contains a 4 Mb-long translocated region from the long arm of
X chromosome, chosen X-translocated region (XTR) [14, 57]. A part of the XTR has undergone inversion due to recombination between the ii mobile elements of LINE-1 family. Both translocation and inversion took identify already afterward separation of human and chimpanzee ancestors [14, 58]. Finally, this region also includes genes
PCDH11Y
and
TGIF2LY
which correspond to
10 chromosome
genes
PCDH11X
and
TGIF2LX
[15]. Around 2% of homo population have signs of recombination between
X
and
Y chromosomes
at the XTR. It should be considered, therefore, as an boosted human-specific pseudoautosomal region PAR3 [fifteen].

Insertions, deletions and copy number variations

Enzymatic machinery of LINE1 retrotransposons not only contrary transcribes its ain RNA molecules, simply as well frequently produces cDNA copies of other cellular transcripts, e.g. host genes or non-coding RNAs [59, threescore] Sometimes a template switch can occur due to opposite transcription, thus resulting in double or fifty-fifty triple chimeric retrotranscripts [61]. Reverse-transcribed copies of the host genes are called processed pseudogenes [62]. Immediately later on primary associates of the man and chimpanzee genomes, nearly 200 human- and 300 – chimpanzee-specific candy pseudogenes were identified. Most of them were copies of ribosomal protein genes which accounted for ~ xx% of species-specific pseudogenes [eight]. However, these numbers were significantly underestimated. For instance, another study revealed already ~ 1800 and 1500 processed pseudogenes of ribosomal protein in the homo 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 six genes compared to the genomes of other great apes such equally chimpanzee (Pan troglodytes), bonobo (Pan paniscus), gorilla (Gorilla gorilla) and orangutan (Pongo pygmaeus) [17]. However, the effigy of vi genes with decreased re-create numbers was certainly an underestimation because hybridization was performed using the probes for man genes. This assay also couldn’t distinguish functional genes and pseudogenes. Anyway, the human being-amplified group was constitute to be enriched in genes involved in central nervous arrangement (CNS) functioning. These were
NAIP
(neuronal apoptosis inhibitory protein),
SLC6A13
(gamma-aminobutyric acid (GABA) transporter),
KIAAA0738
(zinc-finger transcription factor, expressed in brain),
CHRFAM7A
(fusion of acetylcholine receptor gene and
FAM7),
ARHGEF5
(guanine exchange gene),
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 study also revealed increased copy number of Rho GTPase-activating protein
SRGAP2
gene in homo genome [17]. There were besides two truncated human being-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 protein SRGAP2C forms a dimeric circuitous with the normal SRGAP2 and inhibits information technology. Apparently, physiological expression of
SRGAP2C
and
SRGAP2B
could impact human brain development by causing specific increment of spine density and extension of maturation of pyramidal neurons in homo neocortex [18].

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

Finally, substantial differences in copy numbers were reported for transposable elements (TEs). According to various estimates, the number of man-specific TE insertions varied from 8 [26] to 15,000 copies [27]. It was estimated that humans have approximately twice every bit many unique TE copies as the chimpanzees [viii, 26]. Since human-chimpanzee ancestral deviation, the almost active TE groups were
Alu, LINE1
and
SVA
which deemed for nearly 95% of all species-specific insertions [26]. The well-nigh numerous group was
Alu, which made over 5 k homo-specific insertions and proliferated approx. Three times more intensely in humans than in chimpanzees [26, 27]. Virtually of chimpanzee-specific
Alu
copies are represented past subfamilies
Alu Y
and
AluYc1, while man-specific insertions are predominantly the members of
AluYa5
and
AluYb8
subfamilies [8, 26]. Withal, both species too have specific inserts of
AluS
and
AluYg6
family unit members.

Besides insertional polymorphism,
Alu
also impacted deviation of the two genomes through homologous recombination. At least 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 instance, the aforementioned
CMAHP
cistron lost its sixth exon due to recombination consequence betwixt the ii
Alu
elements [xx]. Another case is tropoelastin gene. In almost vertebrates, it has 36 exons. During the evolution, primate ancestors accept lost the 35th exon, and and so human ancestors additionally lost the exon 34, also most probably due to recombination between the
Alu
elements [65]. On the other hand,
Alu-Alu
recombinations had significant impact also for the chimpanzee genome: at to the lowest degree 663 such chimpanzee-specific deletions lead to 771 kb Dna loss, and roughly a half of them took place within gene regions [25].

The activities of
LINE-one
transposable elements were comparable in humans and chimpanzees and resulted in over 2000 species-specific integrations [28].
LINE-1
is ~ half dozen kb-long TE harboring ii open reading frames. The majority of
LINE-1
inserts are 5′-truncated, about probably due to apparently abortive contrary transcription [66]. Interestingly, among the man-specific TEs there were several times more than total-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 addition,
LINE-one
elements were responsible for at to the lowest degree 73 human-specific deletions collectively resulting in a loss of virtually 450 kb of genomic DNA [22, 23].

Another family unit termed
SVA
(SINE-VNTR-Alu) elements is represented in the human genome past about g 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-specific type of transposable elements called
CpG-SVA
or
SVAF1, formed by CpG-island of homo gene
MAST2
fused with 5′-truncated fragment of
SVA. This grouping most likely emerged through insertion of an SVA element into the first exon of
MAST2
gene containing a CpG-island. Because of
MAST2
promoter activeness, a chimeric transcript was formed, processed then opposite transcribed by
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 person germ line-specific expression, thus facilitating fixation in the genome [29, xxx]. Finally, like the other major groups of TEs
SVA
elements likewise 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 homo and chimpanzee ancestors, there was too a
HERV-Chiliad (HML-2)
family of endogenous retroviruses that was proliferating in both genomes [31, 32, 68, 69]. Its insertional action resulted in ~ 140 human being-specific copies that formed ~ 330 kb of human Dna [31,32,33,34], some of them existence polymorphic in homo populations [69,70,71,72,73,74]. In turn, the chimpanzee genome has at least 45 species-specific insertions of these elements [37, 38]. In improver, two new specific retroviral families –
PtERV1
and
PtERV2
with 250 totally chimpanzee-specific copies, arose already in the chimpanzee genome [8, 39].

The new copies of transposable elements can appear in the genome non only through insertions merely also due to duplications of genomic DNA. For instance, several hundred copies of recently integrated
HERV-K (HML-2)
family provirus
К111
were found in centromeres of fifteen dissimilar human chromosomes. They amplified and spread due to recombinations of the enclosing progenitor locus. In contrast, there is only one re-create 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 re-create in the chimpanzees and other higher primates [36].

Furthermore, a human-specific endogenous retroviral (ERV) insert was demonstrated to serve as the tissue-specific enhancer driving hippocampal expression of
PRODH
cistron 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]. Almost all ERV inserts in introns of human genes were fixed in the antisense orientation relative to gene transcriptional management [77], most probably considering of the interference of gene expression with their polyadenylation signals. However, it has a functional result 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 past specifically decreasing their mRNA levels [78].

TE inserts also could play an important role in the speciation. TEs incorporate diverse regulatory elements such equally promoters, enhancers, splice-sites and signals of transcriptional termination, which they utilise 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, fourscore]. In addition, TEs can disrupt gene structures by inserting themselves or through recombinations between their copies [21, 23]. These events could influence gene operation and might crusade the corresponding phenotypic differences [81, 82].

It is worth to annotation that the main complication of the earlier studies was connected with the quality of not-human genomes associates. First of all, there were persisting several thousand gaps in the chimpanzee genome, which made a substantial fraction of Dna inaccessible for comparisons. Second, the final stages of apes genomes assemblies and annotations were performed using the human genome as a template [viii]. This evidently bias results by “humanizing” great ape genomes thereby concealing some human being-specific structural variations. The combination of long-read sequence assembly and full-length cDNA sequencing for de novo chimpanzee genome assembly without guidance from the human genome allowed to overcome this problem [83]. Comparing of de novo sequenced and independently assembled human and swell ape genomes revealed 17,789 fixed human being-specific structural variants (fhSVs), including 11,897 fixed man-specific insertions and 5892 fixed human being-specific deletions. Among fhSVs, a loss of thirteen start codons, 16 finish 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 homo genes, 41 of them were new. The affected genes included for example caspase recruitment domain family unit fellow member 8 (CARD8), genes FADS1 and FADS2 involved in fatty acids biosynthesis, and two jail cell wheel genes WEE1 and CDC25C [83].

Single nucleotide alterations

Human specific single nucleotide alterations constitute ~ 1.23% of our genome. This value was establish by directly comparing human with chimpanzee genomes. Information technology was very close to the previous theoretical estimate of 1.2% calculated using average divergence rate for autosomes, for the time of man and chimpanzee ancestor’s divergence [84]. In the human populations, ~ 86% of all human being specific unmarried nucleotide alterations is fixed and the remainder 14% is polymorphic [viii]. Remarkably, the lowest and the highest human-chimpanzee nucleotide sequence divergences, 1.0 and 1.9%, respectively, were detected in the chromosomes X and Y. Outstandingly, as much as fifteen% of all ancestral CG-dinucleotides underwent mutations either in the human being 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 comparing with the model of the latest common antecedent genome, the chimpanzee has more genes that underwent positive selection than human. This can be explained by the different effective sizes of bequeathed populations of the two species [87]. However, later divergence, transcription factors (TFs) were the fastest evolving grouping of genes, and homo TFs had ~ 1,v times college amino acids exchange rate [viii]. 2nd, genes linked with neuronal functioning also evolved faster in the human lineage [88].

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

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

Several sexual reproduction genes were also amongst the most rapidly evolving and positively selected hits [44, 89], such equally 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 group of highly diverged genes relates to amnesty and jail cell recognition [eight]. A signal mutation in the variable domain of T-cell gamma-receptor TCRGV10 destroyed a donor splice-site, which prevented splicing of the leader intron. Chimpanzees don’t accept this mutation and their gene remains functional [41].

Both species have many specific mutations in the genes involved in sialic acids metabolism –
ST6GAL1, ST6GALNAC3, ST6GALNAC4, ST8SIA2
and
HF1
[8]. Sialic acids, or Northward-acetyl neuraminic (Neu5Ac) and North-glycolyl neuraminic acid (Neu5Gc), are common components of the saccharide cell surface complexes in mammals. Humans are infrequent because they completely lack Neu5Gc on their prison cell surfaces [xc] considering their gene
CMAHP
coding an enzyme – cytidine monophosphate-N-acetylneuraminic acid hydroxylase – responsible for the conversion of CMP-Neu5Ac into CMP-Neu5Gc, has lost its action. It happened because of the loss of a 92-nucleotide exon corresponding to the sixth bequeathed exon, caused by insertion of an AluY element followed by recombination [20, 91].

Moreover, the mechanism of sialic acids recognition was also afflicted in the man lineage. Human gene
SIGLEC11
for sialic acid receptor underwent a conversion with the pseudogene
SIGLEC16
that significantly compromised its ability to bind sialic acids. However, information technology still can bind oligosialic acids (Neu5Acα2–8)two–3, that are highly abundant in the brain. Moreover,
SIGLEC11
demonstrates human-specific expression in microglia [92]. Similarly, the protein SIGLEC12 lost its sialic acid-binding activeness due to human-specific exchange R122C. Nevertheless,
SIGLEC12
cistron is still expressed in macrophages and in several epithelial 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]. However, in both species nigh half of them have lost their activities and became pseudogenes. Even though the final numbers of active genes are equal in homo and chimpanzee, their repertoire is strikingly different – every bit much as 25% of the active olfactory receptor genes are species-specific. This has led to an assumption that the nearly recent common ancestor had more active olfactory receptor genes than modern humans and chimpanzees [forty].

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

Non-coding sequences

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

The biggest number of HARs was observed for the
NPAS3
(neuronal PAS domain-containing poly peptide) gene. It codes for a transcription cistron involved in brain development. The 14 HARs
NPAS3

are located in non-coding regions and most of them may have regulatory functions, as confirmed by enhancer activities demonstrated in jail cell civilization analysis [98].

Rapidly evolving human genome region HAR1 was found in the overlap of 2 non-coding RNA genes:
HAR1F
and
HAR1R.
The former is expressed at vii–19 weeks of embryonic development in the Cajal-Retzius cells of the emerging neocortex. At the later gestation flow and in adulthood
HAR1F
is expressed also in the other parts of the brain. This expression pattern is conserved in all college primates, but human-specific nucleotide alterations affected the secondary structure of this RNA [48, 99]. Another accelerated region HARE5 (HAR enhancer 5) is ~ 1,2 kb long enhancer of
FZD8
cistron. Afterward human being and chimpanzee ancestral departure, their orthologous loci accumulated 10 and 6 nucleotide substitutions, respectively.
FZD8
encodes a receptor poly peptide in the WNT signaling pathway, which is involved in the regulation of brain development and size. In mouse, endogenous HARE5 homolog physically interacts with
Fzd8
core promoter in the neocortex. In transgenic mice with
Fzd8
under 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 evolution and its effect was more pronounced. Embryos with the human HARE5, therefore, showed a marked acceleration of neural progenitor cell wheel and increased brain size [51].

In that location is also a detail 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 tin overlap with the abovementioned HARs [50]. HACNs are enriched near genes related to neuronal functioning, such as neuronal prison cell adhesion [49] and brain development [100]. Based on structural analyses of HACNs, HARs and their genomic contexts, effectually 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 center evolution. Amidst 29 pairs of HARs and their chimpanzee orthologous regions tested in mouse embryos, 24 showed enhancer activeness in vivo. Moreover, 5 of them demonstrated differential enhancer activities between human and chimpanzee sequences [50].

In some other written report, all human enhancers predicted by the FANTOM project [101] were aligned with the primate genomes in order to obtain human-specific fraction [52]. Notably, the fastest evolving human enhancers predominantly regulated genes activated in neurons and neuronal stem cells. Totally, about 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. It was assumed by the authors that recent human-specific enhancers, adaptive, on the one manus, may too touch age-related diseases [52].

Transcriptional regulation

Information technology has been postulated few decades ago that differences betwixt humans and chimpanzees are mostly caused by gene regulation changes rather than by alterations in their poly peptide-coding sequences, and that these changes must affect embryo development [6]. For case, evolutional acquisitions such as 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, generally negative, consequences for an organism. On the other hand, changes in gene regulation could be express to a certain tissue or fourth dimension frame that can enable fine tuning of a factor activeness [105]. Indeed, the fast-evolving sequences (HARs or HACNs) are oft constitute close to the genes agile during embryo- and neurogenesis [48,49,fifty, 100]. For instance, HACNS1 (HAR2) demonstrates greater enhancer action in limb buds of transgenic mice compared to orthologous sequences from chimpanzee or rhesus macaque [106]. A like design was observed for the same HARs related to genes
NPAS3
and
FZD8
that are active during CNS development in embryogenesis [51, 98].

Many studies were focused on finding differences betwixt humans, chimpanzees and other mammals at the level of cistron transcription [107,108,109]. Chiefly, tissue-specific differences within the same species significantly exceeded in aamplitude all species-specific differences in any tissue. The about transcriptionally divergent organs betwixt humans and chimpanzees were liver and testis, and to a lesser extent – kidney and heart [107, 108]. A transcriptional stardom of liver may be a consequence of different nutritional adaptations in the two species. The major differences in testes are largely unexplained but may be related to predominantly monogamous behavior in humans. Surprisingly, the brain was the least divergent organ betwixt humans and chimpanzees at the transcriptional level. In this regard, it is suggested that tighter regulation of signaling pathways in the brain underlies behavioral and cerebral differences [109, 110]. However, it was institute that during development 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 add-on, many differences were identified in the alternative splicing patterns including half dozen–viii% of cistron exons, thus supporting a concept that the differentially spliced transcripts have pronounced functional consequences for the speciation [112].

Another study of transcriptional activity in the forebrain evidenced the college divergence between human being 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 nigh 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
factor 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 also revealed a number of human-specific features. A specific prepare of genes was found whose expression was delayed in humans compared to the other primates. For example, the maximum expression of synaptic genes in the human prefrontal cortex was shifted from ane twelvemonth of age as for the chimpanzees and macaques, to 5 years. Information technology is congruent with the prolonged brain development menses in humans relative to other primates [116, 117]. The results recently published by Pollen and colleagues allowed to wait deeper into the developing human 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 centrality appeared to be stronger activated in human being, peculiarly in radial glia [118].

Epigenetic regulation is another factor that should be considered when looking at interspecies differences in gene expression. High throughput assay 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 assay 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]. Some other active chromatin biomarker is the distribution of DNase I hypersensitivity sites (DHSs), that often signal gene regulatory elements. It was found that 542 DHSs overlapped with HARs, thus existence and so-chosen man accelerated DHSs, haDHSs [121]. Using chromatin immunoprecipitation assay, a number of haDHSs interacting genes were identified, many of which were continued with early on evolution and neurogenesis [3, 121]. In a later study [122], near 3,five 1000 haDHSs were found, that were enriched about the genes related to neuronal functioning [122].

Conclusions

It is now more often than not accepted that both changes in cistron regulation and alterations of protein coding sequences might accept 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 condign the key for finding genetic elements that contributed to human evolution. It is also 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, like CRISPR-CAS [105], open heady perspectives for finding a “needle in haystack” that was truly important for human functional evolution, or probably many such needles. However, at to the lowest degree for at present using these experimental approaches for millions of species specific potentially impactful features reviewed here is impossible due to high costs and labor intensity. In turn, an culling 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 likewise equally high throughput simulation of functional changes caused by altered protein structures. The differences revealed could be also analyzed in the context of mammalian and primate-specific evolutionary trends, e.g. by using dN/dS approach to measure out evolutionary rates of structural changes in proteins [115] and enrichment by transposable elements in functional genomic loci to judge regulatory development of genes [116]. Apart from the single-cistron level of data analysis, this information could exist aggregated to expect at the whole organismic, developmental or intracellular processes e.g. by using Gene Ontology terms enrichment analysis [117] and quantitative analysis of molecular pathways [118].

And finally, most of the results described here were obtained for the human and chimpanzee reference genomes, which were built each using DNAs of several individuals. Nowadays the greater availability of whole-genome sequencing highlighted the side by side challenge in human and chimpanzee comparing – populational genome diversity. For example, the recent report [123] of 910 native African genomes was focused on the fraction of sequences absent from the reference Hg38 genome assembly. Every bit many as 125,715 insertions missing in the Hg38 was identified with the boilerplate number of 859 insertions per individual, making up a full of 296,5 Mb. These findings clearly propose that the current version of the homo genome assembly can lack nearly 10% of the genome information. 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 Deoxyribonucleic acid and 167 predicted novel genes missing in the reference genome assembly was discovered [124].

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

So far in that location were not so many studies published on the topic of non-reference human being and chimpanzee genome comparison. However, some estimates tin be made. In the contempo study of 1000 genomes from the Swedish population [126] there were identified totally 61,044 clusters totally making ~ 46 Mb of human DNA that were absent-minded from the reference Hg38 human being genome associates. These clusters were called by the authors “new sequences” (NSs). Equally expected, NSs were enriched in unproblematic repeats and satellites and varied greatly amid the individuals. The near part of NSs (32,794) aligned confidently to the non-reference sequences from the same written report of 910 African genomes [123]. Finally, as many as 18,773 NSs were present also in the chimpanzee PT4 genome assembly. In terms of protein coding sequences, 143 orthologous chimpanzee genes contained a total of 2807 NSs, where 4 genes were strongly enriched: EPPK1, OR8U1, NINL, and METTL21C. Positioning of NS insertions in the human genome revealed that 2195 of them located inside 2384 genes, where 85 NS insertion events were found within the exons of 82 genes [126].

Another research consortium studied non-repetitive not-reference sequences (NRNR) in the genomes of xv,219 Icelanders [127]. A total of 326,596 bp of NRNR Deoxyribonucleic acid was found, where ~ 84% was formed by just 244 insertions longer than 200 bp. Notably, comparison with the chimpanzee genome revealed that over 95% of the NRNRs longer than 200 bp were nowadays also in the chimpanzee genome assembly, thus indicating that they were ancestral [127]. Thus, the lack of information on genome populational diverseness could impact the total extent of homo and chimpanzee interspecies divergence past 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 idea of the need, firstly, to create, and secondly, to compare human and chimpanzee pan-genomes.

Availability of data and materials

Not applicable.

Abbreviations

Mya:

Million years ago

Mb:

Megabase (million base of operations pairs)

kb:

Kilobase (thousand base pairs)

HAR:

Homo accelerated region

HERV:

Human endogenous retrovirus

LINE:

Long interspersed nuclear element

PAR:

Pseudoautosomal region

TE:

Transposable element

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Acknowledgements

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

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This article has been published as office of BMC Genomics Volume 21 Supplement vii, 2020: Selected Topics in “Systems Biology and Bioinformatics” – 2019: genomics. The full contents of the supplement are available online at https://bmcgenomics.biomedcentral.com/manufactures/supplements/book-21-supplement-vii.

Funding

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

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

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Correspondence to Anton A. Buzdin.

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Suntsova, One thousand.V., Buzdin, A.A. Differences between human and chimpanzee genomes and their implications in gene expression, protein functions and biochemical properties of the two species.
BMC Genomics
21
(Suppl seven), 535 (2020). https://doi.org/10.1186/s12864-020-06962-8

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Keywords

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

Which Organisms Dna Will Differ From the Chimpanzee the Most

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