To survive, living things adapt to their surroundings. Occasionally a genetic variation gives one member of a species an edge. That individual passes the beneficial gene on to its descendents. More individuals with the new trait survive and pass it on to their descendents. If many beneficial traits arise over time, a new species—better equipped to meet the challenges of its environment—evolves.
Like gravity and plate tectonics, evolution is a scientific theory. In science, a theory is the most logical explanation for how a natural phenomenon works. It is well tested and supported by abundant evidence. It means quite the opposite from our informal use of the word theory, which implies an untested opinion or guess. As a scientific theory, evolution enables scientists to make predictions and drives investigations that lead to new kinds of observable evidence.
Modern humans are the product of evolutionary processes that go back more than 3. We became human gradually, evolving new physical traits and behaviors on top of those inherited from earlier primates, mammals, vertebrates, and the very oldest living organisms.
Humans and monkeys are both primates. But humans are not descended from monkeys or any other primate living today. We do share a common ape ancestor with chimpanzees. It lived between 8 and 6 million years ago. But humans and chimpanzees evolved differently from that same ancestor. All apes and monkeys share a more distant relative, which lived about 25 million years ago.
Human evolution, like evolution in other species, did not proceed in a straight line. Instead, a diversity of species diverged from common ancestors, like branches on a bush. Our species, Homo sapiens , is the only survivor. But there were many times in the past when several early human species lived at the same time. Evolution is the cornerstone of modern biology.
There is no scientific controversy about whether evolution occurred or whether it explains the history of life on Earth. 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, copies [ 27 ]. It was estimated that humans have approximately twice as many unique TE copies as the chimpanzees [ 8 , 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. Besides insertional polymorphism, Alu also impacted divergence of the two genomes through homologous recombination. Of them, 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 gene. In most vertebrates, it has 36 exons. During the evolution, primate ancestors have lost the 35th exon, and then human ancestors additionally lost the exon 34, also most probably due to recombination between the Alu elements [ 65 ].
The activities of LINE-1 transposable elements were comparable in humans and chimpanzees and resulted in over species-specific integrations [ 28 ]. Interestingly, among the human-specific TEs there were several times more full-length LINE-1 elements with intact open reading frames. Because of MAST2 promoter activity, a chimeric transcript was formed, processed and then reverse transcribed by LINE-1 enzymatic machinery 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 , 30 ]. 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 ]. In turn, the chimpanzee genome has at least 45 species-specific insertions of these elements [ 37 , 38 ].
In addition, two new specific retroviral families — PtERV1 and PtERV2 with totally chimpanzee-specific copies, arose already in the chimpanzee genome [ 8 , 39 ].
The new copies of transposable elements can appear in the genome not only through insertions but also due to duplications of genomic DNA. They amplified and spread due to recombinations of the enclosing progenitor locus. Similarly, several dozen copies of a more ancient provirus K 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 ].
Furthermore, a human-specific endogenous retroviral ERV insert was demonstrated to serve as the tissue-specific enhancer driving hippocampal expression of PRODH gene 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 direction [ 77 ], most probably because of the interference of gene expression with their polyadenylation signals.
However, it has a functional consequence of ERV-driven antisense transcripts overlapping with human genes. For two genes, SLC4A8 for sodium bicarbonate cotransporter and IFT for intraflagellar transport protein , 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 various regulatory elements such as promoters, enhancers, splice-sites and signals of transcriptional termination, which they use for their own expression and spread.
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 ]. It is worth to note that the main complication of the earlier studies was connected with the quality of non-human genomes assembly. 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 [ 8 ]. 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 ].
Comparison of de novo sequenced and independently assembled human and great ape genomes revealed 17, fixed human-specific structural variants fhSVs , including 11, fixed human-specific insertions and 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 regulatory regions near genes. Totally, 46 fhSVs deletions were detected that were expected to disrupt human genes, 41 of them were new.
This value was found by directly comparing human with chimpanzee genomes. It was very close to the previous theoretical estimate of 1. Remarkably, the lowest and the highest human-chimpanzee nucleotide sequence divergences, 1. Protein coding sequences are Generally, in comparison with the model of the latest common ancestor genome, the chimpanzee has more genes that underwent positive selection than human.
This can be explained by the different effective sizes of ancestral populations of the two species [ 87 ]. Second, 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 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 acid substitutions: ThrAsn and AsnSer, 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.
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 like microcephaly. During human speciation, this gene evolved under strong positive selection, which is still going on in the modern human population [ 46 ].
Another gene connected 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 lineage [ 47 ]. Several sexual reproduction genes were also among the most rapidly 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 group of highly diverged genes relates to immunity and cell recognition [ 8 ].
A point mutation in the variable domain of T-cell gamma-receptor TCRGV10 destroyed a donor splice-site, which prevented splicing of the leader intron. Sialic acids, or N-acetyl neuraminic Neu5Ac and N-glycolyl neuraminic acid Neu5Gc , are common components of the carbohydrate cell surface complexes in mammals. It happened because of the loss of a nucleotide exon corresponding to the sixth ancestral exon, caused by insertion of an AluY element followed by recombination [ 20 , 91 ].
Moreover, the mechanism of sialic acids recognition was also affected in the human lineage. Another major affected group of genes is for the olfactory receptors.
Humans and chimpanzees have a comparable number of olfactory receptor genes, around , and of them are orthologous in the two species [ 40 ]. However, in both species about half of them have lost their activities and became pseudogenes. This has led to an assumption that the most recent common ancestor had more active olfactory receptor genes than modern humans and chimpanzees [ 40 ]. Non-coding sequences play crucial roles in gene regulation [ 95 , 96 ]. The genes located near HARs are predominantly related to interaction with DNA, transcriptional regulation and neuronal development [ 48 , 97 ].
It codes for a transcription factor 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 cell culture assay [ 98 ]. 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 human-specific nucleotide alterations affected the secondary structure of this RNA [ 48 , 99 ]. After human 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 brain development and size.
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 earlier stages of development and its effect was more pronounced. Embryos with the human HARE5, therefore, showed a marked acceleration of neural progenitor cell cycle and increased brain size [ 51 ]. 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 [ ]. 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 ]. In another study, all human enhancers predicted by the FANTOM project [ ] 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 human-specific neuronal enhancers were identified, and one of them located on the 8q It was assumed by the authors that recent human-specific enhancers, adaptive, on the one hand, may also impact age-related diseases [ 52 ]. 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 [ , ]. Such changes include when, where and how genes are expressed. A plethora of genes involved in embryogenesis have pleiotropic effects [ ] 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 [ ]. Indeed, the fast-evolving sequences HARs or HACNs are often found close to the genes active during embryo- and neurogenesis [ 48 , 49 , 50 , ]. For example, HACNS1 HAR2 demonstrates greater enhancer activity in limb buds of transgenic mice compared to orthologous sequences from chimpanzee or rhesus macaque [ ].
Many studies were focused on finding differences between humans, chimpanzees and other mammals at the level of gene transcription [ , , ].
Importantly, tissue-specific differences within the same species significantly exceeded in amplitude all species-specific differences in any tissue. The most transcriptionally divergent organs between humans and chimpanzees were liver and testis, and to a lesser extent — kidney and heart [ , ].
A transcriptional distinction 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 between 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 cognitive differences [ , ]. However, it was found that during evolution in the human cerebral cortex there were more transcriptional changes than in the chimpanzee [ ]. Among them, the prevailed difference was increased transcriptional activity [ , ].
Another study of transcriptional activity in the forebrain evidenced the higher difference between human and chimpanzee in the frontal lobe [ ]. The functions of frontal lobe-specific groups of co-expressed genes dealt mostly with neurogenesis and cell adhesion [ ].
Furthermore, the analysis of genes associated with communication showed that about a quarter of them was differentially expressed in the brains of humans and other primates [ ]. Remarkably, the KRAB-ZNF gene family is known for its rapid evolution in primates, especially for its human- or chimpanzee-specific members [ ].
The studies of transcriptional timing in the postnatal brain development also 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.
It is congruent with the prolonged brain development period in humans relative to other primates [ , ]. The results recently published by Pollen and colleagues allowed to look deeper into the developing human and chimpanzee brains by applying the organoid model [ ].
Cerebral organoids were generated from induced pluripotent stem cells iPSCs of humans and chimpanzees. Transcriptome analyses revealed genes deferentially expressed in human versus chimpanzee cerebral organoids and macaque cortex.
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.
The analysis of H3K4me3 trimethylated histone H3 is a marker of transcriptionally active chromatin distribution in the neurons of prefrontal lobe revealed human-specific regions, 33 of them were neuron-specific. Another active chromatin biomarker is the distribution of DNase I hypersensitivity sites DHSs , that often indicate gene regulatory elements.
Using chromatin immunoprecipitation assay, a number of haDHSs interacting genes were identified, many of which were connected with early development and neurogenesis [ 3 , ].
In a later study [ ], about 3,5 thousand haDHSs were found, that were enriched near the genes related to neuronal functioning [ ]. It is now generally accepted that both changes in gene regulation and alterations of protein coding sequences might have played a major role in shaping the phenotypic differences between humans and chimpanzees. In this context, complex bioinformatic approaches combining various OMICS data analyses, are becoming 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. However, at least for now 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 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 also analyzed in the context of mammalian and primate-specific evolutionary trends, e. Apart from the single-gene level of data analysis, this information could be aggregated to look at the whole organismic, developmental or intracellular processes e.
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 next challenge in human and chimpanzee comparison — populational genome diversity.
For example, the recent study [ ] of native African genomes was focused on the fraction of sequences absent from the reference Hg38 genome assembly. Furthermore, it also reflects the high degree of genome heterogeneity of the African population [ ]. Similar studies were performed for other populations as well. 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 [ ].
So far there were not so many studies published on the topic of non-reference human and chimpanzee genome comparison.
However, some estimates can be made. As expected, NSs were enriched in simple repeats and satellites and varied greatly among the individuals. The most part of NSs 32, aligned confidently to the non-reference sequences from the aforementioned study of African genomes [ ]. Finally, as many as 18, NSs were present also in the chimpanzee PT4 genome assembly. Positioning of NS insertions in the human genome revealed that of them located within genes, where 85 NS insertion events were found within the exons of 82 genes [ ].
Another research consortium studied non-repetitive non-reference sequences NRNR in the genomes of 15, Icelanders [ ]. Thus, the lack of information on genome populational diversity could impact the total extent of human and chimpanzee interspecies divergence by misinterpretation of polymorphic sequences.
Still, these findings inevitably lead to the idea of the need, firstly, to create, and secondly, to compare human and chimpanzee pan-genomes. Amster G, Sella G. Life history effects on the molecular clock of autosomes and sex chromosomes. Langergraber KE, et al. Generation times in wild chimpanzees and gorillas suggest earlier divergence times in great ape and human evolution. Lu Y, et al. Evolution and comprehensive analysis of DNaseI hypersensitive sites in regulatory regions of primate brain-related genes.
Front Genet. Bauernfeind AL, et al. High spatial resolution proteomic comparison of the brain in humans and chimpanzees. J Comp Neurol. Prescott SL, et al. Enhancer divergence and cis-regulatory evolution in the human and chimp neural crest. Evolution at two levels in humans and chimpanzees.
Lander ES, et al. Initial sequencing and analysis of the human genome. According to Hunt, if you shave a chimp and take a photo of its body from the neck to the waist, "at first glance you wouldn't really notice that it isn't human.
Once, in an African forest, Hunt watched an pound female chimp snap branches off an aptly-named ironwood tree with her fingertips. It took Hunt two hands and all the strength he could muster to snap an equally thick branch. No one knows where chimps get all that extra power. Alternatively, their muscle fibers may be denser, or there may be physiochemical advantages in the way they contract.
Whatever the case may be, the outcome is clear: "If a chimp throws a big rock and you go over and try to throw it, you just can't," Hunt said. Herb Terrace, the primate cognition scientist who led Project Nim, thinks chimps lack a "theory of mind": They cannot infer the mental state of another individual, whether they are happy, sad, angry, interested in some goal, in love, jealous or otherwise.
Though chimps are very proficient at reading body language, Terrace explained, they cannot contemplate another being's state of mind when there is no body language. Why does he think that? It goes back to Nim the signing chimp's linguistic skills. Like an infant human, Nim spoke in "imperative mode," demanding things he wanted.
But infantile demands aren't really the hallmark of language. As humans grow older, unlike chimps, we develop a much richer form of communication: "declarative mode.
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