microRNA genes play an important role in the regulation of transcription of protein-coding genes, modulation of embryonic development, differentiation of embryonic stem cells, tissue formation, etc. In this paper, we conducted a comprehensive study of the most rapidly evolved microRNAs of Homo neanderthalensis and Homo denisova, whose genomes were recently sequenced. Based on the analysis of the functions of the target genes of these microRNAs and changes in the secondary structure of their precursors, it is shown that mutations of microRNA genes could play a prominent role in the evolution of H. neanderthalensis and H. denisova, especially in the development and functioning of their brains.

Key words: Homo neanderthalensis, Homo denisova, microRNA, molecular evolution.

In 2010, the nuclear genomes of Homo neanderthalensis (H. P.) [Green et al., 2010], the first representative of archaic humans that became known to science in the mid - 19th century, and Homo denisova (N. D.) [Reich et al., 2010], an ancient human who lived in the middle of the 19th century, were sequenced., according to the dating of the remains from Denisova Cave in Altai, 50-45 thousand years AGO (Derevyanko, 2011). An analysis of the genome of N. d. that settled in Southern Siberia and Central Asia made it possible to assign them to one of the populations of ancient humans that directly participated in the formation of modern human anatomical and genetic appearance [Ibid.]. Extensive materials obtained as a result of field and laboratory studies indicate that N. D. independently created one of the brightest Upper Paleolithic cultures in Eurasia, which developed over several tens of thousands of years convergently to the cultures of European Neanderthals and Cro-Magnons without any noticeable influences associated with the migration of populations from neighboring regions [Ibid.].

Based on a comparative analysis of the genomes of N. P., N. D., and Homo sapiens sapiens (H. s. s.), estimates of the time of their divergence were obtained - approximately 0.8 million years ago [Reich et al., 2010]. However, the question remains about the most likely gene systems that were subjected to driving selection in the extinct archaic people of the Nehalese and Denisovan types. In this regard, we conducted a compu-

The work was supported by RFBR grants N 09 - 04 - 01641-a, 11 - 06 - 12006-ofi-m-2011; Integration projects of the Siberian Branch of the Russian Academy of Sciences N 113, 119; RAS programs N 6.8, B 26.29 and 24.2; State Contract of the Ministry of Education of the Russian Federation N P857.

page 22

Figure 1. Generalized scheme of the canonical pathway of microRNA maturation.

objective comparison of the N. S. S. genome with the N. P. and N. D. genomes based on the structural and functional organization of the microRNAs encoded by them. This formulation of the problem is due to the following [Hu et al., 2011; Somel et al., 2011]: 1) currently, the connection of the most rapid evolutionary transformations during hominid divergence is becoming increasingly obvious, primarily with changes in the genes of transcription factors and microRNAs; 2) it has recently been shown that mutations in microRNA genes during human formation the modern type may be associated with changes in the development and functioning of the central nervous system. According to the results of our analysis, after the divergence of H. N. and H. D. from a common ancestor, their genomes accumulated differences in a number of microRNAs, including those regulating the expression of genes that function in the tissues of the nervous system, uterus, testicles, immune system, etc.

Current data on the process of microRNA maturation

The microRNA precursor molecule (pre-microRNA) encoded by the corresponding gene has a length of ~80 nucleotides and forms a hairpin-like secondary structure formed by a duplex closed by a loop*. As a rule, pre-micro-RNA is first recognized by the DGCR8/Drosha protein complex, then the Drosha enzyme cuts off the removed part of the stem of the RNA hairpin, then the RNA hairpin with a shortened stem is transferred to the cytoplasm using the Exportin-5 protein, where it binds to the Dicer enzyme that cuts off the loop [Treiber T., Treiber N., 1). As a result, a microRNA duplex with a length of ~20 nucleotides is formed, one of the strands of which is usually a mature microRNA (Ibid.; Yang and Lai, 2011). There are also many alternative pathways for microRNA maturation. For example, it can occur directly from the intron sequences* * of protein-coding genes [Yang and Lai, 2011]. The mature miRNA sequence and sometimes its complementary sequence (miRNA*) affect the expression of protein-coding genes due to complementary binding to messenger RNA (mRNA) in the RISC (RNA-Induced Silencing Complex), suppressing translation and / or initiating mRNA degradation [Treiber T, Treiber N., Meister, 2012; Yang, Lai, 2011]. The efficiency of Dicer pre-microRNA cleavage largely depends on the overall structure of the pre-microRNA sequence.

* The secondary structure of RNA is formed by the complementary interaction of various RNA regions (nucleotides A and U, G and C are connected); in it, complementary regions resembling a hairpin stalk (a helix of two RNA strands) alternate with unpaired regions - loops.

** Intron - a region of the protein-coding gene that does not contain information about the sequence of protein amino acids.

page 23
the length of the hairpin stalk and the presence of unpaired pre-microRNA regions in the stalk [Staregaslan et al., 2011]. Pre-microRNA processing by the Drosha protein is particularly affected by unpaired regions at the base of the hairpin stalk and single-stranded ends of the RNA hairpin, as well as the length of the hairpin stalk [Han et al., 2006]. The pre-microRNA hairpin sequence itself also plays a significant role in this process, since it is important for the interaction of pre-microRNAs with processing modifier proteins [Saj and Lai, 2011].

Selection of rapidly evolved Homo neanderthalensis and Homo denisova microRNA genes

Based on the alignment of the genomes of six primates from the ENSEMBL database (rel. 61), experimentally confirmed genes of human microRNA precursors were selected (according to miRBase, rel. 18), which are identical in humans and chimpanzees, to reconstruct the pre-microRNA consensuses in the H. D. and N. P. genomes, these genomes were represented as short nucleotide sequences that are mapped to the human genome (see fig. http://genome.ucsc.edu/Neandertal/ and http://genome.ucsc.edu/Denisova/). The consensus sequence of pre-microRNAs of ancient humans was compiled from short fragments using nucleotides with the highest reading quality [Green et al., 2010]. Pre-microRNAs were not taken into account: a) not fully sequenced; b) in which the reading quality of at least one nucleotide in the position of the ancient genome that carries a replacement in relation to humans, according to the Phred* scale [Ewing and Green, 1998] was below 30 (according to the recommendations of [Green et al., 2010; Reich et al., 2010]); c) containing a deletion / insertion with a sequencing quality of neighboring nucleotides < 30. As a result, two reference samples of pre-microRNAs were formed: from 114 N. P. genes and from 342 N. D. genes. A three-fold difference in the number of detected orthologous genes* * in N. D. and N. P. may reflect improvements in the technology of genome sequencing in N. D. compared to N. P. [Reich et al., 2010].

It is known that spontaneous substitutions of nucleotides C -> T and G -> A were most frequent during the degradation of fossil DNA [Green et al., 2010; Reich et al., 2010]. Taking this into account, and to avoid possible sequencing errors [Champlot et al., 2010], we excluded from both samples such pre-microRNAs that contain only C -> T and G -> A substitutions with respect to hs. s. and have less than two single-nucleotide substitutions of any other nature. Thus, pre-microRNAs of ancient humans were selected with substitutions that were highly likely to have an evolutionary origin. Finally, using the Blast program, we excluded pre-microRNAs that occur in the genomes of H. s. s., H. d., and H. P. in more than one copy. This was done in order to select pre-microRNAs of ancient humans that were highly likely to have unique functions. As a result, we found the H. s. s. pre-microRNA genes, which are characterized by large differences from the orthologous N. P. and N. D. pre-microRNA genes (Table 1).
Analysis of the impact of evolutionary changes in microRNAs on their maturation and functional specificity

Using experimental information from the miRBase database (rel. 18), we reconstructed the secondary structures of ten H. s. s. pre-microRNAs indicated in Table 1. We projected all the nucleotide substitutions identified when comparing the orthologs of pre-microRNAs in the H. s. s. / H. p. pairs and H. s. s. / H. d. (tab. 1), onto the secondary structures of the corresponding H. s. s. pre-microRNAs, Figure 2 shows two examples of such a projection. The analysis showed that the vast majority of substitutions that distinguish H. D. and H. P. pre-microRNAs from H. S. S. pre-microRNAs (18 out of 24) are located in positions that are significant for the processing or functioning of modern human pre-microRNAs (see Table 1). The probability of observing the presence of pre-microRNAs in the human body is very high. for random reasons, such an arrangement of substitutions, assuming their equally probable distribution over the pre-microRNA sequence, is small***.

* Phred-a program that evaluates the quality of reading (sequencing) of nucleotides.

** Orthologous genes - genes of related organisms that have a common origin and similar nucleotide sequence, which diverged during evolution as these organisms differentiated. Often orthologs retain their functions during evolution; a significant difference in the sequences of orthologous genes may indicate a change in their function during natural selection.

*** A randomization test was used. Along the pre-microRNA sequence, 105 random distributions of substitutions were simulated and their proportion corresponding to the observed distribution was calculated, which reflected the level of statistical significance (p). If the substitution was observed in mature microRNA (and/or microRNA*), then we increased the number of simulated substitutions by 1 and considered that the positions of both simulated substitutions, corresponding to the observed one, they must be located in the mature microRNA region. So the important role of this system was taken into account.

page 24
Table 1. Characteristics of experimentally identified Homo sapiens sapiens pre-microRNA genes that have the greatest evolutionarily significant differences from the orthologous genes of N. neanderthalensis and N. denisova

ENSEMBL-identifier of the H. S. S. pre-microRNA gene.

Evolutionarily significant differences*

Name of microRNA H. s. s.

E-value values of the Blast search for pre-microRNAs in the genome

H. P. or N. D.**

H. S. S. (ENSEMBL, rel. 61)

Homo neanderthalensis

ENSG00000221598

A10G; A19G; G13T

hsa-miR-1249

3x10 - 26

4x10 - 21

ENSG00000211520

T3G; T11G; A21G

hsa-miR-216b

5x10 - 35

3x10 - 24

ENSG00000208036

C73G; C76A

hsa-miR-106b

5x10 - 35

7x10 - 30

ENSG00000207758

A79G; A82G

hsa-miR-532

6x10 - 40

2x10 - 36

ENSG00000207728

C44G; A47G; A52G

hsa-miR-449b

3x10 - 43

4x10 - 38

ENSG00000207579

C11G; G13C; C14A

hsa-miR-662

4x10 - 42

2x10 - 35

ENSG00000207719

T9C; A25G

hsa-miR-623

9x10 - 44

3x10 - 40

Homo denisova

ENSG00000221269

C35A; A38C

hsa-miR-1302 - 8

5x10 - 60

8x10 - 57

ENSG00000216105

T68C; T83C

hsa-miR-943

5x10 - 38

9x10 - 35

ENSG00000207551

C37G; A72G

hsa-miR-608

2x10 - 43

3x10 - 40

* Substitution description format: [Homo sapiens nucleotide] [position] [substituted nucleotide]; positions are given for the H. s. s. pre-microRNA gene. Bold text indicates substitutions located in the positions of the mature microRNA or in the positions of the secondary structure of the H. s. s. pre-microRNA that are significant for its processing.

** Sequences of N. P. and N. d. genome fragments were obtained from data [Green et. al., 2010; Reich et. al., 2010] using the samtools program [Li et al., 2009], which was run with the pileup parameter (N. P. data contains 33,044,622 fragments with a total length of 3,114,859,696 nucleotides, H. d. - 21,810,956 fragments with a total length of 4,620,799,428 nucleotides).

2. Projection of nucleotide substitutions on the secondary structures of orthologous pre-microRNAs of Homo sapiens sapiens (according to miRBase data, rel. 18) using examples of pre-microRNAs

H. neanderthalensis (hsa-miR-1249) and H. denisova (hsa-miR-1302-8).

Pre-microRNA processing sites are indicated in bold; mature microRNAs are indicated in italics; positions containing substitutions with respect to the H. s. s. pre - microRNA sequence are underlined; the type of substitution is indicated by an arrow.

page 25
So, for hsa-miR-1249, it does not exceed 0.0014, for hsa-miR-1302 - 8 - 0,0013. These results indicate that nucleotide substitutions in the H. d. and H. p. premicroRNA genes during their divergence from the common ancestral form with H. s. s. were recorded in functionally significant regions of the pre-microRNA. Consequently, they could have a significant effect on both the processes of microRNA maturation and their functional specificity associated with the regulation of target mRNA expression.

Additionally, ten selected H. s. s. pre-microRNAs were searched for known SNP variants* using the dbSNP database (rel. 136) [Sherry et al., 2001]. None of them were found, which may serve as an indirect argument in favor of the functional significance of these pre-microRNAs in H. s. s. and, consequently, the detected substitutions in orthologous pre-microRNAs of H. d. and H. p.

Identification of target genes for rapidly evolved Homo neanderthalensis and Homo denisova microRNAs

To determine the functional role of the rapidly evolved microRNAs of ancient humans that we identified, we defined the terms of functional annotation of their target genes (biological and molecular processes, features of mRNA expression, etc.). Using starBase** data [Yang et al., 2011], target genes were identified in the H. s. s. genome We identified target genes for three and seven H. s. s. microRNA orthologs, including selected rapidly evolved H. d. and H. p. microRNAs, respectively, and two reference samples of H. d. and H. p. microRNAs containing 342 and 114 pre-microRNAs, respectively. Information about the mRNA/microRNA interaction was confirmed based on starBase data by two or more CLIP-seq experiments and at least one prediction program. For reference samples, it was found that 342 orthologs of H. d. microRNAs have 4,702 target genes in the H. s. s. genome, and 114 orthologs of H. p.microRNAs have 3,893. For target genes of rapidly evolved microRNA orthologs H. D. and H. P. We additionally analyzed multiple alignments of mRNA/microRNA binding sites for four primates: humans, chimpanzees, gorillas, and orangutans (ENSEMBL, rel. 65). Of these, we selected only evolutionarily conservative ones, for which no more than one sequence out of three (chimpanzee, gorilla, orangutan) differs from humans. This was done in order to ensure the evolutionary conservativeness of hominid microRNA targets up to the stage of divergence of H. d. and H. p. from H. s. s. As a result of this selection, it was found that in the H. s. s. genome, three microRNAs orthologous to the rapidly evolved H. d. microRNAs have 136 target genes, and seven orthologous to the rapidly evolved H. d. microRNAs have 715 target genes (Table 2).

For functional annotation of target genes of rapidly evolved microRNAs of ancient humans, we chose two independent sources-the GNF data bank and the GeneOntology database, which are presented in the DAVID Internet service (version 6.7) [Huang, Sherman, Lempicki, 2009] and contain the most complete and meaningful integrated information about the functions of human genes***. The GNF database, created by the Genomics Institute of the Novartis Research Foundation, describes the tissues and organs in which human mRNAs are expressed. The GeneOntology database contains information about the functions of genes and their protein products. These information sources allow us to form an alternative and complementary view of the function of the target genes under consideration.

sequences in the formation of the mRNA/microRNA duplex. If substitutions were observed in other regions of the pre-microRNA (3'-and 5' - single-stranded and double-stranded tails, non-functional microRNA*, hairpin loop), then the number of simulated substitutions corresponded to the observed one. In this case, only the position of the simulated substitutions was taken into account in the analysis. The division of pre-microRNA into regions was carried out taking into account the known data on the mechanism of its processing [Han et al., 2006; Yang and Lai, 2011; Staregaslan et al., 2011; Saj and Lai, 2011; Treiber T., Treiber N., Meister, 2012].

* SNP-BapHaHTbi (Single nucleotide polymorphism) - variants of the DNA sequence containing single-nucleotide differences; they can be found in different individuals of the same species or in homologous sections of homologous chromosomes of the same individual. As a rule, the fewer SNP variants a DNA region has in individuals of the same species, the more functionally significant it is.

** StarBase takes into account both the latest experimental CLIP-seq data on the identification of microRNA-mRNA binding sites obtained on the basis of experimental analysis of RNA-protein complexes involving the Ago protein, and theoretical data on the prediction of potential microRNA-mRNA binding sites by five different algorithms.

*** DAVID (version 6.7) contains 13,113 human genes for which information on tissue-specific expression is available (according to the Novartis Research Foundation Genomic Institute, GNF), and 14,209 human genes for which biological processes are characterized (according to GeneOntology, category "biological process"), as well as many other data.

page 26
Table 2. Examples of protein-coding target genes regulated by Homo sapiens sapiens microRNAs, whose rapidly evolved orthologs are found in N. neanderthalensis and N. denisova

RefSeq-identifier of H. S. S. mRNA regulated by microRNA

Name of the gene

Functions of the protein encoded by the corresponding mRNA

Homo denisova

NM_153047

FYN

Required for brain development and function, plays an important role in regulating axon growth

NM_020465

NDRG4

Expressed in the brain, it is necessary for the functioning of astrocytes, neuroglia cells

NM_002158

FOXN2

Regulates transcription of human T-cell leukemia virus, participates in the immune response to retroviral infection

NM_001077397

IRF2BP2

Modulates interferon-regulated gene transcription, participates in the immune response to viral infection

NM_001124

ADM

It has a hypotensive effect, is found in the blood of hypertensive patients in increased amounts

NM_080881

DBN1

It plays an important role in the process of neuronal growth, and a decrease in its number in the brain leads to memory disorders in Alzheimer's disease

NM_017420

SIX4

Transcription factor involved in differentiation and maturation of nerve cells

Homo neanderthalensis

NM_024749

VASH2

Inhibitor of angiogenesis, inhibits the formation of a network of endothelial cells

NM_020440

PTGFRN

Inhibits the binding of prostaglandin F2-a to its receptor (regulates the processes associated with the implantation of a fertilized egg into the uterus)

NMJ81828

NF2

Located mainly in cell contacts, it inhibits cell growth and inhibits the growth of tumors

NM_006472

TXNIP

Inhibits the activity of thyreoredoxin (an antioxidant protein)

NM_012465

TLL2

Protease specifically required for embryogenesis affects the formation of the dorso-abdominal axis and skeleton

NM_003373

VCL

A cytoskeletal protein involved in the attachment of F-actin to the membrane, its defects lead to congestive heart failure and arrhythmia

NM_001145103

SMAD3

Inhibitor of wound healing, mediating the modulation of keratinocyte growth and migration and monocyte chemotaxis; regulates the formation of cartilage and bone, inhibits early healing of bone fractures

To identify the functional characteristics of microRNA target genes that are most often found in their annotations, compared to those of all human genes, we used a randomization test*. For a specific sample of microRNA target genes, the func characteristic was considered and the number of nreal(func) genes whose annotations contained it was calculated. Then, from the complete set of annotated human genes, a set of genes equal in volume to the analyzed sample was formed by random sampling without returning**. The number of n rand(func) genes with the func functional characteristic was calculated for it. The procedure was repeated 5x10 6 times. The number of random samples M in which nrand(func) > nreal(func) was calculated. Next, we calculated the probability of observing the functional characteristic func (p = M/5x10 6) for random reasons in a sample of human genes equal in volume to the analyzed one.

This test was repeated separately for each term of the func annotation and for each of the four target gene samples of H. D. and H. P. microRNAs.,

* The randomization test (resampling) makes it possible to generate the most biologically adequate null hypothesis and, consequently, to more accurately assess the level of statistical significance of the observation [So, Sham, 2011].

** The Perl Math::Random::MT library, which implements the Mersenne Vortex random number generator, was used to generate random numbers [Matsumoto and Nishimura, 1998]. It has a huge period of 2 19937-1, which is more than enough to randomize all human genes.

page 27
It is shown that the frequent occurrence of a certain func characteristic in samples of target genes corresponding to rapidly evolved H. D. and H. P. microRNAs could be related both to the driving selection in the evolution of these ancient humans, and to the incompleteness of the sequenced H. D. and H. P. pre-microRNAs and the fragmentary nature of the detected target genes. Therefore, we selected func characteristics that are significantly common (p < 0.05) in these samples, but not overrepresented (p > 0.3) in the target genes corresponding to the reference samples of H. d. and H. p. microRNAs (Table 3.4). The func characteristics selected in this way can be associated with the most likely gene systems that have been exposed to the following factors:-

Table 3. Examples of tissues and organs where mRNAs of target genes regulated by Homo sapiens sapiens microRNAs are most frequently expressed, whose rapidly evolved orthologs were found in N. neanderthalensis and N. denisova (analysis based on the GNF data bank)

Fabric / Organ

Probability of the observed number of target genes

Rapidly evolved microRNAs

microRNA reference sample

Homo denisova

Prefrontal cortex of the brain

0,0363

0,999

Ganglion ciliare (nerve node responsible for eye movement)

0,0193

0,995

Testicle

0,0122

0,999

Homo neanderthalensis

Medulla oblongata (lower part of the brain stem)

0,034

0,790

Atrioventricular node (a nerve node responsible for heart contractions)

0,038

0,701

See Table 4. Examples of gene functions most frequently encountered in the sample of Homo sapiens sapiens microRNA target genes, whose rapidly evolved orthologs were found in N. neanderthalensis and N. denisova (analysis based on the GeneOntology database)

Abstract GeneOntology of target genes (category "biological process")

GeneOntology ID

Probability of the observed number of target genes

Rapidly evolved microRNAs

microRNA reference sample

Homo denisova

Processes involving many organisms (their interaction)

0051704

0,013

0,841

Regulation of dendrite development

0050773

0,005

0,572

Morphogenesis of the eye

0048593

0,041

0,610

Pregnancy

0007565

0,049

0,998

Homo neanderthalensis

Morphogenesis of the cerebellum

0021587

0,043

0,836

Morphogenesis of the hindbrain

0021575

0,014

0,611

Regulation of vasoconstriction

0019229

0,010

0,771

Response to bacterial lipopolysaccharides

0032496

0,003

0,706

Regulation of axon regeneration

0048679

0,028

0,465

Regulation of cell adhesion by integrin

0033628

0,029

0,464

Regulation of cell adhesion in general (wound regeneration)

0030155

0,003

0,346

page 28

3. Tissues, organs, and functional systems whose function and/or development are regulated by rapidly evolved miRNAs in the N. denisova (A) and N. neanderthalensis (B) lines. A projection on the tissues and organs of H. sapiens sapiens is shown.

It is considered to be a driving selection process for archaic people of the Nehalese and Denisovan types.

Discussion of the results

Let us consider examples of tissues and organs in which the expression of target genes regulated by H. s. s. microRNAs is most frequently observed, whose rapidly evolved orthologs are found in H. P. and H. D. (see Table 3, Figure 3).

Homo denisova. Interestingly, the target genes of rapidly evolved H. d microRNA orthologs are predominantly expressed in the prefrontal cortex, nerve nodes responsible for eye movement, and in the male genitalia-tissues and organs whose functions are related to environmental information perception and reproduction, and can generally be characterized as determining the interaction of ancient humans in the environment. population, which is consistent with the high level of development of the culture of H. D. [Derevyanko, 2011].

Homo neanderthalensis. Apparently, one of the important factors determining the differences between H. P. and H. S. S. was the system of conditioned and unconditioned reflexes determined by the lower part of the brain stem. The evolutionary changes in H. P. compared to H. S. S. may also have been related to the control of heart function.

Let us consider examples of functions (Gene-Ontology terms) that are most often found in the annotation of target genes regulated by H. s. s. microRNAs, whose rapidly evolved orthologs are found in H. P. and H. D. (see Table 4, Figure 3).

Homo denisova. Target genes responsible for pregnancy, eye morphogenesis, and, most importantly, signaling processes that ensure the interaction of organisms in the population may have been most strongly affected by rapid evolutionary changes in H. D. pre-microRNAs. This is consistent with archaeological data on the high level of development of the H. D. culture [Ibid.].
Homo neanderthalensis. The processes occurring in the cerebellum and brain stem may have been most strongly influenced by driving selection due to the accumulation of substitutions in the pre-microRNA of Neanderthals, which is in good agreement with the known archaeological data on the specific structure of these regions in Neanderthals (Drobyshevsky, 2007). Evolutionary changes seem to have affected the damaged tissue regeneration system, namely the regulation of axon regeneration, regulation of vasoconstriction and cell adhesion. This is consistent with the data on the vital activity of H. P., which took place in harsh conditions of both the natural and, possibly, social environment (Mednikova, 2007).

Conclusions

Thus, the present work shows that changes in microRNA genes could make a significant contribution to the evolution of the molecular genetic systems of development and functioning of a number of brain regions of H. P. and H. D., as well as other tissues

* Among the fossils of N. P., most of them are children's and youth skeletons, and often there are dismembered skeletons with traces of severe wounds.

page 29
and organs. According to the results of the analysis, the driving selection associated with the rapid evolution of N. P. and N. D. microRNAs did not affect the same tissues, organs, and functional systems in these two lines of ancient humans. This circumstance may indicate in favor of physiological and anatomical differences between N. P. and N. D. However, the data obtained by us do not allow us to conclude that these differences could contribute to the formation of different subspecies of homo sapiens (N. D., N. P. and N. S. S.). A comprehensive study is necessary using complete information on the genomes of ancient people, paleogenogeography of N. D., N. P. and N. S. S., and archaeological data on their culture.

List of literature

Derevyanko A. P. The Upper Paleolithic in Africa and Eurasia and the formation of a modern anatomical type of man. Novosibirsk, IAET SB RAS Publ., 2011, 560 p. (in Russian)

Drobyshevsky S. V. Evolution of the human brain: analysis of endocranometric signs of hominids, Moscow: LKI Publishing House, 2007, 176 p.

Mednikova M. B. K voprosu ob osobennostei yunosheskoi etape ontogeneza u evropeiskikh neanderthaltsev [On the question of the features of the youthful stage of ontogenesis in European Neanderthals]. - 2007. - N3. - p. 145-153.

Champlot S., Berthelot C., Pruvost M., Bennett E.A., Grange Т., Geigl Е. М. An efficient multistrategy DNA decontamination procedure of PCR reagents for hypersensitive PCR applications // PLoS One. - 2010. - Vol. 5, N 9. - P. e13042.

Ewing В., Green P. Basecalling of automated sequencer traces using phred. II. Error probabilities // Genome Research. -1998. - Vol. 8, N3. - P. 186 - 194.

Green R.E., Krause J., Briggs A.W., Maricic Т., Stenzel U., Kircher M., Patterson N., Li H., Zhai W., Fritz M.H., Hansen N.F., Durand E.Y., Malaspinas A.S., Jensen J.D., Marques-Bonet Т., Alkan C., Prufer K., Meyer M., Burbano H.A., Good J.M., Schultz R., Aximu-Petri A., Butthof A., Hober В., Hoffner В., Siegemund M., Weihmann A., Nusbaum C., Lander E.S., Russ C., Novod N., Affourtit J., Egholm M., Verna C., Rudan P., Brajkovic D., Kucan Z., Gusic I., Doronichev V.B., Golovanova L.V., Lalueza-Fox C., de la Rasilla M., Fortea J., Rosas A., Schmitz R.W., Johnson P.L., Eichler E.E., Falush D., Birney E., Mullikin J.C., Slatkin M., Nielsen R., Kelso J., Lachmann M., Reich D., Paabo S. A draft sequence of the Neandertal genome // Science. - 2010. - Vol. 328, N 5979. - P. 710 - 722.

Han J., Lee Y., Yeom K.H., Nam J.W., Heo I., Rhee J.K., Sohn S.Y., Cho Y., Zhang B.T., Kim V.N. Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex // Cell. - 2006. - Vol. 125, N 5. - P. 887 - 901.

Hu H.Y., Guo S., Xi J., Yan Z., Fu N., Zhang X., Menzel C., Liang H., Yang H., Zhao M., Zeng R., Chen W., Paabo S., Khaitovich P. MicroRNA expression and regulation in human, chimpanzee, and macaque brains // PLoS Genet. -2011. - Vol. 7, N 10. - P. e1002327.

Huang da W., Sherman B.T., Lempicki R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources // Nat. Protoc. - 2009. - Vol. 4, N 1. -P. 44 - 57.

Li H., Handsaker В., Wysoker A., Fennell Т., Ruan J., Homer N., Marth G., Abecasis G., Durbin R. 1000 Genome Project Data Processing Subgroup. The Sequence Alignment/ Map format and SAMtools // Bioinformatics. - 2009. - Vol. 25, N16. - P. 2078 - 2079.

Matsumoto M., Nishimura T. Mersenne twister: A 623-dimensionally equidistributed uniform pseudorandom number generator // ACM Trans, on Modeling and Computer Simulations. - 1998. - Vol. 8, N 1. - P. 3 - 30.

Reich D., Green R.E., Kircher M., Krause J., Patterson N., Durand E.Y., Viola В., Briggs A. W., Stenzel U., Johnson P.L., Maricic Т., Good J.M., Marques-Bonet Т., Alkan C., Fu Q., Mallick S., Li H., Meyer M., Eichler E.E., Stoneking M., Richards M., Talamo S., Shunkov M.V., Derevianko A.P., Hublin J. J., Kelso J., Slatkin M., Paabo S. Genetic history of an archaic hominin group from Denisova Cave in Siberia // Nature. - 2010. - Vol. 468,N7327. - P. 1053 - 1060.

Saj A., Lai E.C. Control of microRNA biogenesis and transcription by cell signaling pathways // Curr. Opin. Genet. Dev. - 2011. - Vol. 21, N4. - P. 504 - 510.

Sherry S.T., Ward M.H., Kholodov M., Baker J., Phan L., Smigielski E.M., Sirotkin K. dbSNP: the NCBI database of genetic variation // Nucleic Acids Res. - 2001. -Vol. 29, N1. - P. 308 - 311.

So K.C., Sham P.C. Multiple testing and power calculations in genetic association studies // Cold Spring Harb. Protoc. - 2011. - Doi: 10.1101/pdb.top95.

Somel M., Liu X., Tang L., Yan Z., Hu H., Guo S., Jiang X., Zhang X., Xu G., Xie G., Li N., Hu Y., Chen W., Paabo S., Khaitovich P. MicroRNA-driven developmental remodeling in the brain distinguishes humans from other primates // PLoS Biol. - 2011. - Vol. 9, N 12. - P. e1001214.

Starega-Roslan J., Krol J., Koscianska E., Kozlowski P., Szlachcic W.J., Sobczak K., Krzyzosiak W.J. Structural basis of microRNA length variety // Nucleic Acids Res. - 2011. -Vol. 39, N1. - P. 257 - 268.

Treiber Т., Treiber N., Meister G. Regulation of microRNA biogenesis and function // Thromb Haemost. - 2012. -Vol. 107, N4. - P. 605 - 610.

Yang J.H., Li J.H., Shao P., Zhou H., Chen Y.Q., Qu L.H. StarBase: a database for exploring microRNA-mRNA interaction maps from Argonaute CLIP-Seq and Degradome-Seq data // Nucleic Acids Res. - 2011. - Vol. 39, Database issue. -P. D202-D209.

Yang J.S., Lai E.C. Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants // Mol. Cell. - 2011. - Vol. 43, N6. - P. 892 - 903.

The article was submitted to the editorial Board on 09.04.12, in the final version-on 12.04.12.

page 30

Permanent link to this publication: