Dyads of GGC and GCC form hotspot colonies that coincide with the evolution of human and other great apes.

doi:10.21203/rs.3.rs-3219593/v1

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Dyads of GGC and GCC form hotspot colonies that coincide with the evolution of human and other great apes.

https://doi.org/10.21203/rs.3.rs-3219593/v1

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published 21 Feb, 2024

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Background: GGC and GCC short tandem repeats (STRs) are of various evolutionary, biological, and pathological implications. However, the fundamental two-repeats (dyads) of these STRs are widely overlooked.

Results: On a genome-wide scale, we mapped (GGC)2 and (GCC)2 dyads in human, and discovered monumental colonies (distance between each repeat <500 bp) of extraordinary density, and in some instances periodicity. The largest (GCC)2 and (GGC)2 colonies were intergenic, homogeneous, and human-specific, consisting of 219 (GCC)2 on chromosome 2 (probability<1.545E-219) and 70 (GGC)2 on chromosome 9 (probability=1.809E-148). We also found directional incremented trend in density and complexity of numerous colonies in human versus other species, such as a colony of 99 (GCC)2 on chromosome 20, that specifically expanded in great apes, and directionally incremented to maximum complexity in human (probability 1.545E-220). Numerous other colonies of evolutionary relevance in human were detected in other largely overlooked regions of the genome, such as chromosome Y and pseudogenes. Several of the genes containing or nearest to those colonies were divergently expressed in human.

Conclusion: In conclusion, (GCC)2 and (GGC)2 form unprecedented genomic colonies that coincide with the evolution of human and other great apes. The extent of the genomic rearrangements leading to those colonies support overlooked recombination hotspots shared across great apes. The identified colonies deserve to be studied in mechanistic, evolutionary, and functional platforms.

human

great ape

(GGC)2

(GCC)2

colony

recombination hotspot

evolution

Short tandem repeats (STRs), also known as microsatellites or simple sequence repeats, are a significant source of evolution and disease ^1–13. Across different categories of STRs, the primary importance of GGC and GCC-repeats stems from a link between those STRs and natural selection for a number of reasons: Firstly, GGC and GCC STRs are predominantly enriched in the genic regions, and especially around transcription start sites (TSSs) ^14,15. Secondly, because of the CpG dinucleotides inherent to those repeats, GGC and GCC STRs are often disrupted by single nucleotide substitutions as a result of C to T transitions ^1,2,16−18. Thirdly, the intact blocks of those STRs are frequently order-specific, such as primate specificity of GGC and GCC STRs in the PRKACB, RASGEF1C, SBF1, SMAD9, and DISP2 genes (Ensembl Genome Brower 108). Fourthly, expanded GGC and GCC-repeats are associated with neurodevelopmental, neurodegenerative, and movement disorders ^19,20.

Cataloging of GGC-repeats of ≥ 4-repeats in human has led to the identification of numerous loci ¹⁴, and suggest that these STRs are specifically associated with human cognition ²¹. There is also support for unambiguous genotypes at certain GGC and GCC STRs in late-onset neurocognitive disorders, such as Alzheimer’s disease and cerebrovascular dementia ^{1–3, 16,18}. However, the fundamental two-repeats of those STRs, i.e., (GGC)2 and (GCC)2, have been largely unexplored. Here we mapped (GGC)2 and (GCC)2 across the human genome, and discovered monumental genomic colonies of those repeats, which were specific to the human species, or were shared across great apes, and showed significant directional incremented complexity and density in human.

(GGC)2 and (GCC)2 dyads formed colonies across the human genome.

In total, 127,770 (GGC)2 and 124,023 (GCC)2 were detected across the human genome (Fig. 1) (https://figshare.com/articles/dataset/_GGC_2_and_GCC_2/22178102), of which 26,199 formed colonies (C) i.e., dyads were less than 500 bp apart from each other (Fig. 2).

In a number of chromosomes, the distribution of the dyads was not proportional to the length of the chromosome (p < 0.000). The occurrence of various size (GGC)2 and (GCC)2 colonies yielded exceedingly significant occurrence of those colonies in statistical terms (Table 1).

Table 1

Poisson probability of various colony sizes.
Colony Size	Probability	Colony Size	Probability
2	0.020541568	26	3.59193E-44
3	0.001554709	27	3.02065E-46
4	8.82523E-05	28	2.44951E-48
5	4.00768E-06	29	1.91787E-50
6	1.51663E-07	30	1.45156E-52
7	4.91946E-09	31	1.06319E-54
8	1.39625E-10	32	7.5439E-57
9	3.52256E-12	33	5.19062E-59
10	7.99825E-14	34	3.46639E-61
11	1.65097E-15	35	2.24877E-63
12	3.12388E-17	36	1.41834E-65
13	5.45617E-19	37	8.70392E-68
14	8.84906E-21	38	5.20078E-70
15	1.3395E-22	39	3.02789E-72
16	1.9009E-24	40	1.71877E-74
17	2.53891E-26	41	9.51854E-77
18	3.20266E-28	42	5.14586E-79
19	3.82732E-30	43	2.71723E-81
20	4.34512E-32	46	3.49232E-88
21	4.69807E-34	51	7.4769E-100
22	4.84879E-36	53	1.3987E-104
23	4.78677E-38	71	1.809E-148
24	4.52864E-40	99	1.545E-220
25	4.11305E-42	219	0

The top largest (GCC)2 and (GGC)2 colonies in human

(GCC)2 colonies

The largest (GCC)2 colony was located on chromosome 2, intergenic, and consisted of a homogeneous colony of 219 (GCC)2 (Fig. 3). This colony was human-specific (Table 2).

The second largest colony was of 99 (GCC)2, located 5 kb downstream of cadherin 4 (CDH4). This homogeneous colony was specific to great apes, and we found a directional incremented complexity and density of this colony in human versus other great apes (Fig. 4).

Table 2

Several of the top largest (GCC)2 and (GGC)2 colonies across human genome.
Colony Formula	Transcript ID	Location	Chr. No.	Biotype
[(GCC)2]219	ENST00000350033.8	Intergenic (14 kb downstream of COPS7B)	2
[(GCC)2]99	ENST00000611855.4	Intergenic (5 kb downstream of CDH4)	20
[(GGC)2]70 (GCC)2	ENST00000358625.4	Intergenic (16kb upstream of WDR5)	9
[(GCC)2]51	ENST00000248139.8	RAB40C (Intron 1)	16	Protein coding
[(GGC)2]41	ENST00000334690.11	Intergenic (21 kb downstream of TRAPPC11)	4
[(GGC)2]38 (GCC)2	ENST00000647814.1	ABCC2 (Intron 25)	10	Protein coding
[(GGC)2]38	ENST00000599198.5	Intergenic (14 kb downstream of CYP2B7P)	19
[(GCC)2]36	ENST00000331035.10	IL3RA (Intron 9 pseudoautosomal region)	y	Protein coding
[(GGC)2]35	ENST00000611820.5	KDM6A (Intron 8)	x	Protein coding
[(GGC)2]33	ENST00000264389.7	Intergenic (109 kb downstream of COPS4)	4
[(GCC)2]32	ENST00000262519.14	Intergenic (118 kb downstream of SETD1A)	16
[(GCC)2]30	ENST00000431648.8	ANKRD20A5P (Intron 15)	18	Transcribed unprocessed pseudogene
[(GCC)2]20 (GGC)2	ENST00000268717.10	Intergenic (160 kb upstream of COPS3)	17
[(GGC)2]11 [(GCC)2]5 [(GCC)3]2 (GGC)4	ENST00000262419.10	KANSL1 (promoter/5′ UTR)	17	Protein coding
[(GGC)2]16 (GGC)3	ENST00000661812.1	TTTY10 (Intron 1)	y	lncRNA
[(GCC)2]8 [(GGC)2]8 (GCC)3	ENST00000255681.7	Intergenic (229 kb downstream of MACROD1)	11
[(GCC)2]11	ENST00000381172.3	XGY1 (Intron 6)	y	Unprocessed pseudogene
[(GCC)2]6 [(GGC)2]4 (GGC)4	ENST00000296490.8	Intergenic (197kb downstream of WDR82)	3

Another instance of directional trend in human versus other species included the RAB40C colony, which was specific to great apes and reached maximum complexity in human (Fig. 5) .

(GGC)2 colonies

The largest (GGC)2 colony was 16 kb upstream of WDR5 gene, and human-specific. This colony was also predominantly homogenous (Fig. 6).

Directional trends were also observed for (GGC)2 colonies in human versus other species. For example, the [(GGC)2]38 colony (Table 2) was specific to great apes, and at its maximum complexity and density in human (Fig. 7).

Chromosome Y harbors numerous colonies of (GGC)2 and (GCC)2.

Human chromosome Y is devoid of colonies of GGC ≥ 4-repeats ¹⁴. However, numerous colonies of (GGC)2 and (GCC)2 were detected on this chromosome, the largest of which at 36 (GCC)2 was homogeneous, human-specific, and located in IL3RA (Fig. 8).

In a number of instances, not only the colonies were human-specific, but also the genes containing those colonies were also human-specific, e.g., in the long non-coding RNA (lncRNA) gene, TTTY10 (Table 2).

Interestingly, we also detected colonies in pseudogenes, such as in XGY1. The colony in this gene was specific to great apes, and reached maximum size in human.

While the literature on the importance of STRs in biological, evolutionary, and pathological terms is growing, the most basic repeats of these elements are largely overlooked. Here we identified unprecedented genomic colonies, resulting from colonization of the dyads of GCC and GGC repeats, i.e., (GGC)2 and (GCC)2. Several of these colonies were human-specific or revealed directional incremented complexity in human versus other species. Based on the above observations and the exceedingly significant occurrence of the identified colonies in statistical terms, we propose that they link to the evolution of the human species. The identified colonies may serve as computer codes for various evolutionary and biological instructions.

The genomic rearrangements resulting in those colonies were also phenomenal with respect to the frequency of those events in the genomic lengths that they occurred. The identified colonies do not match the description of repetitive sequences ²². They do not match segmental duplications either, with respect to the density of the events. Of note, the shortest reported human segmental duplications, copy number variations, and other genomic rearrangements are estimated to involve lengths of ≥ 10 kb of genomic DNA in human ^23–26.

The likely explanation for the occurrence of the identified colonies is recombination, involving the dyads and the flanking sequences to each dyad. In other words, the identified colonies are recombination hotspots. Following comparison of fine-scale recombination rates in human and chimpanzee, Winckler and co-workers reported that local patterns of recombination rate have evolved rapidly, in a manner disproportionate to the change in DNA sequence, and recombination hotspots are rarely (if at all) found at the same locus between human and chimpanzee ²⁷. However, if we assume that the colonies, are at least partially, formed by recombination, then common recombination hotspots at the same locus between the two species are not as rare as previously reported. For example, C99, C51, and C38 appear to be recombination hotspots in great apes, although at higher order of complexity of events in human. These are prime instances in the literature, in which directional incremented density and complexity of repeats at a specific locus in the genome coincide with human evolution. Another interesting instance includes a CT-repeat complex in the PAXBP1 core promoter and 5' untranslated region, which is maximally complex in human versus other species (OMIM: 617621) ²⁸.

Based on our observations, the dyads and flanking sequences to each dyad are involved in the genomic rearrangements. Considering the fact that the common elements across those colonies are the dyads, and not the flanking sequences to each dyad, it is likely that the main reason for the rearrangement hotspots in those colonies are the dyads and not their flanking sequences.

Several of the largest colonies were intergenic or deeply located inside very large introns. For example, C219 and C71 were the largest (GCC)2 and (GGC)2 colonies, respectively, and intergenic. The nearest genes to C219 and C71 were COPS7B and WDR5, respectively, which astonishingly directly interact at the protein level (https://string-db.org/). It has been shown that intergenic distance, and hence genome architecture, is highly non-random. Rather, it is shaped by regulatory information contained in noncoding DNA ²⁹. It is, therefore, not unexpected that expansion of the non-coding genome and its regulatory potential underlies vertebrate neuronal diversity ³⁰. This potential is particularly in line with our observations that the largest colonies are mainly human-specific or are most complex in human versus other species, and several of the genes containing those colonies reveal divergent brain expression in human (https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/) ³¹.

A subset of the (GCC)2 and (GGC)2 colonies were deeply inside very large introns. For a subset of genes, the most important sequences that are of regulatory importance are situated not in the promoters, but rather are located within introns ^32–34.

Whereas human chromosome Y is virtually devoid of GGC and GCC colonies of ≥ 4-repeats, numerous colonies of (GGC)2 and (GCC)2 were detected along this chromosome (https://figshare.com/articles/dataset/_GGC_2_and_GCC_2/22178102), the largest of which at 36 (GCC)2 was located in IL3RA, at the pseudoautosomal regions of chromosomes Y and X. Multi-tissue expression of this gene was strictly human-specific, and non-existent in multiple primate species ³².

A number of the identified colonies were close to lncRNAs. While the targets of many of those lncRNAs are not completely known, lnRNAs are stimulating large interest due to their versatile roles in fine-tuning numerous signaling pathways ³⁵.

Another category of colonies was located in pseudogenes. A number of the identified colonies inside pseudogenes were specific to great apes, and showed directional trend in human. Pseudogenes are abundant in the human genome and had long been thought of purely as nonfunctional gene fossils. Recent observations point to a role for pseudogenes in regulating genes transcriptionally and post-transcriptionally in human cells. Pseudogenes are pervasively transcribed on both strands and are common drivers of gene regulation, which have consequences in health and diseases ^36–38.

The genomic colonies formed by (GGC)2 and (GCC)2 dyads only fractionally overlap with G quadruplex (G4) structures ^4,15,39. G4 structures are DNA tetraplexes that typically form in guanine-rich regions of genomes. Four guanine bases associate with each other through Hoogsteen hydrogen bonds to form a guanine tetrad plane (G-quartet), and then two or more G-quartet planes stack on top of each other to form a G4 structure ⁴⁰. Organisms may have evolutionarily developed G4 into a novel and elaborate transcriptional regulatory mechanism benefiting multiple physiological activities of higher organisms ^41,42.

The supplementary data (https://figshare.com/articles/dataset/_GGC_2_and_GCC_2/22178102) will enable studying a vast number of additional colonies, and further the knowledge of the link between those colonies and the evolution of human and other great apes.

In conclusion, we report a novel genomic phenomenon, in which dyads of (GGC)2 and (GCC)2 form monumental colonies of extreme statistical significance across the human genome. Those colonies are unprecedented across vertebrate genomes with respect to the frequency and in some instances, periodicity of the genomic rearrangements leading to those colonies. Several of the identified colonies were human-specific or directionally incremented in complexity in human versus other great apes. These data support overlooked recombination hotspots shared across great apes, which are of evolutionary relevance in these species. It is warranted that the colonies are further studied in mechanistic, evolutionary, and functional platforms.

Genomic (GGC)2 and (GCC)2 extraction

The UCSC genome browser (https://hgdownload.soe.ucsc.edu) was used to download the latest version of the human genome assembly (GRCh38. p14). The whole-genome abundance of (GGC)2 and (GCC)2 was investigated by creating a Java software package (https://github.com/arabfard/Java_STR_Finder). Our approach of including “GGC” and “GCC” could detect annotations of repeats for those motifs on both forward and reverse strands. The list of the (GGC)2 and (GCC)2 was extracted along with the location of those repeats, and to check the validation of the tool, those repeats were manually inspected on a random basis throughout the genome.

Details of extraction algorithm

The written program computed (GGC)2 and (GCC)2. The method began at the first nucleotide of the human genome, and repeatedly performed a sequence of steps while proceeding across the genome, nucleotide by nucleotide. It studied a window frame of 6(2*3) in the first stage, where 2 was the definition of tandem repetitions (two identical continuous sequences), and 3 was the length of the GGC or GCC core. If the initial half of the sequence within the window did not match the second half, the algorithm advanced one nucleotide. If the nucleotides were equal, the program examined them, and the procedure was repeated until all identical continuous nucleotides that were the same as the core were located. The final chosen sequence, M*3, was presented as a new repeat i.e., (GGC)2 or (GCC)2 with a core length of 3 and 2 repetitions. To find new (GGC)2 and (GCC)2 from the end of the preceding repeat, all stages were repeated. To check the validity of the obtained data, the final list of information was evaluated manually by Ensembl genome browser 109 (https://asia.ensembl.org/index.html). The location of the identified (GGC)2 and (GCC)2 was subsequently identified manually, using the Ensembl database 109. For this purpose, all the output of the algorithm was classified in an Excel file. Subsequently, for each repeat, its start and end points were determined on the genome (the address to reach the sequence was made available in another column) (https://figshare.com/articles/dataset/_GGC_2_and_GCC_2/22178102). To find the colonies, the end and start points of the next repeat were subtracted, and if these points were less than 1 kb, they were identified as candidate colonies. Finally, the list of colonies with (GGC)2 and/or (GCC)2 was highlighted and the number of all colonies was determined (https://figshare.com/articles/dataset/_GGC_2_and_GCC_2/22178102).

Definition of “dyad” included (GCC)2 or (GGC)2. Definition of “colony” included strings of (GGC)2 and/or (GCC)2, which were < 500 bp apart on the genomic DNA. Specific colonies are designated with “C” prefixes throughout the text, where necessary. Definition of “human-specific” was in the context of no trace of (GGC)2 or (GCC)2 in other species. Definition of “homogeneous” refers to colonies that predominantly consisted of not more than one dyad type or repeat length.

Screening selected colonies of (GGC)2 and (GCC)2 in human and other species

Several of the top largest colonies in human were screened in several other mammals, using the Ensembl Genome Browser 109 (https://asia.ensembl.org/index.html) BLASTN program.

Statistical analysis

Assuming that the number of (GGC)2 and (GCC)2 in the whole genome is known, then the number of those elements follows from a Poisson process with an average proportional to the length of the interval. Considering the vast range of colony locations detected, we assumed that these repeats are distributed relatively evenly throughout the genome. Therefore, the probability of occurrence of colonies was calculated by Poisson density function with the following parameter:

$${\lambda }=\frac{\left(26 \text{k}\text{b}\right)\left(\text{G}\text{G}\text{C}\right)2 \text{a}\text{n}\text{d} \left(\text{G}\text{C}\text{C}\right)2 )}{3000000000\left(3\text{g}\text{b}\right)}$$

C: Colony

kb: Kilobase

Gb: Gigabase

STR: Short tandem repeat

TSS: Transcription start site

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Funding

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Acknowledgments

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Authors' contributions

M. A and N. T performed the bioinformatics analyses. M.S performed the statistical analysis. H.B, S. A, S. Kh, and H.R. Kh, contributed to data collection, and provided useful discussions. A. D contributed to coordination. M. O conceived, designed, and supervised the project, and wrote the manuscript, with input from all authors.

Competing interests

None to be declared.

Data availability

All raw data are available in at the following link: https://figshare.com/articles/dataset/_GGC_2_and_GCC_2/22178102

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Dyads of GGC and GCC form hotspot colonies that coincide with the evolution of human and other great apes.

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Abstract

Figures

Introduction

Results

The top largest (GCC)2 and (GGC)2 colonies in human

(GCC)2 colonies

(GGC)2 colonies

Discussion

Conclusion

Methods

Genomic (GGC)2 and (GCC)2 extraction

Details of extraction algorithm

Screening selected colonies of (GGC)2 and (GCC)2 in human and other species

Statistical analysis

Abbreviations

Declarations

Data availability

References

Additional Declarations

Status:

Journal Publication

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