Intragene Higher Order Repeats in Neuroblastoma BreakPoint Family Genes Distinguish Humans from Chimpanzees

Abstract

Much attention has been devoted to identifying genomic patterns underlying the evolution of the human brain and its emergent advanced cognitive capabilities, which lie at the heart of differences distinguishing humans from chimpanzees, our closest living relatives. Here, we identify two particular intragene repeat structures of noncoding human DNA, spanning as much as a hundred kilobases, that are present in human genome but are absent from the chimpanzee genome and other nonhuman primates. Using our novel computational method Global Repeat Map, we examine tandem repeat structure in human and chimpanzee chromosome 1. In human chromosome 1, we find three higher order repeats (HORs), two of them novel, not reported previously, whereas in chimpanzee chromosome 1, we find only one HOR, a 2mer alphoid HOR instead of human alphoid 11mer HOR. In human chromosome 1, we identify an HOR based on 39-bp primary repeat unit, with secondary, tertiary, and quartic repeat units, fully embedded in human hornerin gene, related to regenerating and psoriatric skin. Such an HOR is not found in chimpanzee chromosome 1. We find a remarkable human 3mer HOR organization based on the ~1.6-kb primary repeat unit, fully embedded within the neuroblastoma breakpoint family genes, which is related to the function of the human brain. Such HORs are not present in chimpanzees. In general, we find that human-chimpanzee differences are much larger for tandem repeats, in particularly for HORs, than for gene sequences. This may be of great significance in light of recent studies that are beginning to reveal the large-scale regulatory architecture of the human genome, in particular the role of noncoding sequences. We hypothesize about the possible importance of human accelerated HOR patterns as components in the gene expression multilayered regulatory network.

Start/stop Codon-like Trinucleotides (CLTs) and Extended Clusters as New Language of DNA

“…The stop-TAA CLT has a significant extension, but is of very low frequency. On the other hand, the extension of stop-TAG CLT is sizably larger in some non-alpha satellite HORs, which have primary repeat units of 1.6, 2.4, and 0.55 kb 32,33 sizably larger than alpha satellites (~0.171 kb).…”

“…As a case study, this new method is applied to the following DNA sequences: to human and chim-panzee alpha satellite consensus HORs, to monomeric alpha satellite regions and to no-repeat DNA regions (Table 1 and Supplementary table S1). In these studies the consensus sequences are determined by GRM analysis [25][26][27][28][29][30][31][32][33] of the recent Build 37.2 assembly (Figure 1). First the dinucleotide frequencies in consensus alpha satellites are analyzed (Supplementary table S2).…”

“…Identification and analysis of repeats and HORs and their consensus sequences is performed using the GRM (Global Repeat Map) algorithm [31][32][33] applied to the Build 37.2 and Build 2.2 assemblies of human and chimpanzee genomic sequences, respectively. GRM gives a direct mapping of symbolic DNA sequences into frequency domain providing a global map of repeats.…”

The NBPF Gene Family

“…This HOR pattern is not found in chimpanzee and shows some peculiarities, namely that the repeat unit is much longer than most primary repeat units identified so far and that the HOR is fully embedded within a gene. Additionally, the total absence of tandem repeats of NBPF HOR copies in chimpanzees while 47 tandem repeat HOR copies are present in human genomes reflects a human accelerated HOR pattern that distinguishes humans from nonhuman primates ( Figure 4B) (Paar et al, 2011). It has been shown that genes with an important contribution to human evolution, like the NBPF gene family, are located in human segmental duplications, which are frequently organised around core duplicons (Jiang et al, 2007).…”

“…Figure not drawn to scale. B/ The total number of NBPF monomers and the number of NBPF HOR copies (both tandemly organised and dispersed) gradually increases with evolutionary development, but the tandem repetition of the NBPF HOR copies is exclusive to humans (Modified after Paar et al, 2011, Oxford Journals (2011, reproduced by permission).…”