Combinatorial genomic data refute the human chromosome 2 evolutionary fusion and build a model of functional design for interstitial telomeric repeats

Full text

Tomkins, J.P. 2018. Combinatorial genomic data refute the human chromosome 2
evolutionary fusion and build a model of functional design for interstitial telomeric
repeats. In Proceedings of the Eighth International Conference on Creationism, ed.
J.H. Whitmore, pp. 222–228. Pittsburgh, Pennsylvania: Creation Science Fellowship.
COMBINATORIAL GENOMIC DATA REFUTE THE HUMAN CHROMOSOME 2
EVOLUTIONARY FUSION AND BUILD A MODEL OF FUNCTIONAL DESIGN FOR
INTERSTITIAL TELOMERIC REPEATS
Jerey P. Tomkins, Institute for Creation Research, 1806 Royal Ln Dallas, TX 75010 jtomkins@icr.org
ABSTRACT
Evolutionists allege that human chromosome 2 is the product of an ancient fusion event in an ancient hominid
ancestor descended from apes. However, both the alleged site of fusion and the so-called cryptic centromere of
human chromosome 2 are situated inside active genes negating the idea of fusion. Not only are the alleged genomic
fossils of fusion representative of functional intragenic sequence, but they are also both highly degenerate versions
of their supposed evolutionary beginnings, suggesting something other than an evolutionary origin. Given that these
data strongly refute an evolutionary fusion scenario, it behooves creationists to propose an alternative model for the
functional nature of telomere-like sequences scattered around the internal regions of human chromosomes. Towards
this end, new data based on ENOCODE project data sets is provided that further elucidates the regulatory role of
interstitial telomeric repeat sequences genome-wide, particularly with respect to their transcription factor binding
domain properties and transcription start site associations.
KEY WORDS
Chromosome 2 fusion, DDX11L2 gene, ANKRD30BL transmembrane protein, human evolution, human-chimpanzee,
cryptic centromere, interstitial telomere sequence, transcription factor binding, transcription start site
Copyright 2018 Creation Science Fellowship, Inc., Pittsburgh, Pennsylvania, USA www.creationicc.org 222
INTRODUCTION
One of the most often used arguments explaining human evolution
from a chimpanzee-like ancestor is the alleged fusion of ape
chromosomes 2A and 2B in a telomere-to-telomere fashion,
resulting in human chromosome 2 (Yunis and Prakash 1982; Ijdo
et al. 1991). This scenario attempts to account for the discrepancy
in chromosome numbers between humans and great apes. Humans
have a diploid chromosome complement of 46 while chimpanzees,
orangutans, and gorillas have 48. See Figure 1 for a graphical
depiction of the purported fusion event.
The idea of human chromosome 2 fusion is strongly promoted
despite the fact that all known chromosome fusion events in
extant mammals involve satellite DNA and breaks at or near
centromeres (Chaves et al. 2003; Tsipouri et al. 2008; Adega et al.
2009). All genetic data in living mammals up to this point shows
that telomere-satelliteDNA or satelliteDNA-satelliteDNA are the
hallmark signatures of naturally occurring but rare chromosomal
fusion sites in nature, not telomere-telomere fusions (Chaves et al.
2003; Tsipouri et al. 2008; Adega et al. 2009). Some evolutionists
may counter this data with the argument that telomere-telomere
fusions have been observed in the rearranged aberrant genomes of
human cancer cells. However, these genomic aberrations are not
indicative of normal healthy cells, but instead are the products of
the failure of mechanisms maintaining genomic integrity in cells -
leading to disease and death of the organism (Tanaka et al. 2012;
Tanaka et al. 2014; Tu et al. 2015).
An end-to-end fusion of chromosomes as proposed by evolutionists
for humans would give a head-to-head telomeric repeat signature of
at least 10,000 bases in length due to the fact that human telomeres
range in size between 5,000 and 15,000 bases in length (Tomkins
and Bergman 2011a, b). However, the alleged the fusion site is
exceptionally small in size and only 798 bases in length. Another
signicant aspect questioning the validity of a telomere-telomere
fusion signature is the fact that in evolutionary terms, it is very
degenerate given the alleged 3 to 6 million years of divergence
from a human-chimpanzee common ancestor (Fan et al. 2002).
Given that no major rearrangements within the fusion site appear
to have occurred combined with the lack of transposable element
insertions, the fusion site should be about 98.5% similar to pristine
fused repeats based on standard evolutionary predictions. However,
the 798-base fusion signature is only 70% identical to the sequence
of a hypothetical pristine fusion of the same size based on a pair-
wise global alignment in the Geneious software package.
Some evolutionists may also attempt to claim that the fusion site
and the alleged cryptic centromere are positioned where one might
expect them to be if a fusion occurred. However, an analysis of
the assembled chimpanzee DNA sequences for these chromosomes
(panTro4) reveals that not only are they assembled using human
chromosome 2 as a scaold, but they contain many gaps and are
full of large numbers of meaningless N’s (Tomkins 2017). The
letter N is substituted for nucleotides in the areas of DNA that
contain unknown sequence instead of the letters A, T, G, or C and
the number of N’s inserted does not correspond to actual gap sizes,
which are unknown. At the time of this research, the new panTro5
version of the chimpanzee genome was released and is currently in
Figure 1. Depiction of the evolutionary model in which chimpanzee-
like chromosomes 2A and 2B allegedly fused end-to-end to form human
chromosome 2. Chromosomes are drawn to scale according to cytogenetic
images in Yunis and Prakash (1982).

the process of being compared by this author to the current hg38
version of the human genome, end-trimmed trace reads, and the
previous panTro4 version of chimpanzee. While the new assembly
is likely to be greatly improved, it’s veracity as an unbiased
construction needs to be critically evaluated given the history of
human evolutionary bias in previous versions.
While all of this information is important to consider when
examining the plausibility of the fusion model, the most compelling
data refuting it came when the actual fusion signature was analyzed
in 2013 showing that it’s DNA sequence when read in the minus
strand orientation is a functional transcription factor binding
domain inside the rst intron of the DDX11L2 noncoding RNA
helicase, where it acts as a second promoter (Tomkins 2013; Figure
2). This data was further veried in a follow-up research report
which revealed that the alleged fusion site binds to 11 dierent
transcription factors, including RNA polymerase II, the primary
enzyme that transcribes genes (Tomkins 2017). See Figure 3
showing ENCODE-related data from the UCSC genome browser.
Additional data presented in the Tomkins 2017 paper showed that
along with RNA polymerase binding, is the fact that transcription
initiates inside the fusion-like sequence in a classic promoter-like
expression pattern (Figure 4). As expected, these data implicating
promotor activity also intersect with transcriptionally active
histone marks and active chromatin proles that are key features of
gene promoters. As a whole, these combinatorial results strongly
indicate that the alleged fusion sequence is a gene promoter, not a
random accident of chromosomal fusion.
When the products of the DDX11L2 gene were analyzed, it
was found that it encoded RNA transcripts expressed in at least
255 dierent cell and/or tissue types (Tomkins 2013). The gene
produces RNAs of two dierent lengths—short variants (~1,700
bases long) and long variants (~2,200 bases long). The alleged
fusion site functions as a promoter for the shorter variants (Figure
2). Annotation of the transcripts revealed that they contained the
capacity for complex post-transcriptional regulation through a
variety of microRNA binding sites (Tomkins 2013). A number
of the microRNA binding sites were shared with DDX11 protein
coding gene transcripts (Tomkins 2013). Both the DDX11L2 and
DDX11 genes are signicantly co-expressed together in the same
tissues (Tomkins 2013). Shared microRNA binding sites and co-
expression suggest co-regulation between a protein coding gene
and its noncoding RNA pseudogene counterpart, as revealed in the
well-documented example of the PTEN protein coding gene and
it’s PTEN pseudogene counterpart (Johnsson et al. 2013).
If two chromosomes actually fused, then there would be two
centromeres present and one of them would have to be deactivated
to maintain chromosome stability. Centromeres are specic regions
of chromosomes that play an important role in the assembly of the
kinetochore—a complex structure that plays a key function in the
separation of chromosomes during cell division. Evolutionists
propose that an inactivated centromere in a post-fusion scenario
would degrade over time and become a cryptic genomic fossil,
such as that which is alleged to be present on human chromosome
2.
A recent research report was published seemingly bolstering the
evidence of a cryptic centromere in human chromosome 2 (Miga
2016). The author argues this point based on gene synteny (gene
order) between human and chimpanzee. Of course, the problem
with this premise is based on the articially contrived assembly
of chimpanzee chromosomes 2A and B which are bloated with
gaps and assembled based on the human genome. Using an
argument based on synteny is fallacious because the conclusion
is assumed in the premise. Actual synteny between human and
chimpanzee remains to be resolved until an unbiased assembly of
the chimpanzee genome is produced.
A problem with the alleged cryptic centromere is that its human
alphoid repeat DNA sequence does not closely match chimpanzee
centromeres and chromosomes (Archidiacono et al. 1995; Haaf
and Willard 1997; Tomkins 2017). In addition to the problem of
discontinuity with ape sequence, the alleged cryptic centromere
is exceptionally small compared to a real centromere. It is only
41,608 bases in length, but this length includes non-centromeric
Tomkins ◀Interstitial telomeres and chromosome 2 fusion ▶ 2018 ICC
223
Figure 2. Simplied illustration of the alleged fusion site inside the second intron of the DDX11L2 noncoding RNA gene. The graphic also shows
two versions of short and long transcript variants produced along with areas of transcription factor binding. Arrow in rst exon depicts direction of
transcription.

insertions of two retroelements: a LPA3/LINE repeat (5,957 bases)
and a SVA-E element (2,571 bases) (Figure 5). When we subtract
the insertions of these non-centromeric elements, it gives a length
of only 33,080 bases which is a fraction of the size of normal
human centromeres that range in length between 250,000 and
5,000,000 bases (Aldrup-Macdonald and Sullivan 2014).
However, the most serious problem with the concept of a cryptic
centromere is that it is entirely situated inside the protein coding
gene ANKRD30BL [Ankyrin Repeat Domain 30B Like] (Tomkins
2017). Interestingly, the alleged cryptic centromere sequence
extends across intron and exon regions of the gene with part of it
actually coding for amino acids in the resulting protein (Figure 5).
This type of ankyrin repeat protein is associated with the plasma
membrane in eukaryotic cells and is implicated in the interaction
of the cytoskeleton with integral membrane proteins. (Voronin and
Kiseleva 2008). The fact that the alleged cryptic centromere is a
functional region inside a protein coding gene is at odds with the
idea that it is a defunct centromere.
Not only are both the alleged fusion and cryptic centromere sites
questionable in their sequence as to being evolutionarily derived
from their hypothesized precursors, they both represent functional
intragenic sequence. Given this fusion-negating scenario, it
Tomkins ◀Interstitial telomeres and chromosome 2 fusion ▶ 2018 ICC
224
Figure 4. Transcription start site data taken from the FANTOM4, FANTOM5, and ENCODE cap analysis of gene expression (CAGE) databases for
the genomic coordinates of the alleged 798 base fusion site (http://fantom.gsc.riken.jp).
Figure 3. UCSC genome browser (https://genome.ucsc.edu) view of the DDX11L2 gene, its aligned mRNAs, transcription factor binding, and
transcriptionally active histone tracks in relation to the alleged fusion site.

behooves both creationist and secular researchers to investigate
alternative functions for the types of sequence motifs involved,
particularly the alleged fusion site sequence, which is the chief
hallmark of the whole fusion-based evolutionary story.
The characterization of interstitial telomeric-like repeats across
the human genome has been documented in previous reports
using both cytogenetic and bioinformatic techniques (Azzalin et
al. 2001; Nergadze et al. 2007; Lin and Yan 2008; Ruiz-Herrera
et al. 2008; Bolzan 2017). Based on the evolutionary assumption
that the genome is littered with the non-functional remnants of
stochastic evolutionary processes, very little research has been
done to investigate whether interstitial telomeric-like sites, like
those at the alleged fusion site, might actually serve some useful
purpose. Most research has focused on the evolutionary origins
of interstitial telomeric repeats being accidentally and randomly
transferred from chromosome ends along with the possibility
that the sites of these alleged events might be associated with
chromosome instability and disease (Nergadze et al. 2007; Lin and
Yan 2008; Ruiz-Herrera et al. 2008; Bolzan 2017). However, such
research has been inconclusive as to the denitive association of
these types of sites with human disease (Bolzan 2017). In light
of over a decade of inconclusive research related to attempts at
associating interstitial telomeric-like repeats with chromosome
instability and disease, one evolutionary researcher stated, “future
research should focus on the possible biological signicance of
ITSs by investigating the role of these telomeric-like sequences in
the regulation of gene expression” (Bolzan 2017). In light of the
research I have uncovered regarding the role of the alleged fusion
site in the regulation of gene expression, this statement could not
be more timely or profound.
Towards identifying the possibility of interstitial telomeric-like
repeats having purpose and function within a creation model, like
those found at the alleged fusion site, I have completed a research
project which involves identifying both intact and degenerate
telomeric-like repeats within the internal regions of human
chromosomes and then intersecting their genomic coordinates with
a wide variety of ENCODE project data sets. These results will help
build a creationist model of designed and engineered functionality
for interstitial telomeric repeats.
METHODS
The GRCh38 version of the human genome was downloaded at ftp://
ftp.ensembl.org/pub/release-90/fasta/homo_sapiens/dna/. Each of
the chromosome FASTA les were manually end-trimmed in a text
editor to remove telomeric sequence from both chromosome ends.
Perfect interstitial telomeric motifs (TTAGGG and CCCTAA)
of two tandem repeats or more were identied and binned by
chromosome. The common degenerate telomeric forms of the motif
(TTNGGG and CCCNAA) were also identied in tandem repeats
of two or more and binned by chromosome. Data was outputted
in bed le format containing data columns of chromosome ID,
genome coordinates, feature ID (eg. forward telomere, reverse
telomere). Based on genomic coordinates, each identied telomeric
repeat was then intersected with a variety of ENCODE data sets:
gencode v. 22 gene annotation (www.gencodegenes.org), human
lincRNAs (long intergenic noncoding RNA) genes from hg38
(https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38), lincRNAs
from a publication (Hangauer et al. 2013), robust enhancers,
permissive enhancers, ubiquitous enhancers, transcription start
site association enhancers (http://enhancer.binf.ku.dk/presets/),
remap transcription factor binding (http://tagc.univ-mrs.fr/remap/
index.php?page=download), and the trusight inherited disease
loci (https://support.illumina.com/downloads/trusight_inherited_
disease_product_les.html). ENCODE-related BED les based
on previous versions of the human genome (e.g. hg16 and hg18)
were converted to GRCh38 coordinates using the Python program
CrossMap and the appropriate liftover chain conversion les (http://
crossmap.sourceforge.net). Multiple hits to the same ENCODE-
related target bed le were reduced to a single unique output hit to
remove redundancy produced by multiple overlapping telomeric
repeats at a single locus. Python scripts and modules written by
author Tomkins for locating and intersecting interstitial telomeric
sequence can be viewed and/or downloaded at https://github.com/
jt-icr/interstitial_telomeric_repeats.
RESULTS
In this current study, I have queried the entire interstitial space
of the latest version of the human genome (hg38) using a Python
module I wrote for the identication of perfect and degenerate
interstitial telomeric sequence (ITS) sites comprising signatures of
2 repeats or larger. These ITS sites were then intersected using their
genome coordinates with a wide variety of ENCODE-related data
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Figure 5. The 41,608 base cryptic centromere region on chromosome 2 that is positioned within the ANKRD30BL protein coding gene.

sets described as follows.
The full Gencode22 data set used in this study contains all
comprehensive protein coding gene annotations, all comprehensive
lncRNA gene annotations, all polyA features (polyA_signal,
polyA_site, pseudo_polyA), 2-way consensus (retrotransposed)
pseudogenes, and tRNA genes (Derrien et al. 2012). In total, there
are 195,178 genic features and their corresponding coordinates
in the BED le used for intersecting ITS sites (Table 1).
Approximately 2.7% of these genic features contained at least one
ITS site of 2 repeats or more. Over 5,000 ITS sites of two repeats or
larger intersected with these various Gencode22 annotations.
Long intergenic noncoding RNAs (lincRNA) are long noncoding
RNA genes located in the intergenic protein space in the genome.
Like lncRNA genes, lincRNA genes have complex promoters, are
alternatively spliced and transcribed and tend to be highly cell-
type specic in their expression patterns (Ulitsky and Bartel 2013).
They comprise a hotly pursued area of biomedical research due
to their association with human health and cellular development
(Guttman et al. 2011; Ulitsky et al. 2011; Batista and Chang 2013).
Two dierent lincRNA datasets were queried: the UCSC lincRNAs
and a much larger lincRNA dataset from a publication by Hangauer
et al. (2013) which produced 730 and 300 ITS site intersections,
respectively (Table 1).
Enhancer regions in the genome regulate the proper temporal and
cell type specic activation of gene expression in higher eukaryotes
(Dickel et al. 2013; Andersson et al. 2014). Both transcription factor
binding and transcription start sites are hallmarks of enhancers.
Two data sets of enhancers were used in this study. Robust
enhancers are transcribed at a signicant expression level in at
least one primary cell or tissue sample while all known transcribed
enhancers comprise the permissive set, producing numbers of ITS
intersections of 63 and 64, respectively (Table 1).
Transcription start site associations (TSS) are dened as TSSs that
correlate with transcriptional, epigenetic, and transcription factor
binding within 500 kb of the TSS (Andersson et al. 2014). The
goal of such research is to link enhancers to their target genes.
Therefore, a dataset of 64,621 enhancer TSS associations was
queried with the ITS sites in which 5,002 intersections were found
(Table 1). A surprisingly large 8% of these TSS associated regions
intersected with ITS sites.
Transcription factor binding sites are determined via the biochemical
association (binding) of transcription factors to genomic DNA
sequence (Furey 2012; Mundade et al. 2014). A comprehensive
data set of transcription factor binding sites comprising 8.8 million
genomic locations across the human genome (Grion et al. 2015)
was queried with ITS site resulting in 4,489 intersections.
Given that much of the evolutionary speculation surrounding
the implications of ITS sites as being chromosomal aberrations
and playing a role in chromosome breakage and human disease,
I also decided to determine if they could be associated with
known heritable disease. Therefore, a dataset of 8,801 inherited
disease loci developed by the Illumina Corporation and used in
the screening of human disease (Kingsmore 2012; Saunders et
al. 2012) was queried with the ITS sites. The database contains
550 genes, including coding exons, intron-exon boundaries, and
regions harboring pathogenic mutations. Only 5 ITS sites could be
intersected with disease related loci, and they were all degenerate
ITS of 12 bases in length. This does not implicate them as being
a part of the pathology of the locus, but that they were found in
these genomic segments. Interestingly, all ve were located in
exons of protein coding genes. One ITS site was located in the
last exon of the peroxisomal biogenesis factor 10 (PEX10) gene
on chromosome 1. A second was located in the last exon of the
alkylglycerone phosphate synthase (AGPS) gene on chromosome
2. A third was located in the last exon of the desmoplakin (DSP)
gene on chromosome 6. A fourth was located in the last exon of the
tripeptidyl peptidase 1 (TPP1) gene on chromosome 11. The fth
Tomkins ◀Interstitial telomeres and chromosome 2 fusion ▶ 2018 ICC
226
Data set Number data
set entries
Number
perfect
TTAGGG
intersections
Number
Degenerate
TTNGGG
intersections
Number
perfect
CCCTAA
intersections
Number
Degenerate
CCCNAA
intersections
Total ITS
intersections
Gencode22 195,178 258 2,347 249 2,343 5,197
UCSC lincRNAs 21,131 59 299 85 287 730
lincRNAs from Hangauer et
al. (2013) 59,177 6 138 26 130 300
Permissive enhancers 42,888 3 24 3 34 64
Robust enhancers 38,443 3 23 3 34 63
Enhancer transcription start
site associated regions 64,621 204 2,242 258 2,298 5,002
Remap transcription factor
binding 8,822,477 498 1,740 445 1,806 4,489
Tru-sight inherited disease 8,801 0 4 0 1 5
Table 1. Results from the intersection of genome-wide ITS sites two repeats or larger with various ENCODE-related data sets.

was located in a central exon of the huge 25-exon NPC Intracellular
Cholesterol Transporter 1 (NPC1) gene on chromosome 18.
DISCUSSION
Since my original 2013 publication evaluating the genomic
evidence for fusion, the data refuting the chromosome 2 fusion
hypothesis have become even more compelling. The alleged
fusion site is clearly a functional second promoter in the second
intron of the DDX11L2 gene (Tomkins 2013) and the alleged
cryptic centromere site is a key sequence within the protein coding
gene ANKRD30BL covering both intronic and exonic sequence
(Tomkins 2017).
While the sequence of the alleged cryptic centromere is a unique
coding and noncoding part of a large protein coding gene, the
alleged fusion site represents a regulatory sequence that could have
implications for the genomic mystery of ITS sites genome-wide.
This question also has key importance for building the creation
model of purpose and design within the human genome.
The presence and preponderance of interstitial telomeric-like
repeats in the human genome has been well established by a variety
of cytogenetic and bioinformatics techniques (Azzalin et al. 2001;
Nergadze et al. 2007; Lin and Yan 2008; Ruiz-Herrera et al. 2008;
Bolzan 2017). However, little is known of their possible function
and most research has primarily focused on their evolutionary
origins and the possibility that they might be associated with
chromosome instability and disease. Because of these past
research eorts based on the evolutionary presupposition that
the genome is littered with the remnants of purposeless random
evolution, no research has been done to investigate whether ITS
sites might actually serve some functional purpose. Interestingly,
a recent review by Bolzan (2017) from a naturalistic perspective
on ITS sites stated, “future research should focus on the possible
biological signicance of ITSs by investigating the role of these
telomeric-like sequences in the regulation of gene expression”.
Thus, the purpose of this paper was not to prove that ITS sites are
abundant in the human genome, a fact already well established, but
to ascertain what their role might be based on the premise that the
genome was created with function and purpose, although subject to
degeneration over time, a process commonly referred to as genetic
entropy (Sanford 2010).
The most important nding of this current research was the
conrmation of the possible role of ITS sites in gene regulation as
depicted by the high numbers of ITS sites associated with enhancer
transcription start site associated regions and transcription factor
binding. In addition, the same approximate number of intersections
(~5,000) were also associated with Gencode22 annotations. These
data closely follow the results from the comprehensive analysis of
the alleged fusion site I conducted in two previous reports (Tomkins
2013; Tomkins 2017) and strongly suggest that many ITS sites are
involved in gene regulation, especially in regard to their role in
transcription factor binding and transcription start site activity.
Another interesting minor aspect to this study was the investigation
of the ve intersections of ITS sites with inherited disease loci.
Amazingly, all ve ITS were located in the exons of protein coding
genes. Many exons not only code for proteins, but have also been
found to contain gene regulatory sequence in addition to other
imbedded codes that regulate both transcription and translation
(Tomkins 2015).
CONCLUSION
As a key component of the evolution paradigm, scientists have
argued that human chromosome 2 is the product of an ancient
fusion event in a hominid ancestor following the divergence of
humans and apes based on the alleged genomic remnants of a
fusion event. These telomeric-like genomic signatures are thought
to represent the actual fusion site and a cryptic centromere. Recent
genomic data, however, indicates that both the alleged site of
fusion and the cryptic centromere of human chromosome 2 are
positioned inside functional genes. Furthermore, the alleged site of
fusion has been proven to be a functional promoter in the second
intron of a noncoding RNA gene. Given that these data strongly
refute evolutionary claims, this current study was undertaken to
help develop an alternative creationist model of intelligent design
based on the idea that these features are functional characteristics of
unique engineering by the Creator. By comprehensively intersecting
interstitial telomeric repeats genome-wide with ENCODE-related
data sets, this study helps elucidate the regulatory role of interstitial
telomeric repeat sequences, particularly with respect to their
transcription factor binding domain properties and transcription
start site associations.
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THE AUTHOR
Jerey Tomkins is the Director of Life Sciences at the Institute for
Creation Research (ICR). He has a Ph.D. in Genetics from Clemson
University, an M.S. in Plant Science from the University of Idaho,
and a B.S. in Agriculture Ed. from Washington State University. He
was a faculty member in Genetics and Biochemistry at Clemson
University for a decade, publishing 57 secular research papers and
seven book chapters. Dr. Tomkins specializes in genomics and has
published 27 peer-reviewed creation science journal papers, two
books, and a wide variety of semi-technical articles in the ICR
magazine Acts & Facts.
Tomkins ◀Interstitial telomeres and chromosome 2 fusion ▶ 2018 ICC
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