Mr_Wilford
Member
Wow, this forum has gone quiet 
Guess I'll try and start up some activity! :mrgreen:
As of late, I’ve heard some rather…unique… arguments by a creationist trying to debunk Chromosome 2 being a fused chromosome. Well, while that conversation is long over, I’ve decided to spend several weeks researching to sufficiently refute these claims, as well as the more common ones found in creationist literature. This has been rather exhausting to do, but it’s increased my knowledge a ton, and for that I am grateful. So, without further ado, let’s dive in.
Telomere fusion would cause cancer, right?
Not necessarily. In fact, that isn't possible if the fusion is to be spread genetically. For it to be passed on, the fusion must take place in a gamete, which only undergoes meiosis. Only cells that can undergo mitosis can become cancerous. So while telomere fusions tend to be common aggravators in some cancers, this tends to be not a result of the fusions themselves, but from sister chromatid fusion and prolonged breakage/fusion/bridge cycles, which are interconnected. According to Wikipedia (1.):
However, if two separate chromosomes fuse (as is the case in chromosome 2), not sister chromatids, then the B/F/B cycle is not going to take place, and cancer is not likely to be a result. What’s more, the formation of sister chromatids does not take place in a gamete (where the fusion must take place to be passed on genetically), so cancer is not even a possibility, although other defects might be.
Wouldn’t a telomere-telomere chromosomal fusion cause genetic disorders?
As with all fusions, this is a possibility. If the fusion has left the genes unstable, genetic reshuffling may occur and cause defects in the offspring. However, this is not always the case. People are occasionally born with telomere fusions, and suffer no I'll effects on their person, other than reduced fertility(2.) (This however does not make the spread of a fusion impossible, as discussed below)
Wouldn't a telomere fusion make the individual with the fusion sterile?
No. It might seem this way at first glance. After all, the individual carrying the fusion would have a different chromosome count. So how could it be possible for the individual to reproduce? Could chromosome’s line up and recombine in gametes? If so, how?
Well, as it turns out, it is indeed possible for a fused chromosome to line up and recombine (3.). However, in doing so, the fused chromosome now plays the role of the two that fused to form it, and so it must line up with the unfused partner chromosomes. This is known as a trivalent. Here’s an image demonstrating how this works:
1. A fused chromosome and a pair of matching partner chromosomes
2. The two individual chromosomes line up with the matching locations on the fused chromosome
3. Recombination happens as normal
4. The cell divides, separating the fused chromosome from its two partners
5. Gametes are produced containing either the fused chromosome or the two individual chromosomes.
There are several problems that may arise as a result of this process (But this is not always the case), and this is why there is sometimes reduced fertility in a fusion carrier (although they’re not sterile, and it’s more likely to affect women than men). One example is:
In most cases this would lead to a spontaneous miscarriage. However, in some cases where Chromosome 21 is involved (around 3-5%), if the fused copy plus an extra copy of chromosome 21 is present, Down’s syndrome. In fact, around 3% of those diagnosed with Down’s syndrome have a parent with what is known as a Robertsonian fusion, which is different from a telomere-telomere fusion. I can’t speak on if telomere-telomere fusions would be more or less likely to have similar percentages, but if so, it does not pose a problem for the spread of chromosome 2, as only a fraction of the gametes would have extra/missing DNA (discussed below).
Another problem, that rose by IDer Casey Luskin, is known as the Dicentric problem. Basically, a fused chromosome, particularly a telomere-telomere fusion, would be the fused chromosome would have two centromeres. Since the centromere is the point at which the spindle attaches to the chromosome at mitosis and meiosis, wouldn’t having two centromeres result in the possibility of the spindle attaching at two points on the chromosome, pulling it apart?
Well, not necessarily. For a long time it was assumed all centromeres were pretty much alike, so it was also assumed that they were equally efficient at assembling kinetochores (the actual attachment point for the spindle). A 1994 paper by Beth Sullivan and her lab at Duke University suggests that not all centromeres are equal: centromeres from non-homologous chromosomes appear to assemble kinetochores at different rates. Thus, in a fusion between two non-homologous chromosomes, like that of human chromosome 2, one centromere begins preparing its kinetochores before the other, and by being able to do so may interfere with the other finishing (or even beginning) in time for the next phase of meiosis or mitosis.(4.)
So, when Chromosome 2 first formed as a fusion of Chimp Chromosomes 12 and 13, one of it’s centromeres would have “out competed” the other, and mitosis or meiosis could carry on as normal.
Could Meiosis happen unimpaired?
Although discussed earlier, I’ll simplify it here.
Imagine an individual with a fusion of chromosomes 6 and 7 (6:7). When they breed with a “normal” set of chromosomes, the unfused 6 will pair up with the 6 part of 6:7. Likewise, the unfused 7 will pair up with the fused 7 of 6:7. Once this is accomplished, Meiosis can go on it’s merry way unimpaired, as long as the fusion and it’s unfused counterparts lined up correctly.
(Note: While researching this I found the full explanation for two of the arguments in the comments of a blog post.(5.) It explains it far better than I could hope too. As such, full credit goes to it’s author, Amphiox. The quote will be broken up into two parts so both will be answered separately)
Could viable offspring be produced?
How would a fusion become fixed throughout the population?
But satellite DNA is missing from the fusion site. Shouldn’t it be there if this is a fusion?
What is missing is a specific type of Satellite DNA known as Stsat. Actual satellite DNA, while not in the fusion point, is right next to it. This will be shown later as it ties into another creationist claim.
However, I'll play along and say no Satellite DNA is present.
Observed telomeric fusion events have shown over half of those seen contain no telomeric repeats at all (of which satellite DNA is a part.)(6.) The fact such large-scale deletions can take place means it is no issue for a fusion event at all satDNA would be missing. But what’s more, comparisons of our genome with Gorillas and Chimps has allowed scientists to map out the events involving these chromosomes (and their fusion in our lineage, including the deletion of the satDNA) over the past ten million years.(5.)
Here’s Carl Zimmer’s simplification of it:
I find it ironic that the lack of StSat at the fusion site, which creationists claim is a problem for the fusion model, when taken along with the chimp and gorilla genomes, actually allows us to model the events leading up to it (although the authors of the paper ask for further evaluation to see if alternative models are possible).
Long story short, a lack of StSat is not a problem for the model of chromosome 2 fusion, despite creationist claims that it is, as shown by the very work they quote as supporting them.
This claim originated as a side comment in one of Jeffery Tompkin’s articles, where he claims the proposed model cannot account for the missing StSAT dna (10.).I found no reason to accept this conclusion, especially since Tompkins has been found to be quite wrong on his other claims about chromosome 2 fusion and other similarities between the Human and Chimpanzee genomes (11., 12.), so this seems only like hand waving on his part. However, I’ve emailed the paper’s main author with Tompkins claims. If I get a response, it shall be posted below.
But Jeffery Tompkins found a functional gene in the alleged fusion site, so it couldn’t possibly be the fusion site!
Here comes the real Irony of Creationist Reaserch. I shall break this claim down into several parts:
What is the gene?
The gene in question is the DDX11L2 sequence. As of now, this gene is not classified as a gene, but rather a pseudogene (a broken gene remnant with no known function). It belongs to a higher order gene family known as the DDX11L, members of which are found in both chimpanzees and gorillas. (7.) These genes are actually pseudogenes, not functional genes, and derived from a functional gene initially named CHLR1, which encodes a DNA/RNA helicase. What's interesting, and will be important in a second, is that every gene in this family is located right next to a telomere. There is one exception: the DDX11L2 sequence, which is parked right next to the fusion site.
Does the gene span the fusion site?
In almost all transcripts stored, this sequence is located over 1300 base pairs to one side of the fusion site, so it does not really span it. However, in some of the databases (around 20%[9.]) there are transcript variants that include the head-to-head telomere sequence motifs as one of the introns in the primary transcript. That is basis on which Tomkins claims that the gene spans the site. The fact that 80% of transcripts don't include the actual fusion point is enough to discredit "debunking", but I'll go ahead and explain why a fraction do include the telomere motifs below.
How did 20% of the transcripts get to cover the fusion point in the first place?
The most reasonable inference to be drawn from the 20% that do cross the fusion point is that they represent new transcription start sites that arose after the fusion event. Let me elaborate:
The entire family of DDX11L pseudogenes is expressed as RNA. For this RNA to be made, it must be through the process of transcription. Getting a new transcription start site, which would lengthen the gene enough to where it would cross the fusion point, is not actually very difficult to achieve via mutation.
See, every 4000 base pairs of DNA at random lie these transcription recognition sequences. These sequences are six base pairs long (CTGCAG). However, every 200 base pairs there lies a set of six base pairs that is only off by one nucleotide from a standard code. So, a single mutation of these bits of DNA could produce a new recognition site.
Next there's promoters. Promoters are bits of DNA that initiate transcription of a particular gene and contain the start site. What's more, eukaryotic promoters are extremely flexible in their requirements and cryptic versions may exist at many sites, which only await a transcription factor to be recruited.
In short, the notion of creating a new transcription start site at random is a very minor issue. This is best summed up by Dermitzakis et al.,
Basically, the introduction of a new transcription recognition sequence would lengthen the gene so that a fraction would include the fusion point. Thus, a well known mechanism can easily account for the 20% that do include the fusion point.
But, how can we know this alternate start site represents a new one? Well, it mostly has to do with sequence orientation. As defined by the Costa 2009 paper which first named the DDX11L family, all members have a unique genetic sequence that's fairly well conserved among the gene family. If the telomeric repeats lay within these defined sequences, then that would be an issue for the fusion site as it's not likely a fusion event would create the appearance of an interrupted sequence.
This diagram shows well the transcript variants of the DDX11L2 and where the fusion site is located:
Geneticist David Levin went and looked for any signs of actual DDX-like sequences on both sides of the the fusion point. As he says
Since all of the actual DDX-related sequences lie on one side of the fusion point, that tells us that the gene was there prior to the fusion event.
Now, the exon on the far side of the fusion point is not a DDX-related sequence. This exon lies in a piece of satellite DNA which has a different sequence from what is found in DDX11L pseudogenes. The alien sequence of this exon combined with the fact that all actual DDX sequences reside on one side of the fusion site indicate that this is a new transcription start site which arose after the fusion event took place.
Now for the real kicker:
The exon on the far side of the fusion point used by 20% of transcripts lies within a piece of SatteliteDNA (what he claims is missing) known as Repeat TAR1, Family Telo. I showed that above this alone indicated it's a new, non-DDX start site, but the implications are far more damning.
See the diagram here.
If you run a BLAT search for this satellite sequence, you will find that it is a pretelomeric sequence (TAR stands for Telomere Associated Repeat) with nearly identical sequences found on the ends of chromosomes 1, 2, 4, 8, 10, 13, 19 (both ends), 21 and 22. In fact, two copies of this TAR satellite DNA are present in the center of Chromosome two...around the putative fusion point. Not one small, degenerate one, no, two long sequences on both sides of the fusion point with nearly identical sequence found only on the ends of chromosomes. So we already have a telomere specific signature in the fusion point. But before the creationists try to deny its truly telomeric DNA, there's more to prove it is. For one, here's what Yuxin et al., have to say in their paper on the gene content around the fusion point (13.):
If this is not the result of a fusion, it would seem to be a remarkable coincidence that this exon is in fact part of a larger sequence that has near identical sequences found on the ends of chromosomes, two of which are found in the center of chromosome 2 on both sides of the fusion point. Yet Tomkins want's us to believe this is not a fused chromosome? Really?
This entire region is full of telomere and pretelomeric sequences. It literally screams "telomere." His finding a telomere-specific gene, with a new start site in a handful of variants that itself is in telomere-specific satellite DNA, has just strengthened the idea of chromosome fusion to certainty.
Why does Tompkins claim the pseudogene is highly expressed?
Tomkins lays great emphasis on the observation that transcription factor binding has been found throughout this region. But simple binding says nothing about the specificity of binding or its biological importance. One thing to note is that not all binding is functional, so just because a TF is binding somewhere, it doesn't necessarily mean it's doing anything. Transcription factor binding sites are not difficult to make via mutation, and one showing up inside the intron of the longer transcript is not a surprise, nor does it debunk the idea of telomere-telomere fusion. It could easily have come about after the fusion event.
What are the overall implications of Tompkins findings?
The very fact that the gene he found belongs to a family exclusively found by telomeres parked right by the fusion site does nothing but support what has already been concluded: that the site is indeed a remnant of an ancient telomere-telomere fusion.
The fact that the vast majority of transcripts don't span the fusion point and known mechanisms account for those that do unequivocally debunk the notion Tompkins is trying to push with his "discovery." He has no case, and has only bolstered the case for a fusion event.
This is the Irony of Creationist Research. They set out to debunk Chromosome 2 fusion by looking for “functional” genes, and only find one that supports a fusion model more than it harms it.
There are too few telomere repeats in the fusion site for it to be a fusion site
As stated earlier, we already know large scale deletions can and do take place in these events, half the time resulting in no telomeric DNA left at all at the fusion site. On top of that, telomeres must be short in order to fail and for fusion to happen, so the count would be drastically reduced anyways. Finding only a small number of repeats is in no way surprising, yet creationists still have to account for the telomeric DNA present.
There's a 614 kb region lacking synteny with Chromosomes 2A and 2B in chimps. This refutes any notion of a fusion
Wrong. First off, this claim is a gross exaggeration. The area that lacks synteny is only 126 kb in length (14.). I have no idea how Tomkins, the one who claims this, got 614 kb, though I'd assume through rigging his software like he did with his claim that humans and chimps are only 70% similar.
Here's the list of genes we see around the fusion area:
The genes on the left are all found in this order with the correct orientation on the end of chimp chromosome 2A. The genes on the right are all found in this order with the correct orientation on the end chimp chromosome 2B. The dotted lines in the middle represent the section that lacks synteny and the fusion site itself. The section lacking synteny is about 126 kb in length (not 614 kb) so this represents a mere 0.05% of the entire chromosome.
Here is an image of the genes around the fusion site.
Here, AceofSpades was kind enough to color the regions that DO share synteny with Chromosomes 2A and 2B in chimps.
The unshaded region is the area that lacks synteny. Genes in this region include PGM5, FAM138, WASH, DDX11 (the gene that supposedly spans the fusion site), etc. Multiple copies of these exist in both humans and chimps, and they appear to have been duplicated here several times. These genes are very common in the pretelomeric regions in the genome. Their location nearby the telomeric repeats in the center of the chromosome is, once more, strongly indicative of a fusion event.
Now, how did this area come to be? Turns out, it's well understood. As AceofSpades told me:
And there we go.
So basically, there is no 614 kb area lacking synteny as creationists claim. There is a smaller 126kb region, but how it got this way is well understood. Also, the area is filled with telomere-specific genes. This is highly indicative of a fusion event.
No valid evidence exists for a fossil centromere on human chromosome 2. The alphoid sequences in this region are quite variable and do not cluster with known functional human centromeric sequences. In addition, no ortholog for a cryptic centromere homologous to the alphoid sequence at human chromosome 2 exists on chimpanzee chromosomes 2A and 2B.
I once again thank AceofSpades for handling this one for me (15.). I’ll do my best to paraphrase him, and explain just how wrong this claim is.
Let’s begin.
Alphoid sequences are a type of Satellite DNA, which means that they are an array of tandemly repeating non-coding DNA blocks. What distinguishes alphoid sequences from other types of satellite DNA is that each repeating block is exactly 171 bp in length. Alphoid sequences form a functional part of centromeres, forming the central anchor point in chromosomes that spindles attach to during mitosis and meiosis. Because of this, they are almost exclusively found at centromeres.
So the question is, are there alphoid sequences on Chromosome 2 other than its centromere?
There is indeed. A region of around 41 kb in length lies on the long arm of Chromosome 2, and is filled with Alphoid sequences. This is what it looks like
(See the colored regions at bottom of diagram)
As you can see from the diagram, this sequence of alphoid repeats has been interrupted twice; once by an SVA retrotransposon (below) and once by a LIN element (above in red). AceofSpades has shown the alphoid sequences as parallel blue lines to demonstrate how they repeat. Towards the end is a green region. These represent sequences that are the reverse compliment of the blue, which in turn indicates that at some point in the past a bit of DNA from the opposite strand got attached here in the reverse order.
All of the alphoid sequences are fairly similar. Here is a diagram illustrating the alignment of the alphoid repeats, one from each of the regions in the previous diagram.
So yes, alphoid sequences do appear in a location other than Chromosome 2’s main centromere. But do they necessarily imply that this was once a functioning centromere?
Yes, they do. In fact, they align with a functioning centromere on Chimp Chromosome 2B!
AceofSpades once more ran a BLAT search for the sequences found on the long arm of Chromosome 2 (The first set of 66.7 repeats) against the human genome. This image illustrates the locations on human chromosomes where hits were found. The thickness of the blue lines here represents the range in which these are found. As you can see, sequences that match this are found almost exclusively at centromeres.
The one exception is a region on the long arm of chromosome 9. This might suggest that another fusion has happened on chromosome 9 - this fact deserves more investigation.
Likewise, a BLAT search was ran for the same region within the chimpanzee genome. This image illustrates where hits were found in the chimpanzee genome. As you can see, the hits are found almost exclusively at centromeres (and once again, the long arm of Chromosome 9 is the exception). Most importantly, we find hits exactly where we should find them: at the corresponding centromere on Chimp Chromosome 2B!
But can we be sure these sequences represent the same centromere found on Chromosome 2B?
We can.
The same genes spanning the cryptic centromere on the long arm of Chromosome 2 span the centromeric region on Chromosome 2B in chimps. These genes include:
Finding gene synteny confirms we are looking at related centromeres.
All of this evidence flies in the face of the claim there’s no good evidence for a fossil centromere. There is good evidence for a fossil centromere, as demonstrated above. But now for the piece de résistance:
Remember the LINE sequence earlier that interrupts the alphoid sequences? (diagram)
LINEs (or Long Interspersed Nuclear Elements) are a type of transposon. As the name suggests, they are about 6000 bp long. They are transposons in that (like simple tiny viruses) they are copied around from place to place within our genome. They have special genes within their sequence to encode proteins which will target them specifically, generate a copy and carry that copy to a new random location within our genome. LINEs are still active within the human genome today as we still encounter cases of them popping up in novel locations. LINEs cannot target specific sequences within our genome for insertion and so as a consequence, their proliferation is a stochastic process.
While not impossible for two LINE insertions to happen in the same location, the chances are impossibly high. In the few rare cases where transposons have been found in similar locations in the genome, there are still differences that allow us to identify these as separate events. Finding the same LINE in the same location in separate genomes is indicative of a single insertion that was carried on through common descent.
It turns out that exactly the same LINE is found interrupting alphoid sequences of the same family in exactly the same way (both interrupts happen 166 bases into the 171bp repeat) at the functioning centromere on chimpanzee chromosome 2B!
And here it is!
Pretty remarkable stuff! Here is a diagram illustrating the alignment of the pre-alphoid sequences (green), the LINE sequence (blue) and the post-alphoid sequences (green) between human and chimpanzee. The alphoid sequences have been spaced out to make it easier to identify the 171bp blocks. The two regions are 96.5% identical. Lightly colored bands indicate the nucleotides that differ, and the black gaps are indels.
This LINE insertion is not present in gorillas or other apes, so it likely was inserted after the common ancestor of chimps and great apes diverged down a separate path.
I’ll let AceofSpades sum it up (15.):
There you have it. There is a fossil centromere on chromosome 2, one that aligns well with the centromere of chromosome 2b in chimps. I rest my case.
References:
1. https://en.wikipedia.org/wiki/Breakage-fusion-bridge_cycle
2.http://www.biology-online.org/biology-forum/about16334.html?hilit=Flyers (Post 5, by psms)
3. http://sapientfridge.org/chromosome_count/fertility.html
4. http://www.pandasthumb.org/archives/2009/02/the-rise-of-hum.html
5. http://blogs.discovermagazine.com/loom/2012/07/19/the-mystery-of-the-missing-chromosome-with-a-special-guest-appearance-from-facebook-creationists/#.VdJb-WTF93g
6. http://genesdev.cshlp.org/content/21/19/2495.full
7. http://www.biomedcentral.com/1471-2164/10/250
8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371704/
9. http://sandwalk.blogspot.com/2015/06/creationists-discover-that-human-and.html
10. https://answersingenesis.org/genetics/dna-similarities/alleged-human-chromosome-2-fusion-site-encodes-an-active-dna-binding-domain-inside-a-complex-and-hig/
11.https://www.reddit.com/r/NaturalTheology/comments/28v2ib/chromosome_2_fusion_a_response_to_a_question_on/
12. https://eyeonicr.wordpress.com/2014/06/25/tomkins-70/comment-page-1/#comment-25984 (comments)
13. http://genome.cshlp.org/content/12/11/1651.full
14. https://www.reddit.com/r/junkscience/comments/3mtsto/the_chromosome_2_fusion_site_part_1_a_lack_of/
15.https://www.reddit.com/r/junkscience/comments/3n4vim/the_chromosome_2_fusion_site_part_2_the_fossil/
Guess I'll try and start up some activity! :mrgreen:
As of late, I’ve heard some rather…unique… arguments by a creationist trying to debunk Chromosome 2 being a fused chromosome. Well, while that conversation is long over, I’ve decided to spend several weeks researching to sufficiently refute these claims, as well as the more common ones found in creationist literature. This has been rather exhausting to do, but it’s increased my knowledge a ton, and for that I am grateful. So, without further ado, let’s dive in.
Telomere fusion would cause cancer, right?
Not necessarily. In fact, that isn't possible if the fusion is to be spread genetically. For it to be passed on, the fusion must take place in a gamete, which only undergoes meiosis. Only cells that can undergo mitosis can become cancerous. So while telomere fusions tend to be common aggravators in some cancers, this tends to be not a result of the fusions themselves, but from sister chromatid fusion and prolonged breakage/fusion/bridge cycles, which are interconnected. According to Wikipedia (1.):
Wikipedia said:
However, if two separate chromosomes fuse (as is the case in chromosome 2), not sister chromatids, then the B/F/B cycle is not going to take place, and cancer is not likely to be a result. What’s more, the formation of sister chromatids does not take place in a gamete (where the fusion must take place to be passed on genetically), so cancer is not even a possibility, although other defects might be.
Wouldn’t a telomere-telomere chromosomal fusion cause genetic disorders?
As with all fusions, this is a possibility. If the fusion has left the genes unstable, genetic reshuffling may occur and cause defects in the offspring. However, this is not always the case. People are occasionally born with telomere fusions, and suffer no I'll effects on their person, other than reduced fertility(2.) (This however does not make the spread of a fusion impossible, as discussed below)
Wouldn't a telomere fusion make the individual with the fusion sterile?
No. It might seem this way at first glance. After all, the individual carrying the fusion would have a different chromosome count. So how could it be possible for the individual to reproduce? Could chromosome’s line up and recombine in gametes? If so, how?
Well, as it turns out, it is indeed possible for a fused chromosome to line up and recombine (3.). However, in doing so, the fused chromosome now plays the role of the two that fused to form it, and so it must line up with the unfused partner chromosomes. This is known as a trivalent. Here’s an image demonstrating how this works:
1. A fused chromosome and a pair of matching partner chromosomes
2. The two individual chromosomes line up with the matching locations on the fused chromosome
3. Recombination happens as normal
4. The cell divides, separating the fused chromosome from its two partners
5. Gametes are produced containing either the fused chromosome or the two individual chromosomes.
There are several problems that may arise as a result of this process (But this is not always the case), and this is why there is sometimes reduced fertility in a fusion carrier (although they’re not sterile, and it’s more likely to affect women than men). One example is:
In most cases this would lead to a spontaneous miscarriage. However, in some cases where Chromosome 21 is involved (around 3-5%), if the fused copy plus an extra copy of chromosome 21 is present, Down’s syndrome. In fact, around 3% of those diagnosed with Down’s syndrome have a parent with what is known as a Robertsonian fusion, which is different from a telomere-telomere fusion. I can’t speak on if telomere-telomere fusions would be more or less likely to have similar percentages, but if so, it does not pose a problem for the spread of chromosome 2, as only a fraction of the gametes would have extra/missing DNA (discussed below).
Another problem, that rose by IDer Casey Luskin, is known as the Dicentric problem. Basically, a fused chromosome, particularly a telomere-telomere fusion, would be the fused chromosome would have two centromeres. Since the centromere is the point at which the spindle attaches to the chromosome at mitosis and meiosis, wouldn’t having two centromeres result in the possibility of the spindle attaching at two points on the chromosome, pulling it apart?
Well, not necessarily. For a long time it was assumed all centromeres were pretty much alike, so it was also assumed that they were equally efficient at assembling kinetochores (the actual attachment point for the spindle). A 1994 paper by Beth Sullivan and her lab at Duke University suggests that not all centromeres are equal: centromeres from non-homologous chromosomes appear to assemble kinetochores at different rates. Thus, in a fusion between two non-homologous chromosomes, like that of human chromosome 2, one centromere begins preparing its kinetochores before the other, and by being able to do so may interfere with the other finishing (or even beginning) in time for the next phase of meiosis or mitosis.(4.)
So, when Chromosome 2 first formed as a fusion of Chimp Chromosomes 12 and 13, one of it’s centromeres would have “out competed” the other, and mitosis or meiosis could carry on as normal.
Could Meiosis happen unimpaired?
Although discussed earlier, I’ll simplify it here.
Imagine an individual with a fusion of chromosomes 6 and 7 (6:7). When they breed with a “normal” set of chromosomes, the unfused 6 will pair up with the 6 part of 6:7. Likewise, the unfused 7 will pair up with the fused 7 of 6:7. Once this is accomplished, Meiosis can go on it’s merry way unimpaired, as long as the fusion and it’s unfused counterparts lined up correctly.
(Note: While researching this I found the full explanation for two of the arguments in the comments of a blog post.(5.) It explains it far better than I could hope too. As such, full credit goes to it’s author, Amphiox. The quote will be broken up into two parts so both will be answered separately)
Could viable offspring be produced?
Amphiox said:
How would a fusion become fixed throughout the population?
Amphiox said:
But satellite DNA is missing from the fusion site. Shouldn’t it be there if this is a fusion?
What is missing is a specific type of Satellite DNA known as Stsat. Actual satellite DNA, while not in the fusion point, is right next to it. This will be shown later as it ties into another creationist claim.
However, I'll play along and say no Satellite DNA is present.
Observed telomeric fusion events have shown over half of those seen contain no telomeric repeats at all (of which satellite DNA is a part.)(6.) The fact such large-scale deletions can take place means it is no issue for a fusion event at all satDNA would be missing. But what’s more, comparisons of our genome with Gorillas and Chimps has allowed scientists to map out the events involving these chromosomes (and their fusion in our lineage, including the deletion of the satDNA) over the past ten million years.(5.)
Here’s Carl Zimmer’s simplification of it:
Carl Zimmer said:Eichler and his colleagues put together a diagram to illustrate this ten-million-year saga, which I’ve adapted here.
By comparing human chromosome two to the unfused versions in the chimpanzees and gorillas, Eichler and his colleagues reconstructed the chromosomes in the common ancestor of all three species:
The bands correspond to segments of each chromosome. The colors represent the two ancestral chromosomes (I’ll just call them green and red to keep from getting bogged down in confusing numbers). The hash marks represent regions of very unstable DNA. These areas, which are full of repeating sequences, are prone to accidentally getting duplicated, expanding the chromosome. They’re also where chromosomes are likely to trade chunks with other chromosomes. That’s why the red chromosome has a little green at the end. It had picked up part of the green chromosome earlier than the common ancestor of us, chimpanzees, and gorillas.
The green chromosome then changed:
Three key events are illustrated here. First, the top of the green chromosome flipped (another common type of mutation, called an inversion). Then a chunk of yet another chromosome got stuck to the end of the green chromosome, marked here in pink. And then a new piece of DNA got stuck at the end of the green chromosome, known as StSat, and marked here as a yellow dot.
The ancestors of gorillas then diverged from the ancestors of chimpanzees and humans. They underwent some ten million years of independent evolution, during which time a lot happened. For one thing, the cap on the green chromosome got duplicated and pasted onto other chromosomes, including the red one, and even on the other end of the green one itself. In the illustration below, the yellow and pink segments, along with the adjoining green segment, are represented by a brown oval:
Meanwhile, the ancestors of chimpanzees and humans were evolving. The two chromosomes continued to change, as shown here.
A copy of StSat got glued to the end of the red chromosome, and then the pink and green segments at the top of the green chromosome got flipped.
The chromosomes at the right of the figure show you what our two chromosomes looked like before they got fused. When the human and chimpanzee lineages split, each lineage inherited them. And in each lineage, they evolved in a different way.
In the chimpanzee lineage, the chromosomes didn’t fuse. Instead, this happened:
The caps on both the green and red chromosomes were duplicated massively and ended up on lots of other chromosomes.
And finally, here’s what happened to humans after our ancestors split from chimpanzees:
The two chromosomes fused, and the cap was deleted, including StSat. It could no longer spread around our genome, the way it did in chimpanzees and gorillas.
This study is an important advance in our understanding of how human chromosomes evolved–a subject of medical significance, too, since the duplication of the DNA at the end of chromosomes can cause dangerous mutations that can cause genetic disorders. Plus, it is very cool to see how our chromosomes are, in fact, an ancient patchwork.
I find it ironic that the lack of StSat at the fusion site, which creationists claim is a problem for the fusion model, when taken along with the chimp and gorilla genomes, actually allows us to model the events leading up to it (although the authors of the paper ask for further evaluation to see if alternative models are possible).
Long story short, a lack of StSat is not a problem for the model of chromosome 2 fusion, despite creationist claims that it is, as shown by the very work they quote as supporting them.
This claim originated as a side comment in one of Jeffery Tompkin’s articles, where he claims the proposed model cannot account for the missing StSAT dna (10.).I found no reason to accept this conclusion, especially since Tompkins has been found to be quite wrong on his other claims about chromosome 2 fusion and other similarities between the Human and Chimpanzee genomes (11., 12.), so this seems only like hand waving on his part. However, I’ve emailed the paper’s main author with Tompkins claims. If I get a response, it shall be posted below.
But Jeffery Tompkins found a functional gene in the alleged fusion site, so it couldn’t possibly be the fusion site!
Here comes the real Irony of Creationist Reaserch. I shall break this claim down into several parts:
What is the gene?
The gene in question is the DDX11L2 sequence. As of now, this gene is not classified as a gene, but rather a pseudogene (a broken gene remnant with no known function). It belongs to a higher order gene family known as the DDX11L, members of which are found in both chimpanzees and gorillas. (7.) These genes are actually pseudogenes, not functional genes, and derived from a functional gene initially named CHLR1, which encodes a DNA/RNA helicase. What's interesting, and will be important in a second, is that every gene in this family is located right next to a telomere. There is one exception: the DDX11L2 sequence, which is parked right next to the fusion site.
Does the gene span the fusion site?
In almost all transcripts stored, this sequence is located over 1300 base pairs to one side of the fusion site, so it does not really span it. However, in some of the databases (around 20%[9.]) there are transcript variants that include the head-to-head telomere sequence motifs as one of the introns in the primary transcript. That is basis on which Tomkins claims that the gene spans the site. The fact that 80% of transcripts don't include the actual fusion point is enough to discredit "debunking", but I'll go ahead and explain why a fraction do include the telomere motifs below.
How did 20% of the transcripts get to cover the fusion point in the first place?
The most reasonable inference to be drawn from the 20% that do cross the fusion point is that they represent new transcription start sites that arose after the fusion event. Let me elaborate:
The entire family of DDX11L pseudogenes is expressed as RNA. For this RNA to be made, it must be through the process of transcription. Getting a new transcription start site, which would lengthen the gene enough to where it would cross the fusion point, is not actually very difficult to achieve via mutation.
See, every 4000 base pairs of DNA at random lie these transcription recognition sequences. These sequences are six base pairs long (CTGCAG). However, every 200 base pairs there lies a set of six base pairs that is only off by one nucleotide from a standard code. So, a single mutation of these bits of DNA could produce a new recognition site.
Next there's promoters. Promoters are bits of DNA that initiate transcription of a particular gene and contain the start site. What's more, eukaryotic promoters are extremely flexible in their requirements and cryptic versions may exist at many sites, which only await a transcription factor to be recruited.
In short, the notion of creating a new transcription start site at random is a very minor issue. This is best summed up by Dermitzakis et al.,
Dermitzakis et al. said:
Basically, the introduction of a new transcription recognition sequence would lengthen the gene so that a fraction would include the fusion point. Thus, a well known mechanism can easily account for the 20% that do include the fusion point.
But, how can we know this alternate start site represents a new one? Well, it mostly has to do with sequence orientation. As defined by the Costa 2009 paper which first named the DDX11L family, all members have a unique genetic sequence that's fairly well conserved among the gene family. If the telomeric repeats lay within these defined sequences, then that would be an issue for the fusion site as it's not likely a fusion event would create the appearance of an interrupted sequence.
This diagram shows well the transcript variants of the DDX11L2 and where the fusion site is located:
Geneticist David Levin went and looked for any signs of actual DDX-like sequences on both sides of the the fusion point. As he says
David Levin said:
Since all of the actual DDX-related sequences lie on one side of the fusion point, that tells us that the gene was there prior to the fusion event.
Now, the exon on the far side of the fusion point is not a DDX-related sequence. This exon lies in a piece of satellite DNA which has a different sequence from what is found in DDX11L pseudogenes. The alien sequence of this exon combined with the fact that all actual DDX sequences reside on one side of the fusion site indicate that this is a new transcription start site which arose after the fusion event took place.
Now for the real kicker:
The exon on the far side of the fusion point used by 20% of transcripts lies within a piece of SatteliteDNA (what he claims is missing) known as Repeat TAR1, Family Telo. I showed that above this alone indicated it's a new, non-DDX start site, but the implications are far more damning.
See the diagram here.
If you run a BLAT search for this satellite sequence, you will find that it is a pretelomeric sequence (TAR stands for Telomere Associated Repeat) with nearly identical sequences found on the ends of chromosomes 1, 2, 4, 8, 10, 13, 19 (both ends), 21 and 22. In fact, two copies of this TAR satellite DNA are present in the center of Chromosome two...around the putative fusion point. Not one small, degenerate one, no, two long sequences on both sides of the fusion point with nearly identical sequence found only on the ends of chromosomes. So we already have a telomere specific signature in the fusion point. But before the creationists try to deny its truly telomeric DNA, there's more to prove it is. For one, here's what Yuxin et al., have to say in their paper on the gene content around the fusion point (13.):
Yuxin et al said:
If this is not the result of a fusion, it would seem to be a remarkable coincidence that this exon is in fact part of a larger sequence that has near identical sequences found on the ends of chromosomes, two of which are found in the center of chromosome 2 on both sides of the fusion point. Yet Tomkins want's us to believe this is not a fused chromosome? Really?
This entire region is full of telomere and pretelomeric sequences. It literally screams "telomere." His finding a telomere-specific gene, with a new start site in a handful of variants that itself is in telomere-specific satellite DNA, has just strengthened the idea of chromosome fusion to certainty.
Why does Tompkins claim the pseudogene is highly expressed?
Tomkins lays great emphasis on the observation that transcription factor binding has been found throughout this region. But simple binding says nothing about the specificity of binding or its biological importance. One thing to note is that not all binding is functional, so just because a TF is binding somewhere, it doesn't necessarily mean it's doing anything. Transcription factor binding sites are not difficult to make via mutation, and one showing up inside the intron of the longer transcript is not a surprise, nor does it debunk the idea of telomere-telomere fusion. It could easily have come about after the fusion event.
What are the overall implications of Tompkins findings?
The very fact that the gene he found belongs to a family exclusively found by telomeres parked right by the fusion site does nothing but support what has already been concluded: that the site is indeed a remnant of an ancient telomere-telomere fusion.
The fact that the vast majority of transcripts don't span the fusion point and known mechanisms account for those that do unequivocally debunk the notion Tompkins is trying to push with his "discovery." He has no case, and has only bolstered the case for a fusion event.
This is the Irony of Creationist Research. They set out to debunk Chromosome 2 fusion by looking for “functional” genes, and only find one that supports a fusion model more than it harms it.
There are too few telomere repeats in the fusion site for it to be a fusion site
As stated earlier, we already know large scale deletions can and do take place in these events, half the time resulting in no telomeric DNA left at all at the fusion site. On top of that, telomeres must be short in order to fail and for fusion to happen, so the count would be drastically reduced anyways. Finding only a small number of repeats is in no way surprising, yet creationists still have to account for the telomeric DNA present.
There's a 614 kb region lacking synteny with Chromosomes 2A and 2B in chimps. This refutes any notion of a fusion
Wrong. First off, this claim is a gross exaggeration. The area that lacks synteny is only 126 kb in length (14.). I have no idea how Tomkins, the one who claims this, got 614 kb, though I'd assume through rigging his software like he did with his claim that humans and chimps are only 70% similar.
Here's the list of genes we see around the fusion area:
The genes on the left are all found in this order with the correct orientation on the end of chimp chromosome 2A. The genes on the right are all found in this order with the correct orientation on the end chimp chromosome 2B. The dotted lines in the middle represent the section that lacks synteny and the fusion site itself. The section lacking synteny is about 126 kb in length (not 614 kb) so this represents a mere 0.05% of the entire chromosome.
Here is an image of the genes around the fusion site.
Here, AceofSpades was kind enough to color the regions that DO share synteny with Chromosomes 2A and 2B in chimps.
The unshaded region is the area that lacks synteny. Genes in this region include PGM5, FAM138, WASH, DDX11 (the gene that supposedly spans the fusion site), etc. Multiple copies of these exist in both humans and chimps, and they appear to have been duplicated here several times. These genes are very common in the pretelomeric regions in the genome. Their location nearby the telomeric repeats in the center of the chromosome is, once more, strongly indicative of a fusion event.
Now, how did this area come to be? Turns out, it's well understood. As AceofSpades told me:
And there we go.
So basically, there is no 614 kb area lacking synteny as creationists claim. There is a smaller 126kb region, but how it got this way is well understood. Also, the area is filled with telomere-specific genes. This is highly indicative of a fusion event.
No valid evidence exists for a fossil centromere on human chromosome 2. The alphoid sequences in this region are quite variable and do not cluster with known functional human centromeric sequences. In addition, no ortholog for a cryptic centromere homologous to the alphoid sequence at human chromosome 2 exists on chimpanzee chromosomes 2A and 2B.
I once again thank AceofSpades for handling this one for me (15.). I’ll do my best to paraphrase him, and explain just how wrong this claim is.
Let’s begin.
Alphoid sequences are a type of Satellite DNA, which means that they are an array of tandemly repeating non-coding DNA blocks. What distinguishes alphoid sequences from other types of satellite DNA is that each repeating block is exactly 171 bp in length. Alphoid sequences form a functional part of centromeres, forming the central anchor point in chromosomes that spindles attach to during mitosis and meiosis. Because of this, they are almost exclusively found at centromeres.
So the question is, are there alphoid sequences on Chromosome 2 other than its centromere?
There is indeed. A region of around 41 kb in length lies on the long arm of Chromosome 2, and is filled with Alphoid sequences. This is what it looks like
(See the colored regions at bottom of diagram)
As you can see from the diagram, this sequence of alphoid repeats has been interrupted twice; once by an SVA retrotransposon (below) and once by a LIN element (above in red). AceofSpades has shown the alphoid sequences as parallel blue lines to demonstrate how they repeat. Towards the end is a green region. These represent sequences that are the reverse compliment of the blue, which in turn indicates that at some point in the past a bit of DNA from the opposite strand got attached here in the reverse order.
All of the alphoid sequences are fairly similar. Here is a diagram illustrating the alignment of the alphoid repeats, one from each of the regions in the previous diagram.
So yes, alphoid sequences do appear in a location other than Chromosome 2’s main centromere. But do they necessarily imply that this was once a functioning centromere?
Yes, they do. In fact, they align with a functioning centromere on Chimp Chromosome 2B!
AceofSpades once more ran a BLAT search for the sequences found on the long arm of Chromosome 2 (The first set of 66.7 repeats) against the human genome. This image illustrates the locations on human chromosomes where hits were found. The thickness of the blue lines here represents the range in which these are found. As you can see, sequences that match this are found almost exclusively at centromeres.
The one exception is a region on the long arm of chromosome 9. This might suggest that another fusion has happened on chromosome 9 - this fact deserves more investigation.
Likewise, a BLAT search was ran for the same region within the chimpanzee genome. This image illustrates where hits were found in the chimpanzee genome. As you can see, the hits are found almost exclusively at centromeres (and once again, the long arm of Chromosome 9 is the exception). Most importantly, we find hits exactly where we should find them: at the corresponding centromere on Chimp Chromosome 2B!
But can we be sure these sequences represent the same centromere found on Chromosome 2B?
We can.
The same genes spanning the cryptic centromere on the long arm of Chromosome 2 span the centromeric region on Chromosome 2B in chimps. These genes include:
Finding gene synteny confirms we are looking at related centromeres.
All of this evidence flies in the face of the claim there’s no good evidence for a fossil centromere. There is good evidence for a fossil centromere, as demonstrated above. But now for the piece de résistance:
Remember the LINE sequence earlier that interrupts the alphoid sequences? (diagram)
LINEs (or Long Interspersed Nuclear Elements) are a type of transposon. As the name suggests, they are about 6000 bp long. They are transposons in that (like simple tiny viruses) they are copied around from place to place within our genome. They have special genes within their sequence to encode proteins which will target them specifically, generate a copy and carry that copy to a new random location within our genome. LINEs are still active within the human genome today as we still encounter cases of them popping up in novel locations. LINEs cannot target specific sequences within our genome for insertion and so as a consequence, their proliferation is a stochastic process.
While not impossible for two LINE insertions to happen in the same location, the chances are impossibly high. In the few rare cases where transposons have been found in similar locations in the genome, there are still differences that allow us to identify these as separate events. Finding the same LINE in the same location in separate genomes is indicative of a single insertion that was carried on through common descent.
It turns out that exactly the same LINE is found interrupting alphoid sequences of the same family in exactly the same way (both interrupts happen 166 bases into the 171bp repeat) at the functioning centromere on chimpanzee chromosome 2B!
And here it is!
Pretty remarkable stuff! Here is a diagram illustrating the alignment of the pre-alphoid sequences (green), the LINE sequence (blue) and the post-alphoid sequences (green) between human and chimpanzee. The alphoid sequences have been spaced out to make it easier to identify the 171bp blocks. The two regions are 96.5% identical. Lightly colored bands indicate the nucleotides that differ, and the black gaps are indels.
This LINE insertion is not present in gorillas or other apes, so it likely was inserted after the common ancestor of chimps and great apes diverged down a separate path.
I’ll let AceofSpades sum it up (15.):
There you have it. There is a fossil centromere on chromosome 2, one that aligns well with the centromere of chromosome 2b in chimps. I rest my case.
References:
1. https://en.wikipedia.org/wiki/Breakage-fusion-bridge_cycle
2.http://www.biology-online.org/biology-forum/about16334.html?hilit=Flyers (Post 5, by psms)
3. http://sapientfridge.org/chromosome_count/fertility.html
4. http://www.pandasthumb.org/archives/2009/02/the-rise-of-hum.html
5. http://blogs.discovermagazine.com/loom/2012/07/19/the-mystery-of-the-missing-chromosome-with-a-special-guest-appearance-from-facebook-creationists/#.VdJb-WTF93g
6. http://genesdev.cshlp.org/content/21/19/2495.full
7. http://www.biomedcentral.com/1471-2164/10/250
8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371704/
9. http://sandwalk.blogspot.com/2015/06/creationists-discover-that-human-and.html
10. https://answersingenesis.org/genetics/dna-similarities/alleged-human-chromosome-2-fusion-site-encodes-an-active-dna-binding-domain-inside-a-complex-and-hig/
11.https://www.reddit.com/r/NaturalTheology/comments/28v2ib/chromosome_2_fusion_a_response_to_a_question_on/
12. https://eyeonicr.wordpress.com/2014/06/25/tomkins-70/comment-page-1/#comment-25984 (comments)
13. http://genome.cshlp.org/content/12/11/1651.full
14. https://www.reddit.com/r/junkscience/comments/3mtsto/the_chromosome_2_fusion_site_part_1_a_lack_of/
15.https://www.reddit.com/r/junkscience/comments/3n4vim/the_chromosome_2_fusion_site_part_2_the_fossil/
