May 27, 2004 | David F. Coppedge

DNA: The Mystery of the Ultraconserved Elements

As we proceed into the age of genomics, the DNA codes of more and more animals are coming into focus.  The genomes of humans, chimpanzees, mice, chickens, dogs, rats and pufferfish have been sequenced so far, and more are planned.  Evolutionists expected the ancestry of all living things to be traceable in the genetic code by comparing the DNA of distant vs. closely-related species, but the task has proven far more complicated than expected.  One recent finding has evolutionists really scratching their theoretical heads, as summarized in the May 28 issue of Science:

There are 481 segments longer than 200 base pairs (bp) that are absolutely conserved (100% identity with no insertions or deletions) between orthologous regions of the human, rat, and mouse genomes.  Nearly all of these segments are also conserved in the chicken and dog genomes, with an average of 95 and 99% identity, respectively.  Many are also significantly conserved in fish.  These ultraconserved elements of the human genome are most often located either overlapping exons in genes involved in RNA processing or in introns or nearby genes involved in the regulation of transcription and development.  Along with more than 5000 sequences of over 100 bp that are absolutely conserved among the three sequenced mammals, these represent a class of genetic elements whose functions and evolutionary origins are yet to be determined, but which are more highly conserved between these species than are proteins and appear to be essential for the ontogeny of mammals and other vertebrates.

Why is this unexpected?  According to evolutionary theory, mutations accumulate over time.  Evolutionists believe that fish, birds and mammals all diverged on the family tree and went their separate ways millions of years ago.  Why, then, are there these thousands of sequences that have not changed at all?
    Mutations, in theory, could be harmful, beneficial, or neutral.  If harmful, natural selection should weed them out.  If beneficial, natural selection should preserve them, as Darwin said in a classic passage on gradualism: “Natural selection is scrutinizing the slightest variations, rejecting those that are bad, preserving and adding up all that are good.”  But most evolutionists also consider the gray area between, the “neutral” mutations that cause neither benefit nor harm.  Exposed to mutagens in the environment over vast ages, each section of the genome should accumulate neutral mutations, resulting in genetic drift.  Presumably, the amount of drift between two species (like rats and humans) would be a function of the time since their lineages diverged, assuming a “molecular clock” ticking with a steady mutation rate.  (Is the molecular clock reliable?  See 04/20/2004 headline.)
    Yet there are significant segments of DNA that are 100% identical in the mammalian genomes, despite evolutionists’ belief their ancestries diverged tens of millions of years ago.  The puzzle is even more striking when fish and bird genomes show 95% or greater sequence identity with mammals in these ultraconserved elements for 300 to 400 million years.  How could this be, especially when some parts of the genomes appear to evolve rapidly?  The Darwinian explanation is that the ultraconserved regions have been subject to “purifying selection.”  This presumes that certain stretches of DNA are so important, so indispensable, that natural selection protects them from change and is vigilant about correcting mutations.  Thus, purifying selection is the converse of natural selection: instead of selecting positively for a new function, it selects negatively against change.
    Yet the authors of this paper do not seem completely satisfied with this explanation.  For one thing, not all ultraconserved elements are in the exons of active genes that code for proteins.  Many exist in introns and other regions thought to be “junk DNA.”  Why would natural selection preserve junk to a high degree of accuracy for millions of years?  The implication is that it’s not junk at all, but something vital to the regulation of gene expression.

Non-exonic ultraconserved elements are often found in “gene deserts” that extend more than a megabase.  In particular, of the non-exonic elements, there are 140 that are more than 10 kilobases (kb) away from any known gene, and 88 that are more than 100 kb away. (See also 10/16/2003 headline.)

Indirect evidence suggests that these segments, far distant from genes, are important for regulating embryonic development or act as “distal enhancers” of the genes.  Simple scaffolding they are not.
    It is true that these ultraconserved elements do not extend to distant species, such as between humans and jellyfish or fruit flies; yet extreme conservation is apparent even among the more primitive lineages, going back to the earliest chordates.  The best that evolutionists can explain is that rapid evolution occurred in these regions in the past, then stopped in its tracks: “the bulk of the ultraconserved elements represent chordate innovations that evolved fairly rapidly at first but then slowed down considerably, becoming effectively ‘frozen’ in birds and mammals.”
    When the scientists searched for conservation in shorter segments, they found it everywhere:

A more extensive analysis of paralogs, based on a recent global clustering of highly conserved noncoding human DNA, reveals several further highly conserved intronic and intergenic elements in functionally equivalent positions relative to paralogous genes.  These were not classified as ultraconserved by our stringent criteria.  Indeed, if we merge alignment blocks of 200 bases, each with at least 99% identical columns, we obtain 1974 “highly conserved” elements up to 1087 bp long in the human…. If instead we demand at least a 100-bp exact match between humans and rodents, we get more than 5000 highly conserved elementsTens of thousands more are found at lower cutoffs; for example, there is a 57-bp exactly conserved sequence overlapping an alternatively spliced exon of the WT1 gene which is invariant in mammals and in chickens and is largely conserved in fishes (fig. S1).  The percentage of the conserved elements that overlap with a known coding region steadily rises from 14 to 34.7% as the length criteria defining these elements is reduced from 200 to 50 bp (table S6).
    If experiments with less conserved elements in recent studies are any indication, many of these shorter elements are also functional.

The scientists put these findings into three possible explanations: (1) either strong purifying selection is 20 times better at correcting mutations in these regions, or (2) the mutation rate is 20 times slower, or (3) a combination of both.  The importance of these regions must be extreme if the strong negative selection is the reason; does the conservation of active gene exons create structures that “must be extremely constraining over hundreds of bases of DNA”?  Perhaps, but questions remain for either explanation.  The article concludes on a question mark:

On the other hand, if reduced mutation rates are the explanation, then the existence of regions of a few hundred bases with 20-fold reduced mutation rates would itself be quite novel.  Although neutral mutation rates may vary depending on chromosomal location on a megabase scale, there is to our knowledge no evidence or precedent for the existence of short “hypomutable” or “hyperrepaired” neutral regions.  Finally, the answer could also be a combination of negative selection and better repair in these regions, owing to some vital role that these elements play, such as self-regulating networks of RNA processing control in the case of exonic elements and self-regulatory networks of transcriptional control for non-exonic elements.  In any case, the questions remain: What kind of elements associated with these processes would have arrived relatively early in chordate evolution and then become practically frozen in birds and mammals?  And what mechanisms would underlie this, allowing them to resist virtually all further change?

New Scientist June 3 reports an experiment the deepened the mystery: mice born without the some of the ultraconserved regions do just fine.  This announcement produced “gasps of amazement” at a scientific talk, the article says, because it was assumed if they were so conserved, they must be important for survival.  A team deleted 1000 highly conserved sequences shared between humans and mice, and found the lab mice to be virtually identical with normal mice in every measurement: growth, lifespan, metabolism, and overall development.  One of the deleted segments was over 1.6 million DNA bases long.  Perhaps backup copies exist on other chromosomes for redundancy.  The article puzzles over why some of the ultraconserved regions showed higher levels of conservation than many genes.  “What’s most mysterious is that we don’t know any molecular mechanism that would demand conservation like this,” one researcher said.

1Bejerano et al., “Ultraconserved Elements in the Human Genome,” Science, Vol 304, Issue 5675, 1321-1325, 28 May 2004, [DOI: 10.1126/science.1098119].

It was supposed to be so easy.  Where fossils and comparative anatomy failed to confirm Charlie’s story, the genes would come to the rescue.  Now this.
    The only way the Darwinians can keep their story going now is to propose that evolution is both lightning-fast and then frozen.  Somehow, brainless early chordates invented all kinds of elaborate molecular mechanisms, then put them under the Law of the Medes and the Persians; these regions of DNA could not be altered.  Thenceforth, genomes underwent fantastic degrees of evolution by natural selection, creating flying reptiles, flying birds, flying mammals and flying fish, blue whales, giraffes, lizards, peacocks and people, while these ultraconserved regions, exposed to all the natural forces affecting the other parts of the genome, remained steadfast and immovable.  Strong positive selection played fast and loose with genes, duplicating and recombining and mutating them and adding introns with seeming reckless abandon.  Simultaneously, strong purifying selection kept the ultraconserved regions virtually untouched.  All the while, genetic drift threw in a few neutral mutations at random that somehow didn’t touch the ultraconserved regions.  Ockham would slash away like a knight at this convoluted concoction of explanations.
    These findings may shed additional light on the mystery of introns, those sections of DNA that the transcription machinery cuts out and apparently discards (see 09/03/2003, 09/12/2003, 05/10/2004 and 05/19/2004 headlines).  It would seem evolutionists would predict just the important functional genes to be conserved, if anything; why would introns be conserved, unless they too are vital?  There is clearly much we don’t know yet.  While some differences between animal genes appear to be functions of their assumed ancestral distance, many others do not.  The picture is getting very complicated for the Darwin Party.  God must have had a sense of humor.

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