Life after the Central Dogma
The biotech industry was launched on the scientific myth that organisms
are hardwired in their genes, a myth thoroughly exploded by scientific findings
accumulating since the mid 1970s and especially so since genome sequences have
been accumulating (see Living with the Fluid
Genome, by Mae-Wan Ho ).
We bring you the latest surprises that tell you why our health and
environmental policies based on genetic engineering and genomics are completely
misguided; and more importantly, why the new genetics demands a thoroughly
ecological approach.
ISIS Press Release 16/09/04
Are Ultra-conserved Elements Indispensable?
Geneticists identified elements in the genome that are
‘ultra-conserved’, and thought they must be indispensable for
survival. Not so. Dr. Mae-Wan Ho
reports
The
sources for this
article are posted on ISIS members’ website.
Details here.
The "molecular clock" of mutational changes
Until now, most geneticists believe that the DNA in the genome is
subject to random mutations, most of which are neutral - neither good
nor bad for the organism - so the result is a slow and steady change in DNA
sequences in the genome in the course of evolution. This is the basis of the
"molecular clock" hypothesis, which enables one to estimate, from the changes
in DNA, the time in the past at which certain evolutionary events happened. For
example, when it was that the first human immune deficiency virus (HIV-1) split
off from the monkey virus (SIV), or, much, much further back in evolution, when
the line that led to the human species split off from the one leading to the
chimpanzee.
The molecular clock is known not to be perfect, because different genes
tend to change at different rates, though the rates were not that dissimilar.
So it was always assumed that, averaged over the whole genome, the molecular
clock would give relatively accurate results; particularly, as it seemed, until
quite recently, the genome is full of "junk DNA" of unknown function.
"Ultraconservative elements"
Many surprises lay in store as genome sequences accumulated and,
thankfully, get deposited into one public database, so useful comparisons could
be made. It turns out that not only are there vast hidden treasures among the
"junk DNA", but evidence of highly non-random changes among different stretches
of the DNA, some of which change in concert, some or which change at random,
and others, change almost not at all.
There are 481 segments in the human genome longer than 200 bp that are
100% identical with rat and mouse genomes. Nearly all are also conserved in the
chicken (467/481) and dog (477/481) genomes, with an average of 95.7% and 99.2%
identity, respectively. Many are also significantly conserved in fish (324/481
at an average of 76.8% identity).
Very few of these elements could be traced back to jelly fish,
Drosophila or the nematode worm.
These "ultraconserved" elements are widely distributed in the genome,
occurring on all chromosomes with the exception of the Y chromosome and
chromosome 21. They most often overlap exons in genes involved in RNA
processing or in their introns; or near genes involved in regulation of
transcription and development.
Of the 481 ultraconserved elements, 111 overlap the mRNA of a known
human protein coding gene, including the UTR (untranslated region) and are
partly exonic (belonging to protein coding sequences); 256 show no match to
expressed mRNA and are therefore nonexonic (non-protein coding); while the
remaining 114 are possibly exonic. One hundred of the non-exonic elements are
located in introns (non-coding intervening sequences) of known genes and the
rest are intergenic (between genes). The non-exonic elements, both intronic and
intergenic, tend to congregate in clusters near transcription factors and
developmental genes, whereas the exonic and possibly exonic elements are more
randomly distributed along the chromosomes.
There are 93 known genes that overlap with exonic ultraconserved
elements; these are called type 1 genes. The 255 genes that are near the
non-exonic elements are type II genes. Type I genes tend to be RNA binding or
involved in regulation of splicing. In contrast, type II genes are involved in
regulation of transcription and DNA binding, and are enriched for DNA binding
motifs such as the homeobox.
Nonexonic ultraconserved elements are often found in "gene deserts" that
extend more than a megabase. Of the non-exonic elements, there are 140 that are
more than 10Kb away from any known gene, and 88 that are more than 100Kb away.
The set of 156 annotated genes that flank intergenic ultraconserved
elements is significantly enriched for developmental genes, and in particular,
genes involved in early development, suggesting that many of the associated
ultraconserved elements may be distal enhancers of these early developmental
genes.
Non-exonic elements that lie in introns are also often associated with
developmental genes.
Many elements in the ultraconservative set of 481 are considerably
longer than 200bp. The longest elements (779bp, 770bp and 731 bp) all lie in
the last three introns in the 3’ portion of the DNA polymerase alpha
catalytic subunit on chromosome X, along with other shorter ultraconserved
elements.
If the criterion "highly conserved" sequences with 99% identity
(instead of 100% identity) is used, then there are 1 974 elements, of lengths
up to 1 087bp in the human genome.
There are also 5 000 sequences of more than 100bp in length that are
100% identical in the human, rat and mouse genomes. These appear to be
essential for development in mammals and other vertebrates.
Tens of thousands more are found at lower cutoffs.
Thus, as much as 5% of the genome is more conserved than expected from
neutral mutations occurring at random.
Ultra-conserved elements are indispensable
Researchers from the University of California Santa Cruz in the United
States and University of Queensland, Brisbane, Australia, suggest these
sequences are under negative "purifying" selection for more than 300 million
years, some for at least 400 million years; or else they have very low mutation
rates, or they are subject to perfect repair. It means they must be
‘vital’ for survival.
The rate at which these sequences change in evolution is 20 fold less
than the rest of the genome, including the protein coding regions.
The ultraconserved elements show almost no natural variation in the
human population. Only 6 out of 106 767 bp examined are at validated SNPs,
whereas 119 are expected.
Surprise, surprise
But researchers revealed that mice with big chunks for such
ultraconserved sequences deleted get on very well without them.
Edward Rubin’s team at the Lawrence Berkeley National Laboratory in
California deleted two huge regions of DNA from mice containing nearly 1 000
highly conserved sequences shared between human and mice. One region was 1.6
million DNA bases long, the other over 800,000 bases long. The researchers
expected the mice to show big problems as the result of the deletions.
But the mutant mice were no different from normal mice in every respect:
growth, metabolic functions, lifespan and overall development. "We were quite
amazed," said Rubin, who presented the findings at a meeting of the Cold Spring
Harbor Laboratory in New York earlier this year.
"It may say as much about our inability to detect any phenotypes as it
says about the function of this region, " said David Haussler of the University
of California, Santa Cruz, whose team described the "ultra-conserved regions"
in mammals, "What’s most mysterious is that we don’t know any
molecular mechanism that would demand conservation like this."
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