Are Ultra-conserved Elements Indispensable?

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ISIS Press Release 16/09/04

Are Ultra-conserved Elements Indispensable?

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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

 

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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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