Sunday, January 20, 2008

expressing one's self

For most genes in our genome both maternal and paternal copies are expressed. One notable exception from this is the X chromosome in females. To compensate for the fact that males have only a single X chromosome, female cells compensate by expressing one X chromosome (at least for the majority of genes on the X) by inactivating the other X chromosome. The choice of which X chromosome to inactivate (maternal or paternal) is random (in most mammals), and this choice is made early on in development. Daughter cells in an organism inherit the choice (from the progenitor cell) of silenced X chromosome. This why calico cats are calico (who are all female, apart from rare XXY male calicos), the progenitor cells of different patches of cells have chosen different X's to express resulting in different colors.

There are other genes on the autosomes which express only one copy of the gene (mono-allelic expression). Some of these genes are imprinted, in that the decision of which copy to inactivate is not random but determined by the parent of origin, for example there are a set of genes for which only the copy inherited from the mother is expressed. However, for a number of autosomal genes the choice of which copy to express is random. Many of these randomly inactivated genes reside in particular gene families, e.g. olfactory receptor genes and antigen-specific receptors.

There's a paper out in Science that sets out to identify novel mono-allelic expression genes. Cell lines (immortalized cells) are usually poly-clonal (i.e. not derived from a single cell) and so the signal of random inactivation would be lost due to averaging over the different choices made by different clones. To overcome this the authors created clonal cell lines from single cells, thus the choice of which copy of the gene to inactivate is the same for all of the cells in the cell line.

The authors then used SNP genotyping chips to study RNA expression in these cell lines (a really neat idea). Usually SNP genotyping chips are used to detect what alleles an individual's DNA carries at 500 thousand of SNPs. Imagine an individual who is a heterozygote at a SNP within a gene, the RNA transcripts are produced by transcribing from the DNA and incorporate at random one or other of the alleles at the SNP, such that the RNA transcript from this gene averages out to 50% one allele and 50% the other allele. For mono-allelic expressed genes, only one of the copies of the gene is being expressed and so only one of the alleles is present in the RNA transcripts from the gene. By converting the RNA from there cell lines in to DNA and typing this DNA on the SNP chip, the authors can detect genes where only one of alleles in a heterozygote was being expressed in the RNA. The authors look for genes where the choice of allele expressed flipped in the different cell lines, implying that the different individuals (cell lines) are randomly choosing which alleles to express.

Now this approach is limited, as only genes which have SNPs within them which happen to be heterozygous in the cell lines can be informative. Thus the authors can study only 4000 genes. But they find that nearly 10% of these genes are showing mono-allelic expression. If correct, this is pretty stunning finding as it implies that around 10% of genes in the genome are expressed in a mono-allelic manner. These mono-allelic expression genes are often involved in interactions between cells. The authors also find that many of these mono-allelic expression genes are not 'perfectly' expressing only one of the alleles, many of the genes in some cell lines express both alleles.

How this expression is co-ordinated between the two copies of the gene is unknown, clearly there must be a set of diverse mechanisms that chose which copy to express. Starting to understanding these different mechanisms is bound to lead to some really interesting biology. The authors note that unlike the X chromosome inactivation this is not a chromosome-wide choice of which copy of the chromosome to express, as they see genes that are next to one another expressing the copy of the gene from different chromosomes.

I'm interested in how and why such expression mechanisms evolve. It would be great to see some comparative work in macaque (and/or chimp), showing whether mono-allelic expression of particular genes is conserved or if this is just a temporary evolutionary state for many genes. I'm also interested in the selective cost of mono-allelic expression. If only a single copy of the gene is expressed then the gene is essentially haploid, unmasking recessive deleterious mutations within it. Now this is perhaps mostly compensated for by the fact that different cell lineages make different choices of which allele to express, thus the individual (who is a mosaic of these choices) might usually not be affected by the deleterious mutations, as the cells in which non-deleterious mutation is expressed can compensate. But some mutations will presumably be deleterious enough that once unmasked they can not be compensated for (e.g. gain of function mutations). It is therefore somewhat surprising that the organism is forgoing one of the main supposed advantages of diploidy (the shielding of recessive mutations, see here).

What advantage could an organism derive from this mono-allelic expression? Mono-allelic expression can be involved in creating cellular diversity. For example, only a single ofactory receptor gene of the family ~1,000 olfactory receptors is expressed in a given neuron, thus each neuron has only a single olfactory receptor. Therefore, the expression of only a single copy of an olfactory receptor gene might be a side product of switching off all but one olfactory receptor gene (see here).
Given the sheer number of mono-allelic expressed genes (many imperfectly so), suggests that this is perhaps not what is happening here. One idea is that this the mono-allelic expression is a way of simply controlling (i.e. reducing) gene expression. It will be very interesting to see what comes of further investigations of this kind.


Don said...

I detect high GC content in this blog.

Another interesting corollary to monoallelic expression, at least as it relates to systems of information transfer (like olfaction) is that there should be methods of keeping the information from individual cells separate during transmission of the information. In the case of olfaction it looks like this is accomplished structurally by the wiring patterns of olfactory neurons. But it will be interesting to see other stories emerge; just as there will be different modes of regulation of monoallelic expression, there should be different modes of information transfer.

There is a good paper dissecting the regulation of olfactory receptor choice here.

Anonymous said...