Single parent genes

Geneticists have long thought that for most human genes, alleles from both paternal and maternal chromosomes are equally expressed within a cell. But according to a study published this week in Science, the allelic contribution from either parent can be randomly turned off in more than five percent of genes. This mechanism may allow cells to generate phenotypic diversity from a common genome, the authors say.

"Until this paper came out, it wasn't clear how widespread this phenomenon was," said Mark Bix of St. Jude Children's Research Hospital, who was not an author of the study.

Researchers have previously observed non-random selection of only one allele--called monoallelic expression--in early embryonic development, in the processes of imprinting and X-inactivation. They have also found examples of random monoallelic expression in just a few genes in the immune or nervous system. Andrew Chess and colleagues at Harvard Medical School in Boston set out to determine whether there were other genes that fall into this category of random expression.

The Chess group used a genome-wide screen of 4000 genes in a clonal cell line. They adapted a DNA-based screen to measure RNA levels since RNA, unlike DNA, represents only activated genes. To their surprise, they found that more than 300 genes make an arbitrary, allele-specific choice.

After a single clone selected an allele, its progeny perpetuated the pattern. "There's the primary choice of which allele to express, and this is maintained in cells as they continue to divide," said Chess.

The researchers observed such monoallelic expression in a functionally diverse group of genes, some of which are known to play a role in human diseases. For example, one of the genes expressed amyloid precursor protein, which is involved in Alzheimer disease. Wolf Reik at the Babraham Institute in Cambridge, UK, suggested that this could explain differences in susceptibility to genetic diseases. "If this disease gene is randomly expressed, you could get a different mix of cells that are more healthy or less healthy," he said.

"It's really a lovely study," said Marisa Bartolomei of the University of Pennsylvania School of Medicine, who was not involved with the work. "Every once in a while something comes along in your research area that's really exciting."

The results imply that "phenotypically characterizing a trait is going to be more complicated," she added. "It's not all about the genes and mutations you have."

Reik noted that the high frequency of the effect must be confirmed in other cell types. Indeed, Chess said that future studies will address that question and explore the mechanism of the phenomenon.

One key question, said Bartolomei, is how these genes are chosen to be monoallelic. "Is there a genetic component to this epigenetic phenomenon?" she asked.

Jonathan Scheff
mail@the-scientist.com


Links within this article:

A. Gimelbrant et al., "Widespread monoallelic expression on human autosomes," Science, Nov. 16, 2007.
http://www.sciencemag.org/

Mark Bix
http://www.stjude.org/

J. Weitzman, "Imprinting and methylation," The Scientist, Dec. 2, 2002.
http://www.the-scientist.com/article/display/20904/

M.F. Lyon, "X chromosomes and dosage compensation," Nature, Mar 27-April 2, 1986.
http://www.the-scientist.com/pubmed/3960115

A. Gimelbrant et al., "Monoallelic expression and asynchronous replication of p120 catenin in mouse and human cells," Journal of biological chemistry, Jan 14, 2005.
http://www.the-scientist.com/pubmed/15522875

Andrew Chess
http://chgr.mgh.harvard.edu/chess/index.shtml

T. Toma, "The silencing team," The Scientist, April 5, 2002.
http://www.the-scientist.com/article/display/20311/

K.R. Chi, "Cognitive Clog," The Scientist, July 2007.
http://www.the-scientist.com/article/display/53336/

Wolf Reik
http://www.babraham.ac.uk/devgen/reik.html

Marisa Bartolomei
http://www.med.upenn.edu/cellbio/faculty/bartolomei/