When one is not enough: finding hyper-sensitive genes

Study reveals genetic signatures for childhood developmental disorders caused by the loss of one of the two copies of a gene

When one is not enough: finding hyper-sensitive genes

Screenshot of the gene sensitivity scores in DECIPHER. The colour of the HGNC genes tracks (in the bottom half of the screen) denote haplosensitivity: with red indicating a high probability of haploinsufficiency and green a low probability.

Researchers have uncovered genetic signatures that may allow more accurate diagnosis of developmental disorders in children. These patterns will also be used by researchers to hunt down genes that are particularly sensitive to the natural variation that occurs in the human genome for further research and analysis.

Normally children inherit two versions of every gene: one from their mother and one from their father. This allows a gene to keep working even if one version is lost. However, more than 300 genes have been discovered that will cause developmental disorders if only one version of the gene is present - and more have yet to be identified. In this study, scientists compared these sensitive genes with more than 1000 non-sensitive genes to find common genetic 'signposts' that could then be used to predict whether a gene is likely to be sensitive or not.

"When we compared genes sensitive to the loss of single copy with non-sensitive genes, we found that there were key evolutionary and functional similarities between the sensitive genes. In particular, these genes tend to be longer and to be highly conserved among higher primates. Also we found that they tend to play a role in the early stages of embryonic development and often work in conjunction with other sensitive genes."

Matt Hurles, leader of the study, from the Wellcome Trust Sanger Institute

The study's authors looked at the genomes of more 8,000 apparently healthy people, underscoring the value of using a comprehensive understanding of normal variation to better identify disease-causing variation. They hope that these findings will enable researchers to quickly identify other sensitive genes and target them for further investigation.

"We have built a predictive computer model using the genetic signatures we identified and have rated more than half of all human genes with their probability of being sensitive to loss of one copy. Using this probability map, we expect that fellow researchers will be able to prioritise variants and genes for follow up studies."

Ni Huang, PhD student and first author on the publication, from the Wellcome Trust Sanger Institute

They also hope that this research will enable more accurate diagnosis of developmental disorders.

"Until now, clinicians have tried to diagnose developmental disorders by using the size of a chromosomal deletion, counting the number of genes lost and looking at the function of the genes where this is known. However, this does not take into account the underlying sensitivity of the deleted genes. Using our sensitivity predictions, we are better able to discriminate between deletions we know to cause childhood developmental disorders and those that do not."

Helen Firth, Consultant Clinical Geneticist, Addenbrooke's Hospital, Cambridge

Every individual genome, not just in children with developmental disorders but even in healthy individuals, has more than a hundred genes that have lost one of their functioning copies. Understanding which genes are sensitive and which are not, allows us to interpret more fully personal genomes.

It is not currently well understood why certain genes require both versions to be working to maintain healthy function, but by identifying commonalities between them it is hoped that this will help shed more light on this mystery.

Notes to Editors
Participating Centres
  • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
  • Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas, USA
  • College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
Selected Websites
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