When is a gene not a gene? New catalog helps identify gene variations associated with disease
Distribution of recessive disease genes (blue) and LoF-tolerant genes (red) compared to all protein-coding genes (gray) [DOI:10.1126/science.1215040]
A high-quality reference catalogue of the genetic changes that result in the deactivation of human genes has been developed by a team of researchers. This catalogue of loss-of-function (LoF) variants is needed to find new disease-causing mutations and will help us to better understand the normal function of human genes. In addition, the researchers report that each of us is carrying around 20 genes that have been completely inactivated.
The team refined previous estimations of possible LoF variants by excluding more than half. They accomplished this by identifying errors and real variants that did not seem to affect gene function and eliminating them from the list. They also developed a method of determining whether or not a newly-identified variant could be a likely cause of disease.
Loss of function variants are genetic changes that are predicted to severely disrupt the function of genes. They are known to cause severe human diseases such as muscular dystrophy and cystic fibrosis. Previous genome sequencing projects have suggested that hundreds of these variants are present in the DNA of even perfectly healthy individuals, but could not tell exactly how many.
"The key questions we focused on for this study were: how many of these LoF variants were real and how large a role might they play in human disease?" explains Dr Daniel MacArthur, first author from the Wellcome Trust Sanger Institute. "We looked at nearly 3000 putative LoF variants in the genomes of 185 people from Europe, East Asia and West Africa who were participants of the 1000 Genomes Project."
Working as part of the 1000 Genomes Project, the team developed a series of filters to identify common errors. The filters revealed that 56% of the 3000 LoFs were unlikely to seriously affect gene function. But of the true LoF variants, 100 are typically found in the genome of each European and 20 affect both copies of the gene, and are thus predicted to result in complete loss of gene function.
"We identified 253 genes that can be completely inactivated in one or more participant. This shows that at least 1% of human genes can be shut down without causing serious disease", explains Professor Mark Gerstein, co-author from Yale University. "We were able to use the differences between such "LoF-tolerant" genes and known human disease genes to develop a way of predicting whether or not a newly-discovered change in a gene is likely to be severely disease-causing."
The team found some of these LoFs are quite common and are unlikely to have a significant effect on health. For instance, some can affect the way in which we detect smells or how sensitive we are to sour taste. However, they found that the majority of the LoF variants are rare, with half of them being seen only once in the 185 people. This suggests that most of these variants can be quite harmful.
"Our research will be beneficial for current DNA sequencing studies underway in disease patients," says Dr Chris Tyler-Smith, lead author from the Wellcome Trust Sanger Institute. "In addition, we provide a list of over 1000 loss-of-function variants, and in most cases little or nothing is known about how these genes work or what they do. By studying the people carrying them in detail, we should get new insights into the function of many poorly-known human genes"
The team's long term goal is to study the potential effects all LoF variants have on humans. They will do this by looking at them in people with different diseases, as well as healthy people who have been measured for many different traits.
More information: McArthur et al 'A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes' Published in Science on 17 February 2012. dx.doi.org/10.1126… ence.1215040
Journal reference: Science
Provided by Wellcome Trust Sanger Institute
- Mouse genetic blueprint developed Sep 14, 2011 | not rated yet | 0
- The importance of gene regulation for common human disease Sep 16, 2007 | not rated yet | 0
- Rare gene variants linked to inflammatory bowel disease Oct 10, 2011 | not rated yet | 0
- Third genetic link to osteoarthritis discovered Aug 25, 2011 | not rated yet | 0
- Study suggests rare genetic variants most likely to influence disease Mar 31, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Classical and Quantum Mechanics via Lie algebras
Apr 15, 2011 I'd like to open a discussion thread for version 2 of the draft of my book ''Classical and Quantum Mechanics via Lie algebras'', available online at http://lanl.arxiv.org/abs/0810.1019 , and for the...
- More from Physics Forums - Independent Research
More news stories
Researchers from Queen Mary, University of London have led the largest sequencing study of human disease to date, investigating the genetic basis of six autoimmune diseases.
Genetics 20 hours ago | 4.5 / 5 (4) | 0 |
University of Minnesota Medical School researchers from the Masonic Cancer Center, University of Minnesota, in partnership with the University's Brain Tumor Program, have developed a new mouse model of malignant peripheral ...
Genetics May 20, 2013 | 5 / 5 (1) | 0 |
Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.
Genetics May 16, 2013 | 3 / 5 (1) | 1 |
Informed consent is the backbone of patient care. Genetic testing has long required patient consent and patients have had a "right not to know" the results. However, as 21st century medicine now begins to use the tools of ...
Genetics May 16, 2013 | 5 / 5 (1) | 3 |
Ethicists provide framework supporting new recommendations on reporting incidental findings in gene sequencing
In a paper published in Science Express, a group of experts led by bioethicists in the Center for Medical Ethics and Health Policy at Baylor College of Medicine provide a framework for the new American College of Medical Geneti ...
Genetics May 16, 2013 | not rated yet | 0
For the first time, physicists from the Max Planck Institute for Extraterrestrial Physics (MPE), biologists and physicians demonstrated the synergistic effect of cold atmospheric plasma - a partly ionized ...
54 minutes ago | 5 / 5 (1) | 0 |
(Medical Xpress)—Scientists from the Joint Center for Structural Genomics (JCSG) at SLAC National Accelerator Laboratory have determined the 3-D structure of the chemically active part of an enzyme involved ...
34 minutes ago | not rated yet | 0 |
(Medical Xpress)—Research by U of T Mississauga psychology professor Glenn Schellenberg reveals that two key personality traits – openness-to-experience and conscientiousness—predict better than IQ ...
14 minutes ago | not rated yet | 0 |
Aggressive forms of bladder cancer involve the protein PODXL – a discovery that could hold the key to improved treatment, according to researchers at Lund University, Uppsala University and KTH in Sweden.
24 minutes ago | 5 / 5 (1) | 0
A study from the June issue of Anesthesiology found feedback from the front region of the brain is a crucial building block for consciousness and that its disruption is associated with unconsciousness when the anesthetics ketami ...
54 minutes ago | not rated yet | 0
Parents naturally are concerned for their children's safety, particularly when there is news of a child abduction that happens close to home. Finding the balance between emotions and the "teachable moment" as parents talk ...
44 minutes ago | not rated yet | 0