I've always been bothered by the incidence of MS among identical twins. Studies typically find that when one identical twin is diagnosed with MS, the other has a 20-30% chance of also being diagnosed. I think the chances in the general population are usually said to be in the 1 in 500 to 1 in 1,000 range (or 0.2% - 0.1% chance of getting MS).
The explanations of the identical twin - MS relationship I've read go something like this: since identical twins share the same genetic code, this higher incidence shows that genetics clearly plays a role in MS, but is not the entire story, there are also environmental factors, including pathogens.
I'm no expert, but I'm guessing a vast majority of identical twins grow up in the same home, eating the same/similar food, getting many of the same infectious illnesses etc. It seems to me that even if genetics isn't the whole thing with MS, and the rest is explained by environment and pathogens, then identical twins should both be diagnosed with MS FAR more often than 20-30% of the time, that is, unless we're missing something.
About the only thing my non-scientific mind has been able to come up with to explain why more identical twins aren't both MS-sufferers is genetic mutations of some sort. A quick look around the web for info on genetics and mutations took me to epigenetics. (which has been discussed on this site in detail a year or two back by OddDuck, Raven and BioDocFL). There is a ton of research being done on epigenetics and its influence on disease. I don't have a great understanding of all this, but it really seems that epigenetics is going to greatly advance our understanding of a huge number of diseases, including MS.
First a definition:
What is epigenetics?
In 1942 Conrad Hal Waddington defined epigenetics as 'the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being'. In modern sense the term 'epigenetics' describes heritable changes in genome function that occur without a change in nucleotide sequence within the DNA. For example, when a cell established a particular pattern of 'active' and 'non-active' genes this same pattern will be passed on to a daughter cell even though during cell division all genes are 'shut off' and chromosomes have become tightly wrapped up or condensed. This process allows development of different structures and organs during development. The nucleotides within DNA sometimes become chemically modified. A number of combined, nearby modifications may represent a particular pattern. Such a pattern may serve as a template for passing on its informative message in the form of specific chemical modifications to other molecules. Particular aminoacid groups (e.g. lysines) within proteins such as histones may be modified through acetylation or methylation and serve as transmitters of such information. Such chemical modification patterns are called epigenetic tags. For more information www.epigenome-noe.net/aboutus/epigenetics.php
http://www.epigenome-noe.net/consulting ... ting.php#3
Here's an easy-to-read article from the BBC about epigenetics:
The Ghost in Your Genes
BBC - Biology stands on the brink of a shift in the understanding of inheritance. The discovery of epigenetics – hidden influences upon the genes – could affect every aspect of our lives.
At the heart of this new field is a simple but contentious idea – that genes have a 'memory'. That the lives of your grandparents – the air they breathed, the food they ate, even the things they saw – can directly affect you, decades later, despite your never experiencing these things yourself. And that what you do in your lifetime could in turn affect your grandchildren.
The conventional view is that DNA carries all our heritable information and that nothing an individual does in their lifetime will be biologically passed to their children. To many scientists, epigenetics amounts to a heresy, calling into question the accepted view of the DNA sequence – a cornerstone on which modern biology sits.
Epigenetics adds a whole new layer to genes beyond the DNA. It proposes a control system of 'switches' that turn genes on or off – and suggests that things people experience, like nutrition and stress, can control these switches and cause heritable effects in humans.
In a remote town in northern Sweden there is evidence for this radical idea. Lying in Överkalix's parish registries of births and deaths and its detailed harvest records is a secret that confounds traditional scientific thinking. Marcus Pembrey, a Professor of Clinical Genetics at the Institute of Child Health in London, in collaboration with Swedish researcher Lars Olov Bygren, has found evidence in these records of an environmental effect being passed down the generations. They have shown that a famine at critical times in the lives of the grandparents can affect the life expectancy of the grandchildren. This is the first evidence that an environmental effect can be inherited in humans.
In other independent groups around the world, the first hints that there is more to inheritance than just the genes are coming to light. The mechanism by which this extraordinary discovery can be explained is starting to be revealed.
Professor Wolf Reik, at the Babraham Institute in Cambridge, has spent years studying this hidden ghost world. He has found that merely manipulating mice embryos is enough to set off 'switches' that turn genes on or off.
For mothers like Stephanie Mullins, who had her first child by in vitro fertilisation, this has profound implications. It means it is possible that the IVF procedure caused her son Ciaran to be born with Beckwith-Wiedemann Syndrome – a rare disorder linked to abnormal gene expression. It has been shown that babies conceived by IVF have a three- to four-fold increased chance of developing this condition.
And Reik's work has gone further, showing that these switches themselves can be inherited. This means that a 'memory' of an event could be passed through generations. A simple environmental effect could switch genes on or off – and this change could be inherited.
His research has demonstrated that genes and the environment are not mutually exclusive but are inextricably intertwined, one affecting the other.
The idea that inheritance is not just about which genes you inherit but whether these are switched on or off is a whole new frontier in biology. It raises questions with huge implications, and means the search will be on to find what sort of environmental effects can affect these switches.
After the tragic events of September 11th 2001, Rachel Yehuda, a psychologist at the Mount Sinai School of Medicine in New York, studied the effects of stress on a group of women who were inside or near the World Trade Center and were pregnant at the time. Produced in conjunction with Jonathan Seckl, an Edinburgh doctor, her results suggest that stress effects can pass down generations. Meanwhile research at Washington State University points to toxic effects – like exposure to fungicides or pesticides – causing biological changes in rats that persist for at least four generations.
This work is at the forefront of a paradigm shift in scientific thinking. It will change the way the causes of disease are viewed, as well as the importance of lifestyles and family relationships. What people do no longer just affects themselves, but can determine the health of their children and grandchildren in decades to come. "We are," as Marcus Pembrey says, "all guardians of our genome."
http://www.bbc.co.uk/sn/tvradio/program ... enes.shtml
Here's a summary of the Human Epigenome Project from Pubmed:
Future potential of the Human Epigenome Project.
Expert Rev Mol Diagn. 2004 Sep;4(5):609-18.
Eckhardt F, Beck S, Gut IG, Berlin K.
Epigenomics AG, Kleine Prasidentenstrasse 1, 10178 Berlin, Germany. email@example.com
Deciphering the information encoded in the human genome is key for the further understanding of human biology, physiology and evolution. With the draft sequence of the human genome completed, elucidation of the epigenetic information layer of the human genome becomes accessible.
Epigenetic mechanisms are mediated by either chemical modifications of the DNA itself or by modifications of proteins that are closely associated with DNA. Defects of the epigenetic regulation involved in processes such as imprinting, X chromosome inactivation, transcriptional control of genes, as well as mutations affecting DNA methylation enzymes, contribute fundamentally to the etiology of many human diseases.
Headed by the Human Epigenome Consortium, the Human Epigenome Project is a joint effort by an international collaboration that aims to identify, catalog and interpret genome-wide DNA methylation patterns of all human genes in all major tissues. Methylation variable positions are thought to reflect gene activity, tissue type and disease state, and are useful epigenetic markers revealing the dynamic state of the genome. Like single nucleotide polymorphisms, methylation variable positions will greatly advance our ability to elucidate and diagnose the molecular basis of human diseases.
Here's the latest press release from the Human Epigenome Project:
Towards a DNA Methylation Reference Map of the Human Genome
Human Epigenome Project determines DNA Methylation Profiles of Three Human Chromosomes
The Human Epigenome Project (HEP) is part of an international effort to map the epigenetic marks - collectively known as epigenome or epigenetic code - that provide function to the genetic code. Increasingly, the epigenetic code is seen as important in human health and disease. Today, the Wellcome Trust Sanger Institute and Epigenomics AG announce the mapping of such epigenetic marks constituting DNA methylation reference profiles for three human chromosomes.
The human genome consists of about 3 billion bases and it is the order, or sequence, of these bases that contains the genetic information (genes) to make proteins which in turn carry out all biological functions. The activity of these genes can be modulated by the addition or removal of epigenetic marks such as simple methyl (CH3) groups to some of the cytosine bases. This is one example of an epigenetic change, where the sequence of bases remains unchanged, but genetic activity is altered. In this way, different genetic programmes can be executed from the same genome in different cells.
"Before the HEP, we had only a few glimpses of what epigenomes might look like in different cell types," said Dr Stephan Beck, the Project's Principal Investigator at The Wellcome Trust Sanger Institute. "To understand how a cell executes its particular genetic programme, an epigenetic equivalent of the Human Genome Project is needed to generate a reference against which epigenetic changes can be studied in the context of development, environment and disease. The data released today are another milestone towards this goal."
The latest release of HEP data comprises DNA methylation profiles of human chromosomes 6, 20 and 22. In total, about 1.9 million CpG methylation values were obtained from the analysis of 2,524 DNA amplicons across chromosomes 6, 20 and 22 in 43 samples, derived from 12 different tissues. The results have been analysed in detail and a report will be published in the coming months.
Recognizing the opportunity for a coordinated global effort, a blueprint has recently been drawn up for an international HEP with the aim integrate already ongoing projects including our HEP, the EU-funded Epigenome Network of Excellence and other efforts.
http://www.sanger.ac.uk/Info/News-relea ... 0626.shtml
Epigenetics certainly is a novel, fascinating explanation!
When I attended the EBV think-tank Prof George Ebers presented on genetics and MS and had a number of slides on twins. For indentical twins the chance was nearer 50% of getting MS. And the research had covered twins who had lived apart. He mentioned epignetics as a cutting edge specialism which should shed more light on genes and diseases.
Prof Ebers is being funded by the UK MS Society and should be reporting at the end of the year. Other work is being undertaken in the US.
Unlike some diseases, MS is unlikely to be the result of one gene. In his study of MS in Canadian families, Prof Ebers came across one family with 18 members with MS. I think the researchers are going to conclude that there are different types of MS (and perhaps different genes involved).
It all looks very complicated, but this is one areas where they are getting much nearer to an answer.
In my own mind I'm sure that the answer to the genetic susceptibility to MS lies with epigenetics.
Bromley, I guess your doctor has access to all the best studies on twins, so it's interesting to hear that he figures it's around 50%. If you look in Pubmed, you'll see that all of the studies are in the 20's%, or 30% at the highest. In either case, I'd have thought the incidence in identical twins should be in the 75-95% range if there wasn't another (just my feeling), as yet unknown factor at play. On the genetic studies that will be reporting later this year, I think that will prove to be important, but I'm starting to think that epigenetics will be able to explain more...eventually...after futher study...give it 10 years...aaarrrggghhh!!!
I am still working on my theory relating autoimmune diseases to epigenetics, particularly disruptions of X inactivation (a major epigenetic event) and fragmentation of the X chromosomes. The idea is that there can then be overexpression of some genes that have lost their epigenetic controls. The overexpression could occur particularly when the cell is stressed by viral activity, heat, hormones, heavy metals, amino acid analogs, or other things.
The good news is that I will probably be presenting my theory to the cancer biologists where I work. They will be interested since BRCA1 is involved in X inactivation and BRCA1 mutations are often associated with breast and ovarian cancer. Loss of BRCA1 function may entail loss of proper X inactivation. I think they will be more interested and open minded than the immunologists I presented to several years ago. Plus I think the cancer biologists will understand the molecular biology better.
I have to get back to work now. Keep the discussion of epigenetics going though please.
Team 61: X Chromosome
Our group is interested in the structure, biology and evolution of the human X chromosome. The X chromosome has characteristics that are unique among the chromosomes. The most apparent of these is that females have two X chromosomes while males have an X and a Y chromosome. The X and Y, or sex chromosomes are believed to have been homologues in a common ancestor of the mammals. However, when they were recruited into the sex-determination process, a sequence of events ensued in which the Y chromosome became severely eroded by mutation. The human Y chromosome carries few of the genes found on the X chromosome, which has two particularly important consequences. First, X-linked recessive diseases are manifested in males. And second, a mechanism has evolved to avoid the potential imbalance between males and females of proteins produced from X-linked genes. This process, known as dosage compensation, is achieved by the inactivation of one of the X chromosomes in females. We are mapping and sequencing the human X chromosome to provide the basis to understand its biology and evolution.
(This is going to be really complicated so be warned.)
Notice that they mention in that website about LINE1 elements on the X chromosome. There are an estimated 50,000 LINE1 genes scattered around the genome but the X has 2x the average density, the Y chromosome has 3x. LINE1 genes are supposedly the remains of reverse transcriptases that are inactive. However, it has been estimated that ~30-60 are fully functional reverse transcriptases. If these get expressed, they could initiate reverse transcription in the cell. I read recently that probably a lot more of the LINE1s are functional if you only need the ORF2 (open reading frame). ORF1 codes for a signal protein and ORF2 codes for the actual reverse transcriptase. LINE1 is polycistronic meaning that it actually codes for multiple proteins, something eukaryotes don't usually do.
A general pattern for my theory, at least thinking in terms of lupus and MS being similar, is that:
1. A fragile site on the inactive X chromosome breaks (let's say Xp22-ter is separated from the rest of the X), perhaps during mitosis.
2. The daughter cells inherit the broken X fragment, perhaps uneven distribution, perhaps equal.
3. The fragment in the daughter cell becomes active since it is no longer attached to the portion of the X with the X inactivation genes (Xq13). Now the cell has the potential to express genes from both X chromosomes for that portion of the X. This could lead to overexpression.
4. A stress on the cell (heat, virus, heavy metals, amino acid analogs, etc.) invokes heat shock type gene expression.
5. Because of some overexpression from the X linked genes, there is an over reaction with the heat shock response. In particular, I am thinking of over expression of spermine synthase and spermidine/spermine N1 acetyltransferase at Xp22.1. Polyamine synthesis usually increases during a heat shock response but now, the extra expression of these two enzymes can lead to an imbalance in the spermidine/spermine ratio. Look at what that can do in mice as described in Russell DH & Meier H. ‘Alterations in the accumulation patterns of polyamines in brains of myelin-deficient mice’ J Neurobiol (1975) 6:267-275. These mice have an imbalance of spermidine/spermine and wind up with neurodegeneration. Also see Giorgi, PP 'Spermidine: a constituent of the myelin sheath?' Neurosci Lett 1978: 10:335-40, which suggests that spermidine is important in myelin formation. Overexpression of spermine synthase and spermidine/spermine N1 acetyltransferase would reduce the spermidine in the cell.
6. So now a shift to more spermine (and less spermidine) could disrupt the chromatin exposing other genes, particularly RNA polymerase III genes, such as in Alu elements. There are an estimated 500,000 of these. If they get reverse transcribed (see Dewannieux M., Esnault C. & Heidmann T. "LINE-mediated retrotransposition of marked Alu sequences" Nature Genetics (2003) 35:41-48 ).
they could be autoantigenic since they are GC rich but, as reverse transcribed DNA, they are not in their normal epigenetic context to get methylated properly. Therefore they would appear as bacterial DNA and the body would attack that. Lupus has autoantibodies against Alu DNA and the Ku antigen (which associates with Alu DNA). Also, histones attaching to these Alu DNA fragments would be outside of their normal epigenetic context (the histone code) so they would not be considered normal by the immune system.
In MS the problem is probably occurring in oligodendrocytes so myelin formation is the weak point. In lupus the problem is occurring in cells forming collagen which requires a lot of proline, but proline synthesis competes with polyamine synthesis, so collagen formation is one of the weak points.
There is a lot more I can write about this but I have to get back to work. Sorry about it being so complicated but these are complicated diseases. I wrote it up in ‘Autoimmune disorders result from loss of epigenetic control following chromosome damage’ Med. Hypotheses (2005) 64:590-598.
Autoimmune disorders result from loss of epigenetic control following chromosome damage.
Med Hypotheses. 2005;64(3):590-8.
Drug Discovery Program, SRB-3, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. firstname.lastname@example.org
Multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis share common features in typical cases such as: adult onset, central nervous system problems, female predominance, episodes triggered by a variety of stresses, and an autoimmune reaction. At times, the different disorders are found in the same patient or close relatives. These disorders are quite complex but they may share a common mechanism that results in different, tissue-specific consequences based on the cell types in which the mechanism occurs. Here, it is hypothesized that DNA damage can lead to loss of epigenetic control, particularly when the damaged chromatin is distributed unevenly to daughter cells. Expression of genes and pseudogenes that have lost their epigenetic restraints can lead to autoimmune disorders. Loss of control of genes on the X chromosome and loss of control of polyamine expression are discussed as examples of this mechanism.
http://www.ncbi.nlm.nih.gov/entrez/quer ... &DB=pubmed
Here's another idea about the MS twin data, involving hormones of course.
Steroid hormones: effect on brain development and function
Just wanted to throw it in the mix.Hormone effects on the brain are classified as organizational, occurring during development; cyclical, occurring during maturity; experiential, depending on the individual experiences; and disorganizational, leading to damage and destruction of neural tissue....experiential effects, in which hormone secretion is evoked on an individual basis according to personal life events, are responsible for individual differences even between identical twins having the same genetic constitution. Experiential effects, often involving stress and possibly thyroid hormones, may result in adaptation or may lead to disorganization and damage under extreme and deleterious conditions.
In my rush yesterday I had put in an incorrect reference when discussing reverse transcription of Alu genes. I have corrected the reference now and it is:
Dewannieux M., Esnault C. & Heidmann T. LINE-mediated retrotransposition of marked Alu sequences. Nature Genetics (2003) 35:41-48.
It shows that Alu RNA could be reverse transcribed 300x more easily than other mRNA when LINE1 does the reverse transcription.
As far as a definition of epigenetics, I will try to come up with good examples. For a start, think of the written sentence:
"The cow jumped over the moon."
Think of this as the DNA sequence of a gene. When you read it, it gives you a visual image (the protein).
If I make a genetic change by mutating this 'gene' from cow to horse, the sentence now reads:
"The horse jumped over the moon."
That creates a different image or 'protein'. Maybe that is functional in giving you the basic image intended ('protein') or maybe it is a non-functional 'protein', it does not create the image it should create or perhaps it no longer creates any image for you. I can never go back to the originally intended image (a cow jumping over the moon) without doing another mutation to replace horse with cow in the sentence. So we are stuck forever with the horse. A genetic mutation has occurred.
To demonstrate the epigenetic version of this, the silencing of the gene without mutating it, I can put a piece of paper over the sentence and the image can not be created in your mind because you can not see/read the sentence (the 'DNA sequence of the gene'). If I simply remove the paper you can then read the sentence ('gene') and get the proper image ('protein') of a cow jumping over the moon.
Think of the paper as being DNA methylation and histone methylation which are some of the things that can suppress a gene from being read in the cell. If you remove the DNA methylation and histone methylation from key sites in the gene, particularly in the gene's promoter region, then the gene can be read to create the corresponding protein.
Now think of the sentence twice, in other words we have two copies of the gene (for example as females have two X chromosomes with the same genes).
"The cow jumped over the moon."
"The cow jumped over the moon."
We only want to convey the image once, otherwise we are overdoing it. So we cover one sentence (epigenetic silencing) and let the remaining one be seen to convey the image. If for some reason the paper gets removed from the second sentence by accident, we now have the sentences and the images overexpressed. No mutations occurred, just a loss of the epigenetic silencing.
There, that should be pretty confusing. Good thing I didn't use sheep jumping over a fence! Probably had the same effect though. Wake up.
Identical Twins' Genes Are Not Identical
Scientific American - Identical twins are identical, right? After all, they derive from just one fertilized egg, which contains one set of genetic instructions, or genome, formed from combining the chromosomes of mother and father.
But experience shows that identical twins are rarely completely the same. Until recently, any differences between twins had largely been attributed to environmental influences (otherwise known as "nurture"), but a recent study contradicts that belief.
Geneticist Carl Bruder of the University of Alabama at Birmingham, and his colleagues closely compared the genomes of 19 sets of adult identical twins. In some cases, one twin's DNA differed from the other's at various points on their genomes. At these sites of genetic divergence, one bore a different number of copies of the same gene, a genetic state called copy number variants.
For the rest of the article:
http://www.sciam.com/article.cfm?id=ide ... -identical
I am in San Diego this week for the FASEB meeting (Federation of American Societies of Experimental Biology). I happened to hear a talk yesterday morning by Dr. Claudia Lucchinetti on the patterns of MS and she went on about some other demyelinating diseases. Hers was a special TEVA/Parisi award lecture. It was interesting. I took some notes but don't have time now to relay them.
This afternoon there is a talk by Dr. CD Allis regarding epigentics. He is the leader in trying to decipher the 'histone code'. The idea is that histone modifications (such as methylation or acetylation) in different sites in the genome can signify the potential activity of the underlying genes. Of course there is more to epigenetics than just the histone modification patterns but usually they tie in close with the DNA modifications, and possibly with some non-coding RNAs.
There are a number of lectures I am trying to get to but so many are on at the same time. I am also looking at posters. I was pleasantly surprised to see 3 or 4 posters on DNA as autoantigens in lupus. With all the topics being discussed, we scientists are like kids in a toy store.
Complete 'cookbook' for running a genome published
21 April 2008 - NewScientist.com - Get ready to start hearing "epigenomics" as often as you hear about genomics.
If the genome is like a list of genetic ingredients, then the rules for how those genes are used and when they are switched on and off is the business of epigenetics. The first full piece of this "cookbook" has now been sequenced – a plant's epigenome.
Life often modifies its genetic material without changing the letters of the genetic code. One of the main ways this is done is through the addition of a chemical unit called a methyl group to a gene.
This methylation effectively gums up a gene's copying machinery. It is thought to be an important factor in directing stem cells to develop into different tissues, and problems with methylation are implicated in a number of diseases including cancer and Huntington's.
Joseph Ecker of the Salk Institute in La Jolla, California and colleagues have used a new method to sequence the complete "methylome" of the cress Arabidopsis for every letter of its genetic code, giving a far more detailed recipe than prior efforts.
The work is also an improvement on a technique demonstrated in March by Steven Jacobsen of the University of California, Los Angeles. By removing some of the steps that the method requires, Ecker's team have greatly speeded up the process of sequencing epigenetic data.
The method produces lots of data – the Arabidopsis genome comprises some 120 million DNA bases – so the team has developed open-source software to "browse" the genome and find where methylation is controlling gene expression. The program will be able to track more epigenetic data as it is produced, forming a global resource for collecting and analysing it.
"Capturing this kind of sequence-level information for entire genomes of individual plants or humans is now possible and will soon become routine," Ecker says. "In fact, we have already begun using these methods for sequencing of the human methylome."
Ecker says that the team will look into how methylation affects the development of human stem cells as they change into other types of cells.
Eric Selker, a molecular biologist at the University of Oregon, calls the work a tour de force. He says that the steep drop in the costs and of sequencing in recent years means that the floodgates are open for epigenomics.
"It's amazing what can be done in a small amount of time with this new technique," he says.
Rethinking the Genetic Theory of Inheritance
January 18, 2009 - Physorg.com - Scientists at the Centre for Addiction and Mental Health (CAMH) have detected evidence that DNA may not be the only carrier of heritable information; a secondary molecular mechanism called epigenetics may also account for some inherited traits and diseases. These findings challenge the fundamental principles of genetics and inheritance, and potentially provide a new insight into the primary causes of human diseases.
Your mother's eyes, your father's height, your predisposition to disease-- these are traits inherited from your parents. Traditionally, 'heritability' is estimated by comparing monozygotic (genetically identical) twins to dizygotic (genetically different) twins. A trait or disease is called heritable if monozygotic twins are more similar to each other than dizygotic twins. In molecular terms, heritability has traditionally been attributed to variations in the DNA sequence.
CAMH's Dr. Art Petronis, head of the Krembil Family Epigenetics Laboratory, and his team conducted a comprehensive epigenetic analysis of 100 sets of monozygotic and dizygotic twins in the first study of its kind. Said Dr. Petronis, "We investigated molecules that attach to DNA and regulate various gene activities. These DNA modifications are called epigenetic factors."
The CAMH study showed that epigenetic factors - acting independently from DNA - were more similar in monozygotic twins than dizygotic twins. This finding suggests that there is a secondary molecular mechanism of heredity. The epigenetic heritability may help explain currently unclear issues in human disease, such as the presence of a disease in only one monozygotic twin, the different susceptibility of males (e.g. to autism) and females (e.g. to lupus), significant fluctuations in the course of a disease (e.g. bipolar disorder, inflammatory bowel disease, multiple sclerosis), among numerous others.
"Traditionally, it has been assumed that only the DNA sequence can account for the capability of normal traits and diseases to be inherited," says Dr. Petronis. "Over the last several decades, there has been an enormous effort to identify specific DNA sequence changes predisposing people to psychiatric, neurodegenerative, malignant, metabolic, and autoimmune diseases, but with only moderate success. Our findings represent a new way to look for the molecular cause of disease, and eventually may lead to improved diagnostics and treatment."
An advance online publication of this study will be available on the Nature Genetics website on January 18, 2009.