I'll start by apologizing for the brutally long post.
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