About Genes and Inheritance – by Charles D. Smith, MD

 

It is an amazing fact that microscopic hereditary elements, or genes, represent all the instructions for human growth, development, maturation, and maintenance of the body from conception to death.  There is an identical copy of this information in all of the 10-100 trillion (million-million) cells of the body.  These instructions are like a design blueprint for a house, and just like a blueprint you can only move into the house to live after a lot of work has been done translating the blueprint into a real working structure.  The blueprint is slightly different from person to person, but different enough to account for many differences between us as individuals.

A different explanation is that each gene is like a coded message written on one page of a book.  Genes are strung together in long strands of DNA to form a chromosome, just as pages of a book are bound together into one volume.  Each page of this code, when translated as an instruction, contributes a small part of the body structure.  Several volumes of these pages represent the entire gene code for one person.

Imagine a whole 23-volume set of encyclopedias with red bindings written in this code placed on a bookshelf right above another 23-volume edition of the same encyclopedia but with blue bindings.  The red set you inherited from your father, and the blue set from your mother.  This represents the information in the 46 chromosomes of the human body.  If you had great wisdom you could pick a red volume off the shelf and flip through it, perhaps finding a page containing the code for the eye-color gene that you could read.  Somehow translating this page of code represents eye color.  If you went to the same volume and page in the blue encyclopedia, you might find that the code was slightly different from the code on the same page in the red volume.  The information you now have is the sum of some information from your father and some very similar but not identical information from your mother.  Depending on the information on the same page in both volumes, you end up with either brown or blue eyes.  Somehow the pages of code are woven into a complete story, and that story is us!

So if each of us has two sets of encyclopedias, and we pass copies of this information on to our children, why are our children similar but not the same as us?  Nature has created variation by having each parent contribute only one complete 23-volume set of encyclopedias to each child.  Each set that is passed down is different because the volumes are swapped randomly between the parent's red and blue sets.  So the "red" set we get from our father is a mixture of some of his red and blue volumes.  To add more variation, some of the pages in the volumes we get are swapped with pages of the volumes we did not get from him!  And the same goes for our mother, so there are enough new pairing combinations possible to make each of us unique.

There has been a lot of news lately about "sequencing the human genome".  Basically this means we now have a full set of the code in one edition of this 23-volume human encyclopedia.  One of the surprises was that most of the pages in each volume are blank or meaningless!  Of the several thousands of pages in each of the 23 volumes, only a small fraction, about 1,300 pages in each volume, contain gene codes.  This means that of hundreds of thousands of pages in the whole encyclopedia set; only thirty thousand are "gene pages" with real information.  We know that some of the pages contain the code for things like eye color, but there are many pages where we do not know what the code is for.

What if the information on one of the pages is wrong for some reason?  A slight change in the code on one page can translate into a major problem, a minor problem, or no problem at all.  Getting back to the house blueprint idea, if there is a small error somewhere in the plan, what happens next depends on where precisely the mistake is.  If the error in the plan specifies windows that are slightly larger, the effect might not be noticeable, maybe even an improvement, but if one of the beams holding up the roof is too small, the house could fall in.  We accept many differences between us that are due to variations in the code and do not make much of it –height or eye color for example.  But if the effect of a difference in the code is harmful to health, this difference is classified as a genetic disease.

In Inclusion Body Myopathy, Paget Disease of Bone, Frontotemporal Dementia disease (IBMPFD), sometime in the past, there was a change in one word on one particular page of volume nine of the encyclopedia (we don't know whether it was a red or blue volume nine).  This page gave the code for valosin-containing protein, the cause of IBMPFD.  It is impossible to know why this change occurred, and medical science has no ultimate answer to this question.  No one is at fault for it, and no family deserves to inherit it.  This small change causes all of the problems of IBMPFD disease.  This change has been passed down through generations, but because volumes and pages are swapped for each child, it has been impossible to know who inherited the change until symptoms of weakness, bone changes, or memory loss appeared.

Through research we now can analyze a sample of DNA, the hereditary encyclopedia in each cell of our body, from the blood.  The code on a specific page on volume nine can be read and compared with the same page read from individuals without IBMPFD.  If there is a change, it can be detected this way.  This is great research progress, but detecting the inherited change in the code on the IBMPFD gene is only a first step.  Here are some further questions we need to answer:

1) What are the precise medical details of IBMPFD?  Are there other unrecognized problems besides those in the bone, muscle, and brain?  Are there differences in the age when symptoms appear or in the severity of symptoms between persons affected?  Do symptoms group together?  Are there individuals who have the IBMPFD gene but who never get any symptoms of disease?

2) How does the IBMPFD gene work?  Are other genes involved?

3) What does the gene instruction do, and how is it related to the bone, muscle, and brain?

4) Do some individuals with the IBMPFD gene only have bone and muscle problems, while others with the same gene develop memory loss and dementia?

5) Why do symptoms of IBMPFD appear mainly in adults?  Why are not children affected?

6) Is there some way to predict whether someone with the IBMPFD gene will later get dementia?

7) Is there some way to make up for the IBMPFD gene and prevent symptoms of bone, muscle, or brain disease?

8) Once symptoms of IBMPFD appear, is there any way to improve them?

9) How do we help families understand this complicated disease?