Genetics, pedigree

[Anonymous]

Dear colleagues,
It might seem pretty silly, but I need help with the pedigrees. How do you make the darn thing, what do you take into account. I only understand it to a point (like the way the gene is transmitted, the homogygous state, heterozygous state, % of children affected, carriers and so on). What I don't get is on the darn pedigree diagram, when you make it, how do you "decide" the way males and females get the affected genes or not.
Could you please reffer me to a source that explains it really well, something like "pedigrees for dummies".
Thank you and good luck with your exams!
A.

[Anonymous]

Believe it or not, but you already understand the hardest part, namely "like the way the gene is transmitted, the homogygous state, heterozygous state, % of children affected, carriers and so on". You just need to figure out how to interpret the data from a pedegree, or how to document that data in a pedigree. Maybe all the squares, circles, shaded colors, etc are what's confusing you. So I'll provide it in a more realistic way (male represented by a male, female as a female, etc.) to help you see what is being done. Then you will just need to understand what universal symbols are used and how to construct a pedigree (scroll down). Here goes....




Autosomal Dominant

Only one mutated copy of the gene is needed for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. Example: Huntington disease and Neurofibromatosis 1

A person affected by an autosomal dominant disorder has a 50-percent chance of passing the mutated gene to each child. There is also a 50-percent chance that a child will not inherit the mutated gene.






Autosomal recessive

Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers).
Examples: cystic fibrosis, sickle cell anemia

For an autosomal recessive disorder, two unaffected people who each carry one copy of the mutated gene (carriers) have a 25-percent chance with each pregnancy of having a child affected by the disorder. There is a 75-percent chance with each pregnancy that a child will be unaffected.




X-linked dominant

X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern. Females are more frequently affected than males, and the chance of passing on an X-linked dominant disorder differs between men and women. Example: X-linked hypophosphatemia

The chance of passing on an X-linked dominant condition differs between men and women because men have one X and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, and his daughters will all inherit the condition.

X-Linked Dominant with an Affected Father



A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50-percent chance of having an affected daughter or son with each pregnancy.


X-Linked Dominant with an Affected Mother




X-linked recessive

X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. Example: hemophilia A, Duchenne muscular dystrophy

Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene.


X-Linked Recessive with an Affected Father



With each pregnancy, a woman who carries an X-linked recessive disorder has a 50-percent chance of having sons who are affected and a 50-percent chance of having daughters who carry one copy of the mutated gene.


X-Linked Dominant with an Affected Mother



Mitochondrial

This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. (Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA.) Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children.







Pedigree Construction





Males are always represented by square symbols, females with circular symbols. A line drawn between a square and a circle represents a mating of that male and female. Two lines drawn between a square and a circle indicate a consanguineous mating, the two individuals are related, usually second cousins or closer relatives. When possible, the square should be placed on the left and the circle on the right of the mating line. Generations are connected by a vertical line extending down from the mating line to the next generation. Children of a mating are connected to a horizontal line, called the sibship line, by short vertical lines. The children of a sibship are always listed in order of birth, the oldest being on the left. Sometimes to simplify a pedigree only one parent is shown, the other is omitted. This neither signifies parthenogenic development nor does it signify divinely inspired conception, it merely means the parent left out is not from the family being studied and is genotypically homozygous normal for the trait being studied. Normal individuals are represented by an open square or circle, depending upon the gender, and affected individuals by a solid square or circle. Each generation is numbered to the left of the sibship line with Roman Numerals. Individuals in each generation are numbered sequentially, beginning on the left, with Arabic Numerals. For example the third individual in the second generation would be identified as individual II-3.



Source: National Library of Medicine, UIC

[Anonymous]

Hey Step 1,
Thank you very, very much for your reply, it is extremely helpful!
I really appreciate it a lot, that is something else you know, to take the time to answer somebody's need for help in such a manner. You are a very good person! May only good come your way!
Thank you very much again!
A.

[Anonymous]

Here I am again.
I still have a problem. If I construct the pedigree without taking into account the sexes (I know that's not the way to do it), then it's okay. I do not understand how does one correlate the sexes of the children with the affected and nonaffected states.
For instance in the autosomal recessive pedigree, why does the daughter turn out affected and not the son? How come? I know that theoretically a man and a woman can have 2 daughters and 2 sons. But in the pedigree they don't show the X and Y chromosomes as well (so that you can construct diagrams how we did back in school, like okay, if the Dad gives the Y chromosome then it will be a boy, if the Dad gives the X then it will be a girl).
What am I missing? Are there some principles that are just by convention this way or that way, or what is it?
I just hate that I don't understand it. I can't learn something if I don't understand it.
I know I am a drag, but please enlighten me!
Thank you
A.

[Anonymous]

Hi A. Thanks for the kind words. I remember when I was asking similar questions not long ago and many others helped me. So now I'm helping others. One day soon, you'll probably be answering the same type of questions for others. So don't feel bad about asking because it's all part of our cycle of helping each other .

As far as your question, I hope I'm understanding it correctly. But a pedigree is like a family tree in the sense that it documents the lineage already in existence. A Punnet square (spelling?) is the one which is used to predict probabilities. I think you might be confusing the two by trying to create a pedigree to make predictions. For example, an autosomal dominant gene has a 50% chance of being passed for each child. In reality, the couple might have 4 children where all of them are effected. So on the pedigree, you would document the reality of it, which has all children affected. But on the Punnet square, it would still show the theoretical probability of 50% affected.

Using this idea, you will notice that the above pedigrees are merely examples of what one might see with a given disease process. But there are many different possibilities for any disease process in reality, although the theoretical probability shown on the Punnet square remains constant. Following this, you will find it easier to simply document what you see presented (male as square, affected female as shaded circle, etc) rather than what the probabilities are.

Now let's move on to your specific example. Some genetic diseases are transmitted via sex-linked genes (i.e the X gene). But the majority are passed via other, non sex-linked genes. In the autosomal dominant and recessive examples, it doesn't matter about the sex because the genes are not passed via one of those genes which are sex specific. Therefore, the chances are the same of getting the affected gene whether you're a male or female, and the chances are the same of passing the gene whether you're a male or female. That is why it's not factored into the equation.

But with the sex-linked diseases (i.e. X linked dominant or recessive), the sex must be considered because the disease is actually passed through one of the sex genes (i.e. X gene). Since a female carries two of these and a male carries only one, the probabilities change for passing the gene and receiving the gene from the parents depending on sex. That's why the sex is factored for these diseases.

I'm not sure I explained that well or if I just confused you even more , but let me know if you still have questions and I'll try to provide some examples or something when I have more time. Best of luck.

[Anonymous]

I think I understand now. Thanks again for being so prompt and so thorough, and for leaving the door open for me to ask more questions of you if need be! I admire your knowledge!
Wish you the best!
A.