Genetic Mutation Question

intropy

1st July 2008 - 04:43 PM

Not sure if there are any microbiologists around here, but I have a few quick questions I thought I'd try out anyway.

Triplicate bases in DNA (codons) encode redundantly for amino acids (AA's). (A single AA can have more than one codon.) This means that a random mutation of one base in a gene (a point mutation) can have absolutely no effect.

I want to determine what the odds are of a single point mutation producing an adverse effect in a protein. So far so good. But here's where things get a little fuzzy for me...

I've been told that AA's can be either hydrophilic or hydrophobic. How do these properties affect a protein? Do they change the way a protein folds? If I swap one hydrophilic AA for another equally hydrophilic AA in a peptide chain, does this matter to the protein? Is the same protein produced?

Also, if anyone knows how to get a complete DNA sequence of a short protein, human or otherwise, I would appreciate it immensely. I'm having trouble figuring out how to do so at http://www.ncbi.nlm.nih.gov/

EDIT

Ack, this might be on the wrong board - it says "news" - so forgive me one and all. If there is a moderator who wants to move this to General Science, that would be great.

barakn

1st July 2008 - 09:14 PM

These are very good questions. It's even more complicated than you think. Sometimes an amino acid's charge depends on the pH. Some side chains are bulkier than others. Some amino acids can rotate more than others. Some amino acids can be post-transcriptionally modified and others can't. Some amino acids are at the so-called active site and others are simply structural. Some amino acids are metabolically easier to make. One amino acid can make a covalent bond with another of the same type, others can't. One amino acid is achiral and the others are chiral.
Simply put, it very much depends on the specific situation whether any given amino acid substitution will disable the resulting protein or not.

intropy

1st July 2008 - 10:35 PM

That is simply unbelievable, barakn. (Though I believe you.)

I've understood everything you've said (by wiki referencing) except for one:

QUOTE

Some amino acids are at the so-called active site and others are simply structural.

What does this mean? As for...

QUOTE (->

QUOTE

Some amino acids are at the so-called active site and others are simply structural.

What does this mean? As for...

Simply put, it very much depends on the specific situation whether any given amino acid substitution will disable the resulting protein or not.

I'm wondering whether a single point mutation in the genetic sequence, either transition or transversion, can disable a protein, (or produce a useless string of amino acids.) The possible "information space" for amino acid chains is something like 20^50,000 - using the longest known protein as a maximum length (titin, 26,926 AA's). So there's got to be many useless combinations in there, no? (There might not be, with redundancy at the gene AND amino acid encoding levels [transcription and translation].) Which brings up another question...

If G always pairs with C, and A with T, then when a point mutation occurs, what happens to the pair? Do we get GG's and GT's? Or do BOTH bases mutate to keep the "G with C and A with T law" intact?

barakn

4th July 2008 - 04:56 AM

Many proteins are enzymes, meaning that they catalyze chemical reactions. To do so, the reactant(s) have to bind to a specific spot(s) on the enzyme. They basically fit in this spot like a key in a lock. Sometimes the presence of a reactant (aka substrate) will actually cause the enzyme to shift its shape, bringing the substrate closer to another one so the reaction can take place, or there will happen to be a positive amino acid side chain in just the right place to draw an electron cloud away momentarily, etc.. Amino acids further form the active site are less involved in this crucial process and more tolerant of being switched with another amino acid, typically.

As for your second question, yes, a point mutation near the beginning of the DNA sequence encoding the protein could introduce a stop code where there used to be an amino acid code, and the result would be no protein at all or a short useless chain of amino acids. A mutation could insert a large amino acid in an active site so that the substrate couldn't fit into it. But when considering the information space, consider that there are also many useful but unused combinations* as well.

As for your last question, there are repair enzymes that look for pair mismatches and they will randomly change one or the other to match. a rather in-depth look at one particular repair enzyme

* Note to self: Why does my spell checker not like "combinations"?

intropy

4th July 2008 - 11:36 AM

QUOTE

Amino acids further form the active site are less involved in this crucial process and more tolerant of being switched with another amino acid, typically.

Ahh. Great - thanks. This stuff is so unbelievable.

QUOTE (->

QUOTE

Amino acids further form the active site are less involved in this crucial process and more tolerant of being switched with another amino acid, typically.

Ahh. Great - thanks. This stuff is so unbelievable.

As for your second question, yes, a point mutation near the beginning of the DNA sequence encoding the protein could introduce a stop code where there used to be an amino acid code, and the result would be no protein at all or a short useless chain of amino acids. A mutation could insert a large amino acid in an active site so that the substrate couldn't fit into it. But when considering the information space, consider that there are also many useful but unused combinations* as well.

How do we know, or theorize, that unused ones are useful?

QUOTE

As for your last question, there are repair enzymes that look for pair mismatches and they will randomly change one or the other to match.

Nice. I wasn't aware of this. That these repair enzymes are encoded in the same source that they are checking for errors is simply astounding. What are the odds of any particular enzyme correcting its own definition in the genetic code? (You don't have to answer that one.)

Thanks for the answers and the link - I'm off to check it out.

barakn

5th July 2008 - 06:10 PM

QUOTE (intropy+Jul 4 2008, 05:36 AM)

How do we know, or theorize, that unused ones are useful?

That's what evolution is all about. Life is constantly trying out new variations. If unused variants were never useful then evolution would be impossible.

intropy

6th July 2008 - 10:21 AM

QUOTE

That's what evolution is all about. Life is constantly trying out new variations. If unused variants were never useful then evolution would be impossible.

Oh yeah. Duh. Do we have a partial list yet of proteins that do not occur in the human body now, but did in the past, and could prove useful to us if they were once again produced? Or is the thought that, those proteins were useful at THAT stage, but at THIS stage they have been eliminated for a reason, because...

1) they've become more detrimental than good
2) a newer protein does what they used to do
3) what they used to do is no longer needed

QUOTE (->

QUOTE

That's what evolution is all about. Life is constantly trying out new variations. If unused variants were never useful then evolution would be impossible.

Do we have an idea of the rate "trying out" new variations? (IE, some number of times per minute, day, year, lifetime, etc.)

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