Mutations

A mutation is a change in genetic information. Since genetic information is encoded by the order of the nucleotide bases of DNA, adenine (A), thymine (T), guanine (G), and cytosine (C), a mutation represents some sort of change in that order. Mutations may occur in both somatic and sex cells. Only mutations that occur in sex cells can be passed from parent to offspring.

Types of Mutations

Point Mutations or SNPs

A point mutation or SNP (Single Nucleotide Polymorphism), involves the substitution of a wrong base during the replication process. As the enzyme DNA polymerase chugs down one side of a DNA molecule, forming base pairs to build a new complementary strand, it occasionally adds the wrong base. However, DNA polymerase makes very few errors and it corrects most of those quickly. In addition, there are other enzymes that follow along and "proofread" the nucleotides to be sure that the new nucleotides are actually complementary to the template strand. Any misfits are booted out and replaced with the proper base. Thanks to this magnificent system, DNA is consistently replicated with less than one mistake per billion nucleotides!

Nonetheless, this type of mutation does occur and is responsible for the many subtle and not so subtle variations found within and among species. There are three possible outcomes of an overlooked change of one nucleotide during replication. Surprisingly, the "mistake" may have no affect on the organism. For one thing, the genetic code is such that many amino acids are represented by more than one codon (see also gene expression.) Each individual codon is a three nucleotide sequence. In many instances, there are several sequences that code for the same amino acid, their sequence frequently differing by only one nucleotide. For example, the triplet codons for the amino acid isoleucine are AUU, AUC, AUA, and AUG. Substitution of the the last nucleotide in the DNA sequence coding for this amino acid would result in no change in the resulting protein because isoleucine would be inserted in the protein chain in each case.

On the other hand, an error which changed the first base of the codon to either a U, C, or G would cause the wrong amino acid to be inserted in place of isoleucine. For example, a substitution of a G for the first A in the codon would result in insertion of the amino acid valine instead of isoleucine.

The insertion of the wrong amino acid in a functional region of a protein may cause the protein to be so severely misshapen that it cannot function--even to the point of causing the death of the organism. For example, swapping an A for a T in the gene for hemoglobin results in the insertion of valine instead of glutamine in the protein molecule causing the disease sickle cell anemia.

Normal hemoglobin (eight out of the 146 amino acid units of normal hemoglobin)
Val	His	Leu	Thr	Pro	Glu	Glu	Lys
Sickle-cell hemoglobin (the same section as above as found in Sickle-cell hemoglobin)
Val	His	Leu	Thr	Pro	Val	Glu	Lys
Good red blood cells						Sickle cell blood cells pictures from: www.cc.nih.gov/ccc/ ccnews/nov99/
The function of normal human red blood cells, which are disk-shaped, is to transport oxygen from the lungs to the other organs of the body. Each red blood cell contains millions of molecules of hemoglobin that carries the oxygen. A slight change in the order of the amino acids in the hemoglobin molecule (valine substituted for glutamine), which has only 146 amino acids, causes sickle-cell disease. Abnormal hemoglobin molecules stick together and crystallize deforming the red blood cells. The deformed blood cells then clog tiny blood vessels impeding the flow of blood. Sickle-cell anemia kills about 100,000 people per year in the US

On the other hand, if the substitution affects a less critical region of the protein or occurs in a noncoding (junk) region of DNA, there may be no discernable effect at all. And finally, there are the rare substitutions that are actually beneficial causing the protein to function in such a way as to give the organism a survival advantage.

SNPs are the type of mutations reported in mitochondrial DNA testing for genealogy. Likewise they are used in some tests for Native American Indian heritage.

For more about SNPs in the human genome, I highly recommend the SNP Fact Sheet from the Human Genome Project.

Insertions or Deletions (Indels)
Another type of mutation involves either the insertion or deletion of one or more (some number that is not a multiple of three) nucleotides into a DNA sequence. This type of mutation is known as a frameshift mutation. For an illustration of how devastating this type of mutation can be if it occurs in the coding region of a gene, delete the w from the sentence below.

The cow jumped over the moon.
becomes
The coj umpedo vert hem oon.

The insertion of nucleotides in multiples of three, if not corrected during the culling of introns from messenger RNA, will cause the insertion of an extra amino acid for each three additional nucleotides. Trinucleotide repeats are a sequence of three nucleotides that repeat in tandem and vary in the the number of repeats. Trinucleotide repeat mutations are known to cause at least eight genetic disorders affecting the nervous or neuromuscular system. For more about this topic see http://prl.humc.edu/obgyn/public/genetics/trirep.htm .

YAP an alu insertion

One insertion particularly useful in population studies is the YAP, which stands for "Y chromosome alu polymorphism." Alu is a sequence of approximately 300 base pairs which has inserted itself into a particular region of the DNA. There have been some half a million alu insertions in human DNA; YAP is one of the more recent.

Unstable indels and SNPs are relatively rare and, in the case of the latter, so infrequent that it is reasonable to assume they have occurred at any particular position in the genome only once in the course of human evolution. SNPs and stable alus have been termed "unique event polymorphisms" (UEPs).

Chromosomal Mutations
Some mutations involve all or significant parts of a whole chromosome. An inversion flips over a segment of the chromosome so that the nucleotide sequence of the DNA is backward. Surprisingly, the brilliant little enzymes that coordinate protein synthesis are often, but not always, able to figure this out and use the sequence to direct the proper arrangement of the amino acids anyway. Less easy to compensate for is the actual breakage of a chromosome and consequent loss of a fragment. Sometimes these fragments wander off and attach themselves to another chromosome where they may or may not retain their ability to function.

Junk DNA

Mutations can happen in the junk regions of DNA as well as in the regions that code for proteins. Because junk DNA does not code for protein, these mutations usually have no effect on the individual. They, however, are the mutations that are of value to the genealogist.

Within these nonfunctional stretches are short, moderately repetitive base pair sequences. There are two types of these repetitive sequences. VNTRs (variable number tandem repeats) are repeated sequences that typically range from 10 to 80 bps. These occur fairly frequently in the human genome but there are relatively few different types.

Short tandem repeat (STR) sequences (sometimes called microsatellites) are much shorter (2-10 bps) and may be repeated as many as 100 times at a given location on a chromosome. The human genome contains hundreds of thousands of these STRs all evenly distributed on all the chromosomes. It is the microsatellites on the Y chromosome that are of particular interest to the genealogists seeking to identify their patrilineal line of ancestors.

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