Monday, September 22, 2008

Genetic terms and background information

ADHD Genes

Genes, Chromosomes, DNA and alleles: What are they and how do they relate to ADHD?

Author's Note: I realize that a lot of readers may not have any sort of background in genetics, which is why I constructed this page. If you are unfamiliar with how genes, DNA, Chromosomes, and alleles all tie together, this should serve as a great resource page. I tried to make it as straightforward as possible and use an analogy that makes the concept of genetics easy to follow. A number of other posts deal with the fact that a lot of causes of ADHD are inherited from parents to children. I am posting a number of sections on specific genes and alleles that are tied to the disorder of ADHD. Please check out the resources below:

Genes are comprised of long strings of DNA (typically numbering in the thousands or ten-thousands) and serve as a blueprint instructing the body as to:

1.) Which products (enzymes, hormones, etc.) to manufacture

2.) Where to manufacture the desired products

3.) How much of the products to manufacture

4.) When to stop, inhibit, or shut down manufactured products

Scientists generally agree that there are somewhere between 30,000 and 50,000 different genes in the human system.

DNA is short for the term Deoxyribo Nucleic Acid. It comes in four flavors or bases.

1.) Adenine (abbreviated as "A")
2.) Guanine (G)
3.) Thymine (T)
4.) Cytosine (C)

With all of the genetic diversity and variation among humans out there, it might seem strange that it all comes from four primary bases or options. However, we can see that, with four different options at every spot, we can build up a huge number of different possible sequences. Given the fact that the total length of DNA in humans is around 3 billion bases long, this means that there are an ENORMOUS number of possible combinations at our disposal.

For example, a segment of DNA may be in the following sequence: "CCGATA". This means that a Cytosine is strung to another Cytosine, which is connected to a Guanine, which is connected to an Adenine, which is connected to a Thymine, which is connected to another Adenine.

DNA's structure is typically in the helical form (think of a winding staircase). It can exist either in the single-stranded form or double-stranded form. The double-stranded form contains two strands bound together, winding up in staircase form called a double helix. The double-stranded form is relatively stable, because of a phemonomena called base pairing.

Base pairing:

The four DNA bases (A, T, C and G) tend to pair up with each other in what it called complementary base pairing. "A" tends to pair with "T" and "G" tends to pair with "C". In other words "A" and "T" are complementary, and "G" and "C" are complementary.

For example, consider our earlier sequence of "CCGATA": If this sequence is part of one DNA strand, the other one will typically match up with a complementary strand of "GGCTAT".

Do you see how that works?
CCGATA <---- strand 1 GGCTAT <---- strand 2
The C's on strand 1 match up with the G's on strand 2, the A's on strand 1, match up with the T's on strand 2 and vice versa. This pairing up and bonding between the two strands of DNA makes the DNA double helix quite stable. Since we know how the strands match up with each other, if we can find out the sequence of one strand, we can figure out what the other one would look like. For example, if we have one strand that has the following sequence:


we can predict that the other one will "match up" with


Again, the A's from one strand match up with the T's from the other and the G's from one strand match up with C's from the other and vice versa.

Genes and DNA: The "highway and towns" analogy

Genes actually make up a relatively small percentage of the body's total DNA (thought to be less than 10 or 15%). One of the best ways to think of this is to envision a large highway that connects a number of towns together, but also passes along through long stretches of open country. The "highway" is the DNA, while the towns, (where the functional stuff "happens") are analogous to the specific genes. The stretches of highway in between the towns serve a limited function; their main purpose is to serve as a buffer space between the important towns. Similarly, the vast majority (over 85%) of DNA is not in the genetic region and is of limited function.

Since there are so many genes (towns), in humans, it would make more sense to create multiple highways to incorporate all of them instead of having just one long one. Essentially this is what nature does. It subdivides the DNA into different “bundles” or "groups" called chromosomes. The number of different “highways” varies from species to species; in fruit flies, the number of highways is 4, in humans, the number is 23. Additionally, human beings actually have two “pairs” of highways, one coming from each parent. Going back to our road analogy, think of our highway as a divided one, with one way going eastward and the other going westward. The two highways are “paired up”, that is, they go through the same towns and cover the same stretches of land in between, but there are now two highways instead of one. Therefore, with humans, we (typically) have 23 pairs of chromosomes (highways), for 46 total.

For humans, one of those pairs of highways is sex-determinant. If both highways are marked “X”, then you are female, if one of your highways is “X”, but the other is “Y”, then you are a male (you cannot have both highways or chromosomes as “Y” because your mother can only pass on an “X” chromosome, while your father can pass on either an “X” or a “Y”). While sex determination is a critical function of the sex chromosomes, it is important to realize that these “X” and “Y” highways also contain a number of genes themselves. These genes are referred to as “sex-linked”. If certain traits or inherited disorders show up exclusively or highly disproportionately in males or in females, chances are, at least one “sex-linked” gene is responsible.

Doing a bit of math we can see that with around 30,000-50,000 different genes (towns) and 23 pairs of chromosomes (highways), we would expect a typical highway to contain somewhere from 1000 to 2000 genes (towns). While the number of genes are not evenly distributed (some chromosomes or highways are larger than others), 1000-2000 genes per chromosome is a good estimate. Keep in mind, too, that the genes or towns vary in size as well; some may be cover a much longer stretch of highway than others. The distribution of genes among chromosomes normally does not vary from individual to individual, so you, your sister, your best friend and your next door neighbor will all typically have the exact same number of genes in the exact same order on a particular chromosome.

Taking this analogy a bit further, where we can identify a certain town as a "gene", we can further subdivide that town into smaller sections (think of individual blocks within a town). For example, one of the “ADHD genes” called the Dopamine Beta Hydroxylase Gene (DBH), has a location of “9q34”. What that means is that this gene is located on Chromosome #9 (“Highway 9” to follow the analogy), section “q34”. “q34” actually does not refer to one particular town, it still covers a slightly larger space than that (think along the lines of a county), but it does help narrow the location down quite a bit. Further numbers or letters beyond the “34” (which typically follow a “.”, such as “34.1”), can help narrow the location down even further to the city, and eventually block or even specific building level.

As mentioned, almost all humans carry the same number of genes in the same order, on the same chromosome. In other words, town #487 on chromosome 12 will be the same “gene” for you, as it is for Bob. Additionally, most of the blocks in your 487th town will look exactly the same as they would in Bob’s 487th town. However, there are some specific blocks that will show some variation between your town and Bob’s town. These slightly different forms of the same town are what are referred to as alleles (slightly different forms of the same gene).

Some genes have different alleles that differ in only one spot. For example, the first 8 blocks of your town and Bob’s town may contain the exact same buildings in the same order, but the 9th block in Bob’s town may contain a McDonald’s while yours contains a Burger King. Also, some alleles may differ by having a slightly longer or shorter segment for a particular block. For example, Bob’s town (allele) may have an extra gas station between blocks 15 and 16, while yours may have additional park space between blocks 19 and 20. A genetic analogy to this would be having a few extra pieces of DNA than Bob in a particular section of a gene.

Either way, it is important to remember that your genes and Bob’s genes are over 99% identical, there are just some minor differences such as those mentioned above. However, even these minor differences can have a number of prolific effects. For example, if your town and Bob’s town have the same number of residents, but Bob’s has 3 more gas stations than does yours, who do you think will be better adapted to supply enough gasoline for the town in the event of a fuel delivery truck failing to show up on a particular day? If your town has one additional power station than Bob’s, and a recent heat wave pushes up the power demand for a week, whose town will be better suited?

Similarly, a few small differences in individual variations of the same genes can play notable roles when dealing with disorders such as ADHD. A few key changes can significantly enhance or inhibit levels key proteins or neural chemicals. For example, the compound dopamine is an important signaling agent in the nervous system in which adequate levels are needed for proper brain function in areas such as maintaining an attention span. Not surprisingly, a number of ADHD individuals have lower than normal levels of dopamine in the frontal regions of the brain. Certain genes are responsible for producing key enzymes that aid in the manufacture and delivery of this important brain-friendly compound. Unfortunately, some forms or alleles of these genes are less effective in manufacturing these key enzymes. As a result, individuals with these alleles are more prone to dopamine imbalances in key regions of the brain. As a result, they are more prone to having ADHD. In the context of attention deficit disorders (ADD) and attention deficit hyperactivity disorders (ADHD), we will examine which forms or alleles of specific genes are tied to ADHD.

ADHD Genes

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1 comment: said...

Very useful material, much thanks for this article.