DNA Structure

The Molecular Basis of Inheritance

The invention of the microscope made it possible to observe the structural process of cell division. A fundamental observation was made; growth follows a strict pattern in which one cell can divide, giving rise to two cells. It became clear that during cell division a set of structures, named chromosomes, were assembled.

Chromosomes differed in their physical appearance and always were present in pairs. During cell division, each chromosome was first duplicated and, as the orginal cell divided in two, each "daughter" cell was provided with a complete set of chromosomes present in the "parent" cell. A powerful circumstancial case was developed that the chromosomes contained the genetic material and provided the structural basis for growth as the genetic information was transferred from one cell to its offspring during cell division.

From careful studies of fertilization using isolated egg and sperm it was established that the female and male partners each contributed one of the two chromosomes in each pair to their offspring. Specialized processes were observed in the production of the mature "germ" cells involved in reproduction, eggs and sperm, such that each individual egg or sperm contained precisely one member of each pair of chromosomes. Different organisms can have different numbers of chromosomes. Humans have 46 chromosomes in 23 pairs. In our case, each of our parents contributed 23 chromosomes, one member of each of the 23 pairs contained in every cell of our body.

Although many of the general principles of inheritance were established, the molecular basis for inheritance, the precise character of the "genetic" information, was unknown. In the middle part of this century it became clear that the molecular basis for genetic inheritance resided in a large molecule, or a set of such molecules, associated with the chromosomes. These were composed of a large number of smaller units. The smaller units were "organic" molecules (as opposed to inorganic molecules, composed of metals for example) composed of carbon, nitrogen, hydrogen, and oxygen. They had the properties of weak acids, and since they were contained in the nucleus of cells, became known as nucleic acids.

The work of many investigators established that the large molecule was composed of four different nucleotides (again named for their presence in the nucleus). Each nucleotide was shown to be composed of two parts, a 5 carbon sugar, related to a sugar known as ribose, and one of four organic ring structures known as either a purine, or a pyrimidine. There were two purines, Adenosine and Guanidine, abbreviated as "A" and "G", respectively, and two pyrimidines, Cytosine and Thymidine, abbreviated as "C" and "T". The ribose molecule differed from that observed in other

parts of the cell in that it was lacking an oxygen at attached to one of the five carbons. Since each nucleotide contained ribose missing an oxygen atom, the large molecule became known as "deoxyribonucleic acid," abbreviated as DNA.

A variety of biophysical studies showed that the structure of DNA appeared to be almost crystalline in nature. Chemical studies showed that the nucleotide composition of DNA varied so that one organism would tend to have different proportions of A and G when compared to that from another organism. But within that variation, a strict rule was discovered: the amount of A was always precisely matched by the amount of T, while the amount of G was precisely matched by the amount of C.

Modern molecular biology began when James Watson and Francis Crick proposed a model for the molecular structure of DNA consistent with the rules regarding AT and GC compostion and that provided a molecular explanation for how information was stored in DNA an how that information might be copied. The model became known as the "double helix" structure of DNA.

The double helix of DNA can be visualized as an unusual kind of ladder. In a normal ladder the two side rails of the ladder are parallel to one another and connected by rungs. Imagine cutting the ladder down the center of the structure so that each rail has one-half of each rung. Now turn one of the rails end to end and reassemble the ladder. The ladder now has an "antiparallel" structure where the two rails run parallel to one another, but now run in opposite directions so that the "top" of one rail is connected to the "bottom" of the other. Finally, imagine twisting the structure of the ladder so that the two rails wind around one another in a long spiral, a kind of double spiral staircase, that makes a complete turn every few rungs. The ladder is now a double helix (helix is the mathematical name for the spiral structure).

In DNA, each spiral is composed of a very long string of nucleotides coupled to one another by means of an organic phosphate molecule connecting the deoxyribose portion of adjacent nucleotides. Within the double helix, each A is paired with a T, and each G paired with a C. When paired in this way the nucleotides fit together perfectly and are held together by interactions known as "hydrogen bonds." These A would pair precisely with T, the molecular fit of A with C or G was very poor and highly unstable. In the same way, G and C would form precise pairs, while neither would form stable pairing with A or T.

The structure immediately provided the molecular basis of inheritance in that each DNA strand contained the information to construct a perfectly matched partner. The restriction on nucleotide pairing meant that the two strands of one helix could separate and contained the

information needed to produce two helices, each containing one of the two original strands and a newly assembled partner whose sequence of nucleotides was determined by the "parent" strand.

This becomes clearer if we consider how a very short strand of "parent" DNA might divide and make two precisely identical "daughter" strands. Here is a strand containing eight pairs of bases (letters.) Note how the sequence of one strand is "complementary" to the other, a direct consequence of the rules for base paring where A can only pair with T and G can only pair with C.

A T T C G T G C
| | | | | | | |
T A A G C A C G

If the strands are separated, we get two different single strand sequences where each one contains the information required to make a precise duplicate of the original double stranded structure. Thus we get

ATTCGTGC
and
TAAGCACG

The cell is constantly making new "letters" and these can pair with single stranded DNA and then be linked together to make new strands. Thus we can form two identical double stranded structures:

A T T C G T G C
| | | | | | | |
T A A G C A C G

and

A T T C G T G C
| | | | | | | |
T A A G C A C G

Although we have used a short sequence as an example, you can see that very long strands can make precise copies following these simple rules. The double helix structure of DNA thus contained all of the information necessary to replicate itself in a manner exactly paralleling the process of growth where one cell gives rise to two. If the information necessary for constructing a living cell was contained in the sequence of letters, A,T,G,C, in the DNA molecule, that information could be preserved as the double helix molecule separated into two single strands. Since each of the four letters will only pair with one letter, each strand will accurately "code" the construction of a new partner or "complementary" strand. This leads to the formation of two identical double helix molecules and the precise duplication of all of the information contained in the parent DNA molecule in each of the new molecules. Our DNA molecules are extremely long, containing millions of letters in a paired linear sequence. These DNA molecules are packaged into chromosomes. Recall that our DNA contains information equivalent to 200 encyclopedia volumes. Since we have 46 chromosomes, that means that the average chromosome contains the same amount of information as that found in the first five volumes of the Encyclopedia Brittanica.