Primer on Genetics

DNA – the code of life

The physical substrate of inheritance is DNA. Just as computer applications are made of binary digital code, genes are made of digital code contained within DNA. The structure of DNA as discovered by James Watson and Frances Crick over half a century ago resulted in the birth of modern biotechnology. With knowledge of the "master blue print" of life, it is possible to unravel complex biologic concepts that determine how our minds and bodies function. Watson and Crick identified the mechanism of faithful DNA replication which allows the transmission of information as cells divide and transfer traits from 1 generation to the next.

DNA is packaged into chromosomes. We have 2 sets of 23 chromosomes that we inherit from our parents. Each chromosome has 2 strands (dark blue) that are held together by links (chemical bonds) between 4 chemical bases or "nucleotides". These bases fall into 2 groups. The pyrimidines (cytosine and thymine) and the purines (guanine and adenine). Cytosine on one strand and guanine on the other are always are bound to each other. Likewise, adenine and thymine bind to one another. If the sequence on 1 strand is known, the sequence on the other strand can be predicted because of these binding "rules." When DNA replicates the 2 strands become separated and each original strand is used as a template for the synthesis of a complementary strand. Hence 2 exact copies are created.

There are 6 billion total bases in human DNA. A portion (25%) is organized into approximately 30,000 functional units (genes), which code for the structure of different proteins. The order or sequence of the bases in a gene determines the composition of proteins. If an error during DNA replication occurs (a "mutation"), the "code" becomes altered and the composition and function of the proteins specified by the DNA sequence may be compromised. These mutations are heritable, being passed from one cell to its descendants and even from one person to their children. Over the course of human evolution millions of base changes ("polymorphisms") have been introduced into mankind's genes (the "gene pool") as "spelling mistakes". Some of these changes are deleterious and cause disease, others are neutral and have no discernable effect on human health and others may actually result in functional improvement in certain environments.

Inherited sites of sequence variability where the new base occurs over 1% of the time are referred to as "single nucleotide polymorphisms" (SNPs). In the example provided here, a cytosine/guanine pair has become changed to a thymidine/adenine pair. The mutation that caused the alteration in the ancestral sequence may have occurred many generations ago. All the descendants of person 1 (top) will have a CG base pairing at the SNP position and all the descendants of person 2 (bottom) will have a TA base pairing at this position. As the mutation site is inherited it always will be found in the same place. Since the entire sequence of all the human DNA (the "genome") has been determined and each base given a serial number on the chromosome in which it occurs, the SNP sites can be catalogued. To date approximately 5 million SNPs have been identified and each one has been assigned a "reference SNP" (rs) number.

SNPs and Disease

With so much variability discovered in the human genome, researchers have new ways to research the genetic basis of human inheritance. Many attempts to correlate inherited SNP variations with common human diseases have occurred. Small amounts of risk have been discovered for diseases such as diabetes, colon cancer, prostate cancer, asthma, inflammatory bowel disease and Alzheimer's disease. Typically such associations are discovered after the analysis of millions of SNPs in thousands of patients, making this research costly and time consuming. As SNP measurement techniques become better and cheaper and human DNA repositories proliferate, the rate of progress will accelerate.