Basic genetics for the clinical neurologist

M R Placzek
2002 Journal of Neurology, Neurosurgery and Psychiatry  
T o the casual observer, the clinical neurologist and molecular geneticist would appear very different species. On closer inspection, however, they actually have a number of similarities: they both use a rather impenetrable language littered with abbreviations, publish profusely without seeming to alter the course of clinical medicine, and make up a small clique regarded as rather esoteric by their peers. In reality, they are both relatively simple creatures who rely on basic sets of rules to
more » ... sets of rules to work in their specialities. Indeed they have had a productive symbiotic relationship in recent years and the application of molecular biological techniques to clinical neuroscience has had a profound impact on the understanding of the pathophysiology of many neurological diseases. One reason for this is that around one third of recognisable mendelian disease traits demonstrate phenotypic expression in the nervous system. The purpose of this article is to demystify the basic rules of molecular biology, and allow the clinical neurologist to gain a better understanding of the techniques which have led to the isolation (cloning) of neurological disease genes and the potential uses of this knowledge. c NUCLEIC ACIDS Deoxyribonucleic acid (DNA) is the macromolecule that stores the blueprint for all the proteins of the body. It is responsible for development and physical appearance, and controls every biological process in the body. DNA is the hereditary material of all organisms with the exception of some viruses which use ribonucleic acid (RNA) and prions, that apparently only contain protein. However, its simple composition meant its great importance in biology was overlooked for many years. It was not until 1952 that Alfred Hershey and Martha Chase, and their experiments on bacteriophage, finally proved that DNA and not the more complex protein was the hereditary material. DNA is made of two anti-parallel helical polynucleotide chains wrapped around each other and held together with hydrogen bonds to form a double helix. The backbone of the helices are made from alternating phosphate and deoxyribose sugars. Each sugar molecule is joined to one of four nitrogenous bases, adenine, cytosine, guanine or thymine. These bases face into the centre of the helix and hydrogen bond with their partner on the opposite strand. Adenine can only form hydrogen bonds with thymine, and guanine is only able to hydrogen bond with cytosine. The entire genetic code relies upon these four bases and their specificity of binding. The direction of the helices are described as either 5′ to 3′ or 3′ to 5′ depending on which carbon atom in the deoxyribose sugar the chain begins and ends with. GENES AND THE HUMAN GENOME DNA therefore is the basic substrate for heredity and is divided into functional units known as genes. Recent estimates suggest there are approximately 30-50 000 genes in the human genome. A gene is a sequence of bases that determine the order of monomers-that is, amino acids in a polypeptide, or nucleotides in a nucleic acid molecule. DNA is organised into a three letter code. Each set of three is called a codon, and with four possible bases in each position, there are 64 different combinations, which are more than enough for 21 amino acids. There is approximately 2 metres of DNA in each of our cells packed into a structure only 0.0002 cm across. (If the DNA from all of our cells were removed and placed end to end the strand would reach to the sun and back several hundred times). This is achieved by packing the DNA into chromosomes. Humans have 23 pairs of chromosomes in the majority of cells in their body. One of each pair is inherited from each parent, and most cells have diploid status, in that they contain homologous pairs of each chromosome. One of these pairs is the sex chromosomes (XY in males and XX in females) and the remainder are called autosomes. Genes are arranged in linear order on the chromosome, each having a specific position or locus. With the exception of the sex chromosomes each pair of chromosomes carry the same genes as its partner. For any particular character coded for by a gene there may be a number of different forms, which are called alleles. If an individual carries J Neurol Neurosurg Psychiatry 2002;73(Suppl II):ii5-ii11 * ii5
doi:10.1136/jnnp.73.suppl_2.ii5 fatcat:kkxtvbl3ondsbpi5jthowb4ryi