Tom Strachan - Genetics and Genomics in Medicine

In writing this book, we have benefited greatly from the advice of many geneticists, biologists and clinicians. We are also grateful to various colleagues who contributed clinical profiles and/or laboratory data for case studies, or who advised on the contents of chapters and/or commented on some aspects of the text, notably the following: Chiara Bettolo, David Bourn, Gareth Breese, Heather Cordell, Jordi Diaz-Manera, Shaun Haigh, Rachel Horton, Majlinda Lako, Richard Martin, Ciaron McAnulty, Robert McFarland, Sabine Specht, Miranda Splitt, and Volker Straub.

DOI: 10.1201/9781003044406-1

Three structures are the essence of life: cells, chromosomes, and nucleic acids. Cells receive basic sets of instructions from DNA molecules that must also be transmitted to successive generations. And DNA molecules work in the context of larger structures: chromosomes.

Many organisms consist of single cells that can multiply quickly. They are genetically relatively stable, but through changes in their DNA they can adapt rapidly to changes in environmental conditions. Others, including ourselves, animals, plants, and some types of fungi, are multicellular.

Multicellularity offers specialization and complexity: individual cells can be assigned different functions, becoming muscle cells, neurons, or lymphocytes, for example. All the different cells in an individual arise originally from a single cell, and so all nucleated cells carry the same DNA sequences. During development, however, the DNA structure within chromosomes is changed to allow specific changes in gene expression that determine a cells identity, whether it be a muscle cell or a neuron, for example.

Growth during development and tissue maintenance requires cell division. When a cell divides to produce daughter cells, our chromosomes and the underlying DNA sequences must undergo coordinated duplication and then be carefully segregated to the daughter cells.

Some of our cells can carry our DNA to the next generation. When that happens, chromosomes swap segments and DNA molecules undergo significant changes that make us different from our parents and from other individuals.

Nucleic acids provide the genetic materialof cells and viruses. They carry the instructions that enable cells to function in the way that they do and to divide, allowing the growth and reproduction of living organisms. Nucleic acids also control how viruses function and replicate. As we describe later, viruses can be highly efficient at inserting genes into human cells, and modified viruses are widely used in gene therapy.

Nucleic acids are susceptible to small changes in their structure ( mutations). Occasionally, that can change the instructions that a nucleic acid gives out. The resulting genetic variation, plus mechanisms for shuffling the genetic material from one generation to the next, explains why individual organisms of the same species are nevertheless different from each other. And genetic variation is the substrate that evolutionary forces work on to produce different species. (But note that the different types of cell in a single multicellular organism cannot be explained by genetic variationthe cells each contain the same DNA and the differences in cell types must arise instead by epigeneticmechanisms.)

In all cells the genetic material consists of double-stranded DNA in the form of a double helix. (Viruses are different. Depending on the type of virus, the genetic material may be double-stranded DNA, single-stranded DNA, double-stranded RNA, or single-stranded RNA.) As we describe below, DNA and RNA are highly related nucleic acids. RNA is functionally more versatile than DNA (it is capable of self-replication and individual RNA sequences can also serve as templates to make a protein, or act as regulators of gene expression). RNA is widely believed to have developed at a very early stage in evolution. Subsequently, DNA evolved; being chemically much more stable than RNA, it was more suited to being the store of genetic information in cells.

Genomeis the collective term for all the differentDNA molecules within a cell or organism. In prokaryotessimple unicellular organisms, such as bacteria, that lack organellesthe genome usually consists of just one type of circular double-stranded DNA molecule that can be quite large and has a small amount of protein attached to it. A very large DNA-protein complex such as this is traditionally described as a chromosome.

Eukaryotic cells are more complex and more compartmentalized (containing multiple organelles that serve different functions), and they have multiple different DNA molecules.