DNA and its discovery timeline

In plants and animals, DNA is organised into 23 pairs of chromosomes within the nucleus of the cell. One member of each pair is inherited from the mother and one from the father. Most DNA molecules are double-stranded helices of two long chains of repeating units called nucleotides. Each nucleotide consists of a sugar and phosphate group (which makes up the backbone of the chain) and a base attached to the sugar (Figure 15.1). The bases are adenine (A), thymine (T), guanine (G) and cytosine (C). Virtually every single cell in the body contains a complete copy of the approximately 3 billion DNA base pairs. A series of three bases encodes for a particular amino acid, with for example ACT, ACC, ACA and ACG coding for threonine, and ATG coding for methionine (Table 15.1).

DNA was first identified and isolated by Swiss physician and biologist Friedrich Miescher in 1871, with its double-helix structure discovered and published in 1953 by James Watson, Francis Crick and Rosalind Franklin. However, it was not until 2001 when the first output of the Human Genome Project (HGP) was published that information on the sequence of bases that make up DNA was available. The project was officially launched in 1990 through funding from the US National Institutes of Health (NIH) and Department of Energy, and resolved to sequence 95% of the DNA in human cells within 15 years. During the early years of the HGP, the UK’s Wellcome Trust Sanger Institute became a major partner. In 2003, two years ahead of schedule, the HGP had achieved its major targets (http://ghr.nlm.nih.gov/handbook/hgp) as follows:

• identify all the approximately 20,000–25,000 genes (section of DNA which encodes a protein) in human DNA,
  
• determine the sequences of the 3 billion base pairs that make up human DNA,
  
• store this information in databases,
  
• improve tools for data analysis,
  
• transfer related technologies to the private sector, and
  
• address the ethical, legal, and social issues that may arise from the project.

In 2004 the almost complete (99.7%) sequence of human DNA was available.

DNA is divided into coding and non-coding regions, with coding regions constituting less than 2% of the total DNA, with the other 98% referred to as junk DNA with unknown biological function. However, unsurprisingly, it is becoming evident through initiatives such as the Encyclopaedia of DNA Elements (ENCODE) Consortium that a large proportion of this non-coding DNA does have essential roles.

Genetic variability

A mutation is the term used to describe a change in the base sequence and structure of DNA (Figure 15.2). Such mutations can be minor, with a change to only a single base in the DNA sequences referred to as a single-nucleotide polymorphism (SNP), right through to changes in the number of chromosomes. The functional consequence (penetrance) of the genotype varies between no detectable impact on phenotype, through to mutations with complete penetrance where all carriers of the mutation develop the trait or disease.

An SNP occurs every 100–300 bases and SNPs account for over 90% of all genetic variability. When a SNPs occur in the coding region of DNA, they may be silent, non-sense or missense (Figure 15.3). Silent, as the term suggests, has no impact on the amino acid sequence of the protein. A non-sense mutation results in a premature stop codon and a truncated and often non-functional protein. A missense SNP results in an amino acid change in the protein sequence, with the functional consequences dependent on where in the protein the amino acid change has occurred, and also on whether the physiochemical properties of the replacement amino acid are comparable to the original amino acid. Although with a few notable exceptions, such as sickle cell anaemia, SNPs rarely cause the disease, they may increase the risk, as will be discussed later in this chapter. It is well known that SNPs in non-coding regions also have functional consequences, although the metabolic basis for this is less clear. A SNP in the gene promoter region may have an impact on the expression of the gene, whereas those in intergenic regions may affect the translation of the genetic code into a protein, for example by influencing mRNA stability or motility within the cell.

Structural variants, are operationally defined as genomic alterations (deletions, duplications, copy-number variants, insertions, inversions and translocations) that involve segments of DNA that are between 1 Kb and 3 MB, with smaller (<1 Kb) variations that involve DNA insertions or deletions referred to as INDELS. Repeat sequences are a length or nucleotide sequence that is repeated, with the consequences often dependent on the number of repeats.

Genetics and disease risk

Almost all diseases have some genetic component. A genetic disorder is where the genotype contributes to the aetiology of the disease. For the majority of cases of chronic age-related conditions such as cardiovascular diseases (CVD), Alzheimer’s disease (AD) and osteoporosis, the greater part of the genetic risk is thought to be afforded by multiple low-penetrance SNPs and these disorders are therefore referred to as polygenic. However, a small percentage of the cases of such conditions are caused by high-penetrance single-gene defects (also referred to as Mendalian or monogenic disorders). For example, for AD, mutations in three genes, namely amyloid precursor protein, preselin-1 and preselin-2, have been linked to an early-onset (< 60 years) monogenic form of the disorder, which accounts for less than 5% of all cases. In contrast, the common APOE4 genotype (20–25% of Caucasians) has been genetically linked to the late-onset form of the disease (> 60 years). Individuals with two copies of the APOE4 allele (1–2% of the population) have a 50–90% chance of developing AD by age 85 years, with those with one copy having an approximately 45% chance, compared to a 20% chance in the general population. Furthermore, APOE4 carriers develop AD about a decade earlier than non-APOE4 individuals. However, being an APOE4 carrier is neither necessary nor sufficient to cause the disease. Therefore, this form of AD is considered as polygenic and multifactorial.

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