While they are essential for evolution, defects in DNA synthesis and genomic rearrangements more often lead to genetic (that is inherited) diseases than to any benefit to an individual. You can explore the known genetic diseases by using the web based On-line Mendelian Inheritance in Man (OMIM) database223. To specifically illustrate diseases associated with DNA replication, we will consider a class of genetic diseases known as the trinucleotide repeat disorders. There are a number of such "triplet repeat" diseases, including several forms of mental retardation, Huntington’s disease, inherited ataxias, and muscular dystrophy. These diseases are caused by slippage of DNA polymerase and the subsequent duplication of sequences. When these "slippable" repeats occur in a region of DNA encoding a protein, they can lead to regions of a repeated amino acids. For example, expansion of a domain of CAGs in the gene encoding the polypeptide Huntingtin causes the neurological disorder Huntingdon's chorea.
Fragile X: This DNA replication defect is the leading form of autism of known cause (most forms of autism have no known cause); ~6% of autistic individuals have fragile X. Fragile X can also lead to anxiety disorders, attention deficit hyperactivity disorder, psychosis, and obsessive-compulsive disorder. Because the mutation involves the FMR-1 gene, which is located on the X chromosome, the disease is sex-linked and effects mainly males (who are XY, compared to XX females)224. In the unaffected population, the FMR-1 gene contains between 6 to 50 copies of a CGG repeat. Individuals with between 6 to 50 repeats are phenotypically normal. Those with 50 to 200 repeats carry what is known as a pre-mutation; these individuals rarely display symptoms but can transmit the disease to their children. Those with more than 200 repeats typically display symptoms and often have what appears to be a broken X chromosome – from which the disease derives its name. The pathogenic sequence in Fragile X is downstream of the FMR1 gene's coding region. When this region expands, it inhibits the gene's activity225.
Other DNA Defects: Defects in DNA repair can lead to severe diseases and often a susceptibility to cancer. A OMIM search for DNA repair returns 654 entries! For example, defects in mismatch repair lead to a susceptibility to colon cancer, while defects in translation-coupled DNA repair are associated with Cockayne syndrome. People with Cockayne's syndrome are sensitive to light, short and appear to age prematurely226.
Summary: Our introduction to genes has necessarily been quite foundational. There are lots of variations and associated complexities that occur within the biological world. The key ideas are that genes represent biologically meaningful DNA sequences. To be meaningful, the sequence must play a role within the organism, typically by encoding a gene product (which we will consider next) and/or the information needed to insure its correct “expression”, that is, where and when the information in the gene is used. A practical problem is that most studies of genes are carried out using organisms grown in the lab or in otherwise artificial or unnatural conditions. It might be possible for an organism to exist with an amorphic mutation in a gene in the lab, whereas organisms that carry that allele may well be at a significant reproductive disadvantage in the real world. Moreover, a particular set of alleles, a particular genotype, might have a reproductive advantage in one environment (one ecological/behavioral niche) but not another. Measuring these effects can be difficult. All of which should serve as a warning to consider skeptically pronouncements that a gene, or more accurately a specific allele of a gene, is responsible for a certain trait, particularly if the trait is complex, ill-defined, and likely to be significantly influenced by genomic context (the rest of the genotype) and environmental factors.