‘’I’m afraid you have the gene for Breast Cancer…’’
No, I’m afraid that the quote above is a common misconception and one that this post aims to correct. I know that in previous posts I have emphasized the ambiguity of certain genetic lingo, but in this post I am to enforce the clarity of one such piece of lingo…Mutations.
All the ENCODE hype has certainly brought molecular genetics to the forefront of the scientific stage and such exposure inadvertently highlights some trivial mistakes. On numerous occasions, I have heard people (from all ranges of scientific backgrounds) use phrases very similar to that set at the top of this page. Phrases declaring that ‘he was unlucky to have the gene for Huntington’s disease’ or ‘it was just in her genes...’ and these phrases are, on most instances, incorrect. For we don’t normally have genes that predispose us to being diagnosed with illnesses or conditions; no, these are mutations in our genes. A spontaneous change has occurred in the sequence of our nucleotides or the arrangement of chromosomes meaning we are now at a greater risk or certain to encounter a particular disease or condition. For example, Huntington’s disease is associated with a mutation on chromosome 4 leading to the production of Huntingtin . So, when you hear those people state ‘He just had the gene for Huntington’s…’ please do intervene and mention that actually he had a mutation within his genes that caused his Huntington’s and not otherwise. Just like genes, mutations come in various types and sizes…
Mutational InformationBefore I discuss particular mechanisms of mutation, it is important that iterate that mutations aren’t always deleterious or detrimental; they can be beneficial. Mutations act as the raw material for natural selection after all, a mutation that improves an animal’s phenotype or fitness is actively selected and kept.
Mutations can be tiny, just a change in one nucleotide can cause a mutation, which is incredible when you take into account that the human genome contains 3,200,000,000 nucleotides . These mutations of just a change in one nucleotide are called ‘point mutations’ and do not alter gene length . These mutations can be caused by various different mechanisms; for example, sometimes the base-pairing at the 3rd base of a codon is often relaxed (the Wobble hypothesis) meaning that an incorrect base is tolerated, it is then when this strand of DNA separates to replicate that an incorrect nucleotide is copied and passed down to a new cell . Alternatively, these point mutations can arise via spontaneous chemical changes to the bases, for example deamination of cytosine to form uracil, this change in nucleotide is then replicated during mitosis or meiosis . These point mutations can have devastating effects, considering the tiny scale of the change it truly is astonishing. One example being a link found a few years ago between point mutations found in the mitochondrial genome and the onset of Parkinson’s disease ; quite a brilliant piece of research, displaying the plausible power of such tiny mutations.
Having discussed the power of point mutation, lets move onto a slightly more serious type of mutations. Namely being ‘insertion or deletion events’ or more commonly described in genetic circles as ‘indels’ . Notably, the phrase ‘indels’ is used on occasions simply because the case is quite ambiguous; it could be an insertion that isn’t meant to be there or conversely it could be deletion in other examples that is meant to be there, I guess in some cases we’ll never know. Unlike point mutations, insertions and deletions do alter gene length, insertions increase the length and deletions do the opposite. Interestingly, these events are associated with repetitive base sequences, such as ‘AAA’ or when a combination of bases is repeated over and over, such as ‘CAG’. How these repetitive sequences generate indels is also reasonably well understood. One mechanism is called ‘strand slippage’ which occurs when a repetitive sequence of nucleotides causes a base to loop out. Such an occurrence in the template strand leads to an omission of a nucleotide, as it isn’t replicated, whilst occurrence on the newly synthesized strand leads to an insertion or addition of a nucleotide. Indels can also occur when homologous chromosomes misalign during crossing-over . Moreover, many genetic diseases are caused by the expanding of these repetitive sequences, for example a normal genotype contains 11-13 ‘CAG’ repetitive sequences, but if this expanded to 40-62 copies then ‘spinal and bulbar muscle atrophy’ results; this again shows the power of mutations .
A bigger class of mutation does exist, these are dubbed ‘chromosomal variations/mutations’ but I don’t wish to delve into that discussion here, my aim was to show the massive effects that can result due to the small mutations; simply to highlight the power of mutagenesis.
The Male Mutation BiasI find this interesting. It’s all to do with the replication dependency of mutation and gametogenesis. Look back over the mutation mechanisms that I have briefly described; they are all replication-dependent, only once replication occurs does the mutation establish itself. To explain the male mutation bias fully, a quick reminder of gametogenesis is required. A male keeps generating sperm throughout his whole life, the cell divisions via meiosis keep occurring, whereas females do not produce gametes throughout life, there is a set number of cell division prior to meiosis. Throughout Oogenesis a female’s gametes undergo 24 cell divisions, whereas by the time a male is only 40 years old his gametes have undergone 610 rounds of cell division . It is important to state that new mutations in gametes can only occur through cell division, the male gametes undergo cell division much more meaning they have a much higher mutation rate. This has two important consequences: 1) most new mutation originate from males, circa 4:1 and 2) the older a male the more mutations in his sperm (approx. 2 per year). These consequences were proven by a study conducted in Iceland and explain why autism and schizophrenia are more common in the children of older fathers . The results of the study (published in nature, see previous reference) grounded the male mutation bias in fact. So, I suppose one could declare that the younger a man produces offspring the better? But not too young, as with everything there is a balancing act and if one looks hard enough, evidence can be found to substantiate most claims. But the results of the study by Kong et al do need to be thought about, with older fathers popping up all over the world, we need to step back and think seriously about the possible outcomes before we go rushing into anything. How very interesting.
The Impacts of MutationI have already alluded to a couple of diseases that arise as a result of genetic mutation, but there are many more and living in a world that seems to be ever increasingly aware of nuclear radiation due to power stations (and plausibly weapons I suppose?) it isn’t beyond reason to believe that many more diseases will arise as a result of genetic mutation. I should make obvious that nuclear radiation (amongst other types of radiation and things) is a serious mutagen (mutagen meaning to generate mutation). Everybody is all too aware of the terrible aftermath of the disaster at the nuclear power plant in Chernobyl back in 1986.
If one types in ‘Genetic disorders’ too any available search engine a terribly long list of results will emerge and with our genetic knowledge gaining momentum by the day, the list will only get longer and longer. Genetics has a big future, but I’m afraid that mutations are going to be a big part of that future.
PLEASE NOTE- This article does contain references, but because I wrote it in a word-processing programme and then pasted here, the references were omitted. A version of this article (and previous articles) containing appropriate reference marks and a bibliography (particularly important for the male mutation bias study in Nature) is available at:
http://biochemperspectives.blogspot.co.uk/
