So, why do mutations arise? Because errors can be introduced during DNA replication, transcription, translation, and recombination. So, recombination is an exchange of genetic materials between sister chromatids that really makes us different. So, not all of the chromosome is inherited to progeny the same way, so there are some differences even within one chromosome from one generation to another. So, exposure to mutagens such as chemicals, UV rays, and ionizing radiation could be a reason for a mutation. And aging itself can lead to mutation. And we have a great DNA repair enzyme, especially in the nucleus genes, but there may be some mistakes made and not all the spelling mistakes may be corrected. So, that's how mutations can be introduced and then inherited over generations. So, where do mutations arise? So, germline mutations arise in germ cells that develop into sperms or ovaries, and you know that this is heritable. And somatic mutations arise in somatic cells. This occurs after conception, so can be passed on to their cellular progeny, but not heritable to next generations. So, cancer has heritable mutations, but they also acquire somatic mutations, which may contribute how the cancer spreads, is additional mutation that they acquired after conception. So, mosaicism is a very interesting phenomenon, presence of two or more genetically different sets of cells within a population. So, one example of a disorder is McKeown-Ulbrich syndrome, which has a triad of polyostatic fibrous dysplasia, as well as cafe au lait spots, cafe au lait spots, which are described as coastal Maine rather than coastal California, which is more seen in neurofibromatosis. So, cafe au lait spot is a brownish macules that occurs on the skin, and then they may also have precocious puberty. Hyperthyroidism can be observed in McKeown-Ulbrich syndrome, as well as excess cortisol and growth hormone as well. And you probably already know about McKeown-Ulbrich syndrome. Let's describe types of mutations. So, you have a reference sequence, and when a nucleotide is missing, that's deletion. It could be one nucleotide or multiple nucleotides, that's deletion. And it could also shift the reading frame to make a protein, so different protein may be made after this mutation occurs. And substitution is replacing one nucleotide with another nucleotide. So, there's no change in the number of nucleotides. Insertion is adding another nucleotide into a sequence. So, there's also a shift in the reading frame, so different protein may be produced after that mutation. So, mutation could be more global, since it occurs in the chromosomes. A segment of chromosome may be deleted, so it makes that chromosome shorter than the original chromosome. And it could be duplication. The segment of chromosome may be duplicated, so repeat it, so that makes the chromosome much longer. An inversion happens when the segment of chromosome is kind of flipped, so the location closer to centromere is now further away from the centromere, so closer to telomere. And the insertion happens, the portion of chromosome breaks away and inserts into another chromosome, and if it's, you know, the inserted chromosome becomes longer and the original chromosome becomes shorter. This can happen in reciprocal sense, that piece of one chromosome can insert into another, and then piece of another chromosome can be inserted back to the piece of another chromosome can be inserted back to the original. So, it can be a balanced translocation, that's when there's no loss of genetic material. There may be no disorder manifesting in this case, but unbalanced. If the piece is missing from one of the chromosomes, those genes are totally missing from the human genome, then disorder can result. And another case may be the break point is at the important location, affects the functionality of the genes, then there may be a disease manifestation with a translocation, even if it's balanced. So, let's describe single nucleotide variants. This is the most common type. So, you have the base reference sequence and certain proteins translated, DNA level, RNA level, and protein level. So, silent mutation or synonymous mutation, meaning that same protein is ultimately produced, even though the third nucleotide triplet is different. But most of the time, this has no consequence because the product is the same as the original sequence. But if this comes in a regulatory region, or if there's a cryptic site, splice site present in the T, then there may be abnormalities manifesting, such as in progeria is observed. Nonsense mutation describes changing a triplet codon to a premature stop codon, so there's no protein produced. And typically, this leads to pathogenic, and this is often pathogenic mutation and disease manifestation occurs. So, missense mutation is very common and could be conservative or non-conservative. So, conservative mutation is when the product of mutated triplets leads to a protein that's different amino acid, but similar properties. So, arginine and lysine both are positively charged. So, this may or may not have a severe consequence depending on the size. Sometimes the size matter in protein folding. So, if the size is much different from the original amino acid, then there may be an issue in protein folding. But as far as chemical characteristics, they are similar. Compared to that, to non-conservative, which is no, there's no charge, but polar molecule, and a little smaller than lysine. So, you know, not only the properties different from lysine, but also the size is different. So, this is likely to lead to a disease and could be a disease-causing mutation depending on where in the protein, of course. But, you know, missense is definitely the most common type of mutation that people will see. So, trinucleated bupedexpansion is an interesting disorder. There are some of the examples, well-known examples, are Huntington's fragile X syndrome and myotonic dystrophy. So, Huntington's disorder, there's a CAG triple repeats that occurs in exon one of the HTT gene, Huntington's disease gene. And when this exceeds a certain number, over 40, Huntington's disease manifests. But if it's less than 36, which is within normal limits, then the patient will not develop Huntington's. But there's a phenomenon called anticipation in which the disease phenotype becomes worsens with earlier onset from one generation to next. This is known to be due to slippage during replication. So, these disorders are very interesting, and especially it's adult onset. So, it is difficult to see if you want to test any children because, you know, it doesn't manifest until older adults so that maybe they want to wait until they become adults to be tested so that they can make an informed decision. But that's probably a discussion within the family. So, let's describe zygocity. Zygocity describes the similarity between the alleles. Heterozygous is just one allele affected with a variant. And homozygous is the same variant affecting the both alleles. And compound heterozygous, there are two situations. One's trans, meaning that one variant is one allele, and another variant is on another allele. That's trans. So, one's from the mother, one's from the father. So, cis is the situation where two variances on one allele and one received from one of the parents is totally normal. This happens also. And it's possible that in this case there may be no disease manifestation because it depends on what type of variant these are, but you still have one normal alleles. So, double heterozygous is described by variant on one gene and another variant in another gene of the same disease. So, this may result in a more severe phenotype than just having the heterozygous mutation or variant in one gene. So, let's characterize the genotype into function. So, mutation can be described as loss of function mutation, which is a reduction or loss of one or more of the normal protein function. And gain of function is increase in one or more usual aspect of protein function. And normal function mutation is an interesting one. And gain of function, which is different from the typical protein function. And haploinsufficiency is a 50% of function by the normal allele is insufficient for normal function. So, you really need more than one allele for the normal function of this particular protein. And dominant negative mutation describes abnormal protein actually interferes with the protein produced by normal allele in heterozygous state. So, you know, haploinsufficiency and dominant negative, they seem a little similar, but then what abnormal protein is doing is totally different, because dominant negative actually interferes with the function of the normal protein. So, loss of heterozygosity is loss of one copy of a locus, leaving one copy present at the locus. This happens in cancer. Oh, often, and loss of heterozygosity is usually the second hit that occurs in heritable cancer syndromes. And then that's how often the tumor genesis occurs, even in heritable type of disorders.

mutations

DNA replication

mutagens

germline mutations

somatic mutations