Case 10 - Mutations PDF

Case 10 - Mutations 1. Different types of mutations and their consequences Somatic mutations: mutation in somatic cells - Not transmitted to next generation Germline mutations: transmitted to next generation (mutation in sperm/egg cell) - Every cell in new generation has the same mutation → a...

Case 10 - Mutations 1. Different types of mutations and their consequences Somatic mutations: mutation in somatic cells - Not transmitted to next generation Germline mutations: transmitted to next generation (mutation in sperm/egg cell) - Every cell in new generation has the same mutation → also germs of new generation Chromosomal rearrangements In a class of large-scale mutations, big chunks of chromosomes (but not entire chromosomes) are affected. Such changes are called chromosomal rearrangements. They include: - A duplication, where part of a chromosome is copied. - A deletion, where part of a chromosome is removed. Three types - Terminal - Intercalori - Microdeletion - An inversion, where chromosomal region is flipped around so that it points in the opposite direction. A translocation, where a piece of one chromosome gets attached to another chromosome. A reciprocal translocation involves two chromosomes swapping segments; a non-reciprocal (insertion) translocation means that a chunk of one chromosome moves to another. Reciprocal translocation: two non-homologous chromosomes swap fragments. No genetic material is lost, but the resulting chromosomes are hybrids, each containing segments normally found on a different chromosome. Non-reciprocal translocation: a fragment is removed from a donor chromosome and inserted into a recipient chromosome. The donor chromosome loses a region, while the recipient chromosome gains a region not normally found on that chromosome. In some cases, a chromosomal rearrangement causes symptoms similar to the loss or gain of an entire chromosome. For instance, Down syndrome is usually caused by a third copy of chromosome 21, but it can also occur when a large piece of chromosome 21 moves to another chromosome (and is passed on to offspring along with a regular chromosome 21). Inversion Pericentric → chromosome breaks each half of the centromere → turned upside down. Paracentric → breaks in two places (not including centromere) → turned upside down. Aneuploidy is the phenomenon in which a cell can have one or a couple of chromosomes missing or present in surplus. On the other hand, polyploidy refers to the presence of extra complete sets of chromosomes. If you lose one chromosome or have one to many → balance is off and you will create to much or to less Placement of cut Inversion → depends on where it is cut to know whether it is harmful - If gene is cut half way through it will be faulty - If the whole gene is cut → could be no problem but very rare Translocation → one part of a chromosome is gone - Next generation → no guarantee that you get the chromosome with all the genetic information - Even if you get the 100% of the dna doesn't mean that it is healthy - Can be cut half way through the gene Dna sequence rearrangements - transition → purin to purin or pyrimidin to pyrimidin - transversion → purin to pyrimidin - missense → mutation that causes change in the amino acid sequence - nonsense → mutation causes stop codon → not full protein → inactive - neutral mutation → change in amino acid → both have similar structures → not big change in 3D structure - silent mutation → the amino acid is not changed Point mutation - Deletion - Substitution - Insertion Missense: A missense mutation is a DNA change that results in different amino acids being encoded at a particular position in the resulting protein. Some missense mutations alter the function of the resulting protein. Nonsense: A nonsense mutation occurs in DNA when a sequence change gives rise to a stop codon rather than a codon specifying an amino acid. The presence of the new stop codon results in the production of a shortened protein that is likely non-functional. A frameshift mutation in a gene refers to the insertion or deletion of nucleotide bases in numbers that are not multiples of three. This is important because a cell reads a gene’s code in groups of three bases when making a protein. Each of these “triplet codons” corresponds to one of 20 different amino acids used to build a protein. If a mutation disrupts this normal reading frame, then the entire gene sequence following the mutation will be incorrectly read. This can result in the addition of the wrong amino acids to the protein and/or the creation of a codon that stops the protein from growing longer. In-frame mutations → add or delete as 3 → one amino acid is deleted Neutral mutations are changes in DNA sequence that are neither beneficial nor detrimental to the ability of an organism to survive and reproduce. In population genetics, mutations in which natural selection does not affect the spread of the mutation in a species are termed neutral mutations. Synonymous variants, also called silent mutations, occur when the single base pair substitution maintains the same amino acid, due to the degenerate nature of the genetic code, and consequently do not alter the final protein product. Suppressor mutation; it counteracts the effects of another mutation. A suppressor maps at a different site than the mutation it counteracts, either within the same gene or at a more distant locus. Gene expression with point mutations - promoter mutations → may block or activate transcription - splice site mutations → may black splicing or create new splice signals Reverse mutations Full → fully restored to wil Partial → function of the protein will be fully or partially restored True reversion Indels → looping out in template strand → deletion of a nucleotide in new strand → addition of a nucleotide Spontaneous mutations Occurs in absence of mutagenic agent DNA pol incorporates wrong base -1/100.000 Error not recognized by proofreading -1/100 Error not repaired -1/1000 Chance of point mutation: 10^-10 per base, per replication Mismatch by polymerase: Fixed mutation only from second replication Depurination Spontaneous deamination of cytosine to uracil Induced mutations Caused by exposure to mutagenic agent = mutagen 2. What is the phylogenetic tree, how do you make it? Key points: - A phylogenetic tree is a diagram that represents evolutionary relationships among organisms. Phylogenetic trees are hypotheses, not definitive facts. - The pattern of branching in a phylogenetic tree reflects how species or other groups evolved from a series of common ancestors. - In trees, two species are more related if they have a more recent common ancestor and less related if they have a less recent common ancestor. - Phylogenetic trees can be drawn in various equivalent styles. Rotating a tree about its branch points doesn't change the information it carries. Molecular clock The molecular clock is a figurative term for a technique that uses the mutation rate of biomolecules to deduce the time in prehistory when two or more life forms diverged. The biomolecular data used for such calculations are usually nucleotide sequences for DNA, RNA, or amino acid sequences for proteins. For the past 40 years, evolutionary biologists have been investigating the possibility that some evolutionary changes occur in a clock-like fashion. Over the course of millions of years, mutations may build up in any given stretch of DNA at a reliable rate. For example,the gene that codes for the protein alpha-globin (a component of hemoglobin) experiences base changes at a rate of.56 changes per base pair per billion years1. If this rate is reliable, the gene could be used as a molecular clock. When a stretch of DNA does indeed behave like a molecular clock, it becomes a powerful tool for estimating the dates of lineage-splitting events. For example, imagine that a length of DNA found in two species differs by four bases (as shown below) and we know that this entire length of DNA changes at a rate of approximately one base per 25 million years. That means that the two DNA versions differ by 100 million years of evolution and that their common ancestor lived 50 million years ago. Since each lineage experienced its own evolution, the two species must have descended from a common ancestor that lived at least 50 million years ago. Mutation rates RNA polymerase has a high error rate of about 1 mistake per 100,000 nucleotides due to its lack of proofreading. In humans, this leads to roughly 64 new mutations per generation. Mitochondrial DNA mutates faster (~2.7×10⁻⁵ per base per generation) compared to the nuclear genome (~1.1×10⁻⁸ per base). Mutation rates vary across different DNA regions and organisms, with *Paramecium* having one of the lowest rates (~2×10⁻¹¹ per site). Viruses, especially RNA viruses, have the highest mutation rates, ranging from 10⁻³ to 10⁻⁵ per base per generation. Error rate 10^4 with proofreading 10^6 without proofreading Mitochondria don't have proofreading ORS from mitochondria can cause damage High rate in introns Non synonymous has lower rate Between species → lifespan Humans live much longer than a rat Back mutations → c originally → mutated to t → mutated back to c Jukes-Cantor Model K = -¾ log (1-¾ p) p = probability So if 5 of 20 nucleotides are changed → 0.25 = p K = 0.31 Answer should be bigger then p and positive This model is how we account for bach mutations Anatomy of a phylogenetic tree Parsimony tree When we draw a phylogenetic tree, we are representing our best hypothesis about how a set of species (or other groups) evolved from a common ancestor. As we'll explore further in the article on building trees, this hypothesis is based on information we’ve collected about our set of species – things like their physical features and the DNA sequences of their genes In a phylogenetic tree, the species or groups of interest are found at the tips of lines referred to as the tree's branches. For example, the phylogenetic tree below represents relationships between five species, A, B, C, D, and E, which are positioned at the ends of the branches: Branch point (also called an internal node) You may see trees with a polytomy (poly, many; tomy, cuts), meaning a branch point that has three or more different species coming off of it]. In general, a polytomy shows where we don't have enough information to determine branching order. Parsimony First step: you need to write down all the possible trees 4 genes → 15 trees 5 genes → 105 trees 10 genes → 34 million trees Second step: look where mutations are (which columns) - Look which one is informative The one with the least amount of mutations is the best UPGMA