BIOL 2030 Module 10 PDF

BIOL 2030 Module 10 10.1:Chromosomal Rearrangements M10.1 1 My CV M10.1 Image credit: Sam Beal 3 Genetic variations are at the root of (practically?) everything in biology… This section of the course is about – Types of genetic variation and how they arise Why genetic variations matter How we study/...

BIOL 2030 Module 10 10.1:Chromosomal Rearrangements M10.1 1 My CV M10.1 Image credit: Sam Beal 3 Genetic variations are at the root of (practically?) everything in biology… This section of the course is about – Types of genetic variation and how they arise Why genetic variations matter How we study/detect genetic variation Applications in science and society How we can create new genetic variations (aka ‘genetic engineering’) M10.1 4 Chromosome variations Permanent chromosomal changes. Can be passed on to offspring if they occur in cells that will become gametes (‘germline’ cells). Two general types: 1. Chromosome rearrangement: changes in the structure of individual chromosomes. 2. Variation in chromosome numbers: changes in the number of chromosomes. One or more individual chromosomes are added or deleted. M10.1 5 What is the connection between a chromosomal rearrangement and what is going on here? M10.1 Arjan Haverkamp - originally posted to Flickr as 2009-05-22-14h06m00.IMG_9725l 6 4 types of chromosomal rearrangements: (1) Deletions Loss of a segment, either internal or terminal, from a chromosome. Arise by terminal–ends breaking off (one break) or internal breaking and rejoining of incorrect ends (two breaks). Major effect: loss of genetic information (importance depends on what, and how much is lost). M10.1 7 Deletions: detection Deletion loops can be detected during meiosis Also by a variety of molecular methods that detect lower heterozygosity or gene dosage M10.1 8 Deletions: consequences Loss of DNA sequences. Phenotypic effects depend on the size and location of deleted sequences. Deletions that span a centromere result in an acentric chromosome that will most likely be lost during cell division, may be lethal. Deletions can allow expression of alleles that are normally recessive. Called pseudodominance. Deletions can affect gene dosage. o When a gene is expressed, the functional protein is normally produced at the correct level or dosage. o Some (not all) genes require two copies for normal of protein production; if one copy is deleted a mutant phenotype can result called haploinsufficiency. M10.1 9 One reason (among many) why chromosome variations matter: Genetic Disorders Cri du chat (Gene) dosage matters, especially when lots of genes are involved! M10.1 10 4 types of chromosomal rearrangements: (2) Duplications Repetition of a chromosome segment. Tandem duplication is simplest form. Single gene or cluster of genes can be duplicated. Nothing has been lost, so duplications (especially smaller ones) often have little or no effect on phenotype/viability. Offspring with duplications usually viable. But, some cases, excess or unbalanced ‘dosage’ of gene products (proteins) resulting from duplications can cause problems. Very important in evolution, because extra copies of genes provide raw material for new genes and adaptations. About 5% of human genome consists of duplications. Tandem duplication M10.1 11 Duplications: origins Unequal crossing over of misaligned chromosomes during meiosis generates duplications (and deletions). M10.1 12 Duplications: detection Tandem duplication Also by various molecular methods that detect higher gene dosage. Tandem duplication Duplicated chromosome forms a loop M10.1 13 Duplications: evolutionary consequences Duplication Both copies remain the same Redundancy Alter gene dosage, could have effect One copy becomes inactive Pseudogene M10.1 One copy acquires a new function (Neofunctionalization) Gene families 14 Duplication consequences: neofunctionalization Source of new genes Creates multigene families example: globin gene family ψ = Pseudogenes M10.1 15 Duplication consequences: gene dosage can affect phenotype Gene dosage may affect phenotype. Amount of protein synthesized is often proportional to the number of gene copies present, so extra genes can lead to excess proteins. E.g., Bar region in Drosophila (X chromosome). More copies  fewer eye facets. M10.1 16 Humans have 5-8 salivary amylase gene copies resulting from gene duplication Salivary amylase begins breakdown of starch to sugar in mouth A B C D Which species has experienced duplications of genes active in its mouth that parallel gene duplications that have occurred in humans? M10.1 17 https://doi.org/10.7554/eLife.44628.001 M10.1 18 4 types of chromosomal rearrangements: (3) Inversions Two breaks on a chromosome followed by reinsertion in the opposite orientation can produce an inversion. 1) Pericentric Inversions normal inverted centromere 2) Paracentric Inversions normal inverted centromere M10.1 19 Effects of inversions on phenotype… Often, none! However, sometimes there is an effect on phenotype, driven by the change in position of the gene(s) M10.1 20 Inversion consequences: position effects (location matters – sometimes) Change in position can alter expression, e.g. variegation in Drosophila. Genes in/near chromatin may not be expressed. M10.1 21 Inversion consequences for recombination and production of gametes: suppression of recombination If no crossing over occurs, gametes produced are usually viable because genetic information is not lost or gained. If crossing over occurs…… …outside of inverted region - viable gametes. …within inverted region - some nonviable gametes and reduced recombination frequency. 1) Pericentric Inversions normal inverted 2) Paracentric Inversions normal inverted M10.1 22 Crossing over within a paracentric inversion Crossing over between inverted and non-inverted chromosome (between C and D) M10.1 23 Acentric chromatid is lost Dicentric chromatid Dicentric bridge breaks as the two centromeres are pulled apart Reduced (observed) recombination frequency Reduced fertility M10.1 24 Crossing over within a pericentric inversion Crossing over between inverted and non-inverted chromosome (between C and D) M10.1 25 Reduced (observed) recombination frequency Reduced fertility A B G C D E F G F F G A B B A A B F G M10.1 26 4 types of chromosomal rearrangements: (4) Translocation Exchange of segments between nonhomologous chromosomes, or to a different region on same chromosome. Translocations between chromosomes can be reciprocal (two-way) or non-reciprocal (oneway). If no genetic material is lost, considered a balanced translocation. M10.1 27 Reciprocal translocation: consequences As with inversions, translocations change the position of genes. This can alter expression of gene(s) because of association with different proteins, or formation of new gene products (fusion proteins). Example: ‘Philadelphia’ chromosome Fused BCR-ABL gene 5' section of BCR fused with most of ABL. Protein produce is a fusion that functions improperly – causes chronic myelogenous leukemia (CML), a rare form of cancer that affects certain types of white blood cells M10.1 28 What is the connection between a chromosomal rearrangement and what is going on here? M10.1 Arjan Haverkamp - originally posted to Flickr as 2009-05-22-14h06m00.IMG_9725l 29 Inversions are super interesting because they suppress recombination … Very interesting consequences for adaptation and evolution! Lack of recombination within inversions means that genes within the inversions are free to diverge to produce different adaptations. M10.1 30 Example: Ruff inversion Ruff is a European wading sandpiper. Has 3 types of males. ‘Independent’ males display in leks to attract females. ‘Faeder’ males mimic females, sneak copulations. ‘Satellite’ males look like a somewhat drabber version of Independent males. Faeder and satellite males have a 4.5Mb chromosomal inversion that arose 3.8 million years ago. Faeders came first. Later (ca 500k yr BP) a very rare crossover event restored some of the ‘independent’ version of the chromosome to the ‘faeder’ version, creating the ‘satellite’ version. The inversion is lethal in the homozygous condition!! https://www.newscientist.com/article/dn28493-ruff-bird-orgies-have-four-sexes-thanks-to-asupergene-flip/ M10.1 31 Imagine a cross between 2 ruffs, both heterozygous for the inversion Not Inverted Inverted NOT INVERTED ‘INDEPENDENT’ MALE ‘FAEDER’ MALE INVERTED ‘FAEDER’ MALE NOT VIABLE  Inversion has persisted for 3.8 Million Years because being a ‘Faeder’ is a successful reproductive strategy, despite the ‘cost’ of fertilizations that are homozygous for the inversion, and therefore not viable. Kind of like mutation that produces sickle cell anemia in humans…beneficial effects of being heterozygous outweigh the cost of producing some offspring that are homozygous and not viable. M10.1 32 Genes within alternate orientations of inversion can diverge dramatically even though there is no divergence anywhere else in the genome. No recombination within inversion Sequence divergence between Independents and Satellites (also Faeders) – Inside inversions = large divergence Outside inversions = zero divergence. Similar cases in many other species where genes within inversions have evolved to produce different sets of adaptations. M10.1 Sequence divergence within inversion region = quite a large amount! Sequence divergence outside of inversion region ~= 0 33 What do chromosomal rearrangements have to do temperature adaptations and migratory behaviour in Atlantic Cod? M10.1 34 Cod have a large chromosomal inversion that is millions of years old. Genes inside the inversion influence whether cod are adapted to ‘warmer’ or ‘colder’ water. Cod with both orientations of the inversion live off Nova Scotia, and interbreed. Because recombination inside the inversion is suppressed, the ‘warm’ and ‘cold’ versions of the genes do not get scrambled by recombination. Several other major inversions in cod influence other traits, such as migration. M10.1 35 Important points to understand about chromosome variations Terminology of chromosome types. Different types of chromosomal variations. How they occur. How they are detected. Short-term/immediate consequences : gene/chromosome dosage effects including genetic disorders, position effects, effects on recombination & fertility (including miscarriages). How some types of variations effectively suppress recombination – and how that can affect phenotypic variation and adaptations. Long-term/evolutionary consequences: Pseudogenes, neofunctionalization, new adaptations. M10.1 36 Useful videos: Pericentric inversions in humans: https://www.youtube.com/watch?v=QXU7XojaEOs Robertsonian translocations: https://www.youtube.com/watch?v=vbGw4VanNjk An interesting video about the Chernobyl nuclear reactor in Ukraine, where a catastrophic failure of the reactor (brought about by human error) caused the release of a huge amount of radioactive isotopes: https://www.youtube.com/watch?v=TG-nwQBBfmc M10.1 37