Heredity, Gene Regulation, and Development Mutation A. Overview

Mutation A. Overview 1) A mutation is a change in the genome of a cell.

Mutation A. Overview 1) A mutation is a change in the genome of a cell. 2) Somatic Mutations: - can occur during DNA replication prior to mitosis - can occur during DNA repair - can be caused by exposure to a mutagen - if uncorrected, can be passed to daughter cells. - typically not the source of heritable mutations

Mutation A. Overview 1) A mutation is a change in the genome of a cell. 2) Somatic Mutations: - can occur during DNA replication prior to mitosis - can occur during DNA repair - can be caused by exposure to a mutagen - if uncorrected, can be passed to daughter cells. - typically not the source of heritable mutations 3) Germ-line Mutations: - occur in germ-line cells (tissues that produce gametes or spores) - occur so early in development, before germ-line cells have differentiated, that they affect germ-line cells. - occurs in DNA replication or meiosis, producing mutant gametes/spores

VI. Mutation A.Overview 3) These “changes in a genome” can occur at four scales of genetic organization: - Change in the number of sets of chromosomes ( change in ‘ploidy’) - Change in the number of chromosomes in a set (‘aneuploidy’) - Change in the number and arrangement of genes on a chromosome (gene duplications, deletions, inversions, translocations) - Change in the nitrogenous base sequence within a gene (point mutations) Typically, the larger the change, the more dramatic (and negative) the result

VI. Mutation A.Overview B.Changes in Ploidy - These are the most dramatic changes, adding a whole SET of chromosomes Triploidy occurs in 2-3% of all human pregnancies, but almost always results in spontaneous abortion of the embryo. Some triploid babies are born alive, but die shortly after. Syndactyly (fused fingers), cardiac, digestive tract, and genital abnormalities occur.

VI. Mutation A.Overview B.Changes in Ploidy - These are the most dramatic changes, adding a whole SET of chromosomes 1.Mechanism #1: Complete failure of Meiosis - if meiosis fails, reduction does not occur and a diploid gamete is produced. This can occur because of failure of homologs OR sister chromatids to separate in Meiosis I or II, respectively. Failure of Meiosis I 2n = 4 Gametes: 2n = 4

VI. Mutation A.Overview B.Changes in Ploidy - These are the most dramatic changes, adding a whole SET of chromosomes 1.Mechanism #1: Complete failure of Meiosis - if meiosis fails, reduction does not occur and a diploid gamete is produced. This can occur because of failure of homologs OR sister chromatids to separate in Meiosis I or II, respectively. Failure of Meiosis II 2n = 4 Normal gamete formation is on the bottom, with 1n=2 gametes. The error occurred up top, with both sister chromatids of both chromosomes going to one pole, creating a gametes that is 2n = 4.

VI. Mutation A.Overview B.Changes in Ploidy - These are the most dramatic changes, adding a whole SET of chromosomes 1.Mechanism #1: Complete failure of Meiosis - if meiosis fails, reduction does not occur and a diploid gamete is produced. This can occur because of failure of homologs OR sister chromatids to separate in Meiosis I or II, respectively. - this results in a single diploid gamete, which will probably fertilize a normal haploid gamete, resulting in a triploid offspring. -negative consequences of Triploidy: 1) quantitative changes in protein production and developmental regulation. 2) can’t reproduce sexually; can’t produce gametes if you are 3n.

1) quantitative changes in protein production and regulation. 2) can’t reproduce sexually; can’t produce gametes if you are 3n. 3) Aspidoscelis uniparens is a species that consists of 3n females that reproduce clonally – laying 3n eggs that divide without fertilization. It evolved from the diploid species, A. inornata some organisms can survive, and reproduce parthenogenetically (eggs by mitosis… offspring are clones).

VI. Mutation A.Overview B.Changes in Ploidy - These are the most dramatic changes, adding a whole SET of chromosomes 1.Mechanism #1: Complete failure of Meiosis 2.Mechanism #2: Failure of Mitosis in Gamete-producing Tissue

2n 1) Consider a bud cell in the flower bud of a plant.

2n 1) Consider a bud cell in the flower bud of a plant. 4n 2) It replicates it’s DNA but fails to divide... Now it is a tetraploid bud cell.

2n 1) Consider a bud cell in the flower bud of a plant. 4n 2) It replicates it’s DNA but fails to divide... Now it is a tetraploid bud cell. 3) A tetraploid flower develops from this tetraploid cell; eventually producing 2n SPERM and 2n EGG

2n 1) Consider a bud cell in the flower bud of a plant. 4n 2) It replicates it’s DNA but fails to divide... Now it is a tetraploid bud cell. 3) A tetraploid flower develops from this tetraploid cell; eventually producing 2n SPERM and 2n EGG 4) If it is self-compatible, it can mate with itself, producing 4n zygotes that develop into a new 4n species. Why is it a new species?

How do we define ‘species’? “A group of organisms that reproduce with one another and are reproductively isolated from other such groups” (E. Mayr – ‘biological species concept’)

How do we define ‘species’? Here, the tetraploid population is even reproductively isolated from its own parent species…So speciation can be an instantaneous genetic event… 4n 2n Gametes 2n 4n Zygote 2n 1n Gametes Zygote 2n 3n Triploid is a dead-end… so species are separate

VI. Mutation A.Overview B.Changes in Ploidy - These are the most dramatic changes, adding a whole SET of chromosomes 1.Mechanism #1: Complete failure of Meiosis 2.Mechanism #2: Complete failure of Mitosis 3.Mechanism #3: Allopolyploidy - hybridization 2n = 16 Black Mustard 2n = 18 Cabbage n = 8 n = 9 gametes n = 17 Fertilization produces a cell with non- homologous chromosomes 2n = 34 Polyploidy occurs here; creating a cell with homologous sets New Species

Spartina alterniflora from NA colonized Europe Spartina maritima native to Europe X Spartina anglica – an allopolyploid and a worldwide invasive outcompeting native species Sterile hybrid – Spartina x townsendii Allopolyploidy – 1890’s

VI. Mutation A.Overview B.Changes in Ploidy - These are the most dramatic changes, adding a whole SET of chromosomes 1.Mechanism #1: Complete failure of Meiosis 2.Mechanism #2: Complete failure of Mitosis 3.Mechanism #3: Allopolyploidy - hybridization 4.The Frequency of Polyploidy For reasons we just saw, we might expect polyploidy to occur more frequently in hermaphroditic species, because the chances of ‘jumping’ the triploidy barrier to reproductive tetraploidy are more likely. Over 50% of all flowering plants are polyploid species; many having arisen by this duplication of chromosome number within a lineage.

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘aneuploidy’ (changes in chromosome number) 1. Mechanism: Non-disjunction (failure of a homologous pair or sister chromatids to separate)

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘aneuploidy’ (changes in chromosome number) 1. Mechanism: Non-disjunction (failure of a homologous pair or sister chromatids to separate) 2. Human Examples a. trisomies Trisomy 21 – “Downs’ Syndrome”

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘aneuploidy’ (changes in chromosome number) 1. Mechanism: Non-disjunction (failure of a homologous pair or sister chromatids to separate) 2. Human Examples a. trisomies Trisomy 21 – “Downs’ Syndrome” Trisomy 18 – Edward’s Syndrome Trisomy 13 – Patau Syndrome Trisomy 9 Trisomy 8 Trisomy 22 Trisomy 16 – most common – 1% of pregnancies – always aborted Some survive to birth

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘aneuploidy’ (changes in chromosome number) 1. Mechanism: Non-disjunction (failure of a homologous pair or sister chromatids to separate) 2. Human Examples a. trisomies 47, XXY – “Klinefelter’s Syndrome” Extreme effects listed below; most show a phenotype within the typical range for XY males

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘aneuploidy’ (changes in chromosome number) 1. Mechanism: Non-disjunction (failure of a homologous pair or sister chromatids to separate) 2. Human Examples a. trisomies 47, XXX – “Triple-X Syndrome” No dramatic effects on the phenotype; may be taller. In XX females, one X shuts down anyway, in each cell (Barr body). In triple-X females, 2 X’s shut down.

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘aneuploidy’ (changes in chromosome number) 1. Mechanism: Non-disjunction (failure of a homologous pair or sister chromatids to separate) 2. Human Examples a. trisomies 47, XYY – “Super-Y Syndrome” Often taller, with scarring acne, but within the phenotypic range for XY males

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘aneuploidy’ (changes in chromosome number) 1. Mechanism: Non-disjunction (failure of a homologous pair or sister chromatids to separate) 2. Human Examples b. monosomies 45, XO– “Turner’s Syndrome” (the only human monosomy to survive to birth)

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1. Mechanism #1: Unequal Crossing-Over a. process: If homologs line up askew: A ab B

A ab B VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1. Mechanism #1: Unequal Crossing-Over a. process: If homologs line up askew And a cross-over occurs

Aab B VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1. Mechanism #1: Unequal Crossing-Over a. process: If homologs line up askew And a cross-over occurs Unequal pieces of DNA will be exchanged… the A locus has been duplicated on the lower chromosome and deleted from the upper chromosome

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1. Mechanism #1: Unequal Crossing-Over a. process: b. effects: - can be bad: deletions are usually bad – reveal deleterious recessives additions can be bad – change protein concentration

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1. Mechanism #1: Unequal Crossing-Over a. process: b. effects: - can be bad: deletions are usually bad – reveal deleterious recessives additions can be bad – change protein concentration - can be good: more of a single protein could be advantageous (r-RNA genes, melanin genes, etc.)

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1. Mechanism #1: Unequal Crossing-Over a. process: b. effects: - can be bad: deletions are usually bad – reveal deleterious recessives additions can be bad – change protein concentration - can be good: more of a single protein could be advantageous (r-RNA genes, melanin genes, etc.) source of evolutionary novelty (Ohno hypothesis ) where do new genes (new genetic information) come from?

Gene ADuplicated A Mutation – may even render the protein non-functional But this organism is not selected against, relative to others in the population that lack the duplication, because it still has the original, functional, gene. generations

Mutation – may even render the protein non-functional Mutation – other mutations may render the protein functional in a new way So, now we have a genome that can do all the ‘old stuff’ (with the original gene), but it can now do something NEW. Selection may favor these organisms. Gene ADuplicated A generations

If so, then we’d expect many different neighboring genes to have similar sequences. And non-functional pseudogenes (duplicates that had been turned off by mutation). These occur – Gene Families

And, if we can measure the rate of mutation in these genes, then we can determine how much time must have elapsed since the duplication event… Gene family trees…

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1.Mechanism #1: Unequal Crossing-Over 2.Mechanism #2: Inversion (changes the order of genes on a chromosome)

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1.Mechanism #1: Unequal Crossing-Over 2.Mechanism #2: Inversion (changes the order of genes on a chromosome)

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1.Mechanism #1: Unequal Crossing-Over 2.Mechanism #2: Inversion (changes the order of genes on a chromosome) Chromosomes are no longer homologous along entire length B-C-D on top d-c-b on bottom

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1.Mechanism #1: Unequal Crossing-Over 2.Mechanism #2: Inversion (changes the order of genes on a chromosome) Chromosomes are no longer homologous along entire length ONE “loops” to get genes across from each other… And if a cross- over occurs….

The cross-over products are non- functional, with deletions AND duplications VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1.Mechanism #1: Unequal Crossing-Over 2.Mechanism #2: Inversion (changes the order of genes on a chromosome)

The only functional gametes are those that DID NOT cross over – and preserve the parental combination of alleles VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1.Mechanism #1: Unequal Crossing-Over 2.Mechanism #2: Inversion (changes the order of genes on a chromosome)

Net effect: stabilizes sets of genes. This allows selection to work on groups of alleles… those that work well TOGETHER are selected for and can be inherited as a ‘co- adapted gene complex’ VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1.Mechanism #1: Unequal Crossing-Over 2.Mechanism #2: Inversion (changes the order of genes on a chromosome)

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement 1.Mechanism #1: Unequal Crossing-Over 2.Mechanism #2: Inversion (changes the order of genes on a chromosome) 3.Mechanism #3: Translocation (gene or genes move to another homologous set)

Translocation Downs. Transfer of a 21 chromosome to a 14 chromosome Can produce normal, carrier, and Down’s child.

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement E. Change in Gene Structure 1.Mechanism #1: Exon Shuffling Crossing over WITHIN a gene, in introns, can recombine exons within a gene, producing new alleles. EXON 1aEXON 2aEXON 3a Allele “a” EXON 1AEXON 2AEXON 3A Allele “A”

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement E. Change in Gene Structure 1.Mechanism #1: Exon Shuffling Crossing over WITHIN a gene, in introns, can recombine exons within a gene, producing new alleles. EXON 1aEXON 2aEXON 3a Allele “a” EXON 1AEXON 2AEXON 3A Allele “A” EXON 2aEXON 3a EXON 1A EXON 2AEXON 3A EXON 1a Allele “α” Allele “ά”

Throws off every 3-base codon from mutation point onward VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement E. Change in Gene Structure 1. Mechanism #1: Exon Shuffling 2. Mechanism #2: Point Mutations a. addition/deletion: “frameshift” mutations …T C C G T A C G T …. Normal …A G G C A U G C A … ARGHISALA Mutant: A inserted …T C C A G T A C G T …. …A G G U C A U G C A … ARGSERCYS DNA m-RNA

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement E. Change in Gene Structure 1. Mechanism #1: Exon Shuffling 2. Mechanism #2: Point Mutations a. addition/deletion: “frameshift” mutations b. substitution At most, only changes one AA (and may not change it…) … T C C G T A C G T …. Normal …A G G C A U G C A … DNA m-RNA ARGHISALA Mutant: A for G …T C C A T A C G T …. …A G G U A U G C A … ARGTYRALA

VI. Mutation A.Overview B.Changes in Ploidy C.Changes in ‘Aneuploidy’ (changes in chromosome number) D. Change in Gene Number/Arrangement E. Change in Gene Structure F. Summary Sources of VariationCauses of Evolutionary Change MUTATION: Natural Selection -New Genes: point mutation Mutation (polyploidy can make new exon shuffling species) RECOMBINATION: - New Genes: crossing over -New Genotypes: crossing over independent assortment