HMB265 Human & General Genetics Lecture Notes PDF

HMB265: Human & General Genetics Lecture 12: Quantitative Genetics Professor Belinda Chang Ecology & Evolutionary Biology Dept Cell & Systems Biology Dept Director, Bioinformatics & Genome Biology Chang Lab: Sensory systems Cichlid  Lec...

HMB265: Human & General Genetics Lecture 12: Quantitative Genetics Professor Belinda Chang Ecology & Evolutionary Biology Dept Cell & Systems Biology Dept Director, Bioinformatics & Genome Biology Chang Lab: Sensory systems Cichlid  Lecture Outline Introduction to Quantitative Variation Continuous variation Additive Inheritance P=G+E Reading: Hartwell Genetics textbook, 7th edition, Chapter 2 (emphasis on pages 29-31, 38-39, 48-52)  Phenotypic variation doesnʼt always appear “discrete” (i.e. qualitative), but rather continuous ↑ Height Can genetics explain this kind of variation? Many traits seem quantitative in nature Continuous variation Frequently with a normal distribution Q: Can such traits have a genetic basis? Q: Can simple Mendelian genetics explain this? Many traits influenced by environment Q: Can such traits have a genetic basis? Q: Can simple Mendelian genetics explain this? A trait displaying simple dominance mode of inheritance ↳ one allele dom to another A trait displaying simple dominance mode of inheritance Openpe - ↳ A is absent D have big A Dominance is not always complete Summary of dominance relationships Hartwell, Figure 2.1 Incomplete dominance in Antirrhinum A1 A1 A2 A2 A1 A2 A1 A2 A1 A2 A1 A2 A1 A1A1 A1A2 A2A1A2 A2A2 1 A1A1 (red): 2 A1A2 (pink): 1 A2A2 (white) Hartwell, Figure 2.2 But things arenʼt that simple... Additive inheritance ⑳ding As # o 60 Az allele GLAz < 1 Az allele alleles Additive inheritance Additive inheritance  Additive inheritance Al = 0 B1 = 0 1 Bz = 1 Az = O I I 2 I Z Z 3 I 2 2. 3 B2 Z 3. 3 4 Additive inheritance Additive inheritance Additive inheritance Additive inheritance Additive inheritance defined by mean / standard dev ↳ 68 % of fall betw one stand dev of mean pop. ↳ 96 % fall betw two stand dev of mean Quantitative traits described by a frequency distribution  Genetic origins of a quantitative trait… Two hypotheses: Hypothesis 1: A quantitative trait can be explained on the basis of the segregation of alleles at many loci, where these loci have small, equal, and additive effects. Hypothesis 2: The quantitative trait can be explained on the basis of a few genes with large additive effects. These kinds of traits are said to be polygenic or multifactorial Genetic origins of a quantitative trait… BUT what are we forgetting? Other alterations to Mendelʼs laws Environmental modification Hartwell, Figure 2.23 Consider the environment… Phenotype = Genotype + Environment more continuous I bell curve) Genetic origins of a quantitative trait… if no enu effects ! Genetic origins of a quantitative trait… ear effects make it even more continuous ! - evariation more continuous Genetic origins of a quantitative trait… Occurs with traits that show incomplete dominance complete dominance F no bell curve Incomplete Dominance The heterozygous phenotype is distinct from either homozygous phenotype - an intermediate phenotype Example: Familial Hypercholesteraemia Incomplete Dominance  Phenotype = Genotype + Environment Quantitative (complex) traits can be explained on the basis of the segregation of alleles at multiple loci with additive effects BUT where individual phenotypic classes are masked by the environment - a quantitative trait locus (QTL) Frequency distributions show the contributions of alleles at a QTL to a complex trait How can we determine if there are genetic effects “buried” within a quantitative trait? HMB265: Human & General Genetics Lecture 13: Quantitative Trait Loci Prof. Belinda Chang  Lecture Outline Quantitative Trait Analysis Heritability Broad Sense Heritability Narrow Sense Heritability Reading: Goldberg et al 2024, 8th ed. Genetics textbook, Chapter 25 (emphasis on pages 764-771)  How can we determine if there are genetic effects “buried” within a quantitative trait? How much of this variation is attributable to genetic variation? How can we determine if there are genetic effects “buried” within a quantitative trait? How much of the phenotypic variation is attributable to genetic variation versus environmental variation? phenotype genotyp env b D Y > variation s variation due to ~ of phenotype gen effects + duefor  How can we determine if there are genetic effects “buried” within a quantitative trait? The extent of phenotypic variation that is attributable to genetic variation is known as the BROAD SENSE HERITABILITY of the trait ↳ all possible ways can contribute ! gene If all the phenotypic variation is attributable to genotypic variation, then H2 = 1 (the maximum it can be) If all the phenotypic variation is attributable to environmental effects, then H2 = 0 (the minimum)  What does H2 tell us? If a lot of the phenotypic variation is attributable to genotypic variation, then H2 is close to 1 high High values suggest that genotype is important in determining whether the quantitative trait arises due to segregation of particular alleles BUT H2 does not predict how progeny will perform on the basis of the phenotype of their parents H2 for some traits in humans =  What H2 does and does not tell us What H2 tells us &If H2 is high, the phenotype of an individual is likely to be attributable to its- genotype IN THAT FAMILY - must be measured in > particular G tell us ears in extreme > - What H2 does NOT · enu BSH Y pop · envar ↑ ↳ not helpful for finding dif betw groups/pop moving target geog time What phenotype an individual will have on the basis of its parentsʼ phenotypes Even if H2 is high, an individualʼs precise phenotype cannot - be predicted on the basis of its parentsʼ phenotypes What is going on in other families - H2 is family specific - What H2 tells us Look like they do because of their genes What H2 does NOT tell us What their offspring will look like Why is this the case?  Why H2 is not predictive VP = VG + VE VG = VA + VD + VI VA variation due to additive effects VD variation due to dominance effects VI variation due to epistatic effects  Why H2 is not predictive VD = variation due to dominance effects  Why H2 is not predictive VD = variation due to dominance effects Why H2 is not predictive VI = variation due to epistatic effects Why H2 is not predictive Vi = variation due to epistatic effects  Why H2 is not predictive VP = VG + VE VG = VA + VD + VI VA variation due to additive effects VD variation due to dominance effects VI variation due to epistatic effects If the trait is due to additive effects, it is predictive… What we need is heritability based on additive variation The extent of phenotypic variation that is attributable to additive genetic variation is known as NARROW SENSE HERITABILITY If all the phenotypic variation is attributable to additive variation, then h2 = 1 (the maximum it can be) If all the phenotypic variation is attributable to other genetic & environmental effects, then h2 approaches 0 What h2 does and does not tell us What h2 tells us If h2 is high, the phenotype of an individual is predictable based on the phenotype of its parent IN THAT FAMILY Specific additive-effect genes are involved What h2 does NOT tell us What is happening in other families What the genes are The heights of individuals and their same-sex parent are correlated h2 for some traits in different species HMB265: Human & General Genetics Lecture 14: Genetic Mapping & Complex Traits Prof. Belinda Chang Lecture Outline: Genetic mapping of quantitative traits Quantitative Trait Loci (QTL) Mapping QTL Mapping Complex Traits in Plants From linkage map locus to candidate gene Reading: Goldberg 8th ed. Genetics textbook, Chapter 25 (emphasis on pages 775-778; also page 380) Frary et al Science 2000  Dissection of Quantitative Traits How do we determine which genes are involved in controlling the quantitative trait?  Dissection of Quantitative Traits A number of genes can have a major effect on phenotype A quantitative effect can be attributed to 2 or more important genes contribution L -small quantitative phenotype. QUANTITATIVE TRAIT LOCI (QTL) to Identified using genetic mapping and association of genetic markers with the trait Statistical methods allow the identification of more than one QTL at a time identifies WHERE in genome QTLs are OK, SO HOW IS IT DONE?  STEP 1: Make an informative cross between individuals that are “inbred” relative to each other, and which differ at the trait(s) of interest ↳ so dif alleles that affect trait.  The power of genetics… Dissecting the basis of tomato fruit size Lycopersicon esculentum Lycopersicon pimpenellifolium cv. Giant Heirloom 1g 1 kg Anne Frary et al. (2000) Science 289: 85 -88  The power of genetics… Dissecting the basis of tomato fruit size  The power of genetics… Dissecting the basis of tomato fruit size · identical STEP 2: Determine the frequency distribution in the F2  The power of genetics… Dissecting the basis of tomato fruit size  STEP 3: Use molecular markers to “genotype” the individuals, attempting to find markers that co-segregate with the trait  The power of genetics… Dissecting the basis of tomato fruit size ⑳ ↳ distribution no association 72171 and betwe weight > - Most loci will show this type of segregation pattern  The power of genetics… Dissecting the basis of tomato fruit size smaller nave AzAz - association betw larger havea genotype anenotype -  STEP 4: Use a statistical method to determine if markers are co-segregating (associating) with the trait or not  The power of genetics… Dissecting the basis of tomato fruit size -  The power of genetics… Dissecting the basis of tomato fruit size - Most loci will show this type of segregation pattern  The power of genetics… Dissecting the basis of tomato fruit size STEP 5: Plot the degree of association (logarithm of odds - LOD score) on a linkage map  Odds Ratio Odds Ratio (OR) : Probability of linkage Probability of no linkage LOD = log OR LOD score: Neurofibromatosis Is allele SNP1 linked to the neurofibromatosis gene? Progeny: PPPPPPPR Fig. 12.18, Hartwell  LOD score: Neurofibromatosis Progeny: PPPPPPPR LOD numerator: 2 LOD denominator: O Hartwell, p. 372  LOD score: Neurofibromatosis Progeny: PPPPPPPR ⑭t be, Is allele SNP1 linked to the -> NO! neurofibromatosis gene? LOD ) LOD scores provide statistical evidence for QTL  The power of genetics… Dissecting the basis of tomato fruit size Lycopersicon esculentum Lycopersicon pimpenellifolium cv. Giant Heirloom 1g 1 kg Anne Frary et al. (2000) Science 289: 85 -88  The power of genetics… Dissecting the basis of tomato fruit size Step 1: QTL controlling tomato fruit size were mapped Anne Frary et al. (2000) Science 289: 85 -88  The power of genetics… Dissecting the basis of tomato fruit size Step 1: QTL controlling tomato fruit size were mapped Anne Frary et al. (2000) Science 289: 85 -88  The power of genetics… Dissecting the basis of tomato fruit size Step 2: Create recombinant inbred lines (RILs) ↳ closely related Generated by inbreeding selected individuals, down a lineage Each generation 1-2 siblings within each lineage are inbred, creating a single line of descent from each original F2 individual For plants, this is known as “single seed descent” Inbred for multiple generations (>8) Recombination at each generation creates a “ladder-like mosaic” of maternal & paternal alleles down length of the chromosome Inbreeding for many generations results in each lineage having a unique mosaic, homozygous for either the maternal or paternal allele at each locus Allows “fine mapping” of traits  The power of genetics… Dissecting the basis of tomato fruit size  The power of genetics… Dissecting the basis of tomato fruit size rid of getting neterozygosity by inbreeding.  The power of genetics… Dissecting the basis of tomato fruit size Step 3: Candidate genes in the fw2.2 QTL interval were identified by fine mapping Anne Frary et al. (2000) Science 289: 85 -88 Recombinant chromosomes (NILs) are used to fine-map QTL to a single gene O  The power of genetics… Dissecting the basis of tomato fruit size Step 4: The expression of the fw2.2 candidate gene was examined using RT-PCR. It was expressed to a greater extent in small-fruited plants, as would be predicted - sion expres higher small in Anne Frary et al. (2000) Science 289: 85 -88  The power of genetics… Dissecting the basis of tomato fruit size Step 5: The sequence of the predicted fw2.2 protein was examined to determine if its putative function fits with its role in tomato. It is related to the human proto-oncogene RAS, which is involved in cell cycle control Anne Frary et al. (2000) Science 289: 85 -88  The power of genetics… Dissecting the basis of tomato fruit size Step 6: Genetic engineering was used to test the function of the candidate gene, proving its role in fruit size alte from put in small from locs inbred large and noticed that reduction fw2.2 represses fruit size in size in ↳ proves large (trans complementation) - b causation Large fruit Same large fruit near-isogenic NIL, BUT with the small fruit allele -(inbred) line introduced as a transgene by (NIL) genetic engineering Anne Frary et al. (2000) Science 289: 85 -88 HMB265: Human & General Genetics Lecture 15: Mutation Prof. Belinda Chang  Lecture Outline DNA mutation Consequences of mutation Disease mutation example Use of mutations to determine enzyme pathways Reading: Goldberg et al., 8th edition, Chapter 7, 8, 9 (pages 208, 213-214, 244-246, 261-264, 295 -298)  HMB 265: Mutation! ongoing Mutations are the source of new alleles Mutation is the process whereby genes change from one allelic form to another. The creation of entirely new alleles can occur. Genes mutate randomly, at any time and in any cell of an organism. Can arise spontaneously during normal replication, or can be induced by a mutagen. Only mutations in germ-line cells can be transmitted to progeny. Somatic mutations can not be transmitted. Inherited mutations appear as alleles in populations of individuals. General observations of mutation rates Mutations affecting phenotype occur very rarely Different genes mutate at different rates Rate of forward mutation is almost always higher than rate of reverse mutation Mutation can occur during normal DNA replication Mutation rate can increase after exposure to a -mutagen (a mutation inducer, e.g. UV light, certain chemicals)  Classification of mutations by effect on DNA molecule Wild-type - starting sequence Substitution – base is replaced by one of the other 3 bases Deletion – block of one or more O nucleotide (base) pairs is lost indel muta- Insertion – block of one or more tions nucleotide (base) pairs is added Inversion – 180° rotation of a segment of DNA Reciprocal translocation – parts of 2 nonhomologous chromosomes change places Hartwell, 7th ed, Fig. 7.1 Classification of mutations (cont) Base Substitution – transition A « G (purine « purine) (A·T « G·C) C « T (pyrimidine « pyrimidine) (C·G « T·A) – transversion purine « pyrimidine (e.g. A « C) (A·T « C·G) pyrimidine « purine (e.g. T « G) (T·A « G·C)  Why study mutations? Mutations act as markers for genes. Mutations can disrupt gene function. This allows for the study of how the wild-type gene works.  Definitions Wild-type – the form found in nature (or in a standard laboratory stock); an allele whose frequency is more than 1% of the population Mutant – the form that has changed due to a mutation; an allele whose frequency is less than 1% Forward mutation – changes wild-type allele to a different allele i.e. A+ ® a or d+ ® D Reverse mutation – causes novel mutation to revert back to wild-type allele (reversion) i.e. a ® A+ or D ® d+  Causes of Mutations Spontaneous arise in absence of known mutagen provide “background rate” of mutation i.e. 2-12 x 10-6 mutations per gene per gamete Induced (by geneticist -- mutagenesis) action of mutagen alters nucleotide sequence What causes spontaneous mutations? 1) Depurination 2) Deamination Hartwell Fig. 7.7  What causes induced mutations? 1) X-rays 2) UV light Hartwell Fig. 7.7 What causes induced and spontaneous mutations? 3) Oxidation Hartwell Fig. 7.7  Indel Mutations Often occur in regions of repeated bases Molecular consequences of mutations in coding sequence 1) Silent (synonymous) point mutation Griffiths Figure 16-2  Molecular consequences of mutations in coding sequence 2) Missense (nonsynonymous) point mutation N = Northern blot W = Western blot Griffiths Figures 16-2 and 16-4  Point mutations Comparing nonsynonymous and synonymous rates of point mutations allow for estimates of the strength of selection Neutrally evolving genes have similar rates  Missense mutations differ in severity Conservative substitutes chemically similar amino acid, less likely to alter function or structure of protein Nonconservative substitutes chemically different amino acid, more likely to alter function or structure of protein  Molecular consequences of mutations in coding sequence 3) Nonsense mutation Introduction of a stop codon (UAG, UAA, UGA) N = Northern blot W = Western blot Griffiths Figures 16-2 and 16-4  Molecular consequences of mutations in coding sequence 4) Frameshift mutation N = Northern blot W = Western blot Griffiths Figures 16-2 and 16-4  Molecular consequences of mutations in coding sequence 5) Intragenic suppressor mutations Frameshift mutation: THE FAT CAT ATE THE BIG RAT --Delete C THE FAT ATA TET HEB IGR AT Intragenic suppressor mutation: THE FAT ATA TET HEB IGR AT --Insert A THE FAT ATA ATE THE BIG RAT Mutations outside the coding sequence Example: Splice donor/acceptor site mutations disrupts splice donor/acceptor site, resulting in incorrect retention/excision of intron often leads to large additions or deletions that may cause frameshifts Loss-of-Function Mutations Griffiths (2005) Introduction to Genetic Analysis Consequences of loss-of-function alleles 1) Mutation is recessive (haplosufficiency) Hartwell, 7th ed, Fig. 9.28 Consequences of loss-of-function alleles 2) Haploinsufficiency Hartwell, 7th ed, Fig. 9.28 Gain-of-Function Mutations Excess protein produced in comparison to normal causes an abnormal phenotype Proteins produced with new function or normal protein produced at inappropriate time or place Griffiths (2005) Introduction to Genetic Analysis Disease mutation example: vision Vision commences with activation of rhodopsin in the photoreceptor cells of the eye Hartwell, 7th ed, Fig. 8.12 Disease mutation example: vision Different visual pigments mediate color vision They are homologous, and some occur on the X chromosome Hartwell, 7th ed, Fig. 8.12 Disease mutation example: vision Unequal crossing-over gives rise to natural variation in human R/G vision Hartwell, 7th ed, Fig. 8.13 Mutations provide information about gene function Conclusion: Inborn error of metabolism arose from mutations that prevented a particular gene from producing an enzyme Hartwell, 7th ed, Fig. 8.6 Phenylalanine Metabolic Pathway gene A gene B gene C gene D  Biosynthetic pathways Gene Gene Gene Gene A B C D Enzyme Enzyme Enzyme Enzyme A B C D 1 2 3 4 5  Biosynthetic pathways Gene Gene Gene Gene A B C D Enzyme Enzyme Enzyme Enzyme A B C D 1 2  Biosynthetic pathways Gene Gene Gene Gene A B C D Enzyme Enzyme Enzyme Enzyme A B C D 1 2 3 4 5 3 Mutant organism will grow if compound 3 is supplied  Biosynthetic pathways-example Compound added fewest Mutant A B C D E G 1 - - - + - + 2 - + - + - + 3 - - - - - + 4 - + + + - + 5 + + + + - + Compounds that are used latest in the pathway will support the growth of the most mutants Compounds that are used earliest in the pathway will support the growth of the fewest mutants Biosynthetic pathways-example (cont) Compound added fewest Mutant A B C D E G 1 - - - + - + 2 - + - + - + 3 - - - - - + 4 - + + + - + 5 + + + + - + E→A→C→B→D→G Mutant blocked between E and A canʼt be supported by E but can by the rest; etc.  Biosynthetic pathways-example: order of genes Compound added Mutant A B C D E G 1 - - - + - + 2 - + - + - + 3 - - - - - + 4 - + + + - + 5 + + + + - + 5 4 2 1 3 E→A→C→B→D→G HMB265: Human & General Genetics Lecture 16: Transposable Elements Prof. Belinda Chang  Lecture Outline Transposable elements in maize Mechanism of action Retrotransposons DNA transposons Effects of transposons Laboratory use of transposons Reading: Goldberg et al., 8th edition, Chapter 14 (pages 451-457). ⑬ Transposition of genome · often take up a huge portion are selfish they - ↳ carry into that allow self-alive. Movement of small segments of DNA called transposable in a b TE can genome be elements from one position to another in the genome from anywhere 10, 000s one - of times 12 % Broughly of fly genome. Discovered by Barbara McClintock in late 1940s – * in more dif fly around pops discovered awarded Nobel Prize in 1983 DNA had just been fixed positions of chromosomes. from recomb mapping (genes are on ↳ went against findings used maize as model be maze chromosomes are large and easily visualized by light microscopy. ↳ noticed that the arm of chromosome nine kept breaking at particular site. IEs are so small they can't be seen at low resolution of chromosomal Karyotypes CW10FISH) ↳ cloning of TEDNA made it possible to analyze. Hartwell, Canadian ed., Fig. A, p. 295  McClintock’s experiments One strain of corn frequently had break in chromosome 9 -DiDsssoci ation helps cause break Factor element unlinked activator - Another element G Ac required to activate break at Ds locus location. ↳ couldn't map As to a Unusual phenotypes caused by the Ds element - of corn controls several easily scored phenotypes ↓ & some ar m at chroma - at this site of ps , have breakage & if you on OTHER side of chrom , have recessive and if you & if you have breakage of dom alleles , you will have recessive phenotype. have both alleles , if you not prenotype & insertion if you have the of Ps , it disrupts recessive gene , giving have loss from DS if you allows not 7 ↳ SPOTS ! return to cut, is cle that TE  Transposable elements in corn other require elements for mobility Ds = nonautonomous element morenation ↳Cant ↳ purple No other - require elements for Ac = autonomous exicison insertion -> no mobility ↳ recessive stable D element Ac it if we have , exicision promotes Autonomous elements it of Ds and becomes unstable G encode information Ac ↳ it is unstable can catalyze required for own movement and for its own excision movement of very can occasionally come in D , and A nonautonomous elements become ↳ can PS is prob a mutated incomplete element- c-m = c mutable Mechanism of transposition in corn on end inverted repeats recognized by whether its a as or R movement of > - allows transposon > - promote clearage of excision out current location in genone t in insertion new target site doesn't have * DS so transposase on its it can't own Inserted element flanked by a short repeat - - - J dif from inverted repeats * result of cuts in host in DNA Transposable elements are common Bacteria: Several types, inserted several times 44 more than > - Drosophila: Approx.12.5% of the genome ↳ more via reverse transcription Humans: 34% of the genome RNA intermediate of an Two main classes in eukaryotes: Retrotransposons ↳ COPIA and DNA transposons * most (a0 % ) in humans > - CORN ↳ in humans we can see by comacing human with genome ↳ more DNA without RNA intermediate. ancestor chimp humans is due rate of TE in * low to accumulation of muts in TEDNA most imp bac TES seq are those wR- factors resis many drg - - plasmids w genes that encode for : genes are or - anti resist wansposons! (introns) * R-factors are transferred ↳ most genes are non-coding during all conjugation.  to > - similar repovinses Retrotransposons have GAG gere · · ALL - ALL Have an have - pot RNA genes intermediate endonucleases Some have poly A - ↳ encode for reverse ↑ ↳ role in maturation transcriptase have ↳ imp to make it DNA and some back to - long terminal put into genome repeat sequences * also in retrovims b ↳ maturation of RNA ↳ reverse transcriptase O bigger DNA than transpons b more similar to reterovirus C of many same gene retrotrans posons out cell NEVER go ↳ virus es do to infect cells =  2 eles a ~ class DNA Transposons - - ↳ resemble simple transposable ↳ ends are inverted repeats > - recognized by excision and transposase O relocation of P-element - T > - - - - - - D Hartwell 7th ed., Fig. 14.22 Transposable elements in humans retrotransposons O reverse ↳ have transcriptase ↓ O most abundant SIWEs are Aly - - of Aln) ↳ target sites contain (10% inte C same recog sequence that All restriction sequence uses size I complex  How do animals and plants survive with so many mobile elements? breast Alu in Bracha2 : cancer A Lines hemophilia in can't be so recognized inactivated by transposase &↑ anymore inverted Usually inserted into introns 1 in ↑ repeats. Often defective -- unable to transpose again due to mutations - i.e. lack of repeats or active transposase Epigenetic changes from heterochromatin; safe havens BUT—Mutation can occur Hartwell 7th ed., Fig. 14.23 Transposable elements can generate chromosomal rearrangements ALL homologons - sequences Promignment ↳ of chromosomes in middle during chrossing over and promote unequal Co. dif slightly position large regions in one - (in other Hartwell et al. Canadian ed., Fig. 9.28  Transposition can relocate genes near each other 2 TEs somewhat can promote intervening seq & to relocate to another location - be intervening repeats by transposase can be switched b messes up elements regulatory The level of expression of the gene may be altered Hartwell 7th ed., Fig. 14.25 Laboratory uses of transposable elements - O Wildhi Allows for the & transfer of any ↳ helps integrate into genome gene of interest to make Op transgenic flies A = HMB265: Human & General Genetics Lecture 17: Chromosome Packing & Number Prof. Belinda Chang  Lecture Outline Chromosomal packaging Changes in ploidy Sex chromosomes Fetal testing and ethical issues Reading: Goldberg et al. 2024, 8th ed., p. 71, Ch 13 (p. 406-8, 412-7), Ch 15 (p. 470-481). ⑫ Chromosome packaging Nucleosomes Transcription requires nucleosome - around histones ↳ DNA Histones - > Que charge , N2A , H2B , 43 + 14 remodeling J nc ores - * * Differenciated cells retain patterns of chromatin config + gene expression that more condensed than Persist after mitosis er - ↳ be when they divide , regulatory that establish chromatin protiens daughter cells. are in structure (cell memory) * Most genes in Heterochromatin region are silenced! b easier to see regions - darker - strong ger ligh roscope in asion ! G found near centromere * most of y chromosome is heterochromatin. transposabla et. geres in enchromatin (90 % ) * most chromatin Hartwell 7th ed., Fig. 13.4, 13.7, 13.11 structure retain * diffrenciated cells ↳ Chromatin remodeling Histone tail modifications… Nterm tails PTHs binding protiens ↳ influence packing + …alter chromatin structure chromatin + prevent packing ace to lys - > open chromatin met to lyslarg > - open/closed ↳ depending on an X of het chromatic ↳ block spread Hartwell 7th ed., Fig. 13.14, 13.15  X-chromosome inactivation ---- Heterochromatin formation inactivates an entire X chromosome in females - - Random X-chromosome inactivation in females early during development - inactivation is hereditary through cell division i.e. clonal (except reactivated in germ cells) - - don't want > - reason—dosage compensation two copies or a gene inactivated X = Barr bodies ↳ faculative heterochromatin Figure 121-27 in Griffiths, 9e  Mechanism of X-inactivation coating of chromosome ~ inding never sver ~ with XIST RNA = translated & te O hypoacetylation of a Inactivating condens Lys in two histones x center a tion histone methylation in inactivated X even if you delete XIST locks S you start to condense the OTHER X-chromosome it - - ↳ if you add XIST to anto some , condenses  Changes in chromosome number Euploidy: complete sets Aneuploidy: loss or gain of of chromosomes one or more chromosomes ↳ autosomal aneuploidy is usually lethal. Smules s better - i xo female , XXX females are oK : XXymale , ↳ sex chromosomes Monosomy (2N - 1) Trisomy (2N + 1) Tetrasomy (2N + 2)  (euploidy Monoploidy only one set of zw = D chromosomes : Male bees, wasps, and ants & naploid normal State Parthenogenesis – development of unfertilized egg into an embryo (with no fertilization) single set of chromosomes produce gametes by modified meiosis Usually lethal in other systems unmasks recessive lethals if individual survives to adulthood ® no meiosis, sterility Monoploidy can be produced experimentally - onen ↳bano I meosis Monoploid plants have many uses - witesses Ut for nomo visualize recessive traits directly monoploid to introduction of mutations - to make desirable pheno ↳ COLMIN oubling. of chromosomes Hartwell 7th ed., Fig. 15.14  Polyploidy Very common in plants: associated with origin of new species may positively correlate with size and vigor eg. alfalfa, coffee, peanuts are tetraploid eg large apples, pears, grapes are tetraploid eg. large strawberries are octaploid 2x 4x 8x 2x Hartwell et al. (2007) textbook  seteilia sidetetraploid - allchromosomes > derives - createsnew dipia Polyploidy: Autopolyploids Originate within a species eg. Autotriploid (2n + n = 3n) can be spontaneous failure in miosis - = diploid gamete b results in infertile > - engote XX sterile at old As Hartwell 7th ed., Fig. 15.5  Autotriploids are sterile Due to formation of aneuploid gametes, eg. bananas Meiosis Typical - can't pair 3 so 3 randomly decides where to migrate sometimes in f o 9 ID copies ton el o 3 ⑤ of each blanced chromosome gamete ↳ meosis1 to pair together, I pair other up , goes randomly :. unbalanced Hartwell 7th ed., Fig. 15.5  Polyploidy: Autopolyploids Occasionally meiosis can produce balanced gametes · b * if X is SMALL - 2 4 Hartwell 7th ed., Fig. 15.5  Autotetraploids Doubling of 2n chromosome complement to 4n spontaneous doubling that affect drugs formation spindle result in doubling of chrosomal #3 induced by a drug such as colchicine separation happening not aS normal often the source of a new species & -o ↳ doubles by preventing spindle X  Tetraploid meiosis: AAaa x AAaa Bivalents: pairs of synapsed homologous chromosomes and want adaa ? if AAdd CAA) : n(AA) (aa) : 1 - = = 5 pair up x 4 copies of >differently nomologous chromosomes aa phenotype, 1/6 * 1/6 =O O 1/36 Hartwell 7th ed., Fig. 15.6  chromosomes with complete hybrids SPECIES > - from TWO DIF (mule Polyploidy: Allopolyploids hybrid of two or more closely related species partially homologous chromosomes (homeologous) amphidiploid --doubled diploid: doubling in germ cells ↳ parentspecieavoid O - 2  Aneuploidy Loss or gain in the number of individual chromosomes For autosomes: missing No nullisomy: 2n – 2 & missing monosomy: 2n – 1 trisomy: 2n + 1 tetrasomy: 2n + 2 For sex chromosomes, list copies of each chromosome: eg. XXY, XXX, XO, XYY See Table 17-1 in Griffiths  Cause: Nondisjunction Meiotic nondisjunction OR, mitotic nondisjunction See also Hartwell 7th ed results in a mosaic Fig. 15.2  Monosomy 2n - 1 Usually lethal in utero in humans Examples: Monosomy 21: born with severe multiple abnormalities but die shortly after birth other sex chromosomes no Turner syndrome (XO): 99% of affected fetuses are not born. Those who are born have developmental abnormalities. Question: X inactivation occurs in XX individuals. Why are there abnormalities in XO individuals? X inactivation does not occur until the 100-cell stage he in development end ais critical up until Some of the genes on the “inactivated” X chromosome are expressed.  Trisomy 2n + 1 Often lethal in animals owing to chromosome imbalance Examples: Trisomy 21: Down syndrome Trisomy 18: Edward syndrome Trisomy 13: Patau syndrome is due ↑ turner/Clive infertility. of X-linked dosage in germ Klinefelter syndrome: XXY to abnormal of other X means & reactivation only has one an X- > turner every orumrecieves close + defective h reline oogenes is results in 2x dose X-linked theymea > of - Trisomy XYY Trisomy XXX Down syndrome karyotype Trimosy 21 O Lewis (2007) Human Genetics Down syndrome (trisomy 21) Females can be fertile Males infertile Average life expectancy ~40-60 years Risk of having a baby with Down syndrome rises with maternal age G - arrest * oocyte in prophase ↳ have to like stay rucf after age 30 -  Trisomies XXX and XYY XYY: Usually fertile – X pairs with one Y; other Y does not pair and is not transmitted to gametes i.e. X or Y gametes, not XY or YY XXX: Usually fertile - Two X chromosomes pair; third does not pair and is not transmitted i.e. only X gametes, not XX Thus, conditions are not passed on to progeny XXY: One X is inactivated in Klinefelter syndrome D - XY Hartwell et al. Canadian ed., Fig. 9.30 Human chromosome mutations Hartwell et al., p. 313 Genomic hybridization: microarrays - Microarray-based methods for detecting duplication/deletions of at least 50 Kb pieces of human ones) genome (back on to microarray > - Men assay prepare sample DNA - no abnormal + combine with control - ↳ mix w dif flores cent on to Micreaway spot Where you see both , orange does not normal where you see test have region of yellow DNA abnormal lied) duplicated region J ↳ - - Hartwell et al., Canadian ed., Fig. 9.38  Prenatal testing Screening Tests, first trimester not ↳ diagnostic higher incidence Nuchal Translucency, ultrasound > - non-invasive ↳ checks babys fluid under skin neck thicker than normal-down syndrome Maternal serum blood tests (placental hormone levels) Non-invasive Prenatal Testing (NIPT), blood test Diagnostic Tests Chorionic villi sampling (10 to 13 weeks) Amniocentesis (16+ weeks) Chorionic villi sampling invasive villi tissue ↳ sampling < part of placental by small tube putting a ↳ tested for problems carlier 10-12 weeks small risk of miscarige Risk of miscarriage due to the procedure: 1% Hartwell, Can ed, Fig. B, p. 76  Amniocentesis collect amniotic ↓ Inid ↳ fetal cells extracted and analyzed Test results available 1 to 3 weeks later- Risk of miscarriage due to the procedure: 0.5% Hartwell, 7th ed, p. 71; Lewis (2007) Human Genetics  Fetal testing (cont) Look for abnormal karyotypes Possible to screen for biochemical and molecular disorders Tests are done in combination with blood tests for certain fetal proteins and maternal hormones, and with ultrasound tests Preimplantation embryo diagnosis used wirF and analyze ↳ remove cell Screen for mutant alleles prior to implantation First used for CF allele Hartwell, Canadian ed., Fig. 15.1  Ethical considerations Which genetic variants should be screened? Who should have access? Should parents have the right to make any genetic decision? Who should have access to test results? Ethical considerations Hartwell, Canadian ed., Fig. 3.1 HMB265: Human & General Genetics Lecture 18: Chromosomal rearrangements Prof. Belinda Chang  Lecture Outline Deletions Duplications Inversions Translocations Reading: Goldberg et al., 7th ed., Ch 14 (p. 436-7, 441-9, 458-9). Chromosomal mutations  salivary glands visualize > - they undergo -> can sister chromatids under light model-drosophilae 10 rounds to from them y - replication microscope - lawae entering separate wo mitosis ↳ darker bands = more edensation ⑲ Polytene chromosomes used to study * · used to genes in site identify certain hybridization changes in chromosome structure map topin point specific genes. Figure 9.6, Hartwell et al., Canadian ed.  understanding : /single chromosome. site (deletion) and invert 180 at another part when theres 2 DSB , the DNA will ligand (join) together at one. inversion AND deletion If ↳ dif locations homologous : > on DSB at 2 crossing reciprocaltranslocationifswitch ↳ if non-homologous : plea over Deletions Intragenic: small deletion within gene usually - don't go back lethal espir Multigenic: many genes deleted homozygous Del (Df) homozygotes usually inviable D Gene imbalance in Del heterozygotes (might result in haploinsufficiency) Hartwell et al., Canadian ed., Fig. 9.2 consequences XY) mutations be most Lethality (XX or usually die for most. survival essential - 1 genes are ↳ smaller (intragenic) more likely to result in VIABLE MOMOZYGOUS but usually they - die. 2 Deletion neterozygotes usually survive if other homologons has copy of deleted gene but still might show... mutant prenotypes be of : 1.. Haplo insufficiency : lowered dosage Deletions 2. Large Deletion loop failure to pair gen mapping betw portions of ↑ > gere is. homologous I can see I chromosomes 8 neiosis under during lead uM