Study Guide Chapters 2 & 3 PDF

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Chapter 2 and 3:  

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Monohybrid cross: “Principle of Segregation” o Alleles are segregated (=separated) during gamete formation (Mendel’s First Law) Dihybrid cross: “Principle of Independent Assortment” (Mendel’s Second Law) o Alleles from locus B are assorted to gametes at proportions predicted for that locus, independent how alleles from locus A are assorted. Trihybrid Genetic Cross o Trihybrid cross = three pairs of elements that assort independently, such as RrYyPp o For any pair, phenotypic ratio = 3:1 o For two pairs, phenotypic ratio = 9:3:3:1 o Trihybrid cross pattern of segregation and independent assortment is identical to dihybrid, with the phenotypic ratio = 27:9:9:9:3:3:3:1 When and how during gamete formation are alleles segregated and (independently) assorted? o What happens in dihybrid cross?  P1 (AABB) x P2 (aabb) (i.e. gametes-P:AB x ab)  F1: AaBb forms gametes AB, ab, Ab, aB  During meiosis I:dominant and recessive versions of A locus (located on large chromosome) and B locus (located on small chromosome), distributed (= pulled into different gametes). “A chromosome” independent of what happens with “B chromosome”. o Meiosis I:  2n > 1n (cell goes from diploid to haploid); alleles are segregated and independently assorted (generating new or P gametes) o Meiosis II:  Haploid cell undergoes mitotic cell division; sister chromatids separated (sisters identical if no crossover recombination) Four possible F1 gametes (carrying independently assorted chromosome sets) from dihybrid cross fertilize at random (Punnett Square) Or with three chromosomes (trihybrid) eight different gametes How do we know that chromosomes are important for inheritance? o DNA is material of inheritance (Avery-experiment) and chromosomes are made of DNA (plus proteins) o Every eukaryotic cell contains chromosomes o Chromosome pairs with same size and shape separate from each other during meiosis (reminds of Mendelian factors) o Number and shape of chromosomes in nucleus of somatic cell invariant in a given species (i.e. defines species) o “chromosome complement” = complete chromosome set for particular eukaryotic species (it complements all possible mutations in a genome) Chromosomes o Chromosomes in somatic cells present in pairs.  Example:  Humans: 23 pairs of chromosomes,

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 fruit flies: 4 pairs of chromosomes. o Cells with two similar sets of chromosomes are called diploid. o Explains why Mendel observed heterozygosity Cytogenetics: How can we determine the number of chromosomes in a given species? o Chromosomes become visible only during mitosis or meiosis due to condensation o Invisible in interphase: G1,S,G2 o Best visible:  Mitosis: starts in prophase, maximum in metaphase  Meiosis: prophase meiosis I (maximum in pachytene) Two types of cell division o There are 3 events necessary for successful cell division:  Genetic information copied (S-phase, DNA replication)  The 2 copies of genetic information separated from one another  Cell divides o Two types of cell division:  Mitosis  Meiosis Chromosome segregation in meiosis and mitosis differ o Common:  DNA replicated (S-phase)  Chromatin condenses (chromosomes become visible) o Different:  Mitosis:  one nuclear division  Sister separation  Meiosis:  two nuclear divisions  homolog separation The Mitotic Cell Cycle: Mitosis

o Karyotype: o The particular chromosome complement of an Individual’s metaphase cells as defined by number and morphology of chromosomes. CHROMOSOME MORPHOLOGY

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o Inheritance of Chromosomes o Germ cells (=gametes): haploid, contain one set of chromosomes, one member of each of the diploid chromosome pairs. o Haploid gametes unite in fertilization to produce diploid somatic cells (= zygote) o Chromosomes in pairs: because one of each pair comes from mom and dad. Stages of Meiosis o There are 2 cell divisions in Meiosis, each of which has 4 main stages:  Meiosis I: Prophase I, Metaphase I, Anaphase I, Telophase I  Meiosis II: Prophase II, Metaphase II, Anaphase II, Telophase II Meiosis o Two successive nuclear divisions o Results in four daughter cells, each genetically different and containing one haploid set of chromosomes o Meiosis is a more complex and considerably longer process than mitosis and usually requires days or even weeks (and may be arrested for decades e.g. in female humans) o In animals, meiosis takes place in specific cells called meiocytes o The oocytes form egg cells and the spermatocytes form sperm cells o In the females of both animals and plants, only one of the four products develops into a functional cell (the other three disintegrate as pole bodies) Stages of Prophase I of Meiosis I o There are 5 Main Stages of Prophase I:  Leptotene: the chromosomes first become visible as long, thread-like structures  Zygotene: synapsis of homologous chromosomes begins = bivalent  Pachytene: crossing-over between homologs  Diplotene: chromosome repulsion, however, they remain held together by crossconnections resulting from crossing-over. Each cross- connection, called a chiasma is formed by a breakage and rejoining between nonsister chromatids  Diakinesis: maximum chromosome contraction Prophase Meiosis I o Pairs of equivalent paternal and maternal chromosomes closely associate with each other along their length (pairing & synapsis). o Chromosomes that pair are said to be homologous chromosomes or homologs. o Each member of a pair of homologs consists of two sister chromatids, thus, pairing of homologous chromosomes produces a structure containing four chromatids. o After pairing and during synapsis, DNA in homologs is broken and newly joined, resulting in exchange of flanking chromosome arms o Consequence: Crossing over/ chiasma (pl chiasmata) o Crossovers formed by homologous recombination

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Outline of Meiosis II o The second nuclear division resembles a mitotic division, but there is no DNA replication. o Metaphase II, the chromosomes align on the metaphase plate o Anaphase II, sister chromatids are separated into opposite daughter nuclei . o Net result of two divisions: four haploid nuclei, each containing a single sister chromatid from each pair of homologous chromosomes. Consequences of meiosis o Formation of four haploid cells, each with one complete copy of the genome o Genetic recombination  crossing-over in prophase I (pachytene)  independent assortment of nonhomologous chromosomes  results in genetic diversity o Meiosis occurs at a fixed point in the life cycle of all sexually reproducing organisms

Chapter 4 Special case of monohybrid cross: Pedigree Analysis o Humans not pure-breeding (heterozygous for most loci) o (Usually) not inbreeding o pedigree analysis used to predict individual genotypes and mode of transmission of single gene traits o Like in pea breeding, dominant allele upper case, recessive lower case o Modes of inheritance: o Autosomal  Dominant  Recessive o X-linked  Dominant  Recessive o Y-linked  If two copies of Y, from same father! Autosomal dominant: o In example, father is affected with dominant phenotype Autosomal dominant inheritance o Parent to child transmission - “vertical transmission.” o No generation skipped o Males and females equally affected. o Each child of an affected parent has a 1-in-2 (50%) chance of being affected. o Male to male transmission can occur. o For rare phenotypes we assume that affected individuals have a single dominant allele. Autosomal recessive inheritance o Notion of “carrier” who is unaffected o Males and females equally affected o Consanguinity & ethnic background

Apparent “horizontal transmission” (multiple affected members of a kindred in the same generation, but no affected family members in other generations) o 25% recurrence risk o In this example both parents are carriers for a mutant recessive gene. o Albinism = absence of pigment in skin, hair, and iris of the eyes Pedigree o Two children, one of each sex, exhibit the trait  Neither parent exhibits the trait o Conclusions:  Recessive (because no parent affected)  Autosomal (because both sexes phenotype)  parents must be heterozygous  2/3 of unaffected children are heterozygous carriers (Axa) Are there exceptions to the “Mendelian ratios”? o If parents form gametes with different genetic content  Sex chromosomes  Cytoplasmic inheritance (mitochondria or chloroplasts)  Some loci are permanently shut-off in one parent (=imprinted) o Two loci affect the same trait  Additive contributions of two loci to a single trait  Epistasis, i.e. mutual dependence of two loci o Phenotype affected by other (genetic or possibly unknown) factors Two sexes prerequisite for sexual reproduction o Need males and females every generation for maintenance of species o >> sex usually not inherited in simple Mendelian fashion o sex: first phenotype mapped to a distinct set of chromosomes = sex chromosomes o Many species: one sex forms only one type of gametes (homogametic, X in mammalian females); other sex forms two types of gametes (heterogametic, X or Y in mammalian males) Chromosomal Sex-Determining Systems o XX-XY: females XX, males XY – all mammals, many plants, insects & reptiles o XX-XO: females XX, males X – some insects (grasshoppers) o ZZ-ZW: females ZW, males ZZ – birds, snakes, butterflies, some amphibians, & some fish Special features of sex chromosome versus autosomes o Few genes on Y chromosome: heterogametic sex (male) has only one functional copy of sex chromosome (hemizygous for alleles on X chromosome) o Two consequences:  1. Recessive mutant alleles on X are always manifest in males, but not in females  While Y chromosome determines just male-related traits, X chromosome carries many loci that determine other traits (e.g. blood clotting, color vision)  2. Dose of genes on X chromosome needs to be adjusted (achieved by inactivating entire X chromosome, observable as Barr body) X-linked Inheritance o

Recessive vs. Dominant Males vs. Females  Female carriers are generally healthy o Carrier Females  50% risk for affected sons  50% risk for carrier daughters o Affected Males  All daughters are carriers  No chance for affected sons (because son always receives Y from dad, X from mom) X-linked dominant o Affected males have no affected sons and all daughters are affected o Affected female has 50% risk of having an affected child o Males are generally more severely affected than females o Affected females tend to have milder disease than affected males. o Ex: Vitamin D-resistant rickets  Rett Syndrome (autism-like progressive symptom) only females affected, since lethal for males Y-linked Inheritance o Y-linked genes  expressed only by males and transmitted to sons  most affect reproduction (mutations often result in sterility) o Pseudoautosomal inheritance’: Crossover recombination transfers Y chromosome part to X chromosome Random X Chromosome Inactivation Occurs Early in Embryonal Female Development (Preimplantation) o Hybrid mouse brain:  If only Xmom active, red protein expressed,  if Xdad active, green protein expressed,  if both active, green + red=yellow Disorders of Human Sex Chromosomes o Turner Syndrome: 45, X  female phenotype, short stature, normal intelligence, sterile o Triple-X Syndrome: 46, XXX  female phenotype, possible fertility problems o Klinefelter Syndrome: 47, XXY  male phenotype, tall stature, sterile o XXYY Syndrome: 48, XXYY  developmental delays , learning disability o Extra X chromosomes often associated with decreased intelligence o Extra Y chromosomes: no substantial phenotypes, tall stature due to pseudoautosomal region 3 non-silenced copies Cytoplasmic (e.g. mitochondrial) Inheritance o o

Mitochondria and chloroplasts carry their own genomes e.g. in higher animals, mitochondrial DNA (mtDNA) mostly inherited from mother Reason: egg (formed by mother) is the major contributor of cytoplasm to the zygote. Sometimes mother contains a small proportion of mutated mitochondrial genomes The more mitochondria with mutated genome individual inherits, the more severe disease-phenotype Genomic Imprinting o Genomic imprinting results in expression of allele from only one parent (monoallelic) o Imprinting affects the expression of a gene, but NOT its primary DNA sequence. o Normal process caused by permanent alterations in chromatin (“epigenetic”). o Epigenetics: Gene sequence unchanged, but chromatin modification makes locus silent so it is not expressed (transcribed into mRNA) o Similarities to X-inactivation, BUT:  For imprinting, only parts of chromosome inactivated, not entire chromosome  Inactivation happens already in parent, NOT in offspring Imprinting : o If imprinted genome region:  inheriting a dominant wild-type allele does not ensure that the offspring exhibits a WT phenotype o Because:  One parental sex (father or mother) Father or mother modifies locus such that it is silenced/not transcribed  the recessive mutant allele from the other parent (that does not imprint) determines the phenotype o Imprints are “reset” during gametogenesis o Imprinting is reversible o Imprinted genes are “reset” during gametogenesis because dad carries one activate allele (received from his mom), but passes on only inactivated alleles. o Failure to switch imprint can lead to disease. o Failure to provide an imprinted gene can also lead to disease.  Chromosomal deletion of an imprinted region How does genomic imprinting work? o Transcription of imprinted alleles either enhanced or repressed. o DNA methylation is involved in the imprinting process. o Form of dosage compensation, since only one allele active Disorders due to defects in imprinting o Prader-Willi syndrome: Only dad alleles expressed while mom-allele inactive. Mutation of dad alleles results in disease although normal (but inactive) mom alleles available. o Angelman syndrome: Overlapping region where only mom alleles active. o Neurologic  Developmental delay  Mental retardation o Skeletal malformations o o o o o

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Short stature Facial dysmorphism

Epistasis: o One locus covers up (is epistatic to) the allele status of the other locus in a dihybrid cross. o Thus: Locus B can affect the F2 phenotype only if A locus is A_, but not if it is aa. o Consequence for pedigree: 3 instead of 4 phenotypes in F2 o Epistasis refers to any type of gene interaction that results in the F2 dihybrid ratio of 9 : 3 : 3 : 1 being modified into some other ratio Same genotype > different phenotypes in different individuals o Variable expressivity: Phenotype apparent to different degrees in different individuals with the same genotype FOR THAT GENE (other, unknown genes affect gene) o Penetrance: Proportion of individuals who exhibit the phenotype predicated by their genotype. (A genotype that is always expressed has a penetrance of 100 percent) Sex-Influenced vs. Sex-Limited o Some phenotypes are influenced by the sex of the individual, but this does not indicate that they are determined by genes on the sex chromosomes. o Sex-Influenced traits are expressed differently in males and females—generally dominant in one sex and recessive in the other.  Ex: male-pattern baldness o Sex-Limited traits are only expressed in one sex  Ex: prostate CA; ovarian CA Are two mutations that result in similar phenotypes in same or different genes? o Mutants are crossed to bring two recessive mutations together in heterozygous form  if phenotype is mutant, mutations are in same gene  they fail to complement (because two non-functional proteins made)  if phenotype is wild-type, mutations are in different genes  Each mutant contributes a normal allele at the other locus  Complementation is due to presence of one normal protein from each locus Complementation o If two mutations complement each other, the mutations are in different genes o Mutations in the same gene do not complement each other o Complementation group: a group of mutations that fail to complement each other (so they must all be alleles of the SAME gene) Chapter 5 Gene Linkage and Genetic Mapping Chapter 6 

Chromosome sets: Normal and abnormal o Chromosome structure and number can be analyzed using light microscopy o Electron-microscopy analysis of DNA molecule itself does not detect mutations or other aberrations (only whether DNA is double or single stranded)

“Cytogenetics” = Inferring a genetic condition from cytological (=microscopy) analysis of cellular chromosome sets “Karyotype”: o Metaphase chromosomes arranged based on  Size  position of centromere  metacentric, submetacentric, acrocentric, and telocentric  banding pattern  “R” bands: rich in genes  “G” bands: poor in genes o Copy of one chromosome missing monosomy (-1) or extra trisomy (+1) 3. o Complete chromosome set extra, i.e. polyploid Structural Chromosomal Abnormalities o “Unbalanced” Rearrangements (=net gain or loss or gene copies) De letion Duplication o “Balanced” Rearrangements (=same number of gene copies, but order along chromosomes changed) Inversion Translocation o Rearrangements infrequent, present only in one gamete > affected individual HETEROZYGOUS o Mapping of deleted chromosome region: Compare banding to wild type (“physical mapping”) o Large deletions often lethal (organism monosomic for that chromosome segment) > if viable, map deletion boundaries Duplications o Duplication = chromosome segment present in multiple copies o Tandem duplications = repeated segments are adjacent, face same direction o How do multiple tandem duplications arise? Unequal crossing-over between mispaired homologous chromosomes during meiotic recombination o Deletions can occur due to unequal crossover between duplicated pigment genes on X chromosome (Red-Green Blindness) Translocation(Balanced): o • Change in location of chromosome segment; no DNA is lost or gained. May change expression = position effect.  • Intrachomosomal  • Interchromosomal  • Reciprocal - segments are exchanged.  • Non-reciprocal - no two-way exchange. o • Several human tumors are associated with chromosome translocations; myelogenous leukemia and Burkitt lymphoma Reciprocal Translocation o translocation heterozygous = one pair interchanged, one pair normal (most likely, since translocation rare) o translocation homozygous = both pairs interchanged Cytological detection of reciprocal translocation o Translocation: interchange of parts between non-homologous chromosomes o

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No loss of genetic information but function of genes close to break site altered (position effects) o Gene expression in translocated gene elevated or decreased o Robertsonian Translocation : Fusion of two acrocentric chromosomes at centromeres > Special case of nonreciprocal translocation o Apparent loss of one chromosome in karyotype in individual where translocation occurred o Genetic information lost in tips of translocated acrocentric chromosomes o Chromosome 21 acrocentric; if involved in Robertsonian translocation, rearrangement leads to familial type of Down syndrome Inversion o Inversion balanced in carrier, causes problems for meiotic homolog segregation, unbalanced gametes (deletions, centromere loss/duplication) o Inversion usually heterozygous since inversion infrequent in population (because carriers sterile due to aneuploid gametes, discussed later) Effects of structural chromosome aberrations on meiotic chromosome segregation? o Many chromosomal aberrations in heterozygote carrier without phenotype o But reduced fertility due to defects in chromosome segregation o Most severe effects on fertility: inversions and translocations (i.e. balanced changes in chromosome structure) o Chromosome inversions > Meiotic missegregation depends on whether inversion includes centromere  Paracentric inversion = next to centromere  Pericentric inversion = around (includes) centromere Abnormalities in number of chromosomes o Euploid = balanced chromosome condition = normal gene dosage o ...