1MCB140 01-26-07 1 MCB140 01-26-07 2Grrrrrr“Once he had isolated pure-breeding lines for several sets of characteristics, Mendel carried out a series of matings between individuals that differed in only one trait, such as seed color or stem length.”MCB140 01-26-07 3Chromosome “theory” of inheritanceMCB140 01-26-07 4Other “theories”• Darwin’s “theory” of evolution• Crick’s central “dogma” of molecular biology• Galileo’s “theory” that the Earth rotates around its axis, and revolves around the Sun2MCB140 01-26-07 5Mendel’s “Particles of Inheritance” (the Genes) Lie on Chromosomes:From Theory in the 1900s to Firmly Established Fact by ~1920MCB140 01-26-07 6Ernest Häckel1866:General Morphology of the Organisms“The nucleus is the part of the cell that is responsible for heredity”Nice idea, but not based on data of any sort (at the time).MCB140 01-26-07 7August Weissman, 1883MCB140 01-26-07 8Recall Darwin’s “gemmules”…somaGerm plasmsomaGerm plasm3MCB140 01-26-07 9Weissman’s somewhat gruesome but, well, persuasive experiment1. Cut off the tail of some mice.2. Breed the tailless mice.3. Get children with tails.4. Cut off their tails.5. Breed them.Repeat 21 times.“Experiments” done by others and cited by Weissman as supporting evidence: centuries and centuries of foot-binding by the Chinese and circumcision by the Jews have not led to the inheritance of either trait.MCB140 01-26-07 10MCB140 01-26-07 11Walther Flemming, 1879Salamander tail fin cells – living cells.Gills – fixed cells.“Beitrage zur kentniss der Zelle und ihre Lebenserscheinungen”“Contributions to knowledge about the cell and of aspects of its appearance that have to do with the fact that it is alive.”a process with threads = mitosis4MCB140 01-26-07 13The object that acquires a color after we stain it: the chromosomeFlemming stained the cell with a dye and found that something inside the nucleus stained quite vigorously. He called it “chromatin” (“stainable material”).In 1888, Waldeyer renamed Flemming’s “threads” – “chromosomes.”MCB140 01-26-07 14A questionWhat – if anything – do the chromosomes have to do with the process of heredity?MCB140 01-26-07 15Theodor Boveri, 1895MCB140 01-26-07 16Boveri, expt 11. Enucleate sea urchin egg by agitation.2. Fertilize this “cytoplasm only” egg with sperm.3. To his surprise, get a larva, but a much smaller one.“… It is not a given number of chromosomes as such that is required for normal development, in as much as these fragments, although they contained only half the normal amount of chromatin and half the number of elements, namely the chromosomes of one sperm nucleus, still give rise to normal plutei.”Pluteus = easel.5MCB140 01-26-07 17 MCB140 01-26-07 18Boveri, expt. 2Enucleate the egg of one species of sea urchin, and fertilize with a sperm of a different species. MCB140 01-26-07 19♀♂MCB140 01-26-07 206MCB140 01-26-07 21E.B. Wilson, 1896“… the maternal cytoplasm has no determining effect on the offspring, but supplies only the material in which the sperm nucleus operates. Inheritance is, therefore, affected by the nucleus alone.”MCB140 01-26-07 22Boveri, expt. 3Let’s make a triploid sea urchin embryo by fertilizing an egg with two sperm.The resulting zygote does divide, but the mitotic spindles are multicentric. Sometimes, this triploid entity even produced a 4-cell embryo. The resulting blastomeres, when separated, invariably failed to develop further. In contrast, the 4 blastomeres from a diploid embryo went on to form 4 plutei.MCB140 01-26-07 23Boveri expt. 3 ctd.“… the next question was whether this unequal distribution of the chromatin is of any influence upon the properties of the four cells. … While the four blastomeres of a normally divided egg are absolutely equivalent to each other, it is seen that the properties of the blastomeres of a doubly fertilized one are different from each other in diverse ways, and to varying extent.All that remains is that not a definite number, but a definite combination of chromosomes is necessary for normal developemnt, and this means nothing other than that the individual chromosomes must possess different qualities.”MCB140 01-26-07 24On chromosomes, chromatids, sisters, nonsisters, and homologsFor that half of the class that did not answer the multiple choice question correctly7MCB140 01-26-07 25Fact 1The human genome contains ~35,000 genes. Each gene is – from a physical perspective – a stretch of DNA. The sequence of base pairs in that DNA encodes the amino acid sequence of a protein (note: this simplified narrative disregards noncoding DNA elements of a gene, such as regulatory DNA stretches, untranslated 5’ and 3’ UTRs, introns, and polyadenylation signals; furthermore, most of the RNA produced by the human genome is noncoding, but you will learn that in graduate school, if you go there).MCB140 01-26-07 26FurthermoreIn principle, it is imaginable that each gene could be on a separate piece of DNA, so the nucleus of a human cell would contain 35,000 separate pieces of DNA.In actual fact, in a human being, the genome is distributed onto 23 pieces of DNA (well, 23 pieces plus one additional somewhat important gene on a separate small piece of DNA, but more on that later).What you call those pieces depends on who you are.MCB140 01-26-07 271 genome = 35,000 genes = 23 pieces of DNAFor now, let us call EACH of those pieces a chromosome. More later on that “for now” bit.We can now ask: those 35,000 genes mentioned earlier –how are they distributed between those 23 chromosomes? In alphabetical order, perhaps? Or, which would be cool – by pathway (in order of appearance in Stryer)? For example, chr. 1 would all the genes for glycolysis, chr. 2 – for the Krebs cycle, and chr. 3 – for oxidative phosphorylation.Or – why not? – maybe different people have a different distribution of genes on their chromosomes? In other words, maybe my chr. 1 has different genes than your chr. 1?MCB140 01-26-07 28Genetic unity of a speciesThis issue has been studied experimentally, and it was found that in a given species, the distribution of genes between chromosomes, and – within each chromosome – their order are both invariant.In other words, if we examine chr. 1 (by the way, they are numbered according to size, eXcept for the X), then in every human being, that chromosome will contain the exact same genes
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