ChromosomesDNA packagingStudying chromosomesNomenclatureChapter 3ChromosomesWhat is the physical unit of inheritance? When asked this question, most peo-ple will answer “genes” or “DNA,” but they would be wrong. We humans havesome 20,000 some genes but we do not inherit 20,000 plus separate physicalunits. Neither do we simply inherit a big piece of DNA. Instead we inherit“packaged genes” or “packaged DNA” and those packages are called chromo-somes (from the Greek chroma or qrwma meaning “color” and soma or svwmameaning “body”). Hence, the physical unit of inheritance is the chromosome.To understand genetics, we must first understand chromosomes.This is a short chapter. We want to introduce terminology to talk aboutgenes, their locations, and DNA structure. More information about chromo-somes and chromosomal anomalies may be found in Chapter X.X.3.1 DNA packagingTo appreciate the way that DNA is packaged, we should first think of three typesof objects—a very, very long piece of twine, several million donuts, and the Eiffeltower. Taking the twine in one hand and a donut in the other, wrap the twinetwice around the donut in the way shown in panel (a) of Figure 3.1. Leavinga few inches of twine free, grab another d onut and loop the twine around ittwice. Repeat this process until you have about six donuts with twine wrappedaround them, giving a structure similar to that in panel (b). Arrange thesedonuts in a circle on the ground right next to the bottom of the tower. Repeatthis with another six donuts an d place them, again in a circle, almost on topof the first six donuts. Continue repeating this process until there is a loop ofthese twine-donut complexes as depicted in panel (c).Eventually, the pile of twine and donuts will become high enough to makeit unstable and in danger of toppling ove r. To prevent this, have a few helperstake the pile of donuts and start circling it around the Eiffel tower to give itsupport, gluing it to the tower if necessary. Proceed with this strategy of loopingtwine around donuts, arranging circles of donuts, and snaking these piles in and1CHAPTER 3. CHROMOSOMES 2Figure 3.1: Packaging of DNA into chromosomes (from HGSS).around all the rigid structure of the tower. When you finally run out of string,jelly donuts, and tower space, you will have created a chromosome. An electronmicroscope image of the human X and Y chromosomes immediately prior to thecell division is given in Figure 3.2.Figure 3.2: Electron microscope imageof the human X and Y chromosomes im-mediately prior to cell division.From http://www.snv.jussieu.fr/vie/dossiers/ky/chromosome%20X%20et%20Y.jpgThe twine in this pro ce du re isthe DNA molecule and the donutsare composed of eight small proteinscalled histones. The DNA-histonecomplex is called a nucleosome.Notsimply a physical structure, modifi-cation of the histone proteins playsa role in the dimmer switch of generegulation and expression. Hence, itis important to know the term nucle-osome and its definition–DNA woundaround a histone protein complex.The term chromatin is used forthe packaging of the nucleosomesaround the protein scaffolds. The ac-tual state of the chromatin d e pendson the cell cycle. The descriptiongiven above applies to the chromo-somes when they are at their greatestdensity–right before cell division. At other times in the cell cycle–and also incells like mature neurons that do not ordinarily divide–the Eiffel tower proteinCHAPTER 3. CHROMOSOMES 3scaffolding is not present, leaving the chromatin as a more thread-like structure.Also, a single chromosome will have sections of densely packed DNA interspersedwith more loosely packed areas.When the cell is not in the process of replication, the density and loosenessof the chromatin is asso ciated with gene expres sion. In the looser areas, genesare usually being expressed (i.e., the dimmer switch is ratcheted up) while genesin the denser sections are often being repressed (the dimmer switch is turneddown and sometimes may be shut off completely).3.2 Studying chromosomesChromosomes were discovered in the middle of the 19th century when early cellbiologists were busily staining cell preparations and examining them under themicroscope. It was soon recognized that the number of chromosomes in spermand egg was half that in an adult organism, and by the 1880s it was conjecturedthat the chromosomes carried the genetic material. Theorizing about geneticsand chromosomes abounded and generated one of the more interesting curiositiesin the history of science. Despite the ability to actually see the genetic materialunder the microscope, for over 20 years early cell biologists were unable toderive the simple laws of segregation and independent ass ortment postulatedby an unknown Austrian monk, Gregor Mendel. Mendel worked these lawsout because of the properties of a mathematical model and to the best of ourknowledge never even saw a chromosome!Today, the study of chromosomes–both in the research lab and in clinicalsettings–is called cytogenetics. There are two major tools used in cytogeneticstoday. The first is the karyotype which is literally a picture of the stainedchromosomes that can be viewed under the light (or fluorescent) microscope.The second is a procedure called fluorescent in situ hybridization or FISH that isused to detect chromosomal microdeletions, i.e., deletions that are too small tosee under a light microscope. Here, we discuss the karyotype and leave FISH foralatersectionafterwehavelearnedmoreaboutmoleculargenetictechniques.AtypicalkaryotypeisgiveninFigure3.3. Karyotypesaremostoftenusedin clinical, pediatric settings. The first maj or reason is to confirm or refinea suspected diagnosis of a known chromosomal anomaly. Testing for Down’ssyndrome in a newborn is a classic example. A second use occurs when a new-born or infant exhibits wide series of physical and medical irregularities. Here,the pediatrician will order a karyotype to see if there is a gross chromosomalabnormality.Construction of a typical karyotype begins with living tissue, usually a par-ticular type of white blood cell called the ly mphocyte obtained from a bloodsample. The lymphocytes are kept alive and dividing in a culture and then, inaseriesofcomplicatedsteps,arestainedandexaminedunderthemicroscope.Pictures are taken of the chromosomes under the microscope. The chromosomesare then cut out of the photographs and pasted onto paper in a certain