- Distinguish amongst genetic (recombination), cytogenetic (metaphase chromosome), and physical maps.
- Differentiate chromosomes cytologically based on their length, centromere position, and banding patterns when stained with dyes.
- Discuss the ultimate physical map which is the DNA sequence of the whole chromosome or genome.
In this chapter, we will be taking a look at the larger picture of chromosomes and of whole genomes, and the various methods which are used to visualize them. Many types of mapping techniques are available to identify single genes that are responsible for disorders, such as Ankylosing spondylitis and cystic fibrosis, as well as the multiple genes responsible for common conditions such as cardiovascular disease and diabetes mellitus. Gene and chromosome mapping are tools which can be used to assist in developing detection, monitoring, diagnosis and treatment regimens for persons suffering from genetic diseases. The advances that have been made in healthcare owe much of their success to the ability of geneticists to view genomes of organisms and analyze chromosomes at a level which allows insight into the transmission and manifestation of genetic diseases.
Before we go any further, let us review some basics about chromosomes and genes. A functional chromosome requires four features as shown in Figure 12.1.1.
Each chromosome is long molecule of double-stranded DNA. They carry genetic information (genes). Chromosome 1, being our largest chromosome has the most genes, about 4778 in total. Many of these genes are transcribed into mRNAs, which encode proteins. Other genes are transcribed into tRNAs, rRNA, and other non-coding RNA molecules. A centromere (“middle part”) is a place where proteins attach to the chromosome as required during the cell cycle. Cohesin proteins hold the sister chromatids together beginning in S phase. Kinetochore proteins form attachment points for microtubules during mitosis. All human chromosomes have a centromere, but not necessarily in the middle of the chromosome. If it is in the centre the chromosome it is called a metacentric chromosome. If it is offset a bit it is submetacentric, and if it is towards one end the chromosome is acrocentric. In humans an example of each is chromosome 1, 5, and 21, respectively. Humans do not have any telocentric chromosomes, those with the centromere at one end, but mice and some other mammals do. The ends of a chromosome are called telomeres (“end parts”). Part of the DNA replication is unusual here, it is done with a dedicated DNA polymerase known as a Telomerase. As with the centromere region there are no genes in the telomeres, just simple, repeated DNA sequences. At the beginning of S phase DNA polymerases begin the process of chromosome replication. The sites where this begins are called origins of replication (ori’s). They are found distributed along the chromosome, about 40 kb apart. S phase begins at each ori as two replication forks leave travelling in opposite directions. Replication continues and replication forks travelling from one ori will collide with forks travelling towards it from the neighboring ori. When all the forks meet, DNA replication will be complete. Chromosomes are long duplex molecules of DNA that are either linear or circular and composed of a relatively constant sequence of nucleotides. There are three different ways of describing the linear contents of a chromosome (Figure 12.1.2): (1) genetic map, (2) cytogenetic map, and (3) physical map (ultimately the sequence).
- Figure 12.1.1 Original by M. Harrington (2017), CC BY-NC 3.0, Open Genetics Lectures
- Figure 12.1.2 NHGRI Fact Sheet- Genetic Mapping (27058469495) by National Human Genome Research Institute (NHGRI) Image Gallery, CC BY 2.0, via Wikimedia Commons
Harrington, M. (2017). Figure 6. Parts of a typical human nuclear chromosome …[digital image]. In Locke, J., Harrington, M., Canham, L. and Min Ku Kang (Eds.), Open Genetics Lectures, Fall 2017 (Chapter 15, p. 4). Dataverse/ BCcampus. http://solr.bccampus.ca:8001/bcc/file/7a7b00f9-fb56-4c49-81a9-cfa3ad80e6d8/1/OpenGeneticsLectures_Fall2017.pdf