Draft:Chromosome mapping

Introduction

Chromosome mapping is a method determining the relative position of genes within a chromosome. This process creates a map that shows genetic information on chromosomes by showing the gene positions and distances between them, represented on a standardised scale. Chromosome mapping helps unravel the organisation, structure and functionality of the genome.

Early development

The concept of chromosome mapping was suggested by biologist Thomas Hunt Morgan in 1911. When he was studying the genetics of fruit flies, he found that some traits were different from Mendel’s Law of Independent Assortment and with evidence on genetic linkage. Morgan’s discovery that the white eye gene in Drosophila was located on the X chromosome led to the identification and mapping of other X-linked genes. The resulting chromosome map revealed a linear arrangement of genes [1]. However, the application of genetic mapping to humans did not become common until the 1950s, due to the challenge of identifying which traits were caused by genetic mutations. In 1980, the discovery of Restriction Fragment Length Polymorphisms (RFLPs) made mapping easier and pushed forward the development of comprehensive chromosome maps. In the late 1980s, a rough maps encompassing the whole chromosomes were constructed successfully. In mid-1990s, the refinement of statistical analysis methods enabled researchers to construct a whole-genome genetic map covering all chromosomes [2].

Human Genome Project

One of the major milestones in chromosome mapping is the Human Genome Project, an worldwide collaboration to determine the full sequence of the entire human genome, based on genetic information obtained from chromosomes. The project was initiated in 1990 and achieved near completion in 2003, findings were subsequently published in 2004 for worldwide and public access [3]. While continuous refinement was ongoing to tackle the remaining gaps in human genome sequence. Ultimately, the complete, gapless sequence of the human genome was mapped in 2022 and published globally, indicating the progression of genomic research.

Method

Chromosome Mapping is important for investigating the arrangement of chromosome. There are two types involved for mapping chromosomes: genetic mapping and physical mapping.

Genetic mapping

Genetic Mapping investigates the inheritance pattern of chromosomes based on linkage analysis, recombination frequencies. Specifically, whether genes are linked or unlinked based on their respective distance, located on the same/different chromosome - determines the genes either being inherited together (linked) or inherited independently (unlinked) [1]. Centimorgan (cM) is a unit that measures the probability (1%) of recombination occurring between markers during meiosis. Through studying recombination of DNA markers and genes in chromosomes, it provides further insights on inheritance patterns and possibility of variations occurring [4].

Molecular markers

DNA molecular markers help to detect genetic variations in the genome for pinpointing the locations, which are for generating genetic maps. The typical molecular markers used in genetic mapping include: Restriction Fragment Length Polymorphisms (RFLP) : Cleavage of chromosomal DNA by restriction enzymes, to determine the size of DNA fragments and their inheritance pattern. Single Sequence Length Polymorphisms (SSLP) : repetitive DNA sequences with variable number tandem repeats: microsatellites and minisatellites. Simple Nucleotide Polymorphisms (SNP) : variations in genome with different nucleotides, at specific positions in chromosomes.

Physical mapping

Physical Mapping investigates the physical distance of DNA sequences in chromosomes, through their variable banding patterns. Fluorescence In Situ Hybridisation (FISH): labelling DNA probe with fluorescence and subsequently hybridised to chromosomes, in order to locate specific DNA sequence on chromosome. Cytogenetic mapping - using distinct banding patterns of chromosomes when observed under light microscope, to locate positions of genes involved. The bands are labelled numerically to identify specific regions in the chromosome. Restriction mapping - using different restriction enzymes, which generates distinct restriction sites and different sizes of DNA fragments. Which helps the identification of restriction site locations.

Disease diagnosis

Chromosome mapping can help identify the location of specific genes on chromosomes. It involves studying the inheritance patterns of genetic markers or variations within families or populations to determine the association between these markers and the presence of a particular disease or trait, allowing researchers to make predictions about the genes they think are causing the mutant phenotype. An example of a disease where chromosome mapping has been instrumental is Cystic Fibrosis (CF). CF is a genetic disorder caused by mutations in the CFTR gene located on chromosome 7. By mapping the CFTR gene to this specific region on chromosome 7, researchers have been able to understand the genetic basis of CF, develop diagnostic tests, and work towards targeted treatments [5].

Pharmacogenomics

Chromosome mapping helps in identifying genes that are involved in drug metabolism, drug targets, or drug transporters. By studying the inheritance patterns of genetic markers associated with drug response in different populations, researchers can identify regions on chromosomes that are likely to contain genes influencing drug response. This helps evaluating the effects and effectiveness of drugs. Moreover, mapping enables the development of genetic tests that can predict an individual's response to specific medications. By analyzing genetic markers associated with drug response, researchers can develop pharmacogenomic tests that assess a patient's genetic profile and determine their likelihood of benefiting from a particular drug or experiencing adverse reactions. This fosters the development of personalized medicine. For example, Warfarin, a commonly prescribed anticoagulant, has been extensively studied in relation to genetic factors and chromosome mapping. Research has identified genetic variants associated with warfarin-related bleeding, such as single nucleotide polymorphisms (SNPs) on chromosome 6 [6]. Additionally, genes like VKORC1 on chromosome 16 have been strongly associated with warfarin dose variability, highlighting the role of genetic variations in determining individual responses to warfarin treatment [7].