Year: 2020
Type: article
Abstract: Genetics is the study of heredity or how living organisms receive common traits, i.e. observable or detectable characteristics, from previous generations. Genes are the units of inheritance and provide the mechanism for the passing on of these traits. For example, children will generally look like their parents because they have inherited genes from their parents, 50% of their father's genes and 50% of their mother's genes. Genetics is the science of identifying the various traits that are passed from one generation to the next, and to explain the mechanisms for this transmission. Genetics is of importance regarding the expression of the blood groups as the varieties of blood group antigens that we recognize on the surface of red blood cells result from variations in the genetic code. It is of value to understand the way in which blood group characteristics are passed on from generation to generation and the genetic events associated with their expression; this knowledge helps in the classification and understanding of the blood groups, gives insight into the management of haemolytic disease of the fetus and newborn and provides input into parentage testing and personalised transfusion medicine. Much of the progress in the field of blood group serology, as well as the classification of blood groups into systems, has been possible because of genetic studies. Work in the field of genetics began with discoveries made in the mid-19th century by Gregor Mendel, an Augustinian monk in St Thomas's Abbey in Brno, in the present-day Czech Republic. Mendel, who is known as the ‘father of modern genetics’, planted a small strip of garden to experiment on hybridization in plants (hybridization is the process of breeding individuals or plants from genetically different populations, thus producing a hybrid). He used his own living quarters to hybridize mice as part of his investigations into heredity but stopped this line of investigation as it was not considered proper for a monk to be investigating the breeding of mice. He also experimented with bees, but his work with garden peas is the most widely known and will be used here to present a sample of his findings. Mendel compared seven different characteristics in peas that appeared to be inherited independently of each other. Between 1856 and 1863 he cultivated and carried out measurements on close to 30 000 plants. One of the characteristics that he measured was the height of the plant. In the parental generation he mixed or ‘crossed’ tall (T) pea plants with short pea plants (t). The first generation resulting from this cross, called the first filial, or F1, generation were all found to be tall. He then crossed the tall plants of the F1 generation with each other and in the second filial generation, F2, tall and short plants were produced in a ratio of 3:1. Mendel reasoned that all the F1 generation plants were tall because the factor determining tallness in plants is dominant over the factor for determining shortness. When the two characteristics were inherited together, plants therefore grew tall. Table 1 shows a Punnett square diagram to illustrate the F1 crossing of tall and short pea plants. The Punnett square shows the probabilities of offspring inheriting a particular genotype, by pairing the four possible combinations of alleles for that characteristic, from maternal and paternal origin. In its simplest form the diagram consists of four squares, each showing one of the possible genetic combination, with a probability of 25%. A unique word for the ‘factor’ of inheritance described by Mendel was not introduced until 1909, when the Danish botanist Wilhelm Johannsen first used the word ‘gene’. He was also the first researcher to clearly make the distinction between the appearance of an individual (the phenotype) and that individual's genetic traits (the genotype). ‘Allelomorph’, meaning ‘other form’ and now shortened to ‘allele’ was the name given for the alternative forms of a gene that are found at the same location, or locus, on a chromosome. In the example of Mendel's pea plants, the gene ‘T’ (for tall), and ‘t’ (for short) are alleles. It is customary to depict dominant alleles with upper case letters, and recessive alleles with lower case letters, and in italics, as shown in the diagrams. All offspring of the F1 generation are tall plants because T (tallness) is dominant over t (shortness). When these hybrid tall plants (F1) were ‘selfed’ (crossed amongst themselves), a quarter of the F2 generation plants were short. Table 2 shows the F2 crossing of hybrid offspring of F1. Mendel therefore reasoned further that a hidden ‘recessive’ factor for shortness was manifested only if two recessive characteristics were inherited, one from each parent. In F2, 75% of offspring are tall pea plants and 25% are short pea plants (ratio of 3:1). This is because any plant that inherits a T allele for tallness, either in single or double dose, grows to be a tall plant because T is the dominant allele. As a result of his studies, Mendel was able to establish two laws that are still considered the basis of genetics: This law states that different traits are inherited independently of each other. In other words, the manifestation of one trait will not affect the manifestation of another. For example, the inheritance of eye colour is independent of the inheritance of body height. Note: It is now known that independent assortment only applies to characteristics that are not genetically linked. Genetically linked genes from unrelated characteristics, such as male sex and red-green colour blindness are inherited together, meaning that a male with red-green colour blindness will pass the colour blindness gene on to his daughters, who will carry the colour blindness gene as a recessive. If this recessive gene is passed on, by the carrier mother, to a male child, that individual will have red-green colour blindness. Inheritance of observable or detectable characteristics (traits) takes place from one generation to the next. The genetic material responsible for every trait is found in the nucleus of every nucleated cell in the body. This genetic material is called chromatin and consists of deoxyribonucleic acid (DNA), a long molecule that is made up of simple units called nucleotides that are arranged in a specific order. The order of the nucleotides carries the genetic information of the individual, much as the arrangement of letters on a page make up the words and hence the content. The ‘language’ used by DNA is called the genetic code and contains all the instructions necessary for the construction and operation of the organism. When it is necessary for cells to reproduce themselves as a result of growth, tissue repair or cell death, the chromatin undergoes changes; rod-shaped organelles called chromosomes are formed within the cell nucleus as a result. Figure 1 depicts a body cell showing the cytoplasm, nucleus and chromosomes (23 pairs per nucleated cells), with an enlargement of one of the pairs of chromosomes to show the gene loci (the positions of the genes on the chromosomes). Chromosomes consist of two strands of DNA, like the upright supports of a ladder, linked together by strips that resemble the rungs or steps of the ladder, and twisted into a spiral. Each ‘rung’ consists of two nucleotide bases linked together in a strictly regulated way, and it is the order of these bases that provides the genetic code, or the identity stamp of the organism (such as a human). Each section of DNA and its nucleotide bases that contains the code for a specific characteristic is referred to as a ‘gene’, and each chromosome contains many different genes distributed along its length. The chromosomes are arranged in pairs inside the nucleus of body cells and these pairs are called homologous chromosomes, one passed on from each parent. Cells with two sets of chromosomes, which are most of the cells in the body, are called diploid (or body) cells, while the sex cells (ova or egg cells and sperm cells) have only one set of chromosomes and are called haploid cells. DNA has two major functions. One is to reproduce itself, in the process of mitosis, and the other is to provide the recipe or code to produce the proteins which are necessary for ongoing life. In order to reproduce itself, i.e. in the duplication of the chromosomes, DNA is unzipped into two complementary DNA strands when the two nucleotides making up each ‘rung’ separate. Each strand of the original molecule then acts as a template for the synthesis of a new complementary DNA strand, resulting in two new chromosomes, each identical in every way to the original. In the production of proteins, the DNA is unzipped into two complementary strands as before, by the separation of the two nucleotides making up each ‘rung’. One strand of the DNA is used as a template by an enzyme called ribonucleic acid (RNA) polymerase to synthesize a short length of messenger RNA (mRNA) through a process known as transcription. Although chemically slightly different from DNA, this mRNA contains the same information that was encoded by the DNA in a similar sequence of nucleotides, i.e. the recipe, encoded by the gene, to produce a specific protein. Following the assembly of the mRNA, the two strands of DNA reunite, reforming the unaltered chromosome. The mRNA migrates from the nucleus to the ribosomes in the cytoplasm of the cell where the sequence of nucleotides in the mRNA (i.e. the recipe for the protein) is translated into a sequence of amino acids. Each sequence of three nucleotides codes for one amino acid, and these amino acids are linked together to form the protein. In summary, the protein encoded by the gene located on the chromosome is thus, through the process of transcription followed by the process of translation, produced (in most cases) faultlessly in the ribosomes of the cell. See ‘Molecular genetics’ later in this section for more details on this process. Humans can produce over 100 000 different proteins, which gives some measure of the amount and complexity of information encoded in the DNA. Figure 2 is a simplified diagrammatic representation of DNA and RNA. Chromosome typing may be carried out in the laboratory for diagnostic purposes, and to identify chromosomal abnormalities. This process is called karyotyping and is achieved by stimulating a sample of human cells to duplicate themselves in the laboratory. When the duplication is fairly advanced the process can be halted, the chromosomes stained with dye and analysed using the appropriate computer software. This digital method has largely replaced the former method whereby the chromosomes were photographed through a microscope and the photographs analysed. The human genome consists of 46 chromosomes: 22 pairs of autosomes, and one pair of sex chromosomes, called X and Y. The X chromosome is more than five times larger than the Y chromosome and carries approximately ten times as many genes. Human females typically have two X chromosomes, and males typically have one X and one Y chromosome. Most cells within the body can reproduce themselves. There are two types of cells; body or somatic cells, and sex cells or gametes. When body cells replicate themselves, the result is two daughter cells that are identical to the parent cell, each with a full complement of chromosomes. When sex cells are produced the result is four daughter cells, each of which has half the genetic material that was present in the parent cell i.e. one of each of the pairs of chromosomes. The duplication process carried out by body cells is called mitosis, and the reduction division carried out by the gametes is called meiosis. Both processes go through several stages at the end of which, so-called daughter cells are produced. Both processes are complex and therefore only the outline of the stages during cell division is described. In the description, each stage is identified by N, being the number of chromosomes within the nucleus of the cell during that stage (1N = 23, 2N = 46, i.e. the total number of chromosomes in humans, and 4N means double the full complement). Mitosis must ensure that one copy of each chromosome – and only one copy – ends up in each daughter cell after cell division. Each diploid daughter cell therefore contains the full genetic complement of the original parent cell Fig. 3. Meiosis is the form of cell division that produces four haploid sex cells, or gametes, that each contain a single copy of each chromosome carried by the parent cell. Four haploid (i.e. cells with half the quota, or 23 chromosomes instead of 23 pairs of chromosomes) daughter cells (or germ cells as they are also called) are produced. Each germ cell contains half the genetic complement, drawn randomly from the genetic material of both parents. One of the four germ cells produced by a human female matures into an ovum, i.e. egg, whereas all four of the germ cells produced by a human male mature into sperm. Figure 4 illustrate the mitotic process in a simplistic form and compares it with the process of meiosis. Chromosomal crossing over refers to the process during which a pair of chromosomes, which are aligned during the first phase of meiosis, exchange a segment of their DNA. Crossing over most commonly occurs when similar regions on matching chromosomes separate and then re-join to the other chromosome. This results in an exchange of genes between the chromosomes, that is, a new assortment of genes on each chromosome, but no new genes. Figure 5 shows the process of crossing over. Recombination during meiosis allows more random selection between the two alleles that occupy the same position, as it serves to shuffle the alleles between the paired chromosomes. In practice it is found that the frequency of recombination is not the same for all genes. Recombination is influenced greatly by the physical distance between one gene and another. If two genes are located close together, the likelihood that they will be separated is less than if they are located further apart. This is termed ‘genetic linkage’. Although crossing over usually occurs between the same regions of paired chromosomes, this is not always the case. Sometimes dissimilar lengths of chromosome can be exchanged, resulting in an unbalanced recombination. This means a duplication of genes on one chromosome and a deletion of the same genes on the other chromosome, which can have serious consequences when it occurs during meiosis, and the affected cell becomes part of a gamete. When a characteristic is always inherited with another unrelated characteristic, it is called genetic linkage. Sex-linked characteristics are easier to identify than linkage between characteristics on autosomes, as they travel with gender. Several well-known characteristics are inherited on the X chromosome, such as haemophilia A and red–green colour blindness. Most sex-linked characteristics are found on the X chromosome (rather than the Y chromosome) because it is much longer and carries many more gene loci. Recessive X-linked characteristics are manifested in male offspring (who have only one copy of the X chromosome, and hence one copy of the allele) whereas female offspring (who have two copies of the X chromosome) are the carriers, as Fig. 6 shows, using the sex-linked inheritance of haemophilia A as an example. All human genetic information is encoded in DNA molecules consisting of two complementary twisted strands of millions of nucleotides arranged into a double helix (like a spiral ladder) through non-covalent interactions. These are the chromosomes. Each nucleotide is composed of a pentose (a sugar molecule containing five carbon atoms), with a phosphate group attached to the fifth carbon atom (C5) of the pentose and a base attached to the first carbon atom (C1) of the pentose. The sugar molecules form the uprights of the ladder-like structure and are linked together by the phosphate molecules, while the ‘rungs’ of the ladder are the complementary bases, linked together by hydrogen bonds. Variations in the chemical composition of the bases give rise to four different nucleotides: two purines (adenine - A, and guanine - G) and two pyrimidines (cytosine - C, and thymidine - T). The four nucleotides bind to each other in DNA in a strict way - adenosine is always paired with thymidine (A-T) and cytosine is always paired with guanine (C-G) to form the rungs of the ladder, shown in Fig. 7. This complementary binding between the bases accounts for two important properties of DNA. First, using chemical treatments or high temperature, DNA can be opened from the double helix form to a single-stranded form by breaking the hydrogen bonds between the bases. Second, DNA molecules have both a head end and a tail end, determined by the carbon atom on deoxyribose sugar, which is free to join with another deoxyribose sugar to extend the length of the chain. The carbon atoms of deoxyribose are numbered 1, i.e. #1, through 5, i.e. #5, and as they join to form the DNA ladder, carbon #5 of one deoxyribose sugar joins to carbon #3 of the next deoxyribose. Therefore, each DNA strand has a 5′ (5 prime) end, i.e. the chain ends with an unbound 5′ carbon, and a prime) end i.e. the chain ends with an unbound and are commonly in the When single strands of DNA pair together to form DNA, the two ladder in i.e. they are but in The in one sequence to of the other Figure shows the double helix form of a DNA all of testing for blood group are on two that and are and that of binding is in on the two strands of DNA. There are of variations in the order these nucleotides can on the The sequence in which these four nucleotides the genetic code that the production of all proteins, red cell variations in the sequence of nucleotides in a gene can to an individual different for example eye colour or blood A gene is a segment of DNA that a protein and each gene a specific known as the A can be by one of alleles. A gene is composed of regions that amino acids and regions which not amino acids are by a process called to the The mRNA is a copy of DNA. its synthesis in the the mRNA is and to the cytoplasm where ribosomes it into proteins that give to the antigens to the Each sequence of three bases a on the mRNA strand one amino acid the is the code for while is the code for or provides a the end of the There are only possible 4 of which the amino acids and three are There are more than are amino acids because some amino acids are encoded by more than one for example and all code for the amino acid of DNA always at the or transcription Figure the process of DNA transcription and to a protein. The is the observable of gene expression and the of its genes. the or of antigens in the which may be determined by the It is possible for the to be by such as the in in as a of show and while the to the are only in possible and resulting are possible from the pairing of genes from and If the same alleles for a characteristic are present at a given on both chromosomes the the individual is called and is considered for a This is by two identical letters, for example, or when the alleles on the two chromosomes are the individual is called and is considered a hybrid for the This is by two different letters – using the former example, individual is termed when is only one copy of the allele a individual who has a allele on one chromosome. males are for the genes that are found on the X chromosome, as the genes are not present on the Y chromosome. females may be either or for these genes. that are encoded by alleles at the same are called and of the blood group are a pair of an individual with the is for and the red cells have a double of A dominant gene is a gene that the same both in the and in In blood if the gene is the is always when the allele is of the individual is or for that allele. For example, in the blood group the A gene is dominant is the and individuals who are as well as who are the A alleles are that the of both alleles when two different alleles are in the if the allele for the is present as well as the allele for the the red cells will carry both these A recessive gene is only in the and has no if another allele is also Therefore, only when inherited from both parents, can a recessive gene Figure shows the genetic inheritance with a of the dominant – a of the recessive and – a with both dominant and recessive alleles. Although the of DNA during and meiosis is it is not always place during and the DNA from the original. This is called a and can within any part of the DNA, resulting in a to the genetic code. This may result in a in the characteristics of the protein for which the gene provides the code. this to the production of cells. When a takes place at the of meiosis, the in the protein can be passed on to the This may have no or the may have important For example, cell and by only a single amino acid, by a of the This is a the other a result in a to the organism and the of in the The specific i.e. and to a specific human chromosome, of the genes for blood group expression are known and in Fig. of genes or gene that have been to particular blood group systems, by the of have been to single on of the 22 for or on the X chromosome for 2 The individual chromosomal are on the by the of the for The for each chromosome is the (the in the with the short and the long from the each (the structure at the end of the chromosome) each is numbered with the to the numbered and the next, and and each of these major can contain and if three this it is possible to the of a gene on a specific chromosome. For example, the gene for the antigens of the is located on chromosome number at to Figure from with Several genetic events that new blood group antigens and have been can at the of the chromosome or of part of the the gene or or the or duplication or nucleotide or of events associated with blood group are single nucleotide crossing crossing gene or other gene of a single nucleotide in the of the gene, i.e. a to an A, may be used as an example. This can have one of three no amino acid determined by the a in the identity of the encoded amino acid or of a that an amino acid into a Most antigens of blood groups from For example, a single nucleotide in the gene for the of the in the and a single nucleotide in the gene for the in the of variations are in the and This is the of a single nucleotide or DNA A deletion of nucleotides in of three in the DNA sequence will the and result in the of one or more amino acids and a protein with different of three nucleotides in the DNA structure of or in other than three will result in of the mRNA a new amino acid sequence and a new will the production of an protein. blood group as a result of deletion of nucleotides, or genes. and which is the of a single nucleotide or DNA a of a nucleotide into a given DNA sequence may a in the DNA The in the blood group i.e. is an example of a by a nucleotide is a process in which of the are by RNA and the are together to produce A single nucleotide at either the or the of the DNA may the and of the or after the during the production of the mRNA, resulting in the code for the protein being If this code was the template for a blood group the not be produced. The of the blood group is an example of this mechanism in Chromosomal is the of a segment from one chromosome to another chromosome (i.e. a chromosome that is not from the same This can in and where of one chromosome are to another chromosome. of blood group antigens that may be by this mechanism are A, and Crossing is the exchange of of a gene between homologous chromosomes (i.e. chromosomes from the same This may during meiosis if the same gene has homologous aligned or if two homologous genes crossing over occurs in the and blood group that are encoded by two homologous genes on the same chromosome. The genes for the blood group have three major A, and one of these can occupy the on a particular chromosome. The A and alleles are and is an that not produce any detectable Therefore, when either A or is inherited, it is always is only in the of A or when inherited in double from each such individuals are and their is the other one a group A (or individual is (or or (or in laboratory This may be using or by a Table shows blood group and the possible group A has not been into in the Table 4 shows that it is possible for parents who in the laboratory as group A and group who are genetically and to have offspring of group A, or The loci on chromosome 1 consists of two homologous and the former and the and The gene through duplication of the gene at some in The genes are close together in and separated by an unrelated small of the and of the two many between these two genes have and in hybrid genes. These are to and exchange between of the gene can join the gene and of gene can join the gene, new hybrid genes. to hybrid proteins and new antigens and This of of how many antigens are i.e. antigens that are some individuals as and are able to make that is the segment of the
Source: ISBT Science Series
DOI: 10.1111/voxs.12592
Authors: B. Armstrong, R. Wilkinson, Reviewer for Second Edition: Lilian Castilho
Language: English
Topic: Blood groups and transfusion
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4242610172