Of the characteristics which distinguish the animate world from the inanimate, one in particular occupies the thoughts of medical students (particularly male medical students) more than any other, the need to reproduce. This is of course the core of the science of genetics.
Our bodies have evolved to carry out that one function as successfully as possible. However, most cells will do so only in a supporting role, they are not themselves destined to be transmitted. As geneticists, we draw a distinction between the germ cells which provide the continuity of life from one generation to the next, and the somatic cells which are all the rest. When a sperm fertilises an egg to create a zygote, the embryo begins to develop. Initially all the cells are capable of giving rise to any part of the embryo or its extraembryonic tissues. However, after about 6 or 7 divisions, some cells have become irreversibly programmed to give rise only to a subset of possible cell or tissue types and this process of irreversible differentiation continues until all the organs have been constructed. During this process, a small number of progenitor germ cells are sequestered until rudimentary gonads (testes or ovaries) have formed when the germ cells migrate into them. At this stage germ cells are neither sperm nor egg cells, they are precursers, spermatogonia or oogonia. In their own way they are every bit as differentiated as any other (somatic) cell of the body. There is no way that a spermatogonium will ever be able to differentiate into a liver cell for instance. However, the germ cells contain the potential to be transmitted to the next generation and contribute one half of the DNA of the next individual.
Under the influence of the surrounding somatic component of the testis or ovary the germ cells multiply by successive mitotic divisions. In the male this process continues throughout life but in females it stops prior to birth. In other courses you will learn about the hormonal influences acting on the cells, the female reproductive cycle etc., but this need not concern us here where we simply need to consider what happens to the chromosomes to ensure that only (and exactly) half of the genetic material is transmitted to the next generation via a sperm or an egg.
The reduction in chromosome number from diploid to haploid is accomplished by the specialised cell divisions of meiosis. Cells prepare for meiosis by replication of their genetic material as for mitosis. However, instead of a single division as in mitosis, meiosis consists of two consecutive divisions as shown in the diagram:
Gregor Mendel is famous today but was relatively unknown outside Czechoslovakia in his lifetime. He was the first scientist to deduce clear and rational laws which could explain the process of inheritance. Unfortunately, few medical students are interested in the genetics of peas! However, it turns out that the rules which Mendel deduced from studies of peas are equally applicable to human inheritance and it is convenient to follow his train of logic beginning with characteristics determined by a single gene and moving on to the complications introduced by multiple genes. If you are interested to read a translation of his original paper then click here.
Mendel began by collecting varieties of pea which differed from each other in clearly defined ways. The pea flower has anthers and a stamen which are very close together. It will self fertilise in normal cicumstances. It is possible to remove the anthers before they are ready to produce pollen and to cross fertilise the pea plant by bringing pollen from another plant on a paint-brush. Mendel allowed his plants to self fertilise for a number of generations until he was certain that they were true breeding, i.e. that the offspring always resembled the parent for the characteristics under consideration. Then he began his experiments.
Characteristics studied by Mendel
|
Characteristic |
Dominant allele |
|
axial or terminal flowers |
axial flowers |
|
round or wrinkled seeds |
round seeds |
|
yellow or green seed interiors |
yellow interiors |
|
violet or white petals |
violet petals |
|
tall or dwarf plants |
tall plants |
|
fat or shrunken ripe seed pods |
fat pods |
|
green or yellow unripe pods |
green pods |
First he took a pair of parental strains differing at a single characteristic, for instance, a round seed strain and a wrinkled seed strain, and wisely he intercrossed them in each direction (i.e. "round" pollen onto "wrinkled" stigma and also "wrinkled" pollen onto "round" stigma). In fact it made no difference that he tried each parent as the male or the female but it might have done. The plants resulting from this mating, the first filial generation or F1, were all examined. All had the appearance of one of the parental strains, in this case, the round one. Mendel defined the visible characteristic as the dominant one. The F1 plants were then allowed to self fertilise to produce a second filial generation or F2.
A surprising result occured in the F2 generation, wrinkled seeded plants reappeared! Mendel counted more than enough F2 plants to be able to say that the "wrinkled seed" plants were one quarter of the offspring. The characteristic which had disappeared and had now reappeared Mendel described as recessive. Mendel went on to allow each F2 plant to self fertilise. He found that the wrinkled seed plants (and their offspring) were true breeding like the original wrinkled seed parental strain. One third of the round seeded plants were also true breeding (as were their offspring). The remaining two thirds of the round seeded plants behaved exactly like the F1.
The phenomenon could be explained if it were assumed that each plant had two copies of the factor influencing the trait. We now call the factor responsible a gene, we say that more than one form of the gene can exist and we call those alternative forms alleles. Mendel explained the results by suggesting that each plant contained two alleles which did not blend together but which remained unchanged. In the next generation the plants passed one or other allele at random into a gamete to be combined with a gamete from the other parent. The non-blending followed by separation into the next generation is the Rule of Segregation.
We can distinguish in the above cross two sorts of individual, true breeding individuals with both alleles the same, and individuals in which the two alleles continue to segregate. We call the former homozygotes and the latter heterozygotes or carriers. The gene which we are considering is said to be homozygous or heterozygous respectively. We can also distinguish between an individual's outward appearance, its phenotype, and its inward genetic constitution, its genotype.
A convenient method of predicting the relative ratios of the progeny in any cross is by means of a Punnett Square an example of which is shown in the above diagram. The gametes from each parent are placed on the margins and at the intersections of the rows and columns are written the resulting offsprings' geneotypes and, if we wish, their phenotypes.
The alternation of two genes in individuals and one gene in gametes is of course reminiscent of the behaviour of chromosomes, diploid in most tissues but haploid in sperm and egg. We now know the reason why this is so, genes are carried on chromosomes, encoded in the DNA.
Before we consider human Mendelian inheritance it is convenient to consider the symbols used to draw pedigrees.
Generations are numberered from the top of the pedigree in uppercase Roman numerals, I, II, III etc. Individuals in each generation are numbered from the left in arab numberals as subscripts, III1 , III2, III3 etc.
Most human genes are inherited in a Mendelian manner. We are usually unaware of their existence unless a variant form is present in the population which causes an abnormal (or at least different) phenotype. We can follow the inheritance of the abnormal phenotype and deduce whether the variant allele is dominant or recessive.
A dominant condition is transmitted in unbroken descent from each generation to the next. Most matings will be of the form M/m x m/m, i.e.heterozygote to homozygous recessive. We would therefore expect every child of such a mating to have a 50% chance of receiving the mutant gene and thus of being affected. A typical pedigree might look like this:
Examples of autosomal dominant conditions include Tuberous sclerosis, neurofibromatosis and many other cancer causing mutations such as retinoblastoma
A recessive trait will only manifest itself when homozygous. If it is a severe condition it will be unlikely that homozygotes will live to reproduce and thus most occurences of the condition will be in matings between two heterozygotes (or carriers). An autosomal recessive condition may be transmitted through a long line of carriers before, by ill chance two carriers mate. Then there will be a ¼ chance that any child will be affected. The pedigree will therefore often only have one 'sibship' with affected members.
a) A 'typical' autosomal recessive pedigree, and b) an autosomal pedigree with inbreeding:
If the parents are related to each other, perhaps by being cousins, there is an increased risk that any gene present in a child may have two alleles identical by descent. The degree of risk that both alleles of a pair in a person are descended from the same recent common ancestor is the degree of inbreeding of the person. Let us examine b) in the figure above. Considering any child of a first cousin mating, we can trace through the pedigree the chance that the other allele is the same by common descent. Let us consider any child of generation IV, any gene which came from the father, III3 had a half chance of having come from grandmother II2, a further half chance of being also present in her sister, grandmother II4 a further half a chance of having been passed to mother III4 and finally a half chance of being transmitted into the same child we started from. A total risk of
½ x ½ x ½ x ½ = 1/16
This figure, which can be thought of as either
or
is known as the coefficient of inbreeding and is usually given the symbol F.
Mendel went on two consider what happened if he crossed plants together which differed with respect to more than one character trait (a so-called dihybrid cross).
What Mendel discovered can be put very simply, the two characteristics behaved completely independently of each other. He called this the rule of independent assortment. Here is an example of a cross between a strain which produced smooth yellow seeds and one with wrinkled green seeds.
The classes of offspring in the F2 occur in the well known 9:3:3:1 ratio, 9 Yellow smooth : 3 green smooth : 3 yellow wrinkled : 1 green wrinkled. This ratio is the result of the two genes behaving completely independently of each other in the cross.
The Punnett sqare is a fine method of working out straightforward events. However, not all life is straightforward! Most of you have some background in mathematics and will have covered elementary probability. For those who have not, I strongly recommend reading Mange and Mange pp50-57.
The probability of an event is the chance that it will happen. The probability of tossing a coin to land heads up is just slightly less than ½ (I did once have a coin stick on its edge in the mud and my unsporting opponent, instead of allowing the throw to be taken again like a gentleman, insisted that by calling "heads" I had lost the toss!).
The topics include Meiosis, Mendel, pedigrees and autosomal dominant and recessive inheritance.
The relevant questions at the end of chapters 3 and 4 in Mange and Mange and chapter 4 in Lewis are worth trying. In addition:
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