5.1 THE TWO WORLDS OF GENETICS
I. MENDELIAN INHERITANCE
Our present-day understanding of genetics is based on the discoveries of Gregor Mendel, an abbot of an Augustinian monastery in Moravia (now in Slovakia). Mendel published his findings on the inheritance of characteristics of plant hybrids in 1866, only seven years after Darwin's Origin of Species. Darwin died two years before Mendel, unaware of Mendel's solution to the puzzle of inheritance. Mendel's work remained unnoticed until 1900. In an ironic parallel to Wallace and Darwin's co-discovery of natural selection, Mendel was rediscovered by three independent researchers--De Vries, Correns, and Tschermak who had essentially duplicated the results reported 34 years earlier.
Mendel came from a town of skilled gardeners. His home was one of grinding poverty and his only chance for education was at the local monastery. He was too sensitive for the priesthood and the anxiety of exams would disable him for months. Mendel was a gifted teacher and was largely self-taught. On his second try in the state teacher's exam, he passed every part--except botany. His methodical research on peas was done on a 120' x 20' plot of a monastery garden which fellow monks derisively described as Mendel's 'pea plantation.'
Not long after Mendel's publication, he became an abbot of his monastery. His duties kept him from doing further research. He became hugely overweight and harbored a peculiar fear of being buried alive. He died in 1884 recognized as a religious leader, but unknown as a scientist. Most of Mendel's experimental notes and records were burned by the monks.
This section assumes you have been exposed to Mendelian genetics. The presentation is deliberately eclectic in style, intended to illustrate the ideas and terms essential for a practical understanding of genetics.
(1) Phenotypes are seen and genotypes are hidden.
A phenotype ('phenomenon') is the observable characteristic of a plant or animal. It is what you see. A phenotype is the expression of the genotype. Specific phenotypes are referred to as traits or characters (the definitions of the two terms differ slightly).
A genotype ('genes') is the genetic endowment. The genetic endowment is all of the information contained in the genes, much of which is hidden.
(2) The essence of Mendelian heredity is that genetic units are particulate. To say it differently, the genotype consists of discrete units.
(a) A gene is the basic unit of heredity. For Mendel it was an abstract hypothetical unit.
(b) In time each gene could be mapped to a specific location on the nuclear chromosomes, called a gene locus.
(c) With the birth of molecular biology in the 1950s, genes are understood for their molecular makeup and their ability to replicate.
(3) Keep this in mind: simple Mendelian genetics discussed in this article resides in the nuclear DNA. The mitochondria in the cytoplasm also contains DNA. Only mothers can pass on mitochondrial DNA. We get none from our fathers (the spermatozoa contains nuclear DNA but no cytoplasm). The mitochondrial genome is small, but it has a high mutation rate. Incidentally, there are some obscure mitochondrial genetic diseases--they are transmitted only by the mother. They do not conform to Mendelian genetic patterns.
(4) Mendelian genes occur in pairs. All of the possible genes that can occur at a given location are called alleles. How many can there be?
In any individual at a given locus, there can only be one or two alleles. There can be one, two, or many alleles in a population. The locus for G6PD has an astonishing 320 different alleles. (My note: G6PD is an enzyme deficiency that affects 10% of the world's population in areas where malaria is common.)
In Mendel's study with peas, each locus had only two alternate alleles. Mendel worked with seven traits in peas. Each was an either/or situation: tall/short, curly/straight, wrinkled/smooth, green/yellow and so on. His studies worked so successfully because he had the good fortune to pick traits with each gene on a different chromosome and not linked in any way. They all functioned independently, an illustration of Mendel's 'law of independent assortment.'
A system with three possible alleles is the celebrated ABO blood type. We can say that there are three alleles, a, b, and o. From them, four phenotypic expressions are possible; A, B, AB, and O. An individual can have one or two alleles, but only one phenotype. Alleles a and b are dominant; allele o is a recessive.
Clover and the evening primrose have more than 50 alleles. If Mendel had chose one of these for study, he would have gotten nowhere and would have been lost in obscurity. The mathematical possibilities become staggering when there are many alleles.
(5) Each pair of genes has two possibilities. In the homozygote each of the two genes in the gene pair at a given locus are identical. The heterozygote has two different genes in the gene pair at a given locus. Heterozygotes are often called hybrids. Sometimes, heterozyotes have advantageous traits.
(6) In the homozygote with two identical alleles, the phenotype expressed is always the same. But, in the heterozygote there are two (different) alleles at a given location. Which one is expressed in the phenotype? Here, Mendel made an intellectual leap without any knowledge of chromosomes or DNA. The allele for yellow always predominated over the allele for green. Thus was born the concept of dominant for the trait that is expressed and recessive for the trait that isn't expressed. The unambiguous expression of Mendelian characters in peas are called complete dominance and complete recessiveness.
In real life, dominant and recessive become extremes along a continuum. Genotypes a and b in the ABO blood type are called codominant because they are both expressed in the phenotype blood type AB in the person with a and b genotype. Genotype o is recessive and can only appear phenotypically as phenotype O blood in the homozygote genotype oo.
Blood types show a geographical distribution. This suggests that in some regions, the frequency of blood types may result from selection by infectious disease. Indeed, the carrier of blood allele b has some protection against infantile diarrhea. Alleles a and b protect against plague and allele o against bronchial pneumonia. Recall how we said that epidemic disease have affected recent human evolution? These diseases have likely been a selective agent favoring one blood type over another.
Let me mention here very briefly that the founder affect can also account for the incidence of the ABO alleles in isolated populations. The o allele appears at a very high frequency amongst Native Americans.
Another trait that has long interested anthropologists is the sickle cell allele. The sickle cell allele distribution in the Old World correlates quite well with the incidence of malaria. The unfortunate person with two sickle cell alleles (a homozygote, correct?) will develop the disabling genetic disease sickle cell anemia. A person with just one sickle cell allele (a heterozygote) develop only traces of the genetic disease--which in the areas of the world with malaria, offers a selective advantage in coping with malaria.
Malaria and the sickle cell trait illustrate two things for us. First, in the heterozygote, there is incomplete dominance. Secondly, the allele for sickle cell is a genetic adaptation to a disease. Why doesn't such a deleterious gene just disappear? It is the heterozygote advantage in malarial environments that accounts for maintaining the disease gene at a high frequency.
There are other genetic diseases that offer a heterozygote advantage. Tay-Sacks is lethal in the homozygote but offers resistance to tuberculosis in the heterozygote. It appears in some Eastern European Jewish populations--who years ago lived in crowded ghettos. Cystic fibrosis is disabling in the homozygote, but appears to offer an advantage in surviving diseases with massive intestinal fluid loss such as cholera.
When there are many alleles, they form a series, each with a relative degree of dominance or recessiveness in relation to each other. An example is coat color in rabbits. Variation in coat color is probably helpful for camouflage in different environments.
II. NONMENDELIAN CHARACTERS / QUANTITATIVE VARIATION
By the time Mendel's work was rediscovered in 1900, a rival school of genetics was well established in Britain and elsewhere. It owes its origins to the remarkable and eccentric Francis Galton, a cousin of Charles Darwin. Starting with an article on 'Hereditary Talent and Character' published the same year as Mendel's paper (1865), he spent many years investigating family resemblances.
Like his cousin Charles Darwin, Galton's own father wanted him to study medicine. When arriving in London, however, Galton's father died and left him a sizeable inheritance. Instead of going to school, Galton traveled extensively; his adventures in Africa brought him membership in the Royal Society. Between 1850 and 1900, Galton wrote over 200 scientific articles and books which revealed a predisposition to quantify things. (My note: Galton had received his degree from Trinity in mathematics.) Galton demonstrated the permanence of fingerprints. How did he do so? He studied serial impressions made by Sir William Herschel of his own fingers and those of others at different times.
Sir Francis Galton (1822-1911) was the founder of the study of human inheritance. Galton established the scientific study of fingerprints, the idea of regression (a core concept in modern statistics), published the first weather maps, attempted to test the efficacy of prayer, merged photographs in an attempt to idealize the criminal or aristocratic face, and founded the first human genetics department at University London. Galton was particularly interested in twin studies. He was knighted in 1909.
Galton was devoted to quantifying observations and applying statistical analysis. His Anthropometric Laboratory, established in 1884, recorded from his subjects (who paid him threepence for the privilege) their weight, sitting and standing height, arm span, breathing capacity, strengths of pull and of a squeeze, force of blow, reaction time, keenness of sight and hearing, color discrimination and judgments of length.
Except for color blindness, these are quantitative, continuously variable characters. In one of the first applications of statistics, he compared physical attributes of parents and children and established the degree of correlation between relatives. By 1900 he had established a large body of knowledge about the inheritance of such attributes and a tradition (biometrics) in their investigation.
III. RESOLVING THE DIFFERENCES BETWEEN MENDELIAN GENETICS AND BIOMETRICS
When Mendel's work was rediscovered, a controversy arose. The Mendelian geneticists saw genetics as the study of the transmission and segregation of Mendelian genes. Even if the phenotypic variants involved were rare or trivial. The biometricians saw genetics as the statistical study of evolutionarily important variation, normally in quantitative characters. The two fields seemed to be at odds with each other--the discrete and the continuous.
Theoretical resolution to the conflict was achieved by the geneticist Ronald Fisher in 1918 who demonstrated that the characters favored by the biometricians could be described in Mendelian terms if they were governed by the simultaneous action of many genes. Thus, Fisher demonstrated that characters governed by a large number of independent Mendelian characters (polygenec characters) would display the quantitative variation and family correlations described by the biometricians.
A parallel debate developed in evolution. Mendelian particulate genetics was seemingly at odds with gradual change that was implicit in Darwinian theory. X-ray studies by Muller suggested that mutations would appear as sudden genetic 'jumps' rather than in a smooth, gradual manner. The two sides achieved a consensus about 1930, summarized by Julian Huxley as the Modern Synthesis. Ironically, many now accept Stephen J Gould's suggestion that evolution does occur in a 'punctuated equilibrium' fashion.
In principle, Fisher's description of polygenic inheritance unified genetics. In human genetics, however, the studies of Mendelian and quantitative characters have tended to continue as separate traditions. Few investigators feel at home in both worlds.
IV. MAKING SENSE OF MENDELIAN AND POLYGENIC CHARACTERS
(1) Mendelian traits are discrete, or discontinuous because their phenotypic expressions do not overlap. They fall into clearly defined categories. In Mendel's peas there were green peas or yellow peas and nothing in between. In the ABO system there were four totally distinct phenotypes with no intermediates.
Before we go on, let us emphasize one basic idea so obvious that it often isn't mentioned: Mendelian traits are generally NOT influenced by the environment. They are under tight genetic control. I am unaware of any environmental way to change a person's blood type.
Mendelian pedigree patterns fall into five groups based on the chromosomes involved and dominance or recessivity. We will briefly cover these in the unit on chromosomes. In humans, some 5000 Mendelian characters are known. Many are obscure biochemical traits. There is an on-line database updated weekly through the Internet (Genome Database at http://www.ncbi.nlm.nih.gov/Omim
The clinical application of Mendelian genetics is not always clear cut. Many human characters that are generally dominant will sometimes skip a generation. This is called nonpenetrance. Sometimes a character will only be partially expressed; this is appropriately called partial penetrance. This can be a vexing problem for genetic counselors.
Some genetic diseases are late-onset. The genotype is fixed at conception but the disease does not manifest itself until adult life. A good example is Huntington's disease. In its phenotypic expression, it is a neural degeneration that appears late in life. It is a dominant character and the child of a carrier of the allele has a 50% chance of inheriting it.
Many conditions show what is called variable expression. Different family members show different features of the syndrome. Another unusual tendency is called anticipation. In this situation, the disease manifested becomes more severe with each succeeding generation.
(2) Polygenic or continuous traits have a wide range of phenotypic expression that form a graded series. Examples are such characteristics as skin color, body size, brain size, and intelligence. While Mendelian characters are governed by only one genetic locus, polygenic characters are governed by several loci. Polygenic traits lend themselves to measurement. This is why Galton and the biometricians of his discipline treat them statistically.
Many polygenic traits are influenced by environmental conditions. The combined action of genetics and environment produces traits with a continuous distribution. In some instances the influence of environment can be significant.
All physical traits measured and statistically treated in fossils are polygenic in nature. Metric and non-metric characteristics of teeth appear to be polygenic.
Can you stand three more terms? Nonmendelian characters may depend on two, three or many genetic loci. When there are two or more loci, and environmental factors are considered also, the term multi factorial is used. When only a small number of loci are involved, some authors call that oligogenic. The underlying issue illustrated by these three terms is this: Mendelian and polygenic are not two mutually exclusive categories. They fit into a continuum between the two extremes.
Sometimes one allele has an effect on several traits. This is called pleiotropy. An example of this appears in chickens; the alleles that cause white feathers also slow down overall body growth.
V. HUMAN CHROMOSOMES
The successful staining of the chromosomes (literally, "colored bodies") in the 1870s opened a new dimension in genetics. Human somatic (body) cells contain 46 chromosomes arranged in 23 pairs. T. H. Morgan at Columbia did the initial mapping of chromosomes by correlating mutations in fruit flies to specific chromosomal sites. Nuclear DNA resides within the chromosomes. (My note: some somatic cells in humans contain many more chromosomes--and red blood cells have none. Striated muscle cells and megakaryocytes of the bone marrow have many more.
In this discussion we are ignoring the haploid number of 23 that appear in sex cells.
In humans, 22 of the 23 pairs are called the autosomes. This is an important term to know. The literature will often refer to 'autosomal dominant' or 'autosomal recessive' inheritance. The term 'autosomal' refers to any of the 22 non-sex chromosomes.
The 23rd pairs are designated by their approximate physical configuration as 'X' or 'Y'. Females are XX. Males are XY. Some Mendelian patterns depend upon the action of genes on the X chromosome. The literature will often refer to 'X-linked dominant' or 'X-linked recessive' inheritance. The term 'X-linked' refers to a linkage to the X chromosome.
The X chromosome is much larger than the Y chromosome. The human X chromosome contains numerous important genes, including some for teeth. Many linkages with it are confirmed. The Y chromosome is smaller and the great bulk of it is genetically inert. While there are no Y linked diseases, some Y chromosome linkages are claimed.
The Y chromosome is somewhat analogous to mitochondrial DNA. You'll recall that mitochondrial DNA is inherited matrilineally. The Y chromosome is inherited only by males from males. Little variation has been found on it and it contains few functional genes.
Human chromosomes have been classified in groups on the basis of their variations in size and position of their centromere (the site where they seem to attach in mitosis). Such an arrangement is known as a karyotype.
Chromosomes are studied at the metaphase stage of mitosis. With appropriate chemical treatment and staining, the chromosomes can be separated into groups and the individual chromosomes identified. Bands produced in the staining process represent repetitive sequences of DNA. They are very helpful in karyotyping.
The two chromosomes that form a pair are said to be homologous. Exchanges between them occurs during meiosis. That exchange is called crossing over or recombination and it are a normal event. It contributes to genetic variation. Chromosomal rearrangements are considered significant in evolution.
Exchanges between nonhomologous pairs are called translocations. They are often useful in genetically engineered plants, but are pathological in humans.
The traits in Mendel's peas functioned independently and he called that independent segregation. There are many exceptions, however. These become important in human genetics. They are best understood by understanding them as chromosomal geography.
Genes on the same chromosome tend to be inherited together. This is called linkage. Genes on homologous chromosomes also display linkage. There is a phenomenon-called crossover wherein sections of chromosomes rearrange themselves along the length of the chromosome. If you keep this in mind, then you will understand that linkage is strongest for genes physically close together on the same chromosome.
Do not confuse crossovers with mutation. Crossover is a rearrangement of the existing genetic units strung along homologous chromosomes. Mutation is a new variation at the molecular level.
Except in special circumstances, autosomal linkage is very difficult to establish simply by doing a pedigree analysis. In contrast, sex-linked inheritance can be revealed in pedigree analysis.
VI . POSTSCRIPT: THE THIRD WORLD OF MITOCHONDRIAL GENETICS
The mitochondria in the cytoplasm also contains DNA (mtDNA for short). Only mothers can pass on mitochondrial DNA; we get none from our fathers. The spermatozoa transmit only nuclear DNA. The mitochondrial genome is small, but it has a high mutation rate. It is in a circle rather than the well-known nuclear style double helix. This feature has been the basis of mtDNA reports on human origins popularly known as the 'Eve Hypothesis'--a whole realm of discussion that is beyond the realm of this article. Mitochondrial DNA is so unusual that it merits a bit of review here.
The mtDNA is small in size and a high percentage is encoding (thus little 'junk' DNA). It seems related to purple bacteria. According to the endosymbiont hypothesis, mitochondria were independent organisms acquired by simple anaerobic cells 1.5 billion years ago when oxygen began to accumulate in the earth's atmosphere. Mitochondria are important for energy production and are most numerous in cell types with high energy needs such as brain and striated muscle cells.
Why is the mtDNA mutation rate ten times than that of the nuclear rate? It undergoes replication many times during the cell cycle--not just during cell division. It therefore has more opportunity for mutation.
While the vast majority of individuals carry mtDNA that is identical, sometimes a mixed population of normal and mutant mitochondria can occur in a single cell. This condition is called heteroplasmy.
A number of mitochondrial diseases are known. Since transmission of mitochondria is through the maternal line, the inheritance of mitochondrial diseases tends to be maternal. Some expressions of mitochondrial disease, however, exhibit autosomal and sex-linked pedigrees. To my knowledge, no dental aberrations are mitochondrial in origin.
VII. HARDY-WEINBERG AND GENES IN POPULATIONS
The Hardy-Weinberg rule illustrates some counterintuitive aspects of gene behavior. Imagine that 60 dental students are shipwrecked on an island along with another 40 students from the Republic of Albina where everybody is an albino. Nature takes its course and they randomly mate with each other and have children.
Now consider, normal pigmentation is dominant to albinism. People used to think that 'dominant' genes were stronger. Not so. Assume that mating is random (they only make love at night). If there is no selection, the allele frequencies will not change. The albino recessive trait will persist at the 60/40 ratio unless some selection for or against it occurs. The Hardy-Weinberg rule shows that in the absence of any process such as selection or mutation, allele frequencies do not change.
There is an especially good explanation of the Hardy-Weinberg rule on page 290 of the Cambridge Encyclopedia cited below. There will be more discussion of Hardy-Weinberg in subsequent units.
Bunney, S The Cambridge Encyclopedia of Human Evolution. New York: Cambridge University Press, 1994.
Edey, M. and Johanson, D. Blueprints Solving the Mystery of Human Evolution. New York: Penguin Books, 1989.
Griffiths, A. et al An Introduction to Genetic Analysis. New York: W. H. Freeman and Company, 1996.
Harrison, G. et al Human Biology, 3rd ed. New York: Oxford University Press, 1993.
Huxley, J. Evolution The Modern Synthesis. New York: Harper and Brothers Publishers, 1943.
Lewontin, R. Human Diversity. New York: Scientific American Library, 1995.
Relethford, J. The Human Species, 3rd ed. Mountain View: Mayfield Publishing Company, 1996.
Strachan, T. and Read, A. Human Molecular Genetics. New York: Bios Scientific Publishers/Wiley-Liss, 1996.