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The science of genetics was the center of a scientific revolution from the middle of the 20th century until today. We have entered an era of genomic medicine in which your genome will be used to predict your response to drugs, and will allow you to develop an individual plan of preventative care against diseases that you are at risk to develop. The biotechnology industry is producing new products from genetically engineered life forms, and we are transitioning to the world of synthetic biology in which the code of life will be used to direct manufacturing, provide sustainable energy, and do much more than we can presently imagine. The pace of change continues to accelerate, and there is room for each of you to make an important contribution to the world of the future.
I will do everything possible to allow you to succeed in this course, but you have to do your part:
I'm so excited about genetics that I put the core of the course on ten slides. We will go over each of these key developments in genetics in more detail later. Here are the key developments.
Mendel 1866: Hereditary units are particles that we now call genes.
Flemming 1882: When cells divide in mitosis, the nuclear material organizes itself into chromosomes ("colored bodies") that are carefully partitioned to daughter cells in a precise way.
Garrod 1908: Metabolic errors are hereditary. There are individuals with inherited alterations in their biochemistry.
Sturtevant 1913: Genes are in a linear array. Sturtevant made the first genetic maps as an undergraduate researcher.
Bridges 1916: Genes are on chromosomes.
Beadle and Tatum 1941: Every enzyme in a biochemical pathway is controlled by an individual gene. By extension, genes control the structure of proteins.
Avery, MacLeod, McCarty 1944: Genes are made of DNA.
Watson, Crick 1953: Structure of DNA. This immediately suggests how DNA can be copied (replicated).
Nirenberg, Khorana, Holley 1966: Genes encode proteins using a triplet code.
Venter, Collins (and many others) 2001: Human genome sequenced. Dr. Szauter had his genome sequenced in 2012, and it is publicly available.
Research on teaching genetics shows that the best approach is to present the three "threads" of the story at increasing levels of detail at every stage of the course, rather than teaching one thread at a time in a linear way. The three threads are Heredity, Chromosomes, and DNA to Trait.
Taking the concepts from the ten slides and mapping them to the three threads gives us this story.
Heredity: Genes are units of heredity. Genes are in a linear array.
Chromosomes: The central feature of cell division is the careful division of the nuclear material organized into chromosomes.
One discovery unites these two threads: Genes are on chromosomes.
DNA to Trait: Genes are made of DNA. Genes encode proteins. DNA is code.
We begin our discussion of chromosomes by asking why we are not studying Mendel first. Mendel published his work on heredity in 1866. It was translated and widely distributed. Few people read it, those who read it did not understand the implications. Mendel's work was ahead of his time for some reason. Three groups rediscovered Mendel after replicating his results in 1900.
What happened between 1866 and 1900 to make Mendel comprehensible? Cytology, and the discovery of chromosomes.
We began with a figure from Flemming's work in 1882. Flemming discovered that the nuclear material resolved itself into chromosomes ("colored bodies") that were very carefully partitioned into daughter cells. Much of the rest of cell division seems haphazard, so the careful orchestration of chromosomal division during mitosis made it seem that there was something important about chromosomes.
We looked at a field of onion root tip cells and saw how the length of interphase relative to M phase could be estimated from such a figure. The class tried classifying cells in mitosis into the four phases: prophase, metaphase, anaphase, and telophase. Some cells were easier than others.
We looked at the chromosomes of human, dog, horse, mouse, and chicken. Two things were apparent: the number of chromosomes for all of these animals was always an even number. There was always a sex chromosome pair (XY for male mammals, XX for female mammals, ZW for female chickens, ZZ for male chickens). Other than the sex chromosome pair, the two homologous chromosomes in each pair look very much the same.
We went over chromosome behavior in mitosis in a simplified organism that has one pair of homologous chromosomes. These chromosomes replicate during interphase and appear as pairs of sister chromatids at the start of mitoisis. At metaphase of mitosis, our simplified organism has one pair of chromosomes, two homologous chromosomes, and four chromatids. The sister chromatids that make up a single chromosome are identical copies.
At anaphase, sister chromatids separate and begin to move to opposite poles of the spindle apparatus. At telophase, they reach the end of their journey and the cell divides.
Chromosomes decondense at the end of telophase. After interphase, when they appear again, they have replicated, and each chromosome consists of two sister chromatids as before.
We all traveled back in time to 1882. Mendel's 1866 paper lies unread in our library. We have just learned of Flemming's description of mitosis. I took the role of an academic of the day, who after Aristotle and Leeuwenhoek (1677) took the view that sperm contained preformed homunculi that grew into individuals when the male seed was planted in female ground. I rejected the contrary hypothesis that both sexes contribute an organizing principle to the embryo.
I presented two arguments in favor of my position.
The first argument was the argument from authority. Aristotle, the great natural philosopher, gave us the principle of preformation, and Leeuwenhook (with whom I share Dutch ancestry) was the first to describe spermatozoa, observing preformed homunculi within them. I stood before the class to represent these august and venerated thinkers and challenged the class to refute me.
One brave soul refuted the argument from authority by asserting that Aristotle had been wrong about other things (the sun orbiting the earth, for example), and that a person's pedigree and reputation were not merits to his argument, which must be based on evidence and reason. This was a great win for the core principle of science, and I conceded the point.
The second argument was based on Flemming's observation of chromosomes. The chromosome number remains constant when cells divide. I cited this as evidence to favor preformation, as the number of chromosomes in the sperm would then determine the number of chromosomes in the embryo. If the egg contributed chromosomes, the number of chromosomes would double every generation.
A radical theorist in the class proposed a special set of cell divisions peculiar to the formation of gametes that allowed the chromosome number to be reduced by half in gametes. Fertilization would then allow the restoration of the chromosome number. As we had not yet observed such a process in 1882, I conceded that while it was possible, I did not concede the point.
Yet another student pointed out that sex chromosome pairs were different in men and women. If men contributed all of the chromosomes to the embryo, it would be impossible to give birth to a girl. I countered weakly that no one understood women anyway before conceding the point on this argument.
The argument was resolved experimentally by the observations on meiotic cytology by Sutton and Boveri in 1903, who observed that homologous chromosomes paired in meiosis before undergoing two divisions to produce haploid gametes with a reduced chromosome number, which was restored to the diploid number upon fertilization.
We began our discussion of meiosis with a summary: it is a process in diploid germ cells in which a single round of replication is followed by two divisions to produce haploid gametes.
We looked at some figures from the book to compare mitosis and meiosis. We looked at some organisms (moss, for example) which differ from us in that the haploid phase grows into free-living, photosynthetic individuals who get together later to form free-living diploids that undergo meiosis to make more haploids. In humans and other animals, by contrast, we spend most of our time as diploids, with fragile haploid gametes exchanged privately.
We looked at meiosis in our ideal organism with one pair of homologous chromosomes to understand the two divisions.
The first meiotic division is unusual in that paired homologous chromosomes segregate from each other to produce haploid cells that are ready for another division.
The second meitoic division looks like a mitotic division of haploid cells.
We looked more carefully at the paired homologous chromosomes that make up a bivalent at late prophase of meiosis I. We looked at the cartoons of paired homologous chromosomes in the book, then at micrographs of actual bivalents, which have a far more complex structure (see for example the figure at Scitable, showing a bivalent from a salamander with an accompanying drawing).
In looking at the figure, we see all four chromatids of the tetrad. The sister centromeres are paired with each other but not with their homologs. We see sites of strand exchange called chiasmata (singular: chiasma). In contrast to mitotic chromosomes, where sister chromatids are held together only near the centromere, in the bivalent we see sister chromatid cohesion along the entire length of the chromosomes. The combination of chiasmata and sister chromatid cohesion holds the bivalent together.
We should ask ourselves at this point why the cell goes to this amount of trouble to build everything that we see in the bivalent. The answer comes from the analysis of the mitotic cell cycle.
One of the cell cycle checkpoints is the metaphase checkpoint. The biochemistry of this process is well understood, but too complex to go into at this point. Basically, every kinetochore in mitosis sends a chemical signal that says, "Not yet." Once the kinetochore has formed a stable attachment to one of the spindle poles, meaning that the kinetochore on the sister chromatid has formed an attachment to the opposite pole, the "Not yet" signal is no longer sent. Once there is complete silence in the cell (not even a single kinetochore is signaling "Not yet"), the Anaphase Promoting Complex cleaves a protein that inhibits a protease called separase. Separase cuts the cohesin complex that holds sister chromatids together, and mitotic anaphase is triggered.
The purpose of the metaphase checkpoint is to ensure that all chromosomes have two sister chromatids whose kinetochores are oriented to opposite poles of the spindle apparatus before proceeding to anaphase.
It would be great to be able to use the metaphase checkpoint from mitosis during meiosis I. In order to do this, we need to hold the bivalent together with chiasmata and sister chromatid cohesion so that sister kinetochores can co-orient to the same pole for meiosis I.
Meiosis II is just like a mitotic division of haploid cells.
Discussion of this subject always raises the question of why there is meiotic recombination. The standard answer in many textbooks is that meiotic recombination increases genetic diversity. This is simply not correct; shuffling a deck of cards does not increase the diversity of the deck, there are still four suits of thirteen cards each, no matter what the order. Population geneticists do not stand behind the claim that recombination increases diversity, and we should be careful not to repeat this misconception except as necessary to get exam points in dogmatic courses.
The immediate consequence of reducing meiotic recombination is to increase the frequency of nondisjunction. We will discuss this evidence later; for now, let us look at some of the consequences of nondisjunction in humans, leading to aneuploid syndromes.
We looked at a drawing from the book that shows nondisjunction at meiosis I. In this case, both homologous chromosomes of a single pair go to one pole, while no member of that chromosome pair goes to the other pole. The rest of the chromosome set segregates normally.
We looked briefly at the karyotype and phenotype produced by each of three human aneuploid syndromes.
Trisomy 21 (Down Syndrome): Individuals with an extra copy of chromsoome 21. This produces mental retardation, although recently there have been great strides in raising these individuals in an enriched environment to improve their development. They commonly have heart defects, usually have some extent of hearing loss, and are at greatly elevated risk of leukemia. They have a characteristic facial appearance that is easily recognized.
Turner Syndrome (45,X): Individuals monosomic for the X chromosome and lacking a Y chromosome are said to have Turner Syndrome. They are phenotypically female and are recognized at birth by a webbed neck, which is easily corrected surgically. They show primary amenorrhea (they never begin to menstruate) and are sterile. They have short stature and a broad chest. They have specific cognitive defects but are not considered retarded.
Klinefelter Syndrome (47,XXY): XXY humans are phenotypically male. They are not always recognized at birth, but the condition is normally apparent at puberty. They have hypogonadism and reduced fertility. They have less muscle mass than is typical for males and have a female-like distribution of body fat, with broad hips and gynecomastia. They are at increased risk for diseases that have a higher prevalence in females, like autoimmune disease and breast cancer. They have some specific cognitive defects, but are not considered retarded.
All three of these human aneuploid syndromes provide us with the opportunity to consider two kinds of questions.
First, how do these arise? We can ask whether nondisjunction is at the first or the second meiotic division, and whether either parent can give rise to the aneuploid gamete.
Second, we can ask what these conditions tell us about the role of chromosomes in development. All three types of individuals can be recognized by their phenotype. Although these people are normally karyotyped to confirm the diagnosis, there is never any surprise at their chromosomal composition. Conversely, individuals with normal phenotypes are never found to have these particular karyotypes.
A student suggested that the aneuploid syndromes show that chromosomes influence development, presumably because they carry genes. We will take up this question in greater detail next time.