Text Assignment: Chapter 17, 525 - 547; Chapter 21, pages 636-639 (to start of Quantum Speciation only). The parts of these notes describing imprinting should also be studied as supplemental text material. They contain information not in the textbook.
Major concepts
Introduction: This lecture completes the discussion of chromosomal abnormalities begun in the previous lecture. It then surveys human aneuploidies involving both altered numbers of chromosomes and altered chromosomes. This is followed by a discussion of genetic imprinting, in which a chromosome is silenced for a generation or more without any alteration of its genetic content. Finally, there is a brief description of the chromosomal abnormalities observed in cancer cells..
Translocation: The transfer of a segment of one chromosome onto another is known as a translocation. An interstitial translocation is a one-way event, in which a segment of one chromosome is moved to a different chromosome, with no loss of material from the second chromosome. This results in a chromosome with a deletion and another chromosome with a translocated sequence inserted into it. Together, these two altered chromosomes still possess the full set of genetic material that they started with (figure 17.19a). A reciprocal translocation involves the swapping of segments between two chromosomes, resulting in two chromosomes with translocations, which together possess the full set of genetic material from both original chromosomes (figure 17.19b).
Meiotic pairing of chromosomes with translocations: Recriprocal translocations of roughly equal size can result in a cross-shaped pattern of pairing of homologous regions (figure 17.20). During meiotic anaphase I, several possible patterns of segregation can occur, leading either to genetic balance or genetic imbalance in the resultant gametes (fiure 17.21). The pattern known as alternate segregation is the only one to yield genetic balance, producing two gametes with normal chromosomes and two carrying the balanced translocation. The pattern known as adjacent segregation generates genetically unbalanced gametes with duplication of portions of one of the chromosomes and deletion of portions of the other.
Fusion and fission of centromeres: A process known as Robertsonian translocation or Robertsonian fusion (figure 17.23) can form a single metacentric (or telocentric) chromosome from two acrocentric chromosomes and thus reduce the total number of chromosomes. Similarly, chromosomal (centric) fission can split a metacentric (or telocentric) chromosome into two acrocentric chromosomes, causing an increase in chromosomal number. However, this is a rare event because a second centromere must be acquired for both parts to survive as independent chromosomes.
Evolution of human chromosome 2: Closely related species often differ substantially in chromosome number because of fusion or fission of chromosomes. Thus, some cytologists prefer to count the total number of chromosomal arms when comparing such species. An example of apparent fusion can be seen in chromosomal differences between humans and other higher primates. Substantial similarities are evident when the banding patterns of most of their chromosomes are compared (figure 21.3, page 636). However, human chromosome 2, which is nearly metacentric, gives the appearance of having been generated by centric fusion of two nonhomologous chromosomes that are essentially acrocentric in the great apes, causing humans to have 46 chromosomes instead of 48. Except for selected regions that exhibit clear differences, the overall genomes of humans and the great apes are strikingly similar both in chromosomal banding patterns and in base sequence homology.
Example of inversions between species: Boxed example 21.1 and figure 21.4 illustrate two inversions that differentiate the comparable chromosome of the orangutan from human chromosome 3 and the corresponding chromosomes of the chimpanzee and gorilla. Careful examination of figure 21.3 also reveals a number of other apparent inversions during primate evolution Human chromosome 4 appears to differ from the corresponding chimpanzee chromosome by a pericentric inversion. Human chromosomes 5, 9, and 12 also appear to differ from the comparable chimpanzee chromosomes by pericentric inversions. The genes carried at or near the break points for these and other chromosomal rearrangements are of special interest to scientists seeking to understand the genetic differences between humans and the great apes.
Isochromosomes: An isochromosome is defined as a chromosome with two identical arms. This anomaly can arise either as a result of centric fusion of two acrocentric homologues, or as a product of a crossover in the loop region of a pericentric inversion (figure 17.24). The attached X-chromosome in Drosophila is an example of an isochromosome.
Position effect: Rearrangement of portions of a chromosome can alter the environment that a gene finds itself in, which in turn can alter its level of expression. This phenomenon, which is called a position effect, is seen clearly in the eyes of female Drosophila that are heterozygous for the sex-linked white-eyed mutation. When the white-eyed locus is moved to a position near the centromere, the level of expression of the wild type allele is weakened, giving the eye a mottled red appearance (figure 17.25), rather than a fully dominant wild-type red-eyed phenotype. (Note that our textbook fails to mention that the phenomenon that is illustrated occurs in the heterozygous state.) Generally gene expression is diminished when a locus is moved to a more heterochromatic location. However, in certain cases, such as the rolled locus in Drosophila, the gene is normally expressed from a heterochromatic location and does not express normally when moved to an euchromatic location (boxed example 10.3, page 309). Any modification that changes the environment of a gene can have a position effect. However, the phenomenon is most commonly associated with inversions and translocations.
Human karyotype nomenclature: Human aneuploidies, including changes both in chromosome number and structure are analyzed in section 17.4 of our textbook (pages 534-542), together with imprinting and aneuploidies associated with cancer. Before examining these topics, it may be useful to review the nomenclature used for human karyotypes (table 17.4 and page 535). The standard order for presenting karyotypic information is:
Human aneuploidies: Because of dosage compensation, individuals with sex chromosome aneuploidies are usually viable, and sometimes only minimally affected. However, autosomal monosomies and trisomies in humans are generally not viable beyond infancy. Without dosage compensation, the alteration of the ratio of genes carried on the affected chromosome relative to those in the rest of the genome has severe phenotypic effects, which are usually fatal during embryonic development or soon after birth.
Down syndrome: The one exception is trisomy of chromosome 21 (one of the smallest of the human chromosomes), which is responsible for most cases of Down syndrome (a few cases are caused by translocations that result in the presence of extra copies of genes from chromosome 21, as described below). Individuals with Down syndrome have low IQ and a characteristic physical appearance. Their life expectancy is substantially reduced and nearly all who survive into their 40's exhibit symptoms similar to Alzheimer disease. The nondisjunction leading to Down syndrome can occur in either parent, but the risk is greatest during oogenesis in older mothers (figure 17.26). This nondisjunction appears to be part of a generalized risk of nondisjunction that increases for all of the human chromosomes as maternal age increases (figure 17.27).
Familial Down syndrome caused by translocation: In addition to Down syndrome caused nondisjunction leading to trisomy of chromosome 21, there are also cases that are caused by translocation of a substantial part of chromosome 21 to another chromosome. By far the most frequent is a Robertsonian translocation that fuses the long arm of chromosome 14 to the long arm of chromosome 21 (both are acrocentric, as shown in figures 10.18 and 11.2 -- If you look at figure 10.31, please remember that chromosome 14 is incorrectly labeled as chromosome 8 in that figure). Adjacent segregation of the translocation during meiosis can result in gametes that carry two copies of parts of chromosome 21. Individuals who end up with two normal chromosomes 21 plus the translocation carried on another chromosome are trisomic for the region of chromosome 21 responsible for Down syndrome (figure 17.30). Two things should be noted about this example: first, it represents only about 4% of all cases of Down syndrome. The vast majority of Down syndrome is caused by a simple trisomy of chromosome 21 with no translocation involved (figure 17.1). Secondly, some normal siblings will carry balanced translocations (figure 17.30). Such individuals are sometimes referred to as translocation heterozygotes. Their progeny will be at risk for Down syndrome, which is not normally inherited. However, as pointed out in on page 538, the risk is lower than would be expected from simple Punnett square calculations, probably due to the high rate of spontaneous abortion of Down syndrome fetuses.
Edwards syndrome and Patau syndrome: Live births also occur for trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome) and rarely for a few others, but the severe developmental defects seen in such individuals invariably result in death in infancy or early childhood.
Cri-du-chat syndrome No human monosomies other than Turner's syndrome are viable. However, loss of a portion of one copy of chromosome 5 can result in the live birth of a severely afflicted child with cri-du-chat syndrome. The name is French for "cry of the cat", based on the cry of the afflicted infants, which has a sound like the a meow of a cat. The severity of the affliction varies greatly with the extent of the deletion of the short arm of chromosome 5. The overall incidence of this syndrome is estimated to be about 1 in 50,000 live births.
Human sex chromosome aneuploidies: We have already examined the effect of sex chromosome aneuploidies in Lecture 28. Because of dosage compensation, aneuploidies involving the X chromosome have far less effect than autosomal aneuploidies. Aneuploidies of the Y chromosome have very little effect because of lack of essential genes on the Y chromosome, which is not present in females. In brief summary, sex chromosome aneuploidies cause the following phenotypes:
XO = Turner Syndrome (female, sterile, distinctive phenotype)
XXY = Kleinfelter Syndrome (male, sterile, some feminization)
XXX = metafemale (variable effects, often minor)
XYY = tall male, many show no other effects.
Imprinting: Imprinting is a phenomenon in which a gene behaves differently when inherited from one parent than from the other. Typically one parental copy of the gene is totally inactivated, such that the individual has only one functional copy of that gene, received from the other parent. This phenomenon is similar in some ways to the inactivation of one of the X-chromosomes in each cell of most female mammals (including human females), which was discussed in lecture 28 (textbook pages 436-437). However, it differs in two important aspects: the effect is on single genes rather than an entire chromosome, and the inactivation is specific for the copy of the gene from one of the parents, rather than being randomly determined. Depending on the individual gene, it can be either the maternal or the paternal copy that is inactivated. (As an aside, it should be noted that in certain species, such as kangaroos, the X chromosome derived from the father is uniformly inactivated in all cells of female progeny. However, such patterns are the exception, rather than the rule, among mammals in general.)
Insulin-like growth factor-II (IGF-II): One of the better studied examples of imprinting is the Igf2 gene in mice, which codes for IGF-II. This is a particularly convenient system to use for studying imprinting, since Igf2 knockout mice (which totally lack the ability to synthesize IGF-II) have been generated and found to be smaller than normal, but both viable and fertile. Crosses of these mice with wild-type mice have verified that imprinting occurs and have shown that the maternally-derived gene is the one that is inactivated. The Igf2 phenotype of a mouse is always determined by the allele inherited from the father, with no phenotypic effect whatsoever from the maternal allele. Thus, the progeny of an Igf2-minus father and a wild-type mother will all be dwarf despite the fact that they carry an inactivated wild-type allele from their mother. Conversely, the progeny of a mutant mother and a wild-type father will always be normal sized.
Reactivation in the male: Imprinting does not involve any change in the coding sequence of the gene. When a dwarf male mouse that carries a paternally-derived Igf2-minus allele and an inactivated maternally-derived wild-type allele is mated to any type of female, half of the progeny will be normal sized due to reactivation of the maternally-derived wild-type allele that is now passed to the progeny from the male, and the other half will be dwarf due to the mutant allele passed to them from the male. Because of imprinting, the genotype of the mother has no effect on the phenotype of her progeny in such a cross.
Nomenclature of imprinting: Be sure that you understand how to describe imprinting. The allele that is TURNED OFF is said to be imprinted. Do not use the term "imprinted" to describe the allele that remains active!
Mechanism: The exact mechanism responsible for imprinting is not yet fully understood, but there are data suggesting that methylation may be involved. There is also some information suggesting that interaction with an enhancer may be disrupted for imprinted genes, but the details have not been fully worked out. Whatever the mechanism may be, it is fully reversible when an inactivated gene passes through a parent of the opposite sex. Also, some imprinted genes are inactivated in the female, while others are inactivated in the male. Thus, the gene for the IGF-II receptor, which is also subject to imprinting, is expressed from the maternal chromosome, with the paternal copy inactivated.
The need for genomes from two parents: Because imprinting turns off different sets of genes in gametes derived from each sex, it is absolutely essential for an embryo to receive both a maternally-derived genome and a paternally-derived genome. Experiments in which two haploid nuclei from the same sex are artificially introduced into activated mouse eggs have shown that normal development cannot be obtained either in embryos with two maternal genomes (gynogenones) or in embryos with two paternal genomes (androgenones).
Uniparental disomies: In more sophisticated manipulations, embryos have been generated that contain complete genomes from both parents, except that both copies of one particular chromosome are from the same parent. These experiments suggest that the total number of imprinted genes is probably relatively small. One such study was done with mouse chromosome 11, which carries the Igf2 gene. Embryos with maternal disomy 11 are smaller than normal, whereas embryos with paternal disomy 11 are larger than normal. These results are consistent with the presence of maternal imprinting of the Igf2 gene and a normal pattern of expression of only one copy of that gene. Thus, when two non-imprinted paternally-derived copies are present, the embryos become larger than normal. The data also suggest that no other chromosome 11 genes that are essential for survival or normal development are subject to imprinting, since no effects other than differences in size are observed in the uniparental disomies. There is, however, a locus called H19, located only 90 kb from Igf2 that is paternally imprinted, It is transcribed from the maternally-derived chromosome, but not from the paternally derived chromosome (the opposite of Igf2). However, the RNA is never translated.
Imprinting in humans: Another well studied case of imprinting occurs in humans. There is a deletion of the region designated q15 to q17, near the centromere on the long arm of human chromosome 15. This deletion causes two different syndromes, depending on which parent it is inherited from. When the deletion is from the father, it produces the Prader-Willi syndrome, whereas when it is from the mother, it produces the Angelman Syndrome. Except for mental retardation, which the two share in common, these two syndromes have quite different phenotypes. There are a total of five genes in the deleted region that are known to be imprinted. Four of them are maternally imprinted and the fith is paternally imprinted. Lack of expression of two of the maternally imprinted genes, ZNF127 and IPW is associated specifically with Prader-Willi syndrome, and lack of expression of the paternally imprinted gene UBE3A is believed to be the cause of Angelman syndrome. There are also rare cases in which uniparental disomy (both copies of chromosome 15 from the same parent) has been shown to be the cause of the two disease states. These cases are similar to the uniparental disomies in mice discussed above, except that they have arisen spontaneously, apparently as a result of complementary nondisjunction of chromosome 15 in both parents (figure 17.32).
Aneuploidies in cancer cells: Aneuploidy is extremely common in cancer cells, and in some cases can be shown to be a primary cause of certain types of cancer. One of the best studied cases is the Philadelphia chromosome that is frequently present in chronic myelogenous leukemia, a cancer of the bone marrow. The Philadelphia chromosome is chromosome 22 that has undergone a reciprocal translocation that has replaced most of its long arm with a shorter segment from the tip of the long arm of chromosome 9. This translocation has generated a fusion protein, which consists of the N-terminal portion of the BCR protein and most of the ABL protein. The fusion protein retains normal ABL protein activity and is made in much greater amounts than normal ABL, which is a signaling protein involved in cellular growth control. Its unregulated activity results in excessive proliferation of the leukemic cells.
Other genes associated with cancer: Boxed example 17.6 describes a deletion, which apparently resulted from an abnormal crossover caused by a deletion. This deletion was associated with retinoblastoma, a tumor of the retina in children, which appears to be caused by loss of both copies of a tumor resistance gene (one because of the deletion, and the other as a result of a somatic cell mutation). More commonly this type of tumor is seen in children who are heterozygous for a recessive mutation, such that random mutation in any retinal cell can cause loss of the second copy and development of a retinoblastoma tumor. Chapter 24, which we will not have time to study in this course, deals with the genetics of cancer. A small part of the very complex network of gene products involved in cellular growth control is illustrated in figure 24.3. Some of the genes that are involved are briefly summarized in Table 24.1, including both the ABL gene and the Retinoblastoma (RB1) gene. The table provides OMIM numbers for anyone who may wish to pursue the individual genes further. It should also be noted that cancer cells tend to be genetically unstable and typically become progressively more aneuploid as the cancer becomes more advanced and aggressive. Many of the aneuploidies are thought to further remove restraints on uncontrolled mutiplication by causing additional disruption of the growth control network summarized in figure 24.3.