This is old Lecture 19
Text Assignment: Chapter 9, Pages 243-260 (includes chapter end material for entire chapter)
Major concepts
Detection of altered chromosomes: The term heterokaryotipic is sometimes used (but not in out textbook) to describe individuals with homologous chromosomes that differ from each other. Such differences are most easily seen during pairing of homologous chromosomes, which occurs during meiotic prophase and also in certain types of somatic cells, such as the salivary glands of larval Drosophila. Sequences that are present in different orders on the two homologous chromosomes and sequences that are only present on one of them form a variety of loops and other convoluted structures as the homologous areas attempt to match up as closely as possible. Such structures can often be observed during meiotic prophase, although the small size and incomplete condensation of meiotic chromosomes may make detailed studies difficult.
Polytene chromosomes: The giant polytene chromosomes in the salivary glands of larval Drosophila are particularly well suited for observation of imperfectly matched pairing. Each chromosome has duplicated itself many hundred times, with all of the strands perfectly aligned, creating a structure that is readily visible with the light microscope even while the chromosomes remain relatively extended. In addition, the bound proteins and the folding of the DNA that does occur give the chromosomes a distinctive banded appearance (Figures 2.17 and 2.18) that allows an expert to identify localized regions in great detail. Also, the two homologous chromosomes are paired, allowing loops and other forms of mispairing to be observed in much greater detail than is usually possible with meiotic chromosomes (Figure 9.21).
Deletions: A deletion is the absence of a chromosomal segment that is present in a wild type chromosome. Deletion of a segment at the end of a chromosome is called a terminal deletion. If both ends of the chromosome are in place and an internal segment is missing, the deletion is called an intercalary deletion. During meiotic or somatic pairing of homologs, deletions cause the formation of loops that consist of the portion of the normal chromosome that has nothing to pair with because of the deletion (fig 9.21). Duplications cause very similar appearing loops, as described below.
Dominant lethal deletions: Deletions of moderate size often have dominant phenotypes that are lethal when they are homozygous (because of missing genes) . (Recall that this is how the dominant yellow lethal mutation in mice operates, as described at the end of the lecture 7 notes). The example discussed in the textbook is the classic Notch deletion in Drosophila, which was originally detected as a dominant X-linked mutation that causes the posterior margins of the wings to be notched in heterozygous females. This deletion is presumed to be lethal in hemizygous males since they are never recovered. Thus, it can presumably also be viewed as a dominant lethal in homozygous females, as suggested in the textbook. However, actual detection of the lethality is not as simple as implied because there are no viable males to provide a second deleted X-chromosome in crosses with heterozygous females.
Partial hemizygosity: Deletions cause heterozygotes to be hemizygous for the deleted genes. This in turn results in a phenomenon sometimes called pseudodominance in which recessive alleles on the homologous normal chromosome are expressed in a hemizygous manner that superficially resembles dominance. We have already observed a similar phenomenon for X-linked genes in XY males. The textbook describes hemizygous behavior for several X-linked markers, including white eye, facet eye, and split-bristle in female Drosophila that are heterozygous for the dominant lethal deletion mutation called Notch (Table 9.4). The deletion loop that occurs in a Notch heterozygote helps to pinpoint the chromosomal location of the loci that exhibit hemizygous behavior in such heterozygotes (Figure 9.21).
No reversion of deletions: Another feature of deletion mutants is that they are non-reverting, since they reflect sequences that are totally absent and thus cannot be restored to functionality by a second mutation. Deletions that are large enough to span several genes are usually lethal when homozygous, and can cause pathology even when heterozygous due to gene dosage imbalances. A well known example is the human cri-du-chat (cry of cat) syndrome in newborn infants that are heterozygous for a deletion in the short arm of chromosome 5 (See Fig. 9.9 and a brief description of the syndrome on pages 234-234).
Duplications: Duplications of chromosomal material that occur on the original chromosome fall into three classes. Tandem duplications have extra copies of a chromosomal segment adjacent to the original and in the same orientation. Reverse duplications have an extra copy adjacent to the original, but in the opposite orientation. Duplications that are inserted into other parts of the original chromosome in either orientation are referred to as displaced duplications. Note that a duplication that is no longer on the original chromosome is called a translocation (discussed separately below).
Duplication loops: During pairing of chromosomes that are heterozygous for a duplication, duplicated sequences that are unable to find a partner form a duplication loop. A very similar loop is seen when a deletion is present in one of the homologs (Fig. 9.21). Duplications and deletions often occur concurrently, either as the result of breakage and rejoining of crossed chromosomes or as a consequence of unequal crossover (Fig. 9.22). Unequal crossing over is particularly likely to occur at the site of a pre-exisitng duplication, which facilitates achieving a good match at the point of crossover, even when the overall chromosomal alignment is distorted (Fig. 9.23).
Bar eye: The Bar eye mutation in Drosophila is a classic example of a duplication. The phenotypic effect of the Bar locus is to limit the number of facets in the eye. Wild type eyes have about 800 facets. The Bar mutation, which consists of a short duplication of the region contianing the Bar locus, reduces the number to about 70 in homozygous females (B/B) and in hemizygous males (B/Y), with about 350 in the heterozygoous female (B/+) (see Fig. 9.23). Unequal crossing over within the Bar duplication can give rise to wild type gametes that contain only one copy of the Bar locus, and Double Bar (also called Ultrabar) gametes that contain three tandem repeats of it (Fig. 9.23). Double Bar (BD) reduces the number of eye facets to about 25 when homozygous or hemizygous.
Gene redundancy: It is important to recognize that not all duplications are abnormal. Many genes, such as those coding for the various ribosomal RNAs, are highly repeated in the normal genomes of most species, often in the form of tandem repeats. In addition, the genomes of higher organisms contain substantial amounts of other repetitive DNA, including some sequences with very high levels of repetition that are species specific and do not have any known genetic function.
Evolutionary role of gene duplication: There is substantial evidence that gene duplication has played a major role in the evolution of higher organisms. Complex genomes, such as those of humans, contain large families of closely related genes with slightly different funcitons that appear to have arisen through duplication followed by divergence of function, with one copy maintaining the original funciton while others have become modified in ways that have allowed them to acquire new functions.
Inversions: Reversal of the sequence of genes on a segment of a chromosome is called an inversion. Inversions that do not include the centromere are called paracentric, whereas those that do include the centromere are called pericentric. Inversions cause the formation of chromosomal loops in which one of the strands is crossed. When crossing over occurs within an inversion loop, a variety of chromosomal abnormalities can be generated (Figure 9.26).
Dicentric and acentric chromosomes: Crossing over in a paracentric inversion loop can result in the formation of a chromosomes with two centromeres that will form a dicentric bridge during anaphase I of meiosis. The reciprocal crossover products will be acentric chromosomes that do not contain centromeres and are thus lost during anaphase.
Duplications and deletions: A variety of duplications and deletions are generated when crossing over occurs in pericentric inversions. Note that the dicentric and acentric chromosomes generated by crossing over in paracentric loops can also be viewed as duplications and deletions that include the centromere.
Position effect: Inversions can also alter the environment that a gene finds itself in, causing a position effect, such as that seen with the white eye color locus (previously cited on page 182 and figure 7.2 and further explained on pages 248-250).
Evolutionary consequences: Crossing over within inversion loops generates non-functional chromosomes and thus reduces the number of fertile gametes produced. However, in certain cases rendering the products of crossing over infertile appears to keep specific combinations of alleles together in ways that can provide a selective advantage. The evidence for this is the maintenance of inversions in certain wild populations, such as Drosophila pseudoobscura.
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 deleted chromosome and a chromosome with a translocation, which together still possess the full set of genetic material of both. 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 of both.
Recriprocal translocations of roughly equal size can result in a cross-shaped pattern of pairing of homologous regions (Fig 9.27b). During meiotic anaphase I, several possible patterns of segregation can occur, leading either to genetic balance or genetic imbalance in the resultant gametes (Fig. 9.27c). The pattern known as alternate segregation is the only one to yield genetic balance.
Familial Down syndrome caused by translocation: The textbook describes cases of familial Down syndrome (trisomy 21) that are caused by translocations involving chromosomes 21 plus 14 (pages 251-252). 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 (Fig. 9.29). 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 (Fig. 9.12). Secondly, some normal siblings will carry balanced translocations (Fig. 9.29). Such individuals are sometimes referred to as translocation heterozygotes. Their progeny will be at risk for Down syndrome, which is not normally inherited.
Fusion and fission of centromeres: A process known as Robertsonian fusion (page 251 of textbook) 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. Translocations can arise from Robertsonian fusion as illustrated in Fig. 9.28. However, interconversions between two acrocentric chromosomes and a single metacentric chromosome can also occur without the involvement of a translocation partner, as described below.
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. 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.
Fragile sites in chromosomes: Fragile sites where chromosomes do not fully condense and are particularly sensitive to breakage have been associated with at least two types of human hereditary pathology. The first, fragile X syndrome, is now known to involve a gene near the end of the long arm of the X-chromosome that contains a triplet repeat sequence. Normal individuals appear to have about 50 repeats. Individuals with between 50 and 200 repeats are generally normal, but are considered to be "carriers" because their children are at increased risk. Individuals with above 200 repeats are directly at risk, although the actual disease syndrome has only about 80% penetrance in hemizygous males and 30% penetrance in heterozygous females (it is considered dominant with limited penetrance). Symptoms include mental retardation and a variety of characteristic phenotypic features. The second more recently discovered fragile site is the FHIT (fragile histidine triad) on chromosome 3, which is associated with lung cancer and to a lesser extent with a variety of other cancers.
Please note that this is the last lecture on the traditional genetics of heredity. Beginning with the next lecture, we will move on to the molecular aspects of genetics.