University:
California State University, Northridge
Course:
BIOL 360 | Genetics
Academic year:

2007
Views:

41

Pages:

30
Author:

zadiramiys

Variations in Chromosome Structure & Function Ch. 8 1 INTRODUCTION ! Genetic variation refers to differences between members of the same species or those of different species – Allelic variations are due to mutations in particular genes – Chromosomal aberrations are substantial changes in chromosome structure " These typically affect more than one gene " They are also called chromosomal mutations 2 Alterations in Chromosome Structure ! There are two primary ways in which the structure of chromosomes can be altered – 1. The total amount of genetic information in the chromosome can change " Decrease: Deficiencies/Deletions " Increase: Duplications & Insertions – 2. The genetic material may remain the same, but is rearranged " Inversions " Translocations 3 Alterations in Chromosome Structure ! Deletion – loss of a chromosomal segment ! Duplication – repetition of a chromosomal segment – Inversion – A change in the direction of genetic material along a single chromosome ! Translocation – A segment of one chromosome becomes attached to a nonhomologous chromosome " Simple translocations – One way transfer " Reciprocal translocations – Two way transfer 4 Variations in Chromosome Structure: Deletions ! part of a chromosome is missing. ! Deletions start with chromosomal breaks induced by: ! " Heat or radiation (especially ionizing). " Viruses. " Chemicals. " Transposable elements. " Errors in recombination. Deletions do not revert, because the DNA is gone (degraded) Fig. 8.2 A deletion of a chromosome segment 5 Variations in Chromosome Structure: Deletions ! The effect of a deletion depends on what was deleted. – A deletion in one allele of a homozygous wildtype organism may give a normal phenotype " while the same deletion in the wild-type allele of a heterozygote would produce a mutant phenotype. – Deletion of the centromere results in an acentric chromosome that is lost, usually with serious or lethal consequences. " No known living human has an entire autosome deleted from the genome. 6 Variations in Chromosome Structure: Deletions ! Human disorders caused by large chromosomal deletions are generally seen in heterozygotes, since homozygotes usually die. – The number of gene copies is important. – Syndromes result from the loss of several to many genes. ! Examples of human disorders caused by large chromosomal deletions: – Cri-du-chat (“cry of the cat”) syndrome (OMIM 123450), resulting from deletion of part of the short arm of chromosome 5 (Figure 8.4). – The deletion results in severe mental retardation and physical abnormalities. 7 Variations in Chromosome Structure: Duplications ! Duplications result from doubling of chromosomal segments, and occur in a range of sizes and locations (Figure 8.5). Fig. 8.5 Duplication, with a chromosome segment repeated 8 Variations in Chromosome Structure: Duplications –Tandem duplications are adjacent to each other. –Reverse tandem duplications result in genes arranged in the opposite order of the original. –Tandem duplication at the end of a chromosome is a terminal tandem duplication – (Figure 8.6). 9 Duplications add material to the genome 10 Variations in Chromosome Structure: Duplications ! ! An example is the Drosophila eye shape allele, Bar, that reduces the number of eye facets, giving the eye a slit-like rather than oval appearance (Figure 8.7). – The Bar allele resembles an incompletely dominant mutation: " Females heterozygous for Bar have a kidney-shaped eye that is larger and more faceted than that in a female homozygous for Bar. " Males hemizygous for Bar have slit-like eyes like those of a Bar/Bar female. – Cytological examination of chromosomes showed that the Bar allele results from duplication of a small segment (16A) of the X chromosome. 11 Fig. 8.7 Chromosome of Drosophila strains 12 Duplication loops form when chromosomes pair in duplication heterozygotes ! In prophase I, the duplication loop can assume different configurations that maximize the pairing of related regions 13 Variations in Chromosome Structure: Inversions ! Inversion results when a chromosome segment excises and reintegrates oriented 180° from the original orientation. – There are two types (Figure 8.8): 14 Variations in Chromosome Structure: Inversions ! Linked genes are often inverted together. – The meiotic consequence depends on whether the inversion occurs in a homozygote or a heterozygote. ! A homozygote will have normal meiosis. ! The effect in a heterozygote depends on whether crossing-over occurs. – If there is no crossing-over, no meiotic problems occur. – If crossing-over occurs in the inversion, unequal crossover may produce serious genetic consequences. 15 Inversion heterozygotes reduce the number of recombinant progeny ! Inversion loop in heterozygote forms tightest possible alignment of homologous regions 16 Recombination involving inversions ! Heterozygous Pericentric Inversion: – – – – ! One normal gamete One gamete with inversion One gamete with a duplication and deletion. One gamete with reciprocal duplication and deletion. Heterozygous Paracentric Inversion: – – – – One normal gamete One gamete with inversion Two deletion products Some material lost. 17 Gametes produced from pericentric and paracentric inversions are imbalanced 18 Variations in Chromosome Structure: Inversions ! In an inversion, the total amount of genetic information stays the same – Therefore, the great majority of inversions have no phenotypic consequences ! In rare cases, inversions can alter the phenotype of an individual – Break point effect " The breaks leading to the inversion occur in a vital gene – Position effect " A gene is repositioned in a way that alters its gene expression ! About 2% of the human population carries inversions that are detectable with a light microscope – Most of these individuals are phenotypically normal – However, a few an produce offspring with genetic abnormalities 19 Translocations ! A chromosomal translocation occurs when a segment of one chromosome becomes attached to another. ! There are two main types of medically important translocations: 1. Reciprocal (balanced) Translocations 2. Robertsonian (unbalanced) Translocations ! Both types of translocations are capable of causing disease in humans. 20 Fig. 8.11 Translocations 21 Reciprocal Translocations ! In reciprocal translocations two non-homologous chromosomes exchange genetic material – Reciprocal translocations arise from two different mechanisms " 1. Chromosomal breakage and DNA repair " 2. Abnormal crossovers ! Reciprocal translocations lead to a rearrangement of the genetic material – not a change in the total amount – Thus, they are also called balanced translocations. 22 Robertsonian Translocations ! In Robertsonian Translocations the transfer of genetic material occurs in only one direction ! Robertsonian translocations are associated with phenotypic abnormalities or even lethality. ! Example: Familial Down Syndrome – In this condition, the majority of chromosome 21 is attached to chromosome 14. – The individual would have three copies of genes found on a large segment of chromosome 21 " Therefore, they exhibit the characteristics of Down syndrome 23 Robertsonian Translocation ! This translocation occurs as follows: – Breaks occur at the extreme ends of the short arms of two non-homologous acrocentric chromosomes – The larger fragments fuse at their centromeic regions to form a single chromosome – The small acrocentric fragments are subsequently lost. – This type of translocation is the most common type of chromosomal rearrangement in humans. ! Robertsonian translocations are confined to chromosomes 13, 14, 15, 21 – The acrocentric chromosomes 24 Meiosis in Robertsonian Translocation 25 Chromosomal Mutations and Human Tumors ! Most human malignant tumors have chromosomal mutations. – The most common are translocations – There is much variation in chromosome abnormalities, however, and they include simple rearrangements to complex changes in chromosome structure and number. – Many tumor types show a variety of mutations. – Some, however, are associated with specific chromosomal abnormalities. 26 Translocations ! Usually phenotypically normal; no net loss or gain of material in most cases. ! If breakpoint alters promoter context, gene regulation may be altered – e.g.: Burkitt Lymphoma: t(8;14): ! puts the protooncogene c-myc next to the immunoglobulin heavy chain locus, – resulting in overexpression of c-myc ! If breakpoint occurs within a gene, the gene function may be altered – e.g.: CML : t(9;22): Bcr-Abl fusion product. 27 t(14;18): Folicular Lymphoma Enhancer 28 t(8;14): Burkitt Lymphoma Enhancer 29 t(9;22): Chronic Myelogenous Leukemia 30

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