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Chromosome Mutations Reading Tutorial INTRODUCTION The sperm and egg cells (gametes) required for sexual reproduction are produced by meiotic cell division. Gametes are haploid cells. In humans, each gamete contains 23 chromosomes (22 are autosomes and 1 sex chromosome; either X or Y). In males, the four haploid cells produced by meiosis all specialize and become sperm. In females, the cytoplasm is divided unevenly to produce one large, haploid ovum (egg) and three small haploid cells called polar bodies. The polar bodies are little more than discarded sets of chromosomes and eventually disintegrate. Animation of meiosis http://www.sumanasinc.com/webcontent/animations/content/meiosis.html WHAT ARE CHROMOSOME MUTATIONS? Mutations that alter the number or structure of the chromosomes in the cells of an organism are called chromosome mutations. Changes in chromosome number involve the loss or gain of an entire chromosome. Changes in chromosome structure involve alterations in the number of genes, type of genes or sequence of genes on a chromosome. HOW DO CHROMOSOME MUTATIONS ARISE? Known causes of chromosome mutations including errors during DNA replication, errors during meiosis, and exposure to DNA mutating factors. The cause for some chromosome mutations is still unknown. We will focus on the events during meiosis that lead to chromosome mutations. Changes in chromosome structure can occur when there is an uneven exchange of genes during crossing over in prophase I. Changes in chromosome number occur when homologous chromosomes fail to separate properly during anaphase I. Most faulty gametes are never fertilized or fail to develop when fertilized. A study published by the NIH on first trimester miscarriages reveals 61% were due to chromosomal abnormalities. (www.ncbi.nlm.nih.gov/pubmed/16232180) If the faulty gamete is fertilized and develops, the fetus is born with a genetic syndrome. Genetic syndromes are disorders characterized by a group of typical features or symptoms caused by abnormal chromosomes. http://ocw.tufts.edu/data/20/293257/292180_medium.jpg PART I: MUTATIONS THAT CHANGE THE # OF CHROMOSOMES IN THE GAMETE CELL The mutation that causes gametes to have one extra or missing chromosome is called nondisjunction. NONDISJUCTION Nondisjunction is the failure of a homologous chromosome pair to separate during meiosis. Two of the gametes receive an extra chromosome (both members of a homologous pair). The other two are missing a chromosome (no members of a homologous pair). The normal gamete should have one member of each homologous chromosome pair. 1. Iupui.edu 2. WHAT HAPPENS IF THE FAULTY GAMETE IS FERTILIZED? If a gamete with both members of a homologous pair is fertilized, the embryo will have TRISOMY (three copies of a chromosome). Two of the homologues came from the faulty gamete and one homologue from the normal gamete that fertilized it. If a gamete with no members of a homologous chromosome pair is fertilized, the embryo will have MONOSOMY (one copy of a chromosome). The faulty gamete contributed no homologues while the normal gamete that fertilized it contributed one homologue. Trisomy can occur to the autosomes or sex chromosomes. View the following animation to review all of this material. http://www.sumanasinc.com/webcontent/animations/content/mistakesmeiosis/mistak esmeiosis.swf AUTOSOMAL TRISOMIES (Three copies of a non-sex chromosome) Autosomal trisomies were the most frequent chromosome mutation found in the research study on first trimester miscarriages comprising 37% of the abnormal karyotypes. Sixteen percent of the autosomal trisomies were to chromosome 16. Despite their prevalence, only three autosomal trisomies are compatible with life. The most common (and most viable) is Down Syndrome (Trisomy 21). Edwards Syndrome (trisomy 18) and Patau Syndrome (trisomy 13) are rare and children with these syndromes have a poor prognosis. The viability of Down Syndrome is due to how small chromosome 21 is. This means fewer genes are being overexpressed compared to extra copies of the larger chromosomes. Down Syndrome http://learn.genetics.utah.edu/content/disorders/chromosomal/down/ http://image.slidesharecdn.com/ THE SEX CHROMOSOMES The 23rd pair of chromosomes in humans are the sex chromosomes. Females have an XX chromosome combination and males have an XY chromosome combination. The X and Y chromosome not truly homologous to one another. The X chromosome contains 800900 protein encoding genes while the Y contains 50-60. A small number of genes on both ends of the X chromosome are still homologous to genes on the Y allowing them to behave as a homologous pair during meiosis in males. https://phylogenous.files.wordpress.com/2010/07/physical-picture-of-chromosomes.jpg Homologous Regions Unique to Y Unique to X To keep the number of “working” X chromosomes equal in males and females, one of the two X chromosomes in every cell of the female body is inactivated at random early on in development. This is known as Lyonization or Dosage Compensation. The inactive X chromosome can be seen microscopically as a “Barr Body” on the edge of the nucleus. Lyonization is NOT complete. The genes on the ends of the X chromosome that are homologous to genes on the Y escape deactivation. As you learn about different sex chromosome trisomy and monosomy syndromes, you will notice their symptoms are relatively mild despite the gain or loss of an entire sex chromosome. Extra X chromosomes (in a female or a male) will be deactivated so there is always a single working X in the cell. In a female missing an X chromosomes, the remaining X will be left on in all her cells. The symptoms that do occur when there are extra or missing X chromosomes are because of the small areas along the ends of the X chromosome that escape deactivation. Normal females should have two active copies of these genes. Normal males should have one active copy of these genes. Additional X chromosomes increase the number of working copies of these genes. A missing X chromosome Females missing an X chromosome will have only one copy of these genes. SEX CHROMOSOME TRISOMIES Trisomy of the sex chromosomes include XXX, XXY and XYY. 1. Trisomy X (XXX) is a female with three X chromosomes. This condition occurs in 1 in every 1000 females. Most trisomy X females have no detectable defects except above average height and below normal intelligence. In these females, two of their three X chromosomes are deactivated. 2. XYY (Jacob Syndrome) is a male with one X and two Y chromosomes. Since the Y chromosome only carries 50-60 protein encoding genes, the traits displayed by XYY males are relatively mild. XYY males have higher levels of testosterone. They often have severe acne, are taller than normal, and score slightly lower on IQ tests than their XY counterparts. 3. Klinefelter Syndrome (XXY) http://learn.genetics.utah.edu/content/disorders/chromosomal/klinefelter/ Klinefelter males will deactivate one of their two X chromosomes as a normal female would. AUTOSOMAL MONOSOMY There are no cases of autosomal monosomy. Humans require both members of each homologous pair of autosomes to survive. This is because of a phenomenon known as genetic imprinting. Normal individuals contain two copies of each gene (one from mom and one from dad). During embryonic development, certain genes from each parent are silenced leaving the gene inherited from the other parent as the single working copy. An autosomal monosomy could leave an individual with no working copies of such imprinted genes. www.learngenetics.utah.edu An example of a genetically imprinted gene is IGF2. This gene is located on chromosome 11. The material copy of this gene is silenced so all proteins produced by this gene are transcribed from the paternal copy. SEX CHROMOSOME MONOSOMY Turner Syndrome (XO) occurs when a female has only one X chromosome in her somatic cells. (The O represents a missing X chromosome.) This is the only type of monosomy in humans. Females with Turner Syndrome do not deactivate their only X chromosome. Turner Syndrome http://learn.genetics.utah.edu/content/disorders/chromosomal/turner/ PART II: MUTATIONS THAT CHANGE THE STRUCTURE OF THE CHROMOSOME (ALTER THE NUMBER, TYPE OR ORDER OF THE GENES) DELETION A deletion is caused by the loss of one or more genes from a chromosome. Region B could be a group of several hundred genes. TYPES OF DELETIONS A terminal deletion results in the loss of genes from one end of the chromosome. An interstitial deletion occurs when an internal section of the chromosome is lost and the remaining fragments are joined together. Animation of Terminal and Interstitial Deletions (scroll down to Missing Pieces on the linked page) http://learn.genetics.utah.edu/content/chromosomes/diagnose/ Large deletions are easy to locate on a karyotype because one of the homologues will be considerably smaller than the other. Smaller deletions require close scrutiny. CAUSE OF DELETIONS Deletions usually arise from errors during crossing over in meiosis. As homologous sister chromatids within a tetrad prepare to swap genes, they fail to align properly and the switch is unequal. One sister ends losing a section of genes (a deletion) while the other sister ends up with copies of its own genes and the complement genes from its homologous sister (a duplication). IMPACT OF DELETIONS If both homologs carry the same deletion, the combination is usually lethal suggesting that most regions of chromosomes are necessary for viability. Generally the only viable deletions are small ones to ONLY one of the two homologs. Cri du Chat http://learn.genetics.utah.edu/content/disorders/whataregd/cdc/index.html DUPLICATIONS A duplication occurs when multiple copies of a gene or group of genes is present. The duplicated regions can be located adjacent to one another on the same chromosome, on different areas of the same chromosome, or on entirely different chromosomes. Region B might contain several hundred genes. The cells of the organism have more than two copies of each of the genes within the duplicated region. CAUSE OF DUPLICATIONS As with deletions, duplications are caused by errors during crossing over in meiosis. As homologous sister chromatids within a tetrad prepare to swap genes, they fail to align properly and the switch is unequal and one sister ends up with copies of its own genes and the complement genes from the homologous sister. The other sister loses that section of genes (deletion). GENE DUPLICATION AND EVOLUTION New gene duplications are rarely seen in individuals, but the human genome carries evidence of past duplication events. The extra copies of genes produced by gene duplication may retain their original function allowing the organism to increase the synthesis of the gene product. The genes that code for rRNA and tRNA have duplicates allowing the cell to increase their production. (Large amounts of tRNA and rRNA are needed for protein synthesis.)The number of duplicates is proportional to the size of the genome. E. coli bacteria have 300 duplicates of the tRNA gene and 7 duplicates of the rRNA gene. Humans have 1,300 duplicates of the tRNA gene and 300 of the rRNA gene. INVERSIONS An inversion changes the order of genes on a chromosome. This occurs when two breaks occur on the chromosome and the region between the breaks rotates 180 degrees before rejoining with the two end fragments. TYPES OF INVERSIONS A paracentric inversion does not involve the centromere. A pericentric inversion involves the centromere. The karyotype below shows an inversion on chromosome 16. slh.wisc.edu http://home.comcast.net/~dmgt350/cytogenetics/invert3.htm IMPACT OF INVERSIONS 2% of the human population carries an inversion in one of their chromosomes without knowing it. This is because all of the genes are still present and in the correct amount. Inversions reduce fertility. Problems arise as homologous chromosomes attempt to cross over during prophase I of meiosis because the chromosomes are no longer homologous. The order of genes is not the same. Within the tetrad, an inversion loop forms so that complementary genes can be aligned. The resulting products of meiosis include chromosomes with duplications, deletions and inversions. http://www.google.com/search?q=inversion+loops Animation of Crossing Over with a Chromosome Inversion http://highered.mcgraw-hill.com/olc/dl/120083/bio33.swf TRANSLOCATION A translocation occurs when chromosomes pieces are transferred between nonhomologous chromosomes. Scientists do not fully understand why this happens. The chromosomes that are affected by translocations contain regions with genes that code for antibodies. These genes normally get cut and spliced in different orders to increase the variation in the types of antibodies individuals can produce. One hypothesis is the enzymes responsible for the splicing and rearrangement of antibody genes create translocations when the cut and splice chromosome pieces near the antibody genes by accident. RECIPROCAL TRANSLOCATIONS In a reciprocal translocation, there is an even swap made between two nonhomologous chromosomes (meaning each chromosome loses some of its own genes and gains those from the other). NONRECIPROCAL TRANSLOCATIONS In a nonreciprocal translocation, genes from one chromosome break off and attach to a non-homologous chromosome (one chromosome is losing a section of genes and the other chromosome is gaining that section of genes). Philadelphia chromosome is the result of a nonreciprocal translocation. As you can see in the karyotype below, a portion of chromosome 22 and a portion of chromosome 8 have been translocated to chromosome 9. (Chromosome 9 is now referred to as Philadelphia chromosome.) ROBERTSONIAN TRANSLOCATIONS A Robertsonian translocation occurs when the long arms of two acrocentric chromosomes (where the centromere very is off center) fuse at the centromere and the two short arms are partially or completely lost. Robertsonian translocations are confined to chromosomes 13, 14, 15, 21, and 22. The short arm of each of these acrocentric chromosomes does not carry any essential information. Robertsonian translocations change the chromosome number in the individual’s diploid cells from 46 to 45. The karyotype belong shows a Robertsonian translocation between chromosome 13 and 14. The long arms of 13 and 14 fused to form one chromosome (the large number 13). The short arms were lost resulting in only one copy of chromosome 14. Animation of Translocations (scroll down to translocations on the linked page) http://learn.genetics.utah.edu/content/chromosomes/diagnose/ IMPACT OF TRANSLOCATIONS Individuals that carry translocations may appear perfectly normal. They still have all of the genetic information in the correct amount. As with other chromosome mutations, they are often sterile or paritally sterile because the translocated chromosomes cannot pair and exchange genes properly during prophase I of meiosis. Resulting gamete cells carry duplications and deletions of genes and are often inviable.