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Chromosomes Chromosome Structure • DNA is long and thin and fragile: needs to be packaged to avoid breaking. • Lowest level is the nucleosome, 150 bp of DNA wrapped 1 3/4 times around a core of 8 histone proteins (small and very conserved in evolution). A string of beads. – Modifications of the histones, such as adding acetyl or phosphate groups, affects how tightly condensed the chromatin is, which affects whether it can be transcribed or not. • • • • The nucleosomes coil up into a 30 nm chromatin fiber. This level of packaging exists even during interphase. During cell division, chromatin fibers are attached in loops of variable size to a protein scaffold. The DNA probably attaches at specific AT-rich areas called scaffold attachment regions. The loops may be functional units: active vs. inactive in transcription. Further coiling gives the compact structures we see in metaphase. Centromeres • The centromere is the attachment point for the spindle. – Acentric chromosomes, which don’t have a centromere, don’t attach to the spindle and don’t end up in either nucleus after mitosis. • Sometimes called the “primary constriction” on a chromosome, based on microscopic appearance. • The centromere is a region of DNA on the chromosome. During cell division, a large protein structure, the kinetochore, that attaches to the centromere DNA sequences. The spindle proteins then get attached to the kinetochore. The centromere is many repeats of a about 170 bp element (very difficult to clone in humans but well known in yeast). Called alpha-satellite DNA. The centromere can extend over several million bases of DNA, and contain large amounts of repeated sequence DNA and transposable elements that are also found in other non-centromere locations. • • Telomeres • • Telomeres are the DNA sequences at the ends of chromosomes. Chromosomes that lose their telomeres often fuse with other chromosomes or become degraded. There are telomere-binding proteins that protect the chromosome ends. Telomeres are also needed to ensure complete replication of the DNA: the end-replication problem – – – – DNA polymerase must have a double stranded primer region with a free 3’ – OH to build on. The primer is made of RNA, synthesized by primase. At the 3’ end of the chromosome, the RNA primer gets degraded, leaving a single stranded region of DNA that is about 150 bp long. In the next round of replication, one DNA molecule will be shorter than the other. Process repeats, gradually shortening the chromosomes. Thought to be a cause of cell mortality. More Telomeres • Chromosome shortening is prevented by telomerase, an RNA/protein hybrid enzyme. • Telomerase has a short RNA that is used as a template for a reverse transcriptase: binds to 3’ end of chromosome, then synthesizes DNA extension. This extension acts as a template for regular DNA polymerase, keeping chromosome length intact. • Telomere sequences are multiple repeats of a highly conserved 7 base sequence. Origins of Replication • During the S phase, the DNA in the cell replicates. When S starts, each chromosome has one chromatid, a single DNA molecule and its supporting proteins. After the S phase, each chromosome has 2 identical sister chromatids, held together at the centromere. • DNA replication starts at many different origins of replication along the length of the chromosome. The origins of replication are DNA sequences that bind to DNA polymerase. Euchromatin and Heterochromatin • Chromosomes are about 50% DNA and 50% protein. Together, this complex of DNA and protein is called chromatin. • Euchromatin is the location of active genes (although many genes in euchromatin are not active: depends on cell type). During interphase euchromatin is extended and spread out throughout the cell. • Heterochromatin is darkly staining, condensed, and late replicating. Genes in heterochromatin are usually inactive. – Some heterochromatin is constitutive : always heterochromatin: especially around centromeres. Composed mostly of repeat sequence DNA. – Other heterochromatin is facultative: can be heterochromatin or euchromatin: e.g. inactive X chromosome in females., the Barr body. Chromosomes in the Microscope • Cytogenetics is the study of chromosomes, primarily by microscopy. • Studied in metaphase cells, usually white blood cells or skin cells. • Technique: – Grow cells in tissue culture for a few generations. – arrest cell division at metaphase with colchicine or colcemid (blocks spindle microtubules). – hypotonic treatment swells them and spreads out the chromosomes. – Squash them into a single layer – Stain them to see bands • Before this technique, people thought humans had 48 chromosomes, not 46. • Picture is a karyotype: chromosome pictures cut out and sorted by hand, or by computer. In pre-molecular days, chromosomes were stained with Giemsa stain (G bands)or quinacrine stain (Q bands). Light and dark bands are caused by a combination of differences in DNA composition and chromatin condensation state. Karyotype Analysis • Length varies: longest is chromosome 1, shortest is 21 (should be 22, but mistakes were made early on). • The centromere appears as a constriction: called the primary constriction. – Other, secondary constrictions occur on some chromosomes: areas where the chromosome partially de-condenses. The region beyond the secondary constriction is called a satellite. • Centromere position: centromere index: length of short arm divided by total length. Used to define metacentric, submetacentric, acrocentric. (No human telocentrics) – Most human chromosomes are sub-metacentric. – Only 2 metacentrics and 5 acrocentrics • The short arms of the 5 acrocentric chromosomes contain the ribosomal RNA genes. – The nucleolus, which assembles ribosomes, sits on the ribosomal RNA genes. Thus the short arms of these chromosomes are called the nucleolus organizer region. Nomenclature • • • • Short arm is p (petite) and long arm is q. cen is centromere, ter is terminus (telomere): pter and qter. tel is often used instead. “proximal” means closer to the centromere, and “distal” means father away from the centromere Regions divided at major bands: p1, p2, p3, etc. Then each region is divided into lesser bands; p11, p12, etc (pone-one, not p-eleven). Even smaller bands too: p12.1, etc. FISH • Fluorescence in situ hybridization. • Hybridize a DNA probe labeled with a fluorescent marker to chromosomes, then visualize in fluorescence microscope. • See location of the gene: often can see sister chromatids even. Chromosomes are dyads in mitosis before anaphase. • Picture is translocational Down syndrome. Two copies of 14-21 translocation, plus one copy of normal 14 (green) and one copy of normal 21 (red). • Chromosome painting: use many probes from a single chromosome (there is lots of unique DNA on each chromosome). Good for seeing rearrangements. • An application of FISH: using fluorescently tagged DNA sequences that are specific to a single chromosome. – These are found by isolating individual chromosomes and then amplifying their DNA. – Sequences that aren't unique to that chromosome are removed by hybridizing them to a mixture of the other chromosomes. • • Used to see things like translocations, or to detect human chromosomes in human/mouse hybrid cells. Cancer cells often have very badly rearranged genomes: chromosome painting can help determine which chromosomes are present and how they are connected together. Also used to demonstrate that each chromosome occupies a distinct region of the interphase nucleus (and not all jumbled together). Chromosome Painting Chromosome Number Abnormalities • • • • polyploid: having more than 2 sets of chromosomes. aneuploid: having an extra copy or a missing copy of a single chromosome. (equal numbers of all chromosomes is euploid). mixoploid: having cell lines with different chromosomal constitutions. – mosaics: derived from a single zygote. After a few cell divisions, one cell (and all of its descendants) loses a chromosome – chimeras: derived from the fusion of 2 different embryos. A favorite of crime shows on TV: a person might have blood cells of 2 different types. There are also chromosome structure variations, which we will discuss later. Fate of 1 million conceptions Data from K. Sankaranarayanan, 1979 Mutation research Polyploids • Triploids (69 chromosomes) are usually caused by dispermy: fertilization of the egg by 2 sperm simultaneously. – Usually prevented by 2 things: change in membrane potential when first sperm penetrates, and cortical reaction: release of extracellular matrix material (glycosaminoglycans) that push other sperm away. – Frequency: 2-3% of pregnancies, but most are spontaneously aborted. • Occasionally survive to birth, but die shortly after. – why is triploidy lethal, since all chromosomes are present in equal numbers (euploid)? May be due to X inactivation: only a single X is active in the cell, so there is an imbalance between gene products from the X and gene products from the autosomes. • Tetraploidy (4 sets of chromosomes). Very rare and always lethal. Usually due to failure of first mitotic division: chromosomes replicate and divide, but all end up in the same nucleus. – But diploid/tetraploid mosaics are known The Moment of Fertilization Aneuploidy • • Aneuploid: having an extra or missing chromosome (47 or 45 chromosomes) Two causes: – non-disjunction: paired chromosomes both go to the same pole in meiosis instead of to opposite poles. – anaphase lag: a chromosome moves to the pole so slowly that it doesn’t get incorporated into the nucleus as it forms in telophase. • Effects: fairly well tolerated for the sex chromosomes, but bad for autosomes. All autosomal monosomies and trisomies have been seen, but most are spontaneously aborted. Maternal Age Effect on Aneuploidy Sex Chromosome Aneuploidy • The sex chromosomes are the most tolerant of aneuploidy, due to X chromosome inactivation. Only a few genes are active on extra X chromosomes. • The main possibilities: – – – – – 45,X (XO: Turner syndrome). XXX, XXXX, etc XXY (Klinefelter syndrome). XYY. YY without an X: Embryonic lethal: many essential genes are on the X. Klinefelter Syndrome • Klinefelter syndrome: 47, XXY – A normal human has 46 chromosomes, which can be designated 46, XX or 46, XY • The Y chromosome makes these people male, but the testes are small and produce insufficient testosterone after puberty – This leads to infertility, delayed puberty, a female pattern of body hair and breast development. – Also, tall stature • In some people with Klinefelter’s, the ability to learn language and read is impaired. • Treatment with testosterone alleviates most symptoms. • Klinefelter variants: even more sex chromosomes, like 48, XXYY; 48, XXXY; 49, XXXYY Turner Syndrome • Turner syndrome: 45, X. Often written as “XO”. They have only one sex chromosome, an X. • No Y means they are female, but they lack ovaries and are thus sterile. Also, they don’t produce the surge in estrogen that causes body changes at puberty, although this can be treated with hormones. – Turner’s is often detected when a girl reaches her late teens without entering puberty. • Also: short stature and folds of skin at the neck. • No intellectual impairment in most, but difficulties in spatial perception have also been noted in some cases. Other Sex Chromosome Abnormalities • 47, XYY. Male (due to Y chromosome), tall stature, sometimes slightly sub-normal in intelligence or developmentally delayed. – Once thought to confer “criminality”, but this has been disproven. – Sterility is common due to abnormal chorionic gonadotrophin levels, but testosterone level is normal – Most XYY people are never diagnosed • 47, XXX. Female, with usually normal intelligence and only occasional fertility problems. However, early menopause (age 30 vs. normal age 50) is common. Usually not detected except by accident. Tall stature. • Note the effect of sex chromosome dosage on stature: 3 sex chromosomes = tall, 1 sex chromosome = short. – Seems to be due to the SHOX (short stature homeobox) gene, found on both the X and Y, and not subject to X chromosome inactivation. Autosomal Aneuploidies • • Approximately 2% of sperm cells are aneuploid, with all possible extra and missing chromosomes occurring in equal numbers. However, only 3 trisomies (and no monosomies) occur frequently enough to have a named syndrome: – – – • Trisomy 21: Down syndrome Trisomy 18: Edwards syndrome Trisomy 13: Patau syndrome No monosomies routinely survive to birth. Down Syndrome • • • 47, trisomy-21, Down syndrome, is the most common autosomal aneuploidy. Chromosome 21 is the smallest chromosome. Down syndrome was first described by Dr. John Langdon Down in the 1860’s, long before its cause was found (in 1959). People with Down syndrome have significant intellectual disabilities, along with characteristic facial and body features. – Babies with Down’s are usually identifiable at birth – Heart defects used to kill many at an early age. – Fertility is lower than normal. • People with Down’s often develop Alzheimer Disease at an early age. This fact led to the discovery of a major gene associated with Alzheimer’s: APP, amyloid precursor protein. – The amyloid plaques characteristic of Alzheimer’s are made of a piece of this protein. • Other causes: translocational Down syndrome and mosaic Down syndrome Edwards syndrome • Edwards syndrome, trisomy 18. • A variety of defects: small head, malformations of the kidney and the heart, clenched hands with overlapping fingers. • Severe intellectual disability • Most die before birth. About 8% survive to age 1. A small percentage survive to adulthood. • As with Down and Patau syndromes, translocational and mosaic forms of Edwards syndrome exist. Patau Syndrome • Patau syndrome, trisomy 13. • Most fetuses with this condition die before birth or are spontaneously aborted. Only 5% of those born alive survive for 1 year. • The most characteristic defect is “holoprosencephaly”, which means the brain doesn’t divide into 2 halves. This leads to defects around the midline of the head: – Severe cleft palate and lip – Eyes close together, or even in one orbit, sometimes with only a single eyeball (cyclops). – Severe intellectual disability – Abnormalities of other organ systems: heart, digestive, urogenital, hands and feet Mosaics • A mosaic is an organism which is derived from a single fertilization but which contains cells with two or more different chromosome compositions. • Caused by problems in mitosis in the embryo: non-disjunction, anaphase lag, abnormal replication of a chromosome. – Can occur at any stage in development, but will probably be recognized only if there are a large number of cells of each type. • Most commonly, mosaics involve some trisomic cells, such as mosaic Down syndrome or mosaic Klinefelter syndrome (46/47, XY/XXY) – About 2% of people with Down syndrome are mosaic – Leads to a wide range of phenotypes, depending on which cells are affected. Chimeras • A chimera is an organism which is composed of two genetically different organisms, which have fused together. – Fertilized eggs implant next to each other in the mother’s uterus, and the growing embryos fuse. – Less dramatically, non-identical twins often share blood vessels before birth, and some of their hematopoetic (blood cell forming) cells migrate into the other twin. – Very rarely, an person can be born with both male and female sex organs (ovaries and testes). • A recent case of chimerism: Lydia Fairchild was asked to provide DNA evidence that her children were actually fathered by her ex-husband. The tests showed that he was indeed the father, but that she wasn’t the mother. Further tests showed that the children matched her mother to the extent expected of a grandparent. Finally, DNA tests from Lydia’s cervical smear matched the children, even though DNA from her skin and hair didn’t. The conclusion was that she was a chimera: her reproductive system was formed from a fraternal twin. – http://guardianlv.com/2014/01/pregnancy-no-proof-of-motherhoodwoman-was-her-own-twin-and-the-twin-was-the-mother-of-herchildren/ A geep: a sheep/goat chimera, derived from fused embryos of the 2 species. Chromosome Structure Changes • Caused by chromosome breaks. Two or more breaks often means the wrong ends are attached by the enzymes that repair double stranded DNA breaks. • Two main effects: 1. Sometimes rejoining the wrong ends can result in a broken, non-functional gene at the breakpoint. 2. No effect on the parent, but meiosis produces aneuploid gametes • A version of possibility 1 above: two genes might be fused to give an abnormal phenotype. – – – The Philadelphia chromosome is a translocation between specific parts of chromosomes 9 and 22, t(9;22)(q34;q11) The result is a fusion of the ABL oncogene on chromosome 9 with the BCR gene on chromosome 22. This produces chronic myleogenous leukemia,a form of cancer. Balanced vs. Unbalanced Translocations • • • Most translocations are reciprocal translocations: pieces of 2 different chromosomes break off and switch partners. A balanced translocation has all of the normal diploid number of genes: no gain or loss of genetic material. – Such people are normal in phenotype if none of the above problems pertains. – Abnormal segregation in meiosis will produce aneuploid gametes, leading to sterility or abnormal offspring. Unbalanced translocations have extra or missing genes. – A common result of a balanced translocation going through meiosis – Many genes need to be present in exactly 2 copies, and having 1 or 3 copies leads to abnormality. – The deletion of several of these genes can lead to a syndrome: a group of symptoms or diseases that consistently occur together. Robertsonian Translocations and Isochromosomes • Robertsonian translocation. Also called a centric fusion or a whole arm translocation. – Chromosome breaks near the centromeres in the short arms of 2 acrocentric chromosomes gives one translocation chromosome with both long arms and one with both short arms. Centromeres fuse together. – The short arms of acrocentrics (chromosomes 13, 14,15,21, and 22) often have no vital genes and so can be lost. Mostly they contain multiple copies of the ribosomal RNA genes, so losing a few copies has very little effect. – balanced, but offspring are often aneuploid – cause of translocational Down syndrome, a t(14;21) –long arms of chromosomes 14 and 21. • isochromosomes. Both arms of a chromosome are identical. Caused by unusual crossover event between sister chromatids. Chromosome Structural Variations • --Types: Consider a normal chromosome with genes in alphabetical order: abcdefghi • --deletion: part of the chromosome has been removed: abcghi • --duplication: part of the chromosome is duplicated: abcdefdefghi. • --inversion: part of the chromosome has been re-inserted in reverse order: abcfedghi • --ring: the ends of the chromosome are joined together to make a ring • --translocation: parts of two nonhomologous chromosomes are joined: if one normal chromosome is abcdefghi and the other chromosome is uvwxyz, then a translocation between them would be abcdefxyz and uvwghi. Deletion Duplication Inversion Translocation Deletion Syndromes • Many human genes are sensitive to dosage: they need to be present in 2 copies, and having only 1 copy leads to a syndrome of diseases. – Haploinsufficiency: when having only 1 copy pf a gene leads to a disease phenotype – Most deletion syndromes are the result of haploinsufficiency at several different genes. – However, many genes in the deleted region function quite normally with only 1 copy. • Having a deletion on one chromosome makes all the genes in the deleted region present in only 1 copy. • Deletion breakpoints are usually not the same in different individuals. This leads to slightly different sets of genes being deleted, and consequently slightly different phenotypes. • Most deletion syndromes are new mutations, but some come from parents who had a balanced translocation. • There is also the (rarer) phenomenon of triplosensitivity: having 3 copies of a gene produces a disease condition. Cri du chat Syndrome • Cri-du-chat syndrome (cry of the cat) is a deletion of part of the short arm of chromosome 5 (designated 5p-). – – – – • • • Hear the sound at: https://www.youtube.com/watch?v=TYQrzFABQHQ Babies with this syndrome cry in a characteristic way, which sounds like the meowing of a cat. Small head, intellectual impairment, behavioral problems Distinctive facial features: wide apart eyes, low set ears, small round face Chromosome breakpoints vary, from p13 to p15.2. Also, some are not terminal deletions At least 2 different regions are involved in the syndrome: 5p15.3 for the cry, and 5p15.2 for the facial features and intellectual disability. So far, 2 genes are known to be involved: – – CTNND2 (located at 5p15.2), whose protein product is associated with neuron development TERT (located at 5p15.3), a gene involved with telomerase activity WAGR Syndrome • WAGR syndrome: (WILMS TUMOR--ANIRIDIA-GENITOURINARY ANOMALIES--MENTAL RETARDATION) is caused by a deletion of 11p13. – A subtype is WAGRO syndrome, with the O standing for Obseity. • • • • Wilms tumor affects the kidneys, usually in young children Aniridia: absence of an iris (pigmented region) of the eye Genitourinary anomalies includes malformed sex organs (both male and female) as well as a high risk for gonadoblasatoma, a cancer that affects the testes and ovaries. Genes showing haploinsufficiency: – – PAX6: affects development of the eye WT1: a transcription factor involved in urogenital development Translocational Down Syndrome • Most cases of Down syndrome, trisomy-21, are spontaneous: caused by non-disjunction. However, about 5% of Down’s cases are caused by a translocation between chromosome 21 and another chromosome, often chromosome 14. – – • Both chromosome 14 and chromosome 21 are acrocentric, and the short arms contain no essential genes. (just copies of ribosomal RNA genes) – • • A translocation between 21 and 14 is a Robertsonian translocation Sometimes translocational Down’s is caused by an isochromosome: 2 long arms of chromosome 21 joined together. The reciprocal part of the translocation, the 2 short arms joined, is usually lost. Usually, the carrier parent has a balanced translocation: a normal chromosome 14, a normal chromosome 21, and a translocation chromosome, called t(14;21). No symptoms. During meiosis, one possible gamete that occurs has both the normal 21 and the t(14;21) in it. When fertilized, the resulting zygote has 2 copies of the important parts of chromosome 14, but 3 copies of chromosome 21: 2 normal copies plus the long arm on the translocation. This zygote develops into a person with Down syndrome. – Since this can happen in every meiosis, there is a good chance of having more than one child with Down syndrome in the family: the condition is heritable. Translocational Down’s Punnett Square 1p36 Deletion Syndrome • This syndrome is caused by the deletion of the terminal band of the short arm of chromosome 1. • These deletions are usually too small to be seen in a standard karyotype. For this reason, the 1p36 deletion syndrome wasn’t described until the 1980’s. – Nevertheless, the deletions involve 1.5 to 10 million base pairs of DNA • Characteristic facial features, including a small head, deep set eyes, flat nose, small mouth, pointed chin. • Intellectual disability, prone to seizures, behavioral problems, and developmental delays. Chromosomes from the Wrong Parent • • It is possible to be euploid but still abnormal, because it is necessary to have one set of chromosomes from the father and one set from the mother. The DNA of some genes is modified by adding methyl groups to some C bases. This is called imprinting. – For some genes imprinting is different for male and female gametes, and the gene from the father doesn’t work the same as the gene from the mother, at least in the embryo. • Uniparental diploids: both sets of chromosomes from the same parent. All are very non-viable: – paternal uniparental diploid. Egg loses its nucleus, gets fertilized by an X-bearing sperm, with first mitosis resulting in one diploid nucleus. Result is a hydatidiform mole, has external membranes and structures of an embryo, but no actual embryo. Can become cancerous. – maternal uniparental diploids. Unfertilized egg gets activated. Results in an ovarian teratoma, a disorganized mass of tissues often including hair, bones and teeth, but no external embryonic membranes. Uniparental Disomy • Uniparental disomy: a single chromosome with both copies from one parent. – Results from a trisomic cell losing a chromosome (by non-disjunction in mitosis or anaphase lag) and thus becoming viable. • Best known case is PRADER-WILLI SYNDROME/ANGELMAN SYNDROME, where inheriting 2 copies of the mother’s chromosome 15q gives Prader-Willi and 2 copies of the father’s 15q gives Angelman. – Prader-Willi: "low muscle tone, short stature, incomplete sexual development, cognitive disabilities, problem behaviors, and a chronic feeling of hunger that can lead to excessive eating and life-threatening obesity." – Angelman Syndrome ("Happy Puppet"): "The gait is jerky and puppet-like and behavior is marked by frequent spells of inappropriate laughter. Severe intellectual disability and speech impairment are usually present." Paintings by Juan Carreno de Miranda (above) and Giovanni Francesco Caroto (below) Balanced Translocations and Fertility • • • • Balanced translocations are euploid: 2 copies of every gene. During meiosis (prophase of Meiosis 1), the translocated chromosomes pair up with the normal set of chromosomes, forming a quadrivalent, a structure with 4 chromosomes interacting. When anaphase of M1 occurs, the centromeres in the quadrivalent are pulled to opposite poles. There are 2 main possibilities for segregation: – – • • Alternate segregation: leads to euploid gametes: half the gametes get both normal chromosomes and the other half of the gametes get both translocation chromosomes Adjacent segregation: leads to aneuploid gametes: each gamete gets one normal chromosome and one translocated chromosome. Adjacent and alternate segregation occur at about equal frequencies, so about 1/2 of the gametes are aneuploid. This leads to reduced fertility and recurrent miscarriages. Translocation Segregation Inversions • Large inversions lead to aneuploid gametes, if there is a crossover between the inverted region and the normal homologue. – People with newly originated large inversions are likely to be sterile • There are only a few polymorphic inversions (that is, present in at least 1% of the population) known, and the longest of these is about 4.5 Mbp, about 1/20 of the length of the chromosome. • Bioinformatic methods are detecting many smaller inversions, and they may prove to be more important than currently believed. – The methods are still imperfect, and only a small number have been experimentally validated.