L5 C'some structure and mitosis

L5 C'some structure and mitosis - Chromosome structure and...

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Unformatted text preview: Chromosome structure and mitosis 1 Last Time Pedigree analysis Predicting inheritance outcomes Sum Rule, Product Rule, Binomial Expansion Assessing the validity of genetic hypothesis Chi Square test 2 Chromosome structure and mitosis Chromosome structure Cell division Binary Fission (prokaryotes) Mitosis/Cell cycle (eukaryotes) structures phases 3 Chromosome structure DNA molecule associated proteins Genes are distinct regions of DNA that code for proteins or RNA products 4 Prokaryotic chromosome Circular chromosome nucleoid region http://www.bact.wisc.edu/themicrobialworld/bactDNA1.jpg 5 Eukaryotic chromosome nucleus chromosomes mitochondria (source of extranuclear DNA) 6 Karyotypes spin blood cells add hypotonic solution to pellet spin, fix, stain http://darwin.nmsu.edu/~molbio/diabetes/images/karyo-2.GIF (dyed chromosomes) 7 Homologous chromosomes p q homologous chromosomes of chromosome 1 homepages.uel.ac.uk/V.K.Sieber/solidktp.jpg 8 Homologous chromosome have the same genes in the same order Chromosome 1 1 from mom 1 from dad Genes 9 Different versions of genes are called alleles Homologous chromosomes Genotype? AA Bb cc 10 Scientific paper describing OCA2 gene - eye and hair color (pigmentation) ARTICLE A ThreeSingle-Nucleotide Polymorphism Haplotype in Intron 1 of OCA2 Explains Most Human Eye-Color Variation David L. Duffy,* Grant W. Montgomery,* Wei Chen, Zhen Zhen Zhao, Lien Le, Michael R. James, Nicholas K. Hayward, Nicholas G. Martin, and Richard A. Sturm We have previously shown that a quantitative-trait locus linked to the OCA2 region of 15q accounts for 74% of variation in human eye color. We conducted additional genotyping to clarify the role of the OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white populations. Fifty-eight synonymous and nonsynonymous exonic single-nucleotide polymorphisms (SNPs) and tagging SNPs were typed in a collection of 3,839 adolescent twins, their siblings, and their parents. The highest association for blue/nonblue eye color was found with three OCA2 SNPs: rs7495174 T/C, rs6497268 G/T, and rs11855019 T/C (P values of 1.02 # 10561 , 1.57 # 10596, and 4.45 # 10554, respectively) in intron 1. These three SNPs are in one major haplotype block, with TGT representing 78.4% of alleles. The TGT/TGT diplotype found in 62.2% of samples was the major genotype seen to modify eye color, with a frequency of 0.905 in blue or green compared with only 0.095 in brown eye color. This genotype was also at highest frequency in subjects with light brown hair and was more frequent in fair and medium skin types, consistent with the TGT haplotype acting as a recessive modifier of lighter pigmentary phenotypes. Homozygotes for rs11855019 C/C were predominantly without freckles and had lower mole counts. The minor population impact of the nonsynonymous codingregion polymorphisms Arg305Trp and Arg419Gln associated with nonblue eyes and the tight linkage of the major TGT haplotype within the intron 1 of OCA2 with blue eye color and lighter hair and skin tones suggest that differences within the 5 proximal regulatory control region of the OCA2 gene alter expression or messenger RNAtranscript levels and may be responsible for these associations. American Journal of Human Genetics (2007) 80: 241-252 The pigmentary traits of skin, hair, and eye color combined with high levels of environmental UV exposure are potential modulators of individual risk for developing both melanoma and nonmelanoma skin cancer (NMSC).1 The incidence rate of both NMSC and melanoma is greatest in fair-skinned, sun-sensitive individuals, which indicates the importance of the innate ability to respond to UV light through an increased synthesis of melanin, known as the "tanning response." The quantity and quality of melanin pigmentation is central to the photoprotection of both melanocytes and keratinocytes. The human melanocortin-1 receptor (MC1R [MIM 155555]) protein, expressed on the surface of melanocytes, is a key determinant of photosensitivity,2,3 with variant alleles of this seven-transmembrane G-proteincoupled receptor, present at high frequency in white populations, linked to the high incidences of NMSC and melanoma.4 Other genes involved in melanin biogenesis modify the penetrance of MC1R variant alleles. The gene responsible for oculocutaneous albinism type II (OCA2), which encodes the P protein, is an integral melanosomal membrane protein with an 838-aa ORF that contains 12 transmembranespanning regions.5 OCA2 maps6 to chromosome 15q11.2q12 and is the human homologue of the mouse pink-eyed dilution gene (p) (Entrez Nucleotide accession number NM_000275).7,8 Epistatic interactions between MC1R and the OCA2 gene were first reported to contribute to skin pigmentation phenotypes in a Tibetan population.9 OCA2 transcription is induced following UV-B irradiation of skin,10 and, together with MC1R, plays important roles in control of pigmentation.11 Polymorphisms in OCA2 occur in different populations,12 and this locus underlies the genetic linkage of blue/brown eye (BEY2/EYCL3 [MIM 227220]) and brown hair (HCL3 [MIM 601800]) to chromosome 15, as reported elsewhere.13 Two OCA2 coding-region variant alleles--Arg305Trp and Arg419Gln--were recently shown to be associated with brown and green/hazel eye colors, respectively,14,15 and blue eye color has also been linked to this locus through use of microsatellite16,17 and SNP18 markers. Indeed, our genomewide linkage scan for eye color suggested that 74% of variation in eye color in Europeans could be attributed to a QTL linked to the OCA2 region of chromosome 15q.16 To understand how alleles of the OCA2 gene influence eye color and pigmentation associated with skin-cancer risk, we sequenced all OCA2 exons encoding the P protein. To test for statistical association with pigmentary traits, we typed the exonic polymorphisms detected in our preliminary study combined with those reported in the literature and haplotype-tagging SNPs identified from the From the Queensland Institute of Medical Research (D.L.D.; G.W.M.; Z.Z.Z.; L.L.; M.R.J.; N.K.H.; N.G.M.) and Institute for Molecular Bioscience, University of Queensland (W.C.; R.A.S.), Brisbane, Australia Received September 5, 2006; accepted for publication November 15, 2006; electronically published December 20, 2006. Address for correspondence and reprints: Dr. Richard A. Sturm, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia. E-mail: R.Sturm@imb.uq.edu.au * These authors contributed equally to this work. Am. J. Hum. Genet. 2007;80:241252. 2006 by The American Society of Human Genetics. All rights reserved. 0002-9297/2007/8002-0005$15.00 www.ajhg.org The American Journal of Human Genetics Volume 80 February 2007 241 11 Summary Chromosomes are DNA molecules associated with proteins Chromosomes can be circular (prokaryotes) or linear and contained in nucleus (eukaryotes) Diploid eukaryotic chromosomes occur in homologous pairs Homologous pairs contain same genes, but may differ in alleles 12 Cell division Reproduction HTT P ://M AKO .CC /CO PYR I GHT E Binary Fission (prokaryotes, some eukaryotes) OUS /IM AGE S /PO RN_ B INA RY_ F ISS ION . PNG Growth of multicellular eukaryotic organisms HTTP://WWW.MESOBLAST.COM/IMAGES/IMAGES-MESOBLAST_CELL_DIVISION_STILL.JPG 13 Reproduction: Binary Fission DNA is replicated FtsZ protein assembles at septum new cell wall forms new cells separate 14 The cell cycle 15 Mitotic structures: the mitotic spindle centrosome 16 Types of MTs in mitotic spindle Aster MTs Polar MTs Kinetochore MTs 17 Kinetochores kinetochore microtubules 18 Mitosis: phases 19 Prophase Nuclear membrane dissolves DNA condenses Spindle begins to form 20 Prometaphase Centrosomes move to opposite poles MTs attach to sister chromatids 21 Metaphase Chromosomes align at metaphase plate NOTE arrangement of chromosomes! 22 Anaphase Chromatids move towards poles Polar MTs elongate and push poles of cell apart 23 Telophase Chromosomes located at poles, de-condense Nucleus reforms 24 Cytokinesis Segregation of organelles into newly forming cells Cleavage furrow forms (animals) New cell plate (plants) 25 Summary Cell cycle is made up of two phases: Interphase and mitosis Important mitotic structures include the Mitotic spindle and kinetochores Mitosis progresses through several phases, which result in the allocation of DNA into two daughter cells 26 Ungraded problems Chapter 3: C1 - C5, C15, C16, C21 Chapter 3: E1 27 Next Time Meiosis and sexual reproduction HTTP://WWW.CS.STIR.AC.UK/~PGO/GA/IMAGES/CHROMOSOME_REAL.JPG 28 ...
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