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BB30055: Genes and genomes Genomes - Dr. MV Hejmadi ([email protected]) Lecture 2 – Repeat elements Lecture 2 – Repeat elements • What are repeat elements? • How did they originate? • Why are they important? Repetitive elements Main classes based on origin Tandem repeats Interspersed repeats Segmental duplications 1) Tandem repeats Blocks of tandem repeats at subtelomeres pericentromeres Short arms of acrocentric chromosomes Ribosomal gene clusters Tandem / clustered repeats Broadly divided into 4 types based on size class Size of repeat Repeat block Major chromosomal location Satellite 5-171 bp > 100kb centromeric heterochromatin minisatellite 9-64 bp 0.1–20kb Telomeres microsatellites 1-13 bp < 150 bp Dispersed HMG3 by Strachan and Read pp 265-268 Satellites Large arrays of repeats Some examples Satellite 1,2 & 3 a (Alphoid DNA) - found in all chromosomes b satellite HMG3 by Strachan and Read pp 265-268 Minisatellites Moderate sized arrays of repeats Some examples Hypervariable minisatellite DNA - core of GGGCAGGAXG - found in telomeric regions - used in original DNA fingerprinting technique by Alec Jeffreys HMG3 by Strachan and Read pp 265-268 Microsatellites VNTRs - Variable Number of Tandem Repeats, SSR - Simple Sequence Repeats /STR – short tandem repeats 1-13 bp repeats e.g. (A)n ; (AC)n 2% of genome (dinucleotides - 0.5%) Used as genetic markers (especially for disease mapping) Individual genotype HMG3 by Strachan and Read pp 265-268 Microsatellite genotyping design PCR primers unique to one locus in the genome .a single pair of PCR primers will produce different sized products for each of the different length microsatellites 2) Interspersed repeats A.k.a. Transposon-derived repeats ~ 45% of genome Arise mainly as a result of transposition either through DNA or RNA retrotransposons (retroposons) ‘copy and paste’ DNA transposons (‘cut & paste’) Interspersed repeats (transposon-derived) major types class size Copy % number genome* LINE L1 (Kpn family) L2 ~6.4kb 0.5x106 0.3 x 106 16.9 3.2 SINE Alu ~0.3kb 1.1x106 10.6 LTR e.g.HERV ~1.3kb 0.3x106 8.3 mariner ~0.25kb 1-2x104 2.8 DNA transposon family * Updated from HGP publications HMG3 by Strachan & Read pp268-272 Classes of transposable elements Science 12 March 2004: Vol. 303. no. 5664, pp. 1626 - 1632 3) Segmental duplications Closely related sequence blocks (1-200kb) at different genomic loci Segmental duplications can occur on homologous chromosomes (intrachromosomal) or non homologous chromosomes (interchromosomal) Not always tandemly arranged Relatively recent Segmental duplications Interchromosomal segments duplicated among non homologous chromosomes Prone to deletions/ duplications Nature Reviews Genetics 2, 791-800 (2001); Intrachromosomal duplications occur within a chromosome / arm Prone to translocations Chromosome rearrangements originate from double strand break repair or homologous recombination between repeat sequences Segmental duplications in chromosome 22 Segmental duplications Repeat elements How did they originate? Tandem repeats – replication slippage etc Interspersed repeats – transposition events Segmental duplications – strand exchange, recombination events How are tandem repeats generated in the genome? strand slippage during replication Fig 11.5 HMG3 by Strachan and Read pp 330 strand slippage during replication Fig 11.5 HMG3 by Strachan and Read pp 330 Alu repeats (type of SINE) evolved from processed copies of the 7SL RNA gene Repeat elements Why are they important? Evolutionary ‘signposts’ Passive markers for mutation assays Actively reorganise gene organisation by creating, shuffling or modifying existing genes Chromosome structure and dynamics Provide tools for medical, forensic, genetic analysis Pathogenic potential of Short Tandem Repeats (STR) Reduction or expansion of STR can be pathogenic 1) Unstable expansion of short tandem repeats Characterised by anticipation Large expansions outside coding sequences Modest expansions within coding sequences FRAXA, FRAX E Huntington disease (HD) Myotonic dystrophy (DM1) SCA 1,2,3,6,7, 17 Friedrich ataxia (FA) Kennedy disease Spinocerebellar ataxia 8,11 Unstable deletions of STRs? STRs tend to be deletion hotspots Interspersed repeats are susceptible to deletions/duplications E.g. Kearns-Sayre syndrome- encephalomyopathy External opthalmoplegia Ptosis Ataxia Common 4977bp deletion in mt DNA Cataract Pathogenic potential of segmental duplications Nature Reviews Genetics 2, 791-800 (2001) References 1) Chapters 9 and 11 HMG 3 by Strachan and Read 2) Chapter 10: pp 339-348 Genetics from genes to genomes by Hartwell et al (2/e) 3) Nature (2001) 409: pp 879-891