Download BB30055: Genes and genomes

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