dna rearrangement hotspots in the genome transforming mice ... · sequence similarity • homology:...

DNA rearrangement hotspots in the genome

— transforming mice into man

Bioinformatics course (MTAT.03.239) 17.11.16 Priit Adler

Evolution of species or sequences

• All living organisms are related to each other through evolution.

• Any pair of organism have common ancestor some time in the past, from which they evolved.

• Mutations and selection over long periods of time can result in considerable difference between present-day sequences derived from the same ancestral sequences.

• The base pair composition of the sequences can change due to point mutations (substitutions) and the sequence lengths can vary due to indels (insertions/deletions).

From last time

Sequence similarity• Homology: derived from a common ancestor-gene.

• Orthology: homologous genes in different organisms.

• Paralogy: homologous genes in one organism that derive from gene duplication.

• Gene duplication: a gene is duplicated in multiple copies that can each evolve in separate directions and assume new functions.

From last time

Adding genome rearrangements

• Involves genomic DNA deletion, duplication, inversion and translocations

https://public.ornl.gov/site/gallery/originals/Mouse_and_Human_Genetic_Similarities_-_original.jpg

• ~245 rearrangements

• ~300 large syntethy • blocks

https://twitter.com/torstenseemann/status/524675360697229312

http://www.nature.com/nature/journal/v428/n6982/full/nature02426.html

Human vs Mouse vs Rat X chr

Human vs Mouse vs Rat X chr

http://bioinformaticsalgorithms.com/

Rearrangements and cancer

DNA (chromosomes/genes do happen to break)

Sometimes the repair is not perfect

It can lead to various types of cancer

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065307/

http://bioinformaticsalgorithms.com/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652200/http://bioinformaticsalgorithms.com/

Rearrangements in Breast Cancer model Cell

Line MCF7

How to get from genome Q to genome P

Random Breakage Model

Sort by Reversals

Greedy approach

+1 -7 +6 -10 +9 -8 +2 -11 -3 +5 +4

Breakpoint theorem

+3 +4 +5 -12 -8 -7 -6 +1 +2 +10 +9 -11 +13 +14

2 Break distanceFrom linear chromosome to circular

http://bioinformaticsalgorithms.com/

2-break distance d(P,Q): Minimum number of 2-breaks

transforming genome P into genome Q

Breakpoint Graph

http://bioinformaticsalgorithms.com/

2-break distance between genomes P and Q:

d(P,Q) = blocks(P,Q) - cycle(P,Q)

Fragile Regions in the Human Genome

If Random Breakage Model (RBM) is correct, 2 break distance between Human and Mouse should

be 280/2 = 140

From 2-Break distance theorem we can calculate that 2 break distance between Human and Mouse:

280 synteny blocks 35 cycles in breakpoint graph

280 - 35 = 245

245 != 140

New “better” models

RBM - Random Breakage Model

FBM - Fragile Breakage Model

TFBM - Turnover Fragile Breakage Model

Chapter 6 videos

https://www.youtube.com/playlist?list=PLQ-85lQlPqFOcGz6A3g2ZArRL09Ffpp_N

Bioinformatics Algorithms

An Active Learning Approach

1st Edition:

www.ester.ee/record=b4422219

2nd Edition:

www.ester.ee/record=b4517979

https://youtu.be/yfXeKPt0nw4

http://bioinformaticsalgorithms.com/index.htm

Chapter 5 homeworkhttp://rosalind.info/classes/337/

Due 30.11.16 midnight

tasks 63-73: choose min 4, max 6 tasks