Open access toolkit for nonparametric explorative pattern

mining to detect events relating to disease in large scale genome sequences

Thahir P. Mohamed, Asia D. Mitchell and Madhavi GanapathirajuDepartment of Biomedical Informatics

University of Pittsburgh School of MedicinePittsburgh PA USA

Advancing Practice , Innovation, and Instruction through InformaticsOctober 20, 2008

The Genome Sequence

3 billion nucleotides

20 to 25 thousand genes

Two-thirds of the genome made of repetitive elements (2 billion nucleotides)

ATGGCACTGAGCTCCCAGATCTGGGCCGCTTGCCTCCTGCTCCTCCTCCTCCTCGCCAGCCTGACCAGTGGCTCTGTTTTCCCACAACAGGTGAGAGCCCAGTGGCCTGGGTCCTTAGCAGGGCAGCAGGGATGGGAGAGCCAGGCCTCAGCCTAGGGCACTGGAGACACCCGAGCACTGAGCAGAGCTCAGGACGTCTCAGGAGTACTGGCAGCTGAACAGGAACCAGGACAGGCACGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGGTTGAGGCAGGCAGCCCACTTGAGGTCAGTTTGAGACCAGCCTGGCCAACATGGTAAAACCCCGTCTCTACTAAAAATACAAAAGTTAGCCAGGCTTGGTGGCAGGTGCCTGTAATCCCAGCTACTCGGGAGACTGAGGCAGGAGAATTGCTTGAACCCGCAAGGTGGAGGTTGCACAGTGAGCTGAGATTGCACCACTGCACTCCAGCCTGGCAACAGAGCAAGACTCCATCTCCAAAAAAGAACAGAAATCAATGAAGCACCGAGTGACAGGGACTGGAAGGTCCTAATTCCATGGGTATTTACGGAACCCCTACGCCGTGTGGAGTCTTATTCTAGACAGTGGGGACGAGGCCATGAACAAGGTAGATGAGAGAGGAGATTTCTCCATCCTGGTCAGGGAATTTGTTAAAGACTGATGAAAACATGAATAAATAATTGTGTCTAGTACATTCTATTCGTGAATCTCATAACAGACAGTGGTAGAGTGACCGTGACCCATTCGCCACACAGTAGAGTCACTTTTTTGGTTTGTTTTTTAGAGACAGGGTCTTCCTCTGTTGCTGAGGCTGGAGTGCAGTGGTGCAGTCATAGTTCACTGCAGCCTCAACCTCCTGTGCTCAAGCAATCCTCCCACCTCAGCGTCCCAAGTAGCTGGGACAGCAGGCACATGCCACGGGTTGGGGGACCACAGGCATGGTCAAGGGGCTGGCAGTCAAGCAAGTG

The human genome contains…

Genomic PatternsShort Tandem Repeats (STRs)

Variable Number Tandem Repeats (VNTRs)

CpG IslandsA sequence of > 500 nucleotides C+G content of > 55%High frequency of CG dinucleotides

1 to 6 nucleotides repeated in tandem

Same as short tandem repeatsNumber of repeats variable across individuals

…CGCGCCGGACGTTACGCGCGCCGCGAAACGCGCGCCGGACGGCGCCGCAAACGGCCGCGCGTAC…

Palindromes

300 bp

>1,000 bp

ALU Elements

LINE-1 ElementsRetrotransposon of >1,000 nucleotides High A+T contentPoly A tail

Retrotransposon of ~300 nucleotides withHigh G+C content Recognition site for alu endonucleaseSegment high in A contentA poly A tail

A sequence that is like a normal palindrome (mom, racecar, …)One half is a complement of the other in reverse order.

Genomic Patterns

Disease Relevance

Challenges in Pattern Mining

ScalableGenomes are large 3 billion nucleotides

Genes are small 3 thousand nucleotides

Genomes of different organisms vary greatly in size

FlexibleTypes of patterns differ

There are variations within a single type of pattern

Flexibility in resolution of analysis

NonparametricNew and unknown patterns

Explorative analysis

Computational tools for pattern mining must be…

Currently, there are no tools that are scalable, flexible, and nonparametric for genomic pattern mining

Pattern Mining Toolkit

Applications layer contains programs that utilize features computed by tools layer and also the preprocessed layer to compute specific commonly known patterns such short tandem repeats, DNA palindromes, short and long interspersed nuclear elements, etc.

Foundation Layer

Data Preprocessing:Suffix array computationLongest common prefix array computation

Efficient Preprocessing of Genome Sequence

Repetitive patterns appear next to each other

Allows for efficient computation of patterns

Tools Layer

Locate Specific Patterns

Find Ngram Counts Compare Ngram CountsNgram = CG

Window Count1 762 1083 904 1065 1856 0

Ngram = GCCWindow Chrom A Chrom B

1 42 1002 98 1653 63 794 72 605 25 151

TTAAAAAAAA-TTTTTTAAAA 10 251555TAAAAAAC-GTTTTTAA 8 276649CAAAAAAG-CTTTTTAG 8 312629TCTCTACTAAAAAT-ATTTTTAAAAAAAA 14 364179TGAAAAACA-TGTTTTAAA 9 449648

Tools LayerLarge Repeats Find RegEx

23 17 29441 CAGATTTGAAACACTCTTTTTGT24 93 4161 ATATCTTCGTATAAAAACAAGACA25 123 292054 TTTTCAGAAACTGCTTTGTGATGTG31 255 3983 GAAACGGGATTTCTTTATATTATGCTAGACA

Find Perplexity

5 MB

Explorative pattern analysis in chromosome 19

5 MB

250 KB

Explorative pattern analysis in chromosome 19

5 MB

250 KB

10 KB

Explorative pattern analysis in chromosome 19

Explorative pattern analysis in chromosome 19

5 MB

250 KB

10 KB

1 KB

Feature analysis of the centromere of the X chromosome

Perplexity drops near the centromere region that is highly repetitive, containing ngrams that are unique to this region.

Pattern landscape of chromosome 19

Duplication events

Ackowledgements

Madhavi GanapathirajuThahir Mohamed

Kamiya Mopwani

Thank you! Visit us at

Department of Biomedical Informatics University of Pittsburgh

Cathedral of Learning, University of Pittsburgh

www.dbmi.pitt.edu/madhavi