1. BI820 – Seminar in Quantitative and Computational Problems in Genomics
Gabor T. Marth
Department of Biology
Boston College
Chestnut Hill, MA 02467

2. Sequence variations
Human Genome Project produced a reference genome sequence that is 99.9% common to each human being
sequence variations make our genetic makeup unique
SNP
Single-nucleotide polymorphisms (SNPs) are most abundant, but other types of variations exist and are important

3. Why do we care about variations?
phenotypic differences
inherited diseases
demographic history

4. How do we find polymorphisms?
look at multiple sequences from the same genome region
diverse sequence resources can be used
EST
WGS
BAC
diversion: sequencing informatics

5. SNP discovery -- Methods
Sequence clustering
Cluster refinement
Multiple alignment
SNP detection

6. SNP discovery – Computer tools

7. SNP discovery – Mining Projects
~ 30,000 clones
>CloneX
ACGTTGCAACGT
GTCAATGCTGCA
>CloneY
ACGTTGCAACGT
GTCAATGCTGCA
25,901 clones
(7,122 finished, 18,779 draft
with basequality values)
21,020 clone overlaps
(124,356 fragment overlaps)
ACCTAGGAGACTGAACTTACTG
507,152 high-quality candidate SNPs
(validation rate 83-96%)
Marth et al., Nature Genetics 2001
ACCTAGGAGACCGAACTTACTG

8. SNP databases and characteristics
access to variation data
SNP properties
reliability of information
characterizing known polymorphic sites in sample collections – genotyping

9. Where do variations come from?
sequence variations are the result of mutation events
TAAAAAT
TAACAAT
TAAAAAT
TAACAAT
MRCA
mutations are propagated down through generations
TAAAAAT
TAACAAT

10. Mutation rate higher mutation rate (µ) gives rise to more SNPS MRCA
accgttatgtaga
accgctatgtaga
MRCA
actgttatgtaga
accgctatataga
MRCA

11. Recombination accgttatgtaga accgttatgtaga accgttatgtaga accgttatgtaga

12. Demographic history large (effective) population size N
small (effective) population size N
different world populations have varying long-term effective population sizes (e.g. African N is larger than European)

13. Modeling history stationary collapse expansion bottleneck past presentMD
(simulation)
AFS
(direct form)

14. Ancestral inference
modest but uninterrupted expansion
bottleneck

15. The effects and signatures of selection
selective mutations influence the genealogy itself; in the case of neutral mutations the processes of mutation and genealogy are decoupled

16. Allelic association and haplotype structure
“linkage disequilibrium”
“haplotype blocks”

17. Computer simulations: the Coalescent

18. ? Medical utility? clinical phenotype molecular markers
functional understanding

19. Mapping disease-causing loci
genetic linkage
association between allele and phenotype

20. Forensic applications