Mark de PristoBut 1-2% of 3 billion is still a lot!
What fraction of human genetic variation has now been described?
The fraction of variants that is novel varies by type
• 3-4,000,000 variants per individual– 97.8% of variants in NA12891 are in pilot data
• 10-11,000 nonsynonymous changes– 95% of this class in NA12891 are in pilot data
• 80-100 premature stop codons– 88% of this class in NA12891 are in pilot data
• 50-100 HGMD “recessive disease causing” mutations– 85% of this class in NA12891 are in pilot data
1000 Genomes Project pilot paper
Functional variants are more likely to be rare
Individuals in outbred populations will still carry many variants not in the 1000GP and other similar data sets
• Exponential population growth in last 10,000 years gives long tips to the tree
• In “big” populations, tips are hundreds of generations long, so tens of thousands of private variants per sample, hundreds functional
This behaviour is very dependent on population structure.
In genetic isolates the tree relating haplotypes is smaller, and the tips are shorter
Isolates share recently diverged chromosomes with long shared haplotypes
Case study: Kuusamo
– Settled by 34 families in 1680s– Small indigenous Lapp population
disappeared rapidly– Very little immigration after initial
settlement– Current population ~20 000– Enriched phenotypes, e.g.
scizophrenia
Fit population simulation modelto genotype data from a fixed sample
Best fit model With ~2% migration per generation
“Nx plot”: x% of new sample DNA is shared in segments of length >y
Kimmo Palin
100 founders, no migration4 generations with 2x growth,
8 generations with 1.25x growth
Orcades population simulation
20 subpopulations (parishes), constant size 1/3 of census 1841 size, endogamy within parishes >~50% from records, 40 generations, immigration generations 20-29 (1400-1670)
Kimmo Palin
How much variation do we cover with how much sequence?
In the end, each individual carries private mutations
Kees Albers, Kimmo Palin, Karola Rehnstrom, Leopold Parts, Aylwyn Scally, Jared Simpson, Weldon Whitener