Mark de Pristo

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