Mark de Pristo But 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 premature stop codons – 88% of this class in NA12891 are in pilot data 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 ~ – Enriched phenotypes, e.g. scizophrenia
Fit population simulation model to 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 migration 4 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 ( ) 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