. Genomics: In search of rare human variants. Nature. 2010 Oct 28;467(7319):1050-1. PubMed.


Please login to recommend the paper.


  1. These papers detailing the pilot part of the 1000 Genomes project really mark an enormous resource for biomedical research. These are some of the ways it will help:

    1. As we carry out our genomewide association studies for Alzheimer’s and other diseases, when we see an association, it will tell us which variants are on the chromosome we have found association to (this is called imputation). This means we really don’t need to do any sequencing...or at least, much less sequencing...to have a list of candidate pathogenic variants.

    2. When we find rare variants that predispose to disease, we can go the other way: We can see what haplotype on which they arose, and understand where the mutation may have come from and who else may have the mutation we have found.

    3. A major problem in clinical genetics is knowing when we find mutations in genes which have pathogenic mutations (a good example is the PGRN gene in dementia cases); we cannot always know if the new variant we have found is pathogenic, or harmless, or something in between. These data will help to answer that (see Guerreiro et al., 2010 for a more complete discussion of this).

    These are immediate practical uses for this huge number of data, but the data are much more than this. The observation that we all have about 250 heterozygous gene knockouts and that we all have about 50 heterozygous loss-of-function genes, which would lead to serious illness if they were homozygous, are interesting pieces of data. The information we will get about gene regulation because we know how it varies among people will be invaluable. Our appreciation of population relatedness will also massively increase. Our understanding of the mechanisms of mutation occurrence...the list just goes on and on.

    These publications are landmark events in our appreciation of our own biology.


    . A thorough assessment of benign genetic variability in GRN and MAPT. Hum Mutat. 2010 Feb;31(2):E1126-40. PubMed.

    View all comments by John Hardy

Make a Comment

To make a comment you must login or register.

This paper appears in the following:


  1. Next-Generation Sequencing: Boldly Going Where No Geneticist...