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paleoanthropology, genetics and evolution

whole-genome

  • Finding the scary genes

    Wed, 2012-03-07 21:39 -- John Hawks

    John Lauerman reports in BusinessWeek on his experience participating in the Personal Genome Project:

    “This is probably the most serious variant that we’ve actually seen to date in the study,” Thakuria said. About two out of 1,000 people have the JAK2 variant, which encourages blood cells to grow and divide. The variant is used to diagnose three rare blood disorders, including primary myelofibrosis, which is potentially lethal. “I don’t want you to fret about this,” Thakuria said, before giving me fresh cause for worry: a study, published in 2010, in which 10,507 people in Copenhagen gave blood samples and were followed for as long as 18 years. The Copenhagen researchers went back and analyzed the blood samples: 18 had the JAK2 variant; 14 of those 18 with the variant developed cancer in their lifetimes, and all 18 died within the study period. How, exactly, was this helping?

    Finding that you carry a harmful genetic variant, and that there's nothing you can do about it, is probably the most frightening outcome when obtaining your personal genetic information. Some say they would rather not know about such genes.

    Several others have commented on Lauerman's piece, including Matthew Herper at Forbes, and the 23andMe blog. Naturally, they have different takes.

    Tags: 
    Personal Genome Project
    testing
    biotech
    genomics
    whole-genome
    sequencing
    health

  • Exome sequencing as a stopgap

    Fri, 2011-10-14 12:09 -- John Hawks

    The new Genome Biology has a perspective piece by Jacob Tennessen and colleagues, titled "The promise and limitations of population exomics for human evolution studies" [1]. Exomics is the study of the coding part of the genome, which is only 30 megabases as opposed to the 3 gigabases of a whole genome. Today it is possible to apply methods that sequence only the protein-coding parts of the genome, by combining methods that capture such regions with next-generation sequencing. The result is vastly cheaper than a whole genome, and some of this cost savings can be applied to increase the coverage, which increases the sequence accuracy.

    Tossing away 99% of the genome is not an ideal sampling strategy for many purposes. However, when it comes to phenotype prediction, we can make some predictions about how changes in amino acid sequences will affect protein function. Many important phenotypic changes are caused by non-coding variations in gene regulation, but genetics has not yet reached a state of knowledge where these can be readily predicted. So, if we're sequencing people's genomes for the purposes of finding disease or phenotype variants, exome sequences give much of the information that we can presently evaluate.

    James Hadfield noted the spree of exome sequencing publications at his blog, Core Genomics ("Exome capture comparison publication splurge"). He tags the rationale for

    A lot of people I have talked to are now looking at screening pipelines which use Exome-Seq ahead of WGS to reduce the number of whole Human genomes to be sequenced. The idea being that the exome run will find mutations that can be followed up in many cases and only those with no hits can be selected for WGS.

    I have heard a number of geneticists looking at exome sequencing as an intermediate step in population genetics, a way to increase the size of samples more affordably than whole genome sequencing makes possible at present. I don't think this will last long, as whole genomes offer much more for population genetic analysis and are rapidly dropping in price, but that depends on how technology develops. If we are consistently in the situation where researchers can multiplex 50 exomes at high coverage for the same price as one whole genome, it may make sense to use that strategy for a long time.

    23andMe is starting an exome sequencing project. Daniel MacArthur's comments on G+ and the subsequent reader comments are interesting.

    References

    1. Tennessen JA, O'Connor TD, Bamshad MJ, and Akey JM. 2011. The promise and limitations of population exomics for human evolution studies. Genome biology 12:127.
    Tags: 
    biotech
    sequencing
    whole-genome
    exome
    personalized genomics

  • BROADLY CONSISTENT WATCH II

    Sun, 2005-10-02 23:14 -- John Hawks

    Looking back through the Chimpanzee Genome Consortium (2005) paper, I find this:

    Chimpanzee polymorphisms. The draft sequence of the chimpanzee genome also facilitates genome-wide studies of genetic diversity among chimpanzees, extending recent work. We sequenced and analysed sequence reads from the primary donor, four other West African and three central African chimpanzees (Pan troglodytes troglodytes) to discover polymorphic positions within and between these individuals.

    A total of 1.66 million high-quality single-nucleotide polymorphisms (SNPs) were identified, of which 1.01 million are heterozygous within the primary donor, Clint. Heterozygosity rates were estimated to be 9.5 x 10-4 for Clint, 8.0 x 10-4 among West African chimpanzees and 17.6 x 10-4 among central African chimpanzees, with the variation between West and central African chimpanzees being 19.0 x 10-4. The diversity in West African chimpanzees is similar to that seen for human populations, whearas the level for central African chimpanzees is roughly twice as high.

    The observed heterozygosity in Clint is broadly consistent with West African origin, although there are a small number of regions of distinctly higher heterozygosity. These may reflect a small amount of central African ancestry, but more likely reflect undetected regions of segmental duplications present only in chimpanzees (Chimpanzee Genome Consortium 2005:70, emphasis added).

    I included the context before the "broadly consistent" to be clear about what it refers to. Elsewhere in the article, the consortium identifies "Clint" as a "captive-born descendant of chimpanzees from the West Africa [sic] subspecies Pan troglodytes verus" (CGS 2005:70). So Clint's heterozygosity isn't just broadly consistent with West African origin; it is an example of West African origin.

    Now, the "broadly consistent" is there because the overall heterozygosity estimate for Clint is a bit higher than typical for West African chimps. So why don't they just say that? It's not like Clint's origin is a mystery.

    And there are plenty of good hypotheses for why one captive-born chimpanzee might have slightly higher overall heterozygosity than other members of his subspecies. The paper lists two; others include the possibility that Clint's captive ancestors were taken from different parts of West Africa, or that the captive breeding program avoided inbreeding more than wild chimpanzees. Any of these might be tested; they weren't, so we're left with the "broadly consistent" answer.

    Tags: 
    broadly consistent watch
    chimpanzees
    genomics
    whole-genome
    population structure
    subspecies
    Synopsis: 
    Here, "broadly consistent" means, we didn't bother to test the specifics.
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Neandertals

For years, I've worked on their bones. Now I'm working on their genes. Read more about the science studying these ancient people.

Denisova

From a finger bone of an ancient human came the record of a completely unexpected population. My lab is working on the science of the Denisova genome.

Acceleration

The advent of agriculture caused natural selection to speed up greatly in humans. We're uncovering some of the ways that populations have rapidly changed during the last 10,000 years.

Malapa

Just outside Johannesburg, the Malapa site is producing some of the most exciting finds in human evolution. This site is the headquarters of the Malapa Soft Tissue Project.