Research News from the Howard Hughes Medical Institute (HHMI)

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Duplication architecture of the human genome…

Recent duplication architecture of the human genome. The organization of segmental duplications that are >90 percent sequence identical and >1 kb in length is shown as red bars overlaid on the human genome. Approximately 5–6 percent of the human genome consists of duplicated segments, the majority of which cluster into ~390 duplication hubs. The complex mosaic architecture of one of these duplication hubs in 2p11 is shown in more detail (blue arrow). The ~750 kb consists of 17 gene-rich segments that were duplicatively transposed from the euchromatin to this pericentromeric region 10–20 million years ago. Euchromatic colonization of the region abruptly ceased 10 million years ago.
Julie Horvath and Jeffrey Bailey.

HHMI, February 12, 2009, by Evan E. Eichler PhD — Roughly 10 million years ago, a major genetic change occurred in a common ancestor of gorillas, chimpanzees, and humans. Segments of DNA in its genome began to form duplicate copies at a greater rate than in the past, creating a genetic instability that persists in modern humans and contributes to diseases like autism and schizophrenia. But that gene duplication also may be responsible for a genetic flexibility that has resulted in some uniquely human characteristics.

“Because of the architecture of the human genome, genetic material is constantly being added and deleted in certain regions,” says Howard Hughes Medical Institute investigator and University of Washington geneticist Evan Eichler. “These are really like volcanoes in the genome, blowing out pieces of DNA.”

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Intrachromosomal expansion of a segmental duplication during the evolution of humans and great apes. The figure shows the results of fluorescent in situ hybridization of a 20-kb segmental duplication (low-copy repeat chromosome 16 a) to both interphase nuclei and extracted metaphase primate chromosomes. HSA (human), PTR (common chimpanzee), PPA (bonobo), GGO (gorilla), PPY (orangutan), MFU (macaque), PAN (baboon), (PCR) silver-leaf monkey, and CMO (marmoset). The segment expanded in the great ape lineage and led to the differential restructuring of human and great ape chromosomes. The segment contains one of the most rapidly evolving genes within the human genome (morpheus or nuclear pore interacting protein).
From Johnson, M.E., Viggiano, L., Bailey, J.A., Abdul-Rauf, M., Goodwin, G., Rocchi, M., and Eichler, E.E. 2001. Nature 413:514–519. © 2001 Nature Publishing Group.

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Detection and characterization of structural variation in the human genome. A: Detection of a deletion of the GSTM1 gene by discordant paired-end sequence analysis of fosmid clones (red) against the human reference sequence. B: Sequence comparison between the human genome and the fosmid insert reveals an ~14-kb deletion (green bars indicate intrachromosomal duplications located at the breakpoint). C: A PCR assay designed to the junction of the structural variant shows heterozygotes and homozygotes of both alleles (lane 1, heterozygotes; lanes 2 and 3, homozygotes).

Adapted from Tuzun, E., Sharp, A.J., Bailey, J.A., Kaul, R., Morrison, V.A., Pertz, L.M., Haugen, E., Hayden, H., Albertson, D., Pinkel, D., Olson, M.V., and Eichler, E.E. 2005. Nature Genetics 37:727–732.

Eichler and his colleagues focused on the genomes of four different species: macaques, orangutans, chimpanzees, and humans. All are descended from a single ancestral species that lived about 25 million years ago. The line leading to macaques broke off first, so that macaques are the most distantly related to humans in evolutionary terms. Orangutans, chimpanzees, and humans share a common ancestor that lived 12-16 million years ago. Chimps and humans are descended from a common ancestral species that lived about 6 million years ago.

By comparing the DNA sequences of the four species, Eichler and his
colleagues identified gene duplications in the lineages leading to these
species since they shared a common ancestor. They also were able to estimate
when a duplication occurred from the number of species sharing that
duplication. For example, a duplication observed in orangutan, chimpanzees,
and humans but not in macaques must have occurred sometime after 25
million years ago but before the orangutan lineage branched off.

Eichler’s research team found an especially high rate of duplications in the
ancestral species leading to chimps and humans, even though other
mutational processes, such as changes in single DNA letters, were slowing
down during this period. “There’s a big burst of activity that happens where
genomes are suddenly rearranged and changed,” he says. Surprisingly, the
rate of duplications slowed down again after the lineages leading to humans
and to chimpanzees diverged. “You might like to think that humans are
special because we have more duplications than did earlier species,” he says,
“but that’s not the case.”

These duplications have created regions of our genomes that are especially
prone to large-scale reorganizations. “That architecture predisposes to
recurrent deletions and duplications that are associated with autism and
schizophrenia and with a whole host of other diseases,” says Eichler.

Yet these regions also exhibit signs of being under positive selection,
meaning that some of the rearrangements must have conferred advantages on
the individuals who inherited them. Eichler thinks that uncharacterized genes
or regulatory signals in the duplicated regions must have created some sort of
reproductive edge. “I believe that the negative selection of these duplications
is being outweighed by the selective advantage of having these newly minted
genes, but that’s still unproven,” he said.

An important task for future studies is to identify the genes in these regions
and analyze their functions, according to Eichler. “Geneticists have to figure
out the genes in these regions and how variation leads to different aspects of
the human condition such as disease. Then, they can pass that information on
to neuroscientists, physiologists and biochemists who can work out what
these proteins are and what they do,” he says. “There is the possibility that
these genes might be important for language or for aspects of cognition,
though much more work has to be done before we’ll be able to say that for
sure.”

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