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A Human-Specific Gene in Microglia

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Science  09 Sep 2005:
Vol. 309, Issue 5741, pp. 1693
DOI: 10.1126/science.1114321

Abstract

Recent studies have shown multiple differences between humans and apes in sialic acid (Sia) biology, including Siglecs (Sia-recognizing-Ig-superfamily lectins). Comparisons with the chimpanzee genome indicate that human SIGLEC11 emerged through human-specific gene conversion by an adjacent pseudogene. Conversion involved 5� untranslated sequences and the Sia-recognition domain. This human protein shows reduced binding relative to the ancestral form but recognizes oligosialic acids, which are enriched in the brain. SIGLEC11 is expressed in human but not in chimpanzee brain microglia. Further studies will determine if this event was related to the evolution of Homo.

Recent studies have shown differences between humans and chimpanzees in sialic acid (Sia) biology, including Sia-binding receptors called Siglecs (13). Analysis of the ∼3-kb region of homology between human SIGLEC11 (hSIGLEC11) and pseudogene hSIGLECP16 (Fig. 1A) showed that an ∼2-kb segment (designated A/A′) including the first five exons is 99.3% identical. However, the rest of this region (designated B/B′) has a much lower identity (94.6%). A phylogenetic tree of B/B′ from the human (h) and chimpanzee (c) genomes shows the topology expected from the gene orthology (Fig. 1B). In contrast, the A/A′ tree shows a within-species clustering of hSIGLEC11 and hSIGLECP16 (Fig. 1C), suggesting a recent gene conversion event.

Fig. 1.

Gene structure and phylogenetic analyses. (A) Comparison of SIGLEC11 and the similar region of SIGLECP16. Exons are represented by solid and open boxes. (B and C) Phylogenetic relationships of (B) B/B′ and (C) A/A′. The label at the internode represents bootstrap support for 1000 replications.

Pairwise genetic distances between human and chimpanzee A/A′ regions were calculated, after excluding intron 2 and exons (4) (fig. S1), and compared with the standard human-chimpanzee genetic distance, calculated from downstream intronic regions (0.0141 ± 0.0013). The genetic distance between hSIGLEC11 and hSIGLECP16 is much smaller (0.0049 ± 0.0024), and that between corresponding chimpanzee forms is much larger (0.0337 ± 0.0065). Thus, although the presumed gene duplication event yielding ancestral SIGLEC11 and SIGLECP16 predated the human-chimpanzee common ancestor, the subsequent gene conversion occurred only in the human lineage. Both hSIGLEC11 and hSIGLECP16 are more closely related to cSIGLECP16 than to cSIGLEC11, and the genetic distance between hSIGLEC11 and cSIGLECP16 is nearly the same as that between SIGLECP16 orthologs (4). Thus, hSIGLECP16 converted hSIGLEC11. Inclusion of bonobo, gorilla, and orangutan SIGLEC11 sequences confirmed that this gene conversion occurred only in the human lineage (4) (fig. S2). A search of human single-nucleotide polymorphism databases (4) suggests that it is universal to modern humans.

The converted region includes a 5′ upstream region and exons encoding the Sia recognition domain. We therefore studied the Sia-binding properties of recombinant, soluble Siglec-11 protein. Chimpanzee Siglec-11 showed more robust binding than hSiglec-11 (Fig. 2A), especially to Neu5Gc, the Sia type missing in humans (3). Human Siglec-11 still bound oligosialic acids [(Neu5Acα2-8)2-3], which are enriched in the brain.

Fig. 2.

Sia-recognition and expression patterns (4). (A) Binding of recombinant human and chimpanzee Siglec-11 to Sia-containing probes: 1, Neu5Acα2-3Lac; 2, Neu5Acα2-6Lac; 3, Neu5Acα2–; 4, Neu5Gcα2–; 5, (Neu5Acα2-8)2; 6, (Neu5Acα2-8)3; and 7, (Neu5Acα2-8)5-6. Error bars indicate standard deviation. A405, absorbance at 405 nm. (B) Examples of human and chimpanzee brain and tonsil tissue probed with antibody to human Siglec-11 (brown staining).

Human brain cortex microglia showed strong Siglec-11 staining (5) in eight individuals. However, despite positive macrophage staining in other tissues, microglia showed only occasional staining in five chimpanzees (Fig. 2B) and none in two orangutans. Thus, brain microglia gained specific and prominent Siglec-11 expression in the human lineage, possibly due to changes of regulatory sequences in the 5′ upstream region.

This work also supports the notion that pseudogenes are better called “potogenes” or potential genes (6). We suggest that this human-specific gene conversion event may be related to the evolution of genus Homo. Multiple approaches could shed light on its evolutionary significance, including further analysis of the converted region, promoter studies, calculation of the event timing, detection of Siglec-11 ligands in the brain, and a search for humans with SIGLEC11 mutations.

Supporting Online Material

www.sciencemag.org/cgi/content/full/309/5741/1693/DC1

Materials and Methods

SOM Text

Figs. S1 and S2

Table S1

References and Notes

References and Notes

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