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Cognitive Differences and Population Genetics

From Pickrell, Coop, Novembre, et. al., 2009. Signals of recent positive selection in a worldwide sample of Human Populations.

NRG–ERBB4 pathway Among the top selection candidates shown in Figure 1, we noticed that two—ERBB4 and NRG3—are, in fact, binding partners (Zhang et al. 1997). Although these two genes are large, and thus contain a numberof tested windows, they both are outliers with respect to the rest of the genome even after a conservative Bonferroni correction for the number of windows (empirical P = 0.001 and P = 0.006 in the Middle East for ERBB4 and NRG3, respectively). Further inspection of genes in the NRG–ERBB4 pathway (Kanehisa et al. 2008) revealed a striking alignment of selection signals (Fig. 5A). ERBB4 shows extreme extreme iHS signals in all non-African populations (Fig. 5B,C), NRG3 shows extreme iHS signals in West Eurasian populations, and two other binding partners of ERBB4—NRG1 and NRG2—fall well into the 1% tail of iHS scores in East Asia (Fig. 5A). Further, ADAM17, the gene encoding the enzyme that converts NRG1 to its active form (Mei and Xiong 2008), falls in a region that contains some of the most extreme XP-EHH scores in East Asia (maximum value of XP-EHHinthe region of 4.2 at rs2709591, empirical P = 2 3 10 5). The NRG–ERBB4 signaling pathway is well-studied and known to be involved in the development of a number of tissues, including heart, neural, and mammary tissue (Gassmann et al. 1995; Tidcombe et al. 2003). Variants in genes in this pathway have been associated with risk of schizophrenia and various psychiatric phenotypes (Stefansson et al. 2002; Hall et al. 2006; Mei and Xiong 2008). We suggest that an unidentified phenotype affected by this pathway has experienced strong recent selection in non-African populations

As for the NRG-ErB pathway. From: Zhang, 1997. Neuregulin-3 (NRG3): A novel neural tissue-enriched protein that binds and activates ErbB4:

NRG3 is predicted to contain an extracellular domain with an epidermal growth factor (EGF) motif, a transmembrane domain, and a large cytoplasmic domain. We show that the EGF-like domain of NRG3 binds to the extracellular domain of ErbB4 in vitro. Moreover, NRG3 binds to ErbB4 expressed on cells and stimulates tyrosine phosphorylation of this receptor. The expression of NRG3 is highly restricted to the developing and adult nervous system. These data suggest that NRG3 is a novel, neural-enriched ligand for ErbB4.

From: Hernández-Miranda, Parnavelas, and Chiara, 2010. Molecules and mechanisms involved in the generation and migration of cortical interneurons:

NGRs (neuregulins), a family of growth factors encoded by four structurally related genes (NRG-1, NRG-2, NRG-3 and NRG-4), have been related to important events in the developing nervous system (Falls, 2003a; Anton et al., 2004; Xu et al., 2009). They are ligands for receptor tyrosine kinases of the ErbB family and activate a wide spectrum of intracellular signalling cascades, resulting in the induction of cellular responses in different organs (Buonanno and Fischbach, 2001; Falls, 2003a, 2003b; Anton et al., 2004; Britsch, 2007; Birchmeier, 2009). Several lines of evidence suggest that NRG-1 acts as a chemoattractant for interneurons (Yau et al., 2003; Flames et al., 2004). First, ErB4 is expressed in tangentially migrating neurons and co-localises with the interneuron marker DLX2 (Yau et al., 2003). Secondly, soluble NGR1-Ig is expressed in the cortical proliferative zones, and has been hypothesized to attract migrating interneurons to the IZ/SVZ path (Flames et al., 2004; Ghashghaei et al., 2006). Thirdly, secreted NGR1 is a potent chemoattractant for MGE-derived cells in vitro (Flames et al., 2004). Fourthly, loss-of-function assays have demonstrated that the migration of cortical interneurons depends on ErB4 signalling, and their number is significantly decreased in conditional ErB4 mutants (Flames et al., 2004).

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