Accelerated Evolution of the Pituitary Adenylate Cyclase-Activating Polypeptide Precursor Gene during Human Origin

By Wang, Yin-qiu; Qian, Ya-ping et al. | Genetics, June 2005 | Go to article overview

Accelerated Evolution of the Pituitary Adenylate Cyclase-Activating Polypeptide Precursor Gene during Human Origin


Wang, Yin-qiu, Qian, Ya-ping, Yang, Su, Shi, Hong, et al., Genetics


ABSTRACT

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide abundantly expressed in the central nervous system and involved in regulating neurogenesis and neuronal signal transduction. The amino acid sequence of PACAP is extremely conserved across vertebrate species, indicating a strong functional constraint during the course of evolution. However, through comparative sequence analysis, we demonstrated that the PACAP precursor gene underwent an accelerated evolution in the human lineage since the divergence from chimpanzees, and the amino acid substitution rate in humans is at least seven times faster than that in other mammal species resulting from strong Darwinian positive selection. Eleven human-specific amino acid changes were identified in the PACAP precursors, which are conserved from murine to African apes. Protein structural analysis suggested that a putative novel neuropeptide might have originated during human evolution and functioned in the human brain. Our data suggested that the PACAP precursor gene underwent adaptive changes during human origin and may have contributed to the formation of human cognition.

HUMANS diverged from African apes ~5-7 million years ago (GOODMAN et al. 1998). Genetically, humans and chimpanzees share nearly 99% DNA sequence similarity (FUJIYAMA et al. 2002; HELLMANN et al. 2003; SHI et al. 2003), which seems to contradict the marked biological divergence between them, e.g., the highly developed cognitive abilities in humans. Therefore, the major challenge in the rapidly progressing human and chimpanzee genome comparison studies is to determine the small subset of sequence differences that have phenotypic significance related to species-specific traits (ENARD et al. 2002; STEDMAN et al. 2004). Recent studies on FOXP2 and myosin demonstrated that the humanspecific substitutions in these two genes are related to the phenotypic divergence between humans and nonhuman primates, i.e., the acquiring of language ability and gracilization of masticatory muscles relevant to accelerated encephalization during human evolution (ENARD et al. 2002; ZHANG et al. 2002; STEDMAN et al. 2004).

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-studied neuropeptide that plays a pivotal role in the central nervous system by acting as a neurohormone and a neurotransmitter (DiCiCCO-BLOOM et al. 1998; MONTERO et al. 2000; VAUDRY et al. 2000; HAMELINK et al. 2002; MORETTI et al. 2002). In the human genome, the gene encoding the PACAP precursor (ADCYAPl) is located on chromosome ISpIl (HoSOYA et al. 1992). This region was shown to be related with holoprosencephaly, the most common hereditary development defect of the forebrain in humans (a single-lobed brain structure with severe skull and facial defects) (GOLDEN 1998). Recent studies showed that PACAP is involved in cerebral cortical neurogenesis by eliciting the transition from proliferation to differentiation in cortical precursors (DiCiCCOBLOOM et al. 1998; SUH et al. 2001). Gene knockout studies in mouse revealed altered psychomotor behaviors (HASHIMOTO et al. 2001). The PACAP homolog in Drosophila, amnesiac (amn), was shown to be crucial in adult memory formation (DEZAZZO et al 1999).

The human PACAP precursor gene (ADCYAPl) has five exons encoding a protein of 176 amino acids with PACAP located in the C-terminal region (Figure 1) (HOSOYA et al. 1992). PACAP has two forms, the 38-amino-acid form (PACAP38) and the 27-amino-acid form (PACAP27), which are generated through posttranslational processing by the precursor convertase (VAUDRY et al 2000). The sequence of PACAP has been remarkably conserved in vertebrates during evolution and no amino acid substitution was observed in the mammal species studied so far (MONTERO et al. 2000) (Figure 1).

In this study, we sought to understand the molecular history of the PACAP precursor gene in primates and other vertebrate species. Our results demonstrate an accelerated evolution of the PACAP precursor in the lineage leading to the emergence of humans, which is likely caused by Darwinian positive selection during human evolution. …

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