| 其他摘要 | Human being has many phenotypic differences from other non-human primates, such as bare skin, bipedal walking and language ability. However, the most significant difference is the enlarged brain and highly-developed cognitive abilities in human. It has been shown that the average genomic sequence divergence between human and chimpanzee (the closest relative of human) is very small. Hence, genetically, what makes us human has become a critical question in understanding human evolution. In this study, by utilizing the approaches in genetics and genomics, we aim to answer the question by conducting two studies, the molecular evolutionary analyses of RHOXF2 gene and functional study of human-specific PACAP-related novel peptide. The evolution process of RHOXF2 gene involves Darwinian positive selection, endogenous retroviruses repeat elements, gene segmental duplication, copy-number variation, gene deletion and mRNA expression change. The human-specific PACAP-related novel peptide is an example of protein-coding sequence change, and also involves positive selection and origin of a novel human-specific protein. RHOXF2 gene is a homeobox gene highly expressed in the brain and testis. As a reproductive homeobox X-linked family gene, it has the ability to regulate of the expression of Unc5c, Pltp and Gdap1, suggesting that it not only takes part in spermatogenesis, but also may play an important role in brain development. RHOXF2 gene evolved rapidly in primates. Multi-lineages positive selections were detected during the evolution of primates, especially during the origin of human and chimpanzee. The observed sequence polymorphisms are all non-synonymous in human populations, implying that there is on-going positive selection in contemporary human populations. Surprisingly, our study demonstrated that RHOXF2 has experienced rapid copy number changes in primates, especially in chimpanzee, in which about 6 copies were identified. The frequent copy number changes of RHOXF2 in primates are likley caused by the endogenous-retrovirus-mediated recombinations. During the origin of chimpanzee, even the homeodomain was under a strong positive selection. ThePACAP precursor gene, ADCYAP1, evolved rapidly in the human lineage, and a putative novel human-specific 41-AA peptide was originated by gaining an alpha-amidation site and 17 human specific amino acid changes. We named it as human-specific PACAP-related novel peptide 41(hPRNP41). In this study, our data suggested that hPRNP41 does exist in human. It is distributed in human testis, hypothalamus and plasma. In human plasma, the hPRNP41 concentration is about 10-13-10-14 mol/μl (0.05-0.5ng/ml), comparable to the PACAP concentration. Its concentration is relatively stable in the plasma of healthy human individuals and no variation with gender and age was observed. Mass spectrometry analysis proved that it is alpha-amidated without any other modification. The chemical synthetic hPRNP41 can not change the adenylate cyclase activity of PACAP38 and PACAP27, implying that its function is different from PACAP. |
修改评论