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Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, we examined the evolution of genes involved in diverse aspects of nervous system biology. We found that these genes display significantly higher rates of protein evolution in primates than in rodents. Importantly, this trend is most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution is most prominent in the lineage leading from ancestral primates to humans. Thus, the remarkable phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. In addition to uncovering broad evolutionary trends, our study also identified many candidate genes--most of which are implicated in regulating brain size and behavior--that might have played important roles in the evolution of the human brain.

Abstract: DNA methylation can contribute to the stable transcriptional silencing of mammalian genes. Often times, these genes are important developmental regulators, and their silencing in cell types where they are not supposed to be active is important for the phenotypic stability of the cells. To identify key developmental regulator genes whose expression in terminally differentiated cells may be inhibited by DNA methylation, mouse dermal fibroblasts were demethylated with 5-aza-2′-deoxycytidine, and changes in gene expression monitored by microarray analysis. Endothelin-1 (Et1 or Edn1), which encodes a cytokine with diverse regulatory functions, was among the genes upregulated following demethylation. We found that CpG dinucleotides within a short region in intron 1 of the gene have dramatically higher levels of methylation in Et1-non-expressing fibroblasts and chondrocytes as compared to the Et1-expressing mouse cell line, mIMCD-3. Strong evolutionary conservation of this region implies its role in the cis-regulation of Et1 transcription. To confirm that should Et1 in dermal fibroblasts become aberrantly activated, it could indeed lead to the dysregulation of many downstream genes, we exposed fibroblasts to exogenous ET1 peptide and assayed for transcriptional changes by microarray. ET1 treatment resulted in significant expression changes – primarily downregulation – of a significant number of genes. In particular, Tgfβ2 and Tgfβ3 were among the downregulated genes, which in turn alter the expression status of their many target genes. These data suggest that the stable silencing of Et1 through its associated DNA methylation in intron 1 is critical for the developmental stability of dermal fibroblasts, and perhaps other cell types as well. [Copyright &y& Elsevier]

The most defining biological attribute of Homo sapiens is its enormous brain size and accompanying cognitive prowess. How this was achieved by means of genetic changes over the course of human evolution has fascinated biologists and the general public alike. Recent studies have shown that genes controlling brain development — notably those implicated in microcephaly (a congenital defect that is characterized by severely reduced brain size) — are favoured targets of natural selection during human evolution. We propose that genes that regulate brain size during development, such as microcephaly genes, are chief contributors in driving the evolutionary enlargement of the human brain. Based on the synthesis of recent studies, we propose a general methodological template for the genetic analysis of human evolution. [ABSTRACT FROM AUTHOR]

Postcopulatory sperm competition is a key aspect of sexual selection and is believed to drive the rapid evolution of both reproductive physiology and reproduction-related genes. It is well-established that mating behavior determines the intensity of sperm competition, with polyandry (i.e., female promiscuity) leading to fiercer sperm competition than monandry. Studies in mammals, particularly primates, showed that, owing to greater sperm competition, polyandrous taxa generally have physiological traits that make them better adapted for fertilization than monandrous species, including bigger testes, larger seminal vesicles, higher sperm counts, richer mitochondrial loading in sperm and more prominent semen coagulation. Here, we show that the degree of polyandry can also impact the dynamics of molecular evolution. Specifically, we show that the evolution of SEMG2, the gene encoding semenogelin II, a main structural component of semen coagulum, is accelerated in polyandrous primates relative to monandrous primates. Our study showcases the intimate relationship between sexual selection and the molecular evolution of reproductive genes. [ABSTRACT FROM AUTHOR]

Shows that the ratio between nonsynonymous and synonymous substitution rates displays distinct profiles along the coding regions of the MRG gene family, with peaks corresponding to extracellular domains and valleys corresponding to transmembrane and cytoplasmic domains. Excess of radical amino acid changes characterizing the extracellular domains; Characteristics of the MRG gene family.

Most genes in the human NRY (non-recombining portion of the Y chromosome) can be assigned to one of two groups: X-homologous genes or testis-specific gene families with no obvious X-chromosomal homologues. The CDY genes have been localized to the human Y chromosome, and we report here that they are derivatives of a conventional single-copy gene, CDYL (CDY-like), located on human chromosome 13 and mouse chromosome 6. CDY genes retain CDYL exonic sequences but lack its introns. In mice, whose evolutionary lineage diverged before the appearance of the Y-linked derivatives, the autosomal Cdyl gene produces two transcripts; one is expressed ubiquitously and the other is expressed in testes only. In humans, autosomal CDYL produces only the ubiquitous transcript; the testis-specific transcript is the province of the Y-borne CDY genes. Our data indicate that CDY genes arose during primate evolution by retroposition of a CDYL mRNA and amplification of the retroposed gene. Retroposition contributed to the gene content of the human Y chromosome, together with two other molecular evolutionary processes: persistence of a subset of genes shared with the X chromosome and transposition of genomic DNA harbouring intact transcription units. [ABSTRACT FROM AUTHOR]

Abstract: The generation of human induced pluripotent stem cells (hiPSCs) opens a prospect for regenerative medicine. However, transplantation of somatic cells derived from hiPSCs still harbor many risks such as cells’ incorrect differentiation or over-proliferation, and the worst, tumor formation. Therefore, it’s essential to ravel out these obstacles before their clinical application. Herein, we genetically modified hiPSCs and human embryonic stem cells (hESCs) with a truncated herpes simplex virus delta thymidine kinase (deltaTK) gene driven by EF1α or Nanog promoter to selectively ablate wayward pluripotent stem cells. The results showed that insertion of deltaTK gene did not alter their pluripotency and self-renewal capacity but rendered them sensitive to ganciclovir, which induced elimination of deltaTK+ cells in vitro in a dose and time-dependent manner, most importantly, facilitated both prevention and ablation of tumors in vivo. Furthermore, comparative analysis between transduced hiPSCs and hESCs showed that there was no difference in ganciclovir sensitivity between them. This approach may help to develop safety strategies for clinical application of hiPSCs in regenerative medicine in the future. [Copyright &y& Elsevier]

The roles of fossil human populations in the origin of modern humans have been enigmatic. Earlier (archaic) human populations were biologically similar and were in recurrent temporal and geographic contact, making interbreeding between ancient populations likely. Regardless of the taxonomic status of these populations, adaptive alleles may have introgressed from archaic populations into modern humans. When an introgressed archaic allele has a selective advantage, even rare interbreeding can lead to its spread or fixation in later human populations. Several genetic loci are candidates for such introgression, including microcephalin, a gene influencing brain development. This example may suggest that the evolution of human cognition depended in part on the genetic legacy of archaic groups such as the Neanderthals. [Copyright &y& Elsevier]

The gene Microcephalin (MCPH1) regulates brain size and has evolved under strong positive selection in the human evolutionary lineage. We show that one genetic variant of Microcephalin in modern humans, which arose ∼37,000 years ago, increased in frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection, although the exact nature of the selection is unknown. The finding that an important brain gene has continued to evolve adaptively in anatomically modem humans suggests the ongoing evolutionary plasticity of the human brain. It also makes Microcephalin an attractive candidate locus for studying the genetics of human variation in brain-related phenotypes. [ABSTRACT FROM AUTHOR]

The telomeric region of chromosome 9p is paralogous to the pericentromeric regions of chromosome 9 as well as to 2q13, the site of an ancestral telomere–telomere fusion. These paralogous regions span approximately 200 kb and contain seven transcriptional units, including the previously identified CBWD, FOXD4, PGM5, F379, CXYorf1, and two human Unigene clusters, Hs.115173 and Hs.189160. Within these gene duplicates, the number of expressed paralogous loci varies, from one in PGM5 to all three in CBWD and Hs.115173. FOXD4 shows the most dramatic changes among its paralogs. Two independent insertion/deletion changes created four different carboxy ends of these intronless genes, two of which are within the 2q13 locus. A comparison of KA/KS values among functional paralogs shows these genes evolved rapidly in primates. This study shows the importance of paralogous regions in the generation of transcriptional diversity and highlights the significance that large-scale telomeric duplication may play in this process. [Copyright &y& Elsevier]