Did natural selection for increased cognitive ability in humans lead to an elevated risk of cancer?

Despite the overall genetic similarity that exists between humans and chimpanzees, the species are phenotypically distinct. Among the most notable distinctions are differences in brain size and cognitive abilities. Previous studies have shown that significant differences in gene expression exist between the human and chimpanzee brain. Integration of currently available gene expression data with known metabolic and signaling pathways indicates that the expression of genes involved in the programmed cell death of brain neurons is significantly different between humans and chimpanzees and predictive of a reduced level of neuron apoptosis in the human brain. This pattern of expression is generally maintained in other human organs suggesting that apoptosis is reduced in humans relative to chimpanzees. We propose that a decreased rate of programmed neuron death may have been a consequence of selection for increased cognitive ability in humans. Since reduced apoptotic function is associated with an increased risk of cancer and related diseases, we hypothesize that selection for increased cognitive ability in humans coincidently resulted in an increased risk of cancer and other diseases associated with reduced apoptotic function.     

Testing the chromosomal speciation hypothesis for humans and chimpanzees

Fixed differences of chromosomal rearrangements between isolated populations may promote speciation by preventing between-population gene flow upon secondary contact, either because hybrids suffer from lowered fitness or, more likely, because recombination is reduced in rearranged chromosomal regions. This chromosomal speciation hypothesis thus predicts more rapid genetic divergence on rearranged than on colinear chromosomes because the former are less porous to gene flow. A number of studies of fungi, plants, and animals, including limited genetic data of humans and chimpanzees, support the hypothesis. Here we reexamine the hypothesis for humans and chimpanzees with substantially more genomic data than were used previously. No difference is observed between rearranged and colinear chromosomes in the level of genomic DNA sequence divergence between species. The same is also true for protein sequences. When the gorilla is used as an outgroup, no acceleration in protein sequence evolution associated with chromosomal rearrangements is found. Furthermore, divergence in expression pattern between orthologous genes is not significantly different for rearranged and colinear chromosomes. These results, showing that chromosomal rearrangements did not affect the rate of genetic divergence between humans and chimpanzees, are expected if incipient species on the evolutionary lineages separating humans and chimpanzees did not hybridize.     

肿瘤细胞中基因选择性剪接的研究进展

选择性剪接是高等真核细胞在转录后水平调控基因表达以及产生蛋白质组多样性的重要机制。选择性剪接过程受多种顺式作用元件和反式作用因子相互作用调节。肿瘤癌基因、抑癌基因、肿瘤转移抑制基因可发生选择性剪接，与肿瘤发生发展关系密切，其蛋白异构体参与基因转录、细胞周期和凋亡等生命过程，对肿瘤生长有一定作用。以选择性剪接蛋白异构体为靶点或干预选择性剪接过程，可望进行肿瘤的分子治疗。     

Copy number variation and evolution in humans and chimpanzees

Copy number variants (CNVs) underlie many aspects of human phenotypic diversity and provide the raw material for gene duplication and gene family expansion. However, our understanding of their evolutionary significance remains limited. We performed comparative genomic hybridization on a single human microarray platform to identify CNVs among the genomes of 30 humans and 30 chimpanzees as well as fixed copy number differences between species. We found that human and chimpanzee CNVs occur in orthologous genomic regions far more often than expected by chance and are strongly associated with the presence of highly homologous intrachromosomal segmental duplications. By adapting population genetic analyses for use with copy number data, we identified functional categories of genes that have likely evolved under purifying or positive selection for copy number changes. In particular, duplications and deletions of genes with inflammatory response and cell proliferation functions may have been fixed by positive selection and involved in the adaptive phenotypic differentiation of humans and chimpanzees.     

The role of the FcepsilonRI beta-chain in allergic diseases

The high affinity receptor for IgE, FcepsilonRI, is a multimeric surface receptor that is expressed exclusively as a tetramer on rodent cells, but exists as a tetramer or trimer on human cells. The tetrameric form is expressed on effector cells of allergic responses such as mast cells and basophils and is composed of an IgE-binding alpha-subunit, a beta-subunit and a gamma-subunit dimer. Complexes lacking the beta-subunit are found on human antigen-presenting cells. On mast cells and basophils, FcepsilonRI is essential for IgE-mediated acute allergic reactions. Crosslinking of FcepsilonRI by IgE and multivalent antigen induces a signaling cascade that culminates in the release of preformed mediators and the synthesis of lipid mediators and cytokines. The beta-subunit functions as an amplifier of FcepsilonRI expression and signaling. As a consequence, strongly enhanced mast cell effector functions and in vivo allergic reactions can be observed in the presence of FcepsilonRIbeta. In contrast, a truncated beta-isoform (betaT) that is produced by alternative splicing acts as an inhibitor of FcepsilonRI surface expression. Thus, by producing two proteins with antagonistic functions, the FcepsilonRIbeta gene could serve as a potent regulator of allergic responses. In addition, the genomic region encompassing the beta-chain has been linked to atopy and a number of polymorphisms within the FcepsilonRIbeta gene are associated with various atopic diseases. It remains to be elucidated how these polymorphisms might affect the allergic phenotype. These functions of the beta-chain together with the described genetic linkages to atopy make it a candidate for a role in the pathophysiology of allergic diseases.     

Alternative RNA splicing in the nervous system

Tissue-specific alternative splicing profoundly effects animal physiology, development and disease, and this is nowhere more evident than in the nervous system. Alternative splicing is a versatile form of genetic control whereby a common pre-mRNA is processed into multiple mRNA isoforms differing in their precise combination of exon sequences. In the nervous system, thousands of alternatively spliced mRNAs are translated into their protein counterparts where specific isoforms play roles in learning and memory, neuronal cell recognition, neurotransmission, ion channel function, and receptor specificity. The essential nature of this process is underscored by the finding that its misregulation is a common characteristic of human disease. This review highlights the current views of the biological phenomenon of alternative splicing, and describes evidence for its intricate underlying biochemical mechanisms. The roles of RNA binding proteins and their tissue-specific properties are discussed. Why does alternative splicing occur in cosmic proportions in the nervous system? How does it affect integrated cellular functions? How are region-specific, cell-specific and developmental differences in splicing directed? How are the control mechanisms that operate in the nervous system distinct from those of other tissues? Although there are many unanswered questions, substantial progress has been made in showing that alternative splicing is of major importance in generating proteomic diversity, and in modulating protein activities in a temporal and spatial manner. The relevance of alternative splicing to diseases of the nervous system is also discussed.     

Analyses of human-chimpanzee orthologous gene pairs to explore evolutionary hypotheses of aging

Compared to chimpanzees (Pan troglodytes), the onset of aging appears to be delayed in the human species. Herein, we studied human-chimpanzee orthologous gene pairs to investigate the selective forces acting on genes associated with aging in different model systems, which allowed us to explore evolutionary hypotheses of aging. Our results show that aging-associated genes tend to be under purifying selection and stronger-than-average functional constraints. We found little evidence of accelerated evolution in aging-associated genes in the hominid or human lineages, and pathways previously related to aging were largely conserved between humans and chimpanzees. In particular, genes associated with aging in non-mammalian model organisms and cellular systems appear to be under stronger functional constraints than those associated with aging in mammals. One gene that might have undergone rapid evolution in hominids is the Werner syndrome gene. Overall, our findings offer novel insights regarding the evolutionary forces acting on genes associated with aging in model systems. We propose that genes associated with aging in model organisms may be part of conserved pathways related to pleiotropic effects on aging that might not regulate species differences in aging.     

Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques

Over the course of ontogenesis, the human brain and human cognitive abilities develop in parallel, resulting in a phenotype strikingly distinct from that of other primates. Here, we used microarrays and RNA-sequencing to examine human-specific gene expression changes taking place during postnatal brain development in the prefrontal cortex and cerebellum of humans, chimpanzees, and rhesus macaques. We show that the most prominent human-specific expression change affects genes associated with synaptic functions and represents an extreme shift in the timing of synaptic development in the prefrontal cortex, but not the cerebellum. Consequently, peak expression of synaptic genes in the prefrontal cortex is shifted from <1 yr in chimpanzees and macaques to 5 yr in humans. This result was supported by protein expression profiles of synaptic density markers and by direct observation of synaptic density by electron microscopy. Mechanistically, the human-specific change in timing of synaptic development involves the MEF2A-mediated activity-dependent regulatory pathway. Evolutionarily, this change may have taken place after the split of the human and the Neanderthal lineages.     

Copy number polymorphism and expression level variation of the human alpha-defensin genes DEFA1 and DEFA3

We have defined unexpectedly extensive copy number variation at the human anti-microbial alpha-defensin genes DEFA1 and DEFA3, encoding human neutrophil peptides HNP-1, HNP-2 and HNP-3. There was variation in both number and position of DEFA1/DEFA3 genes in arrays of 19 kb tandem repeats on 8p23.1, so that the DEFA1 and DEFA3 genes appear to be interchangeable variant cassettes within tandem gene arrays. For this reason, the official symbol for this locus has been revised to DEFA1A3. The total number of gene copies per diploid genome varied between four and 11 in a sample of 111 control individuals from the UK, with approximately 10% (11/111) of people lacking DEFA3 completely. DEFA1 appeared to be at high copy number in all great apes studied; at one variable site in the repeat unit, both variants have persisted in humans, chimpanzees and gorillas since their divergence. Analysis of expression levels in human white blood cells showed a clear correlation between the relative proportions of DEFA1:DEFA3 mRNA and corresponding gene numbers. However, there was no relationship between total (DEFA1+DEFA3) mRNA levels and total gene copy number, suggesting the superimposed influence of trans-acting factors. The persistence of DEFA1 at high copy number in other apes suggests an alternative model for the early stages of the evolution of novel genes by duplication and divergence. Duplicated genes present in variant tandem arrays may have greater potential than simple duplications for the combinatorial creation of new functions by recombination and gene conversion, while still preserving pre-existing functions on the same haplotype.     

The chemokine network. II. On how polymorphisms and alternative splicing increase the number of molecular species and configure intricate patterns of disease susceptibility

In this second review on chemokines, we focus on the polymorphisms and alternative splicings and on their consequences in disease. Because chemokines are key mediators in the pathogenesis of inflammatory, autoimmune, vascular and neoplastic disorders, a large number of studies attempting to relate particular polymorphisms of chemokines to given diseases have already been conducted, sometimes with contradictory results. Reviewing the published data, it becomes evident that some chemokine genes that are polymorphic have alleles that are found repeatedly, associated with disease of different aetiologies but sharing some aspects of pathogenesis. Among CXC chemokines, single nucleotide polymorphisms (SNPs) in the CXCL8 and CXCL12 genes stand out, as they have alleles associated with many diseases such as asthma and human immunodeficiency virus (HIV), respectively. Of CC chemokines, the stronger associations occur among alleles from SNPs in CCL2 and CCL5 genes and a number of inflammatory conditions. To understand how chemokines contribute to disease it is also necessary to take into account all the isoforms resulting from differential splicing. The first part of this review deals with polymorphisms and the second with the diversity of molecular species derived from each chemokine gene due to alternative splicing phenomena. The number of molecular species and the level of expression of each of them for every chemokine and for each functionally related group of chemokines reaches a complexity that requires new modelling algorithms akin to those proposed in systems biology approaches.     

Linkage disequilibrium between human leukocyte antigen (HLA) class II and HLA-G--possible implications for human reproduction and autoimmune disease

A line of investigation indicates that one or several genes in the human major histocompatibility complex (MHC) influences reproductive success. Studies have revealed associations between human leukocyte antigen (HLA) class II genes and risk of recurrent spontaneous abortion (RSA) and pre-eclampsia. However, these genes are not expressed at the feto-maternal interface. Furthermore, associations between polymorphisms in the nonclassical HLA class Ib gene, HLA-G, and reproductive outcome have been demonstrated. HLA-G is expressed by extravillous trophoblast during pregnancy, making it a more obvious candidate gene for a possible influence on pregnancy outcome. HLA-G has immunomodulatory functions. We have studied linkage disequilibrium between HLA class II genes, primarily HLA-DRB1 alleles, and HLA-G alleles in women with RSA and their partners (n = 103) and in control women and their partners (n = 92). We found a significant linkage disequilibrium between HLA-DR3 and HLA-G*010102 in both the RSA and control populations. For all four studied HLA loci, the alleles in the haplotype HLA-DRB1*03.DQA1*05.DQB1*02.G*010102 was in clear linkage disequilibrium. This HLA haplotype has repeatedly been associated with different autoimmune diseases but also with RSA. The G*010102 allele includes a 14-bp sequence polymorphism in the 3' untranslated region of the gene, which has been associated with differences in HLA-G mRNA alternative splicing and stability. This 14-bp polymorphism has also been associated with RSA, pre-eclampsia, and outcome of in vitro fertilization. Implications of HLA polymorphism--and other polymorphic genes in the MHC for pregnancy outcome--and for autoimmune diseases during pregnancy are discussed.