Genetic differences between humans and great apes

The remarkable similarity among the genomes of humans and the African great apes could warrant their classification together as a single genus. However, whereas there are many similarities in the biology, life history, and behavior of humans and great apes, there are also many striking differences that need to be explained. The complete sequencing of the human genome creates an opportunity to ask which genes are involved in those differences. A logical approach would be to use the chimpanzee genome for comparison and the other great ape genomes for confirmation. Until such a great ape genome project can become reality, the next best approach must be educated guesses of where the genetic differences may lie and a careful analysis of differences that we do know about. Our group recently discovered a human-specific inactivating mutation in the CMP-sialic acid hydroxylase gene, which results in the loss of expression of a common mammalian cell-surface sugar throughout all cells in the human body. We are currently investigating the implications of this difference for a variety of issues relevant to humans, ranging from pathogen susceptibility to brain development. Evaluating the uniqueness of this finding has also led us to explore the existing literature on the broader issue of genetic differences between humans and great apes. The aim of this brief review is to consider a listing of currently known genetic differences between humans and great apes and to suggest avenues for future research. The differences reported between human and great ape genomes include cytogenetic differences, differences in the type and number of repetitive genomic DNA and transposable elements, abundance and distribution of endogenous retroviruses, the presence and extent of allelic polymorphisms, specific gene inactivation events, gene sequence differences, gene duplications, single nucleotide polymorphisms, gene expression differences, and messenger RNA splicing variations. Evaluation of the reported findings in all these categories indicates that the CMP-sialic hydroxylase mutation is the only one that has so far been shown to result in a global biochemical and structural difference between humans and great apes. Several of the other known genetic dissimilarities deserve more exploration at the functional level. Among the areas of focus for the future should be genes affecting development, mental maturation, reproductive biology, and other aspects of life history. The approaches taken should include both going from the genome up to the adaptive potential of the organisms and going from novel adaptive regimes down to the relevant repercussions in the genome. Also, as much as we desire a simple genetic explanation for the human phenomenon, it is much more probable that our evolution occurred in multiple genetic steps, many of which must have left detectable footprints in our genomes. Ultimately, we need to know the exact number of genetic steps, the order in which they occurred, and the temporal, spatial, environmental, and cultural contexts that determined their impact on human evolution.     

Identifying host targets for drug development with knowledge from genome-wide studies: lessons from HIV-AIDS

Advances in human genomics are now being effectively applied to the search for host factors underlying susceptibility to common diseases. From the steady stream of studies showing association of host genetic factors with viral diseases, it has become clear that host factors contribute substantially to the variability of viral infections in humans. Candidate gene studies that seek to show associations between single-nucleotide polymorphisms (SNPs) with a disease outcome have predominated, but whole-genome association studies (GWAS) have recently appeared. A major goal of these studies is to understand how human genetic variation contributes to individual differences in susceptibility and to exploit this knowledge for targeted drug development.     

Genetic epidemiology: Systemic lupus erythematosus

Systemic lupus erythematosus is the prototype multisystem autoimmune disease. A strong genetic component of susceptibility to the disease is well established. Studies of murine models of systemic lupus erythematosus have shown complex genetic interactions that influence both susceptibility and phenotypic expression. These models strongly suggest that several defects in similar pathways, e.g. clearance of immune complexes and/or apoptotic cell debris, can all result in disease expression. Studies in humans have found linkage to several overlapping regions on chromosome 1q, although the precise susceptibility gene or genes in these regions have yet to be identified. Recent studies of candidate genes, including Fcγ receptors, IL-6, and tumour necrosis factor-α, suggest that in human disease, genetic factors do play a role in disease susceptibility and clinical phenotype. The precise gene or genes involved and the strength of their influence do, however, appear to differ considerably in different populations.     

FcrRIIA基因多态性与牙周炎关系的研究进展

牙周炎是一种由菌斑引起的以牙周软组织和牙槽骨破坏为特征的慢性感染性疾病,其病因尚不明确,目前普遍认为是细菌 感染和宿主防御相互作用的结果,受遗传有关的宿主易感性、环境、行为因素的影响。致病菌的存在是牙周炎发生的必要条件,基 因因素影响宿主在应对细菌免疫应答过程中的强度,从而导致不同程度的牙周组织破坏。许多有关牙周炎基因方面的研究把目 光对准了在免疫调节和新陈代谢中发挥重要作用的物质的基因多态性,比如细胞因子、细胞表面受体、趋化因子、酶以及其他与 抗原识别有关的物质。FcrR 就是其中之一。FcrR 属于免疫球蛋白超家族,主要有FcrRI、FcrRII、FcrRIII 三类,大量研究表明 FcrRIIA 基因多态性与牙周炎的易感性有关。在针对不同种族的调查中,Fc酌RIIA 基因多态性与牙周炎的易感性的研究结果不尽 相同。也提示我们基因多态性的等位基因频率在各个种族之间存在差异,这种基因标识在界定牙周炎病因和预后方面的相关应 用会变得有所不同。基因诊断将会成为未来牙周病预防和治疗的新方向。本文主要对近年来FcrRIIA 基因多态性与牙周炎关系 的研究进展进行了综述。     

Genetic susceptibility to infection with human papillomavirus and development of cervical cancer in women in Brazil

Human papillomavirus (HPV) is considered to be a necessary but not sufficient cause for cervical cancer and, therefore, other factors contribute to the carcinogenic process. A hereditary component for this neoplasia has been reported and several studies indicate that genetic background of the host is important for cervical cancer susceptibility. Among genetic factors that could participate in the susceptibility to this tumor and disease outcome, polymorphic genes of the major histocompatibility complex (MHC), as well as a particular polymorphism in the p53 gene have been intensely investigated. From our analysis of 613 samples in Brazil, we found evidence to indicate that different polymorphic human leukocyte antigen (HLA) genes are involved in the clearance and maintenance of HPV infection. In addition, the homozygous codon 72 p53-Arg gene allele is associated with susceptibility to HPV-associated cervical carcinogenesis. However, supportive and opposing data have been reported in different populations. Therefore, international collaborative studies need to be conducted to define the consistency of the associations described.     

Quantitative trait loci in a bacterially induced model of inflammatory bowel disease

Inflammatory bowel diseases (IBDs) are complex disorders caused by a combination of environmental, microbial, and genetic factors. Genome-wide association studies in humans have successfully identified multiple genes and loci associated with disease susceptibility, but the mechanisms by which these loci interact with each other and/or with environmental factors (i.e., intestinal microbiota) to cause disease are poorly understood. Helicobacter hepaticus-induced intestinal inflammation in mice is an ideal model system for elucidating the genetic basis of IBD susceptibility in a bacterially induced system, as there are significant differences in H. hepaticus-induced disease susceptibility among inbred mouse strains. Infected A/J mice develop acute overexpression of proinflammatory cytokines followed 2?C3?months later by chronic cecal inflammation, whereas infected C57BL/6 mice fail to develop cecal inflammation or increased cytokine expression. The goal of this project was to use quantitative trait locus (QTL) mapping to evaluate genetic factors that contribute to the differential disease susceptibility between these two mouse strains. Using acute cecal IL-12/23p40 expression as a biomarker for disease susceptibility, QTL analysis of H. hepaticus-infected F₂ mice revealed involvement of multiple loci. The loci with the strongest association were located on Chromosome 3 and Chromosome 17, with logarithm of odds (LOD) scores of 6.89 and 3.09, respectively. Cecal expression of IL-12/23p40 in H. hepaticus-infected C57BL/6J-Chr3^A/J/NaJ chromosome substitution mice had an intermediate phenotype, significantly higher than in resistant C57BL/6 but lower than in susceptible A/J mice, confirming the importance of this locus to the immune response to H. hepaticus infection.     

HLA-F研究进展

人类白细胞抗原（human leucocyte antigen,HLA）复合体是人体中基因多态性最高的基因复合体,其多态性与疾病遗传易感性显著相关。人类白细胞抗原-F（human leucocyte antigen-F,HLA-F）属于非经典HLA I类分子中的一员,与HLA-E、-G在结构上十分相似,具有有限的多态性。近年来多数学者聚焦于HLA-F基因转录及分子表达调控、HLA-F表达与临床相关性及HLA-F抗体研制,且取得了重要成果。就HLA-F的研究进展作一综述。     

Meta-analysis for microarray studies of the genetics of complex traits

In comparison to other complex disease traits, alcoholism and alcohol abuse are influenced by the combined effects of many genes that alter susceptibility, phenotypic expression and associated morbidity, respectively. Many genetic studies, in both animal models and humans, have identified genetic intervals containing genes that influence alcoholism or behavioral responses to ethanol. Concurrently, a growing number of microarray studies have identified gene expression differences related to ethanol drinking or other ethanol behaviors. However, concerns about the statistical power of these experiments, combined with the complexity of the underlying phenotypes, have greatly hampered the identification of candidate genes underlying ethanol behaviors. Meta-analysis approaches using recent compilations of large datasets of microarray, behavioral and genetic data promise improved statistical power for detecting the genes or gene networks affecting ethanol behaviors and other complex traits.     

Multiple changes in sialic acid biology during human evolution

Humans are genetically very similar to “great apes”, (chimpanzees, bonobos, gorillas and orangutans), our closest evolutionary relatives. We have discovered multiple genetic and biochemical differences between humans and these other hominids, in relation to sialic acids and in Siglecs (Sia-recognizing Ig superfamily lectins). An inactivating mutation in the CMAH gene eliminated human expression of N-glycolylneuraminic acid (Neu5Gc) a major sialic acid in “great apes”. Additional human-specific changes have been found, affecting at least 10 of the <60 genes known to be involved in the biology of sialic acids. There are potential implications for unique features of humans, as well as for human susceptibility or resistance to disease. Additionally, metabolic incorporation of Neu5Gc from animal-derived materials occurs into biotherapeutic molecules and cellular preparations - and into human tissues from dietary sources, particularly red meat and milk products. As humans also have varying and sometime high levels of circulating anti-Neu5Gc antibodies, there are implications for biotechnology products, and for some human diseases associated with chronic inflammation.     

Historical connectivity,contemporary isolation and local adaptation in a widespread but discontinuously distributed species endemic to Taiwan,Rhododendron oldhamii (Ericaceae)

Elucidation of the evolutionary processes that constrain or facilitate adaptive divergence is a central goal in evolutionary biology, especially in non-model organisms. We tested whether changes in dynamics of gene flow (historical vs contemporary) caused population isolation and examined local adaptation in response to environmental selective forces in fragmented Rhododendron oldhamii populations. Variation in 26 expressed sequence tag-simple sequence repeat loci from 18 populations in Taiwan was investigated by examining patterns of genetic diversity, inbreeding, geographic structure, recent bottlenecks, and historical and contemporary gene flow. Selection associated with environmental variables was also examined. Bayesian clustering analysis revealed four regional population groups of north, central, south and southeast with significant genetic differentiation. Historical bottlenecks beginning 9168–13,092 years ago and ending 1584–3504 years ago were revealed by estimates using approximate Bayesian computation for all four regional samples analyzed. Recent migration within and across geographic regions was limited. However, major dispersal sources were found within geographic regions. Altitudinal clines of allelic frequencies of environmentally associated positively selected outliers were found, indicating adaptive divergence. Our results point to a transition from historical population connectivity toward contemporary population isolation and divergence on a regional scale. Spatial and temporal dispersal differences may have resulted in regional population divergence and local adaptation associated with environmental variables, which may have played roles as selective forces at a regional scale.     

Induced gene expression in human brain after the split from chimpanzee

Despite only approximately 1% difference in genomic DNA sequence, humans and chimpanzees differ considerably in mental and linguistic capabilities, and in susceptibility to some diseases. A recent comparison of gene expression in human and great apes cast some light on the genetic basis of these differences, but more rigorous study is required. Our statistical reanalysis of these microarray data shows that there have indeed been dramatic alterations in the expression of genes in the human brain since the split from chimpanzees, mainly caused by a set of genes with increased (rather than decreased) expression in the human brain.     

Identification of Genetic Determinants of the Sexual Dimorphism in CNS Autoimmunity

Multiple sclerosis (MS) is a debilitating chronic inflammatory disease of the nervous system that affects approximately 2.3 million individuals worldwide, with higher prevalence in females, and a strong genetic component. While over 200 MS susceptibility loci have been identified in GWAS, the underlying mechanisms whereby they contribute to disease susceptibility remains ill-defined. Forward genetics approaches using conventional laboratory mouse strains are useful in identifying and functionally dissecting genes controlling disease-relevant phenotypes, but are hindered by the limited genetic diversity represented in such strains. To address this, we have combined the powerful chromosome substitution (consomic) strain approach with the genetic diversity of a wild-derived inbred mouse strain. Using experimental allergic encephalomyelitis (EAE), a mouse model of MS, we evaluated genetic control of disease course among a panel of 26 consomic strains of mice inheriting chromosomes from the wild-derived PWD strain on the C57BL/6J background, which models the genetic diversity seen in human populations. Nineteen linkages on 18 chromosomes were found to harbor loci controlling EAE. Of these 19 linkages, six were male-specific, four were female-specific, and nine were non-sex-specific, consistent with a differential genetic control of disease course between males and females. An MS-GWAS candidate-driven bioinformatic analysis using orthologous genes linked to EAE course identified sex-specific and non-sex-specific gene networks underlying disease pathogenesis. An analysis of sex hormone regulation of genes within these networks identified several key molecules, prominently including the MAP kinase family, known hormone-dependent regulators of sex differences in EAE course. Importantly, our results provide the framework by which consomic mouse strains with overall genome-wide genetic diversity, approximating that seen in humans, can be used as a rapid and powerful tool for modeling the genetic architecture of MS. Moreover, our data represent the first step towards mechanistic dissection of genetic control of sexual dimorphism in CNS autoimmunity.     

Human-Specific Integrations of the HERV-K Endogenous Retrovirus Family

Several distinct families of endogenous retrovirus-like sequences (HERVs) exist in the genomes of humans and other primates. One of these families, the HERV-K group, contains members that encode functional proteins and that have been implicated in the etiology of insulin-dependent diabetes mellitus (IDDM). Because of potential functional and disease relevance, it is important to determine if there are HERV-K-associated genetic differences between individuals. In this study, we have investigated the divergence and evolutionary age of HERV-K long terminal repeats (LTRs). Thirty-seven LTRs, taken primarily from random human clones in GenBank, were aligned and grouped into nine clusters with decreasing sequence divergence. Cluster 1 sequences are 8.6% divergent, on average, whereas cluster 9 LTRs, represented by the LTRs of the fully sequenced HERV-K10 clone, show an average of only 1.1% divergence from each other. The evolutionary age of 18 LTRs from different clusters was then investigated by genomic PCR to determine presence or absence of the retroviral element in different primate species. LTRs from clusters of higher divergence were detected in monkeys and apes, whereas LTRs in clusters with lower divergence were acquired later in evolution. Notably, LTRs of cluster 9 were found only in humans at all nine loci examined. Genomic Southern analysis with an oligonucleotide probe specific for cluster 9 LTRs suggests that HERV-K elements with this type of LTR expanded independently in the genomes of humans and the great apes. This is the first report of endogenous retroviral integrations that are specific to humans and indicates that some HERVs have amplified much later than previously thought. These elements may still be actively transposing and may therefore represent a source of genetic variation linked to disease development.     

Adaptive differences in gene expression in European flounder (Platichthys flesus)

Population structure was previously believed to be very limited or absent in classical marine fishes, but recently, evidence of weakly differentiated local populations has been accumulating using noncoding microsatellite markers. However, the evolutionary significance of such minute genetic differences remains unknown. Therefore, in order to elucidate the relationship between genetic markers and adaptive divergence among populations of marine fishes, we combined cDNA microarray and microsatellite analysis in European flounders (Platichthys flesus). We demonstrate that despite extremely low levels of neutral genetic divergence, a high number of genes were significantly differentially expressed between North Sea and Baltic Sea flounders maintained in a long-term reciprocal transplantation experiment mimicking natural salinities. Several of the differentially regulated genes could be directly linked to fitness traits. These findings demonstrate that flounders, despite little neutral genetic divergence between populations, are differently adapted to local environmental conditions and imply that adaptation in gene expression could be common in other marine organisms with similar low levels of population subdivision.     

Microsatellite and morphometric variation in Drosophila gouveai: the relative importance of historical and current factors in shaping the genetic population structure

Drosophila gouveai is a cactus-breeding species with a naturally fragmented distribution in central-western and southeastern Brazil. In this study, a neutral genetic marker (microsatellite DNA) and a quantitative trait (wing morphology) were used to investigate the population structure of eight populations of D. gouveai . Quantitative analysis was done using a morphometric approach and multivariate analysis of 17 wing parameters. Drosophila gouveai showed a large degree of genetic population differentiation ( F _ST = 0.245). A molecular analysis of variance showed that the population structure was attributable mainly to genetic differences among the population groups, which were correlated with regional groupings. A Bayesian cluster analysis also identified the same regional groupings as contributing to the population structure. Assignment tests revealed that the current gene flow was very restricted. The divergence in wing morphology among populations was also high, and revealed a geographical pattern that conformed to a latitudinal cline. In contrast to current factors such as migration-drift equilibrium, these results indicated that the genetic population structure of D. gouveai was shaped predominantly by historical factors.