Chromosomal assignment of 20 candidate genes for canine congenital sensorineural deafness by FISH and RH mapping

The analysis of inherited diseases in the domestic dog (Canis familiaris) provides a resource for the continued use of this species as a model system for human diseases. Many different dog breeds are affected by congenital sensorineural deafness. Since mutations in various genes have already been found causative for sensorineural hearing impairment in humans or mice, 20 of these genes were considered as candidates for deafness in dogs. For each of the candidate genes a canine BAC clone was isolated by screening with heterologous human or murine cDNA probes. The gene-containing BAC clones were physically assigned to the canine genome by FISH and the BAC-derived STS-markers were positioned with the RHDF5000 panel on the canine RH map. The mapping data, which confirm the established conservation of synteny between canine and human chromosomes, provide a resource for further association studies in segregating canine populations and the basis for new insights into this common canine and human disease.     

Gene mapping in isolated populations: new roles for old friends?

Population isolates are increasingly being used in attempts to map genes underlying complex diseases. To further explore the utility of isolates for this purpose, we explore linkage disequilibrium patterns in polymorphisms from two regions (VWF and NF1) in three isolated populations from Finland. At the NF1 locus, the Finnish populations have greater pairwise disequilibrium than populations from Africa, Asia, or northern Europe. However, populations from 'New Finland' and 'Old Finland' do not differ in their disequilibrium levels at either the NF1 or the VWF locus. In addition, disequilibrium patterns and haplotype diversity do not differ between a sample from the Aland Islands, Finland, and a collection of outbred Centre d'Etude du Polymorphisme Humain families. These results show that linkage disequilibrium patterns sometimes differ among populations with different histories and founding dates, but some putative isolated populations may not significantly differ from larger admixed populations. We discuss factors that should be considered when using isolated populations in gene-mapping studies.     

Pleiotropic Effects of Immune Responses Explain Variation in the Prevalence of Fibroproliferative Diseases

Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait. Patterns of pleiotropy may be helpful in understanding the underlying causes of an array of conditions in a population. For example, several fibroproliferative diseases are more prevalent and severe in populations of sub-Saharan ancestry. We propose that this disparity is due to selection for an enhanced Th2 response that confers resistance to helminthic infections, and concurrently increases susceptibility to fibrosis due to the profibrotic action of Th2 cytokines. Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated. We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases.     

Recent progress in the genetics of generalized vitiligo

Vitiligo is an acquired disease characterized principally by patchy depigmentation of skin and overlying hair. Generalized vitiligo (GV), the predominant form of the disorder, results from autoimmune loss of melanocytes from affected regions. GV is a “complex trait”, inherited in a non-Mendelian polygenic, multifactorial manner. GV is epidemiologically associated with other autoimmune diseases, both in GV patients and in their close relatives, suggesting that shared genes underlie susceptibility to this group of diseases. Early candidate gene association studies yielded a few successes, such as PTPN22, but most such reports now appear to be false-positives. Subsequent genomewide linkage studies identified NLRPI and XBPI, apparent true GV susceptibility genes involved in immune regulation, and recent genome-wide association studies (GWAS) of GV in Caucasian and Chinese populations have yielded a large number of additional validated GV susceptibility genes.Together, these genes highlight biological systems and pathways that reach from the immune cells to the melanocyte, and provide insights into both disease pathogenesis and potential new targets for both treatment and even prevention of GV and other autoimmune diseases in genetically susceptible individuals.     

Diversity of killer cell immunoglobulin-like receptor genes in four ethnic groups in China

Killer cell immunoglobulin-like receptors (KIRs) show extensive variation in terms of gene content and allelic polymorphisms among different populations. The aim of this study was to analyze the distribution of KIR genes in the Bulang, Nu, Yugu, and Zhuang ethnic groups, which belong to four different language families in China, and thus to provide basic KIR gene and genotype data for these Chinese ethnic groups. Genotyping of 16 KIR genes was performed in 425 unrelated individuals using the polymerase chain reaction-sequence-specific oligonucleotide probe method with the Luminex MultiAnalyte Profiling System. The four framework KIR genes were detected in all four ethnic groups. The activating KIR genes as well as the inhibitory KIR genes showed extreme diversity among these four populations. A total of 35 distinct KIR genotypes were identified, one of which was previously unknown. The four most common genotypes were identified in all four populations and comprised 66.1~91.1% of all the genotypes. The group A haplotype occurred more frequently than the group B haplotype in the Nu, Yugu, and Zhuang populations, as in other East Asian populations. In contrast, the group A and group B haplotypes occurred equally in the Bulang population. The results of the present study suggested that the KIR genes and genotypes are diverse in these four ethnic groups, and each ethnic group has its own characteristic KIR distribution. The findings with respect to KIR gene diversity in these four populations should provide relevant genomic diversity data for the future study of viral infections, autoimmune diseases, and reproductive fitness.     

高血压易感基因的分子进化

利用家系连锁分析、候选基因法及全基因组关联研究均未能有效发现普通人群的高血压易感基因或位点。遗传学研究表明, 人类许多疾病易感性的形成与走出非洲时的环境适应性进化密切相关, 这为高血压遗传学研究提供了新思路。文章系统综述了高血压易感基因分子进化研究的理论基础和最新进展, 介绍了本研究小组运用分子进化思路在中国汉族人群高血压遗传学研究中的发现, 对未来的研究方向进行了展望, 以期为高血压和其他疾病的遗传学研究提供参考。     

Comparative genomics of Helicobacter pylori strains of China associated with different clinical outcome

In this study, a whole-genome CombiMatrix Custom oligonucleotide tiling microarray with 90,000 probes covering six sequenced Helicobacter pylori (H. pylori) genomes was designed. This microarray was used to compare the genomic profiles of eight unsequenced strains isolated from patients with different gastroduodenal diseases in Heilongjiang province of China. Since significant genomic variation was found among these strains, an additional 76 H. pylori strains associated with different clinical outcomes were isolated from various provinces of China. These strains were tested by polymerase chain reaction to demonstrate this distinction. We identified several highly variable regions in strains associated with gastritis, gastric ulceration, and gastric cancer. These regions are associated with genes involved in the bacterial type I, type II, and type III R-M systems. They were also associated with the virB gene, which lies on the well-studied cag pathogenic island. While previous studies have reported on the diverse genetic characterization of this pathogenic island, in this study, we find that it is conserved in all strains tested by microarray. Moreover, a number of genes involved in the type IV secretion system, which is related to horizontal DNA transfer between H. pylori strains, were identified in the comparative analysis of the strain-specific genes. These findings may provide insight into new biomarkers for the prediction of gastric diseases.     

Genetic Variation in TLR Genes in Ugandan and South African Populations and Comparison with HapMap Data

Genetic epidemiological studies of complex diseases often rely on data from the International HapMap Consortium for identification of single nucleotide polymorphisms (SNPs), particularly those that tag haplotypes. However, little is known about the relevance of the African populations used to collect HapMap data for study populations conducted elsewhere in Africa. Toll-like receptor (TLR) genes play a key role in susceptibility to various infectious diseases, including tuberculosis. We conducted full-exon sequencing in samples obtained from Uganda (n = 48) and South Africa (n = 48), in four genes in the TLR pathway: TLR2, TLR4, TLR6, and TIRAP. We identified one novel TIRAP SNP (with minor allele frequency [MAF] 3.2%) and a novel TLR6 SNP (MAF 8%) in the Ugandan population, and a TLR6 SNP that is unique to the South African population (MAF 14%). These SNPs were also not present in the 1000 Genomes data. Genotype and haplotype frequencies and linkage disequilibrium patterns in Uganda and South Africa were similar to African populations in the HapMap datasets. Multidimensional scaling analysis of polymorphisms in all four genes suggested broad overlap of all of the examined African populations. Based on these data, we propose that there is enough similarity among African populations represented in the HapMap database to justify initial SNP selection for genetic epidemiological studies in Uganda and South Africa. We also discovered three novel polymorphisms that appear to be population-specific and would only be detected by sequencing efforts.     

Opisthobranchia (Mollusca, Gastropoda) – more than just slimy slugs. Shell reduction and its implications on defence and foraging

Genetic studies have typically inferred the effects of human impact by documenting patterns of genetic differentiation and levels of genetic diversity among potentially isolated populations using selective neutral markers such as mitochondrial control region sequences, microsatellites or single nucleotide polymorphism (SNPs). However, evolutionary relevant and adaptive processes within and between populations can only be reflected by coding genes. In vertebrates, growing evidence suggests that genetic diversity is particularly important at the level of the major histocompatibility complex (MHC). MHC variants influence many important biological traits, including immune recognition, susceptibility to infectious and autoimmune diseases, individual odours, mating preferences, kin recognition, cooperation and pregnancy outcome. These diverse functions and characteristics place genes of the MHC among the best candidates for studies of mechanisms and significance of molecular adaptation in vertebrates. MHC variability is believed to be maintained by pathogen-driven selection, mediated either through heterozygote advantage or frequency-dependent selection. Up to now, most of our knowledge has derived from studies in humans or from model organisms under experimental, laboratory conditions. Empirical support for selective mechanisms in free-ranging animal populations in their natural environment is rare. In this review, I first introduce general information about the structure and function of MHC genes, as well as current hypotheses and concepts concerning the role of selection in the maintenance of MHC polymorphism. The evolutionary forces acting on the genetic diversity in coding and non-coding markers are compared. Then, I summarise empirical support for the functional importance of MHC variability in parasite resistance with emphasis on the evidence derived from free-ranging animal populations investigated in their natural habitat. Finally, I discuss the importance of adaptive genetic variability with respect to human impact and conservation, and implications for future studies.     

Genetic landscape of the people of India: a canvas for disease gene exploration

Analyses of frequency profiles of markers on disease or drug-response related genes in diverse populations are important for the dissection of common diseases. We report the results of analyses of data on 405 SNPs from 75 such genes and a 5.2 Mb chromosome, 22 genomic region in 1871 individuals from diverse 55 endogamous Indian populations. These include 32 large (> 10 million individuals) and 23 isolated populations, representing a large fraction of the people of India. We observe high levels of genetic divergence between groups of populations that cluster largely on the basis of ethnicity and language. Indian populations not only overlap with the diversity of HapMap populations, but also contain population groups that are genetically distinct. These data and results are useful for addressing stratification and study design issues in complex traits especially for heterogeneous populations. For complete authors’ list of the Indian Genome Variation Database Consortium please see Appendix. For correspondence. E-mail: skb@igib.res.in; Functional Genomics Unit, Institute of Genomics and Integrative Biology (CSIR), Mall Road, New Delhi 110 007, India.     

The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol

Genome-wide association (GWA) studies represent a powerful strategy for identifying susceptibility genes for complex diseases in human populations but results must be confirmed and replicated. Because of the close homology between mouse and human genomes, the mouse can be used to add evidence to genes suggested by human studies. We used the mouse quantitative trait loci (QTL) map to interpret results from a GWA study for genes associated with plasma HDL cholesterol levels. We first positioned single nucleotide polymorphisms (SNPs) from a human GWA study on the genomic map for mouse HDL QTL. We then used mouse bioinformatics, sequencing, and expression studies to add evidence for one well-known HDL gene (Abca1) and three newly identified genes (Galnt2, Wwox, and Cdh13), thus supporting the results of the human study. For GWA peaks that occur in human haplotype blocks with multiple genes, we examined the homologous regions in the mouse to prioritize the genes using expression, sequencing, and bioinformatics from the mouse model, showing that some genes were unlikely candidates and adding evidence for candidate genes Mvk and Mmab in one haplotype block and Fads1 and Fads2 in the second haplotype block. Our study highlights the value of mouse genetics for evaluating genes found in human GWA studies.     

Differential admixture in Latin American populations and its impact on the study of colorectal cancer

Genome-wide association studies focused on searching genes responsible for several diseases. Admixture mapping studies proposed a more efficient alternative capable of detecting polymorphisms contributing with a small effect on the disease risk. This method focuses on the higher values of linkage disequilibrium in admixed populations. To test this, we analyzed 10 genomic regions previously defined as related with colorectal cancer among nine populations and studied the variation pattern of haplotypic structures and heterozygosity values on seven categories of SNPs. Both analyses showed differences among chromosomal regions and studied populations. Admixed Latin-American samples generally show intermediate values. Heterozygosity of the SNPs grouped in categories varies more in each gene than in each population. African related populations have more blocks per chromosomal region, coherently with their antiquity. In sum, some similarities were found among Latin American populations, but each chromosomal region showed a particular behavior, despite the fact that the study refers to genes and regions related with one particular complex disease. This study strongly suggests the necessity of developing statistical methods to deal with di- or tri-hybrid populations, as well as to carefully analyze the different historic and demographic scenarios, and the different characteristics of particular chromosomal regions and evolutionary forces.     

Recent advances in the genetics of osteoporosis

It has been known for over 20 years that osteoporosis is highly influenced by genetic factors. Bone mineral density (BMD) has also been shown to be highly heritable. Other known risk factors for osteoporotic fractures such as reduced bone quality, femoral neck geometry and bone turnover are now also known to be heritable. Susceptibility to osteoporosis is mediated, in all likelihood, by multiple genes each having small effect. Different approaches are being used currently to identify the many genes responsible. These include linkage studies in man and experimental animals as well as candidate gene studies and alterations in gene expression. Linkage studies have identified multiple quantitative trait loci (QTL) for regulation of BMD and, with twin studies, have indicated that the effects of these loci are partly site-dependent and sex-specific. On the whole, the genes responsible for BMD regulation at these QTL have not yet been isolated. Most studies have used the candidate gene approach. The vitamin D receptor gene (VDR), the collagen type I alpha 1 gene (COLIA1) and estrogen receptor gene (ER) alpha have been most widely investigated and found to play a role in regulating BMD, but the effects are modest and together probably account for less than 5% of the heritable contribution to BMD. Genes may vary in their influence of particular intermediate phenotypes, and we now know that not all genes influencing BMD will be important in fracture. In addition, the study of other diseases such as osteoarthritis and metabolic bone syndromes may prove fruitful in highlighting genes which overlap to osteoporosis as well. As large scale genetic testing becomes more cost-effective, recent findings have illustrated the potential of novel approaches. These include combining large multi-national populations for candidate gene analysis, meta-analyses, DNA pooling studies and gene expression studies.     

Ethnic differences in the linkage disequilibrium and distribution of single-nucleotide polymorphisms in 35 candidate genes for cardiovascular diseases

Single-nucleotide polymorphisms (SNPs) are commonly used to study genetics for common diseases and predict pharmacological response. The selection of likely informative SNPs in association studies depends on their allele frequencies and on the linkage disequilibrium (LD) between SNPs, both of which may show interethnic differences. Among three populations consisting of 207 Chinese, 858 French, and 395 Spanish, we compared the allele frequency distributions of 64 intragenic SNPs of 35 candidate genes for cardiovascular diseases. Twenty-eight of these SNPs from 12 genes were also examined for intragenic LD. About 20% of SNPs were restricted to Europeans, being monomorphic in Chinese, among them mostly nonsynonymous coding SNPs and noncoding SNPs. Only 1.6% of SNPs were specific in Chinese, commensurate with the detection of these SNPs almost exclusively in Caucasians. Similarly, these SNPs were more often rare (<0.1 minor allele frequency) in Chinese (44.3%) than in Europeans (31.1%). The variant allele frequencies and intermarker LDs in terms of D' and Delta(2) were highly correlated between French and Spanish populations (r = 0.98-0.99, p < 0.001). However, only moderate correlations of allele frequencies and D' were found between the Chinese and the European populations (r = 0.7 and 0.3, respectively) despite a high correlation of Delta(2) values (r = 0.8). These results suggest that ethnic considerations are important in the selection of SNPs for association studies of candidate genes, as this may affect the power of the study as well as the likelihood of asking relevant questions and getting medically meaningful answers.     

Insight from genome-wide association studies in rheumatoid arthritis and multiple sclerosis

Autoimmune diseases are caused by multiple genes and environmental effects. In addition, genetic contributions and the number of associated genes differ among different diseases and ethnic populations. Genome-wide association studies (GWAS) on rheumatoid arthritis (RA) and multiple sclerosis (MS) show that these diseases share many genetic factors. Recently, in addition to the major histocompatibility complex (MHC) gene, other genetic loci have been found to be associated with the risk for autoimmune diseases. This review focuses on the search for genetic variants that influence the susceptibility to RA and MS as typical autoimmune diseases and discusses the future of GWAS.     

Network Modules of the Cross-Species Genotype-Phenotype Map Reflect the Clinical Severity of Human Diseases

Recent advances in genome sequencing techniques have improved our understanding of the genotype-phenotype relationship between genetic variants and human diseases. However, genetic variations uncovered from patient populations do not provide enough information to understand the mechanisms underlying the progression and clinical severity of human diseases. Moreover, building a high-resolution genotype-phenotype map is difficult due to the diverse genetic backgrounds of the human population. We built a cross-species genotype-phenotype map to explain the clinical severity of human genetic diseases. We developed a data-integrative framework to investigate network modules composed of human diseases mapped with gene essentiality measured from a model organism. Essential and nonessential genes connect diseases of different types which form clusters in the human disease network. In a large patient population study, we found that disease classes enriched with essential genes tended to show a higher mortality rate than disease classes enriched with nonessential genes. Moreover, high disease mortality rates are explained by the multiple comorbid relationships and the high pleiotropy of disease genes found in the essential gene-enriched diseases. Our results reveal that the genotype-phenotype map of a model organism can facilitate the identification of human disease-gene associations and predict human disease progression.     

A Pathway-Based View of Human Diseases and Disease Relationships

It is increasingly evident that human diseases are not isolated from each other. Understanding how different diseases are related to each other based on the underlying biology could provide new insights into disease etiology, classification, and shared biological mechanisms. We have taken a computational approach to studying disease relationships through 1) systematic identification of disease associated genes by literature mining, 2) associating diseases to biological pathways where disease genes are enriched, and 3) linking diseases together based on shared pathways. We identified 4,195 candidate disease associated genes for 1028 diseases. On average, about 50% of disease associated genes of a disease are statistically mapped to pathways. We generated a disease network which consists of 591 diseases and 6,931 disease relationships. We examined properties of this network and provided examples of novel disease relationships which cannot be readily captured through simple literature search or gene overlap analysis. Our results could potentially provide insights into the design of novel, pathway-guided therapeutic interventions for diseases.     

Deviation from baseline mutation burden provides powerful and robust rare-variants association test for complex diseases

Identifying rare variants that contribute to complex diseases is challenging because of the low statistical power in current tests comparing cases with controls. Here, we propose a novel and powerful rare variants association test based on the deviation of the observed mutation burden of a gene in cases from a baseline predicted by a weighted recursive truncated negative-binomial regression (RUNNER) on genomic features available from public data. Simulation studies show that RUNNER is substantially more powerful than state-of-the-art rare variant association tests and has reasonable type 1 error rates even for stratified populations or in small samples. Applied to real case-control data, RUNNER recapitulates known genes of Hirschsprung disease and Alzheimer''s disease missed by current methods and detects promising new candidate genes for both disorders. In a case-only study, RUNNER successfully detected a known causal gene of amyotrophic lateral sclerosis. The present study provides a powerful and robust method to identify susceptibility genes with rare risk variants for complex diseases.     

Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20?years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision.