Functional significance of genetic polymorphisms

Natural genetic polymorphisms are gifts from nature and sources of variations at all levels. The postgenomic era permits new perspectives on interpreting genetic polymorphisms and also poses challenges for scientists to answer system questions. Rather than a comprehensive coverage of genetic polymorphisms upto-date, this review attempts to present some of the results in a somewhat coherent manner to highlight the needs and potentials of pertinent studies.     

Detection of novel centromeric polymorphisms associated with alpha satellite DNA from human chromosome 11

Summary The pericentromeric region of human chromosomes is composed of diverse classes of repetitive DNAs, which provide a rich source of genetic variability. Here, we describe two novel centromeric polymorphisms associated with a subset of alpha satellite repetitive DNA, D11Z1, which is specific for human chromosome 11. Segregation and inheritance of the polymorphisms are demonstrated and their relative frequencies are determined. These polymorphisms may be useful genetic tools for distinguishing between individual chromosome 11 centromeres. In addition, these polymorphisms may be applied to the development of a centromerebased genetic linkage map of chromosome 11. Molecular models for the generation of these polymorphisms are discussed.     

Genetic polymorphisms in lung disease: bandwagon or breakthrough?

The study of genetic polymorphisms has touched every aspect of pulmonary and critical care medicine. We review recent progress made using genetic polymorphisms to define pathophysiology, to identify persons at risk for pulmonary disease and to predict treatment response. Several pitfalls are commonly encountered in studying genetic polymorphisms, and this article points out criteria that should be applied to design high-quality genetic polymorphism studies.     

Molecular genetics of atherosclerosis

Atherosclerosis is a complex multifocal arterial disease involving interactions of multiple genetic and environmental factors. Advances in techniques of molecular genetics have revealed that genetic polymorphisms significantly influence susceptibility to atherosclerotic vascular diseases. A large number of candidate genes, genetic polymorphisms and susceptibility loci associated with atherosclerotic diseases have been identified in recent years and their number is rapidly increasing. In this review we focus on some of the major candidate genes and genetic polymorphisms associated with human atherosclerotic vascular diseases.     

The role of surfactant in asthma

The study of genetic polymorphisms has touched every aspect of pulmonary and critical care medicine. We review recent progress made using genetic polymorphisms to define pathophysiology, to identify persons at risk for pulmonary disease and to predict treatment response. Several pitfalls are commonly encountered in studying genetic polymorphisms, and this article points out criteria that should be applied to design high-quality genetic polymorphism studies.     

Genomic heterogeneity in the density of noncoding single-nucleotide and microsatellite polymorphisms in Plasmodium falciparum

The density and distribution of single-nucleotide polymorphisms (SNPs) across the genome has important implications for linkage disequilibrium mapping and association studies, and the level of simple-sequence microsatellite polymorphisms has important implications for the use of oligonucleotide hybridization methods to genotype SNPs. To assess the density of these types of polymorphisms in P. falciparum, we sampled introns and noncoding DNA upstream and downstream of coding regions among a variety of geographically diverse parasites. Across 36,229 base pairs of noncoding sequence representing 41 genetic loci, a total of 307 polymorphisms including 248 polymorphic microsatellites and 39 SNPs were identified. We found a significant excess of microsatellite polymorphisms having a repeat unit length of one or two, compared to those with longer repeat lengths, as well as a nonrandom distribution of SNP polymorphisms. Almost half of the SNPs localized to only three of the 41 genetic loci sampled. Furthermore, we find significant differences in the frequency of polymorphisms across the two chromosomes (2 and 3) examined most extensively, with an excess of SNPs and a surplus of polymorphic microsatellites on chromosome 3 as compared to chromosome 2 (P=0.0001). Furthermore, at some individual genetic loci we also find a nonrandom distribution of polymorphisms between coding and flanking noncoding sequences, where completely monomorphic regions may flank highly polymorphic genes. These data, combined with our previous findings of nonrandom distribution of SNPs across chromosome 2, suggest that the Plasmodium falciparum genome may be a mosaic with regard to genetic diversity, containing chromosomal regions that are highly polymorphic interspersed with regions that are much less polymorphic.     

Female polymorphisms, sexual conflict and limits to speciation processes in animals

Heritable and visually detectable polymorphisms, such as trophic polymorphisms, ecotypes, or colour morphs, have become classical model systems among ecological geneticists and evolutionary biologists. The relatively simple genetic basis of many polymorphisms (one or a few loci) makes such species well-suited to study evolutionary processes in natural settings. More recently, polymorphic systems have become popular when studying the early stages of the speciation process and mechanisms facilitating or constraining the evolution of reproductive isolation. Although colour polymorphisms have been studied extensively in the past, we argue that they have been underutilized as model systems of constraints on speciation processes. Colouration traits may function as signalling characters in sexual selection contexts, and the maintenance of colour polymorphisms is often due to frequency-dependent selection. One important issue is why there are so few described cases of female polymorphisms. Here we present a synthetic overview of female sexual polymorphisms, drawing from our previous work on female colour polymorphisms in lizards and damselflies. We argue that female sexual polymorphisms have probably been overlooked in the past, since workers have mainly focused on male-male competition over mates and have not realized the ecological sources of genetic variation in female fitness. Recent experimental evolution studies on fruit flies (Drosophila melanogaster) have demonstrated significant heritable variation among female genotypes in the fitness costs of resistance or tolerance to male mating harassment. In addition, female-female competition over resources could also generate genetic variation in female fitness and promote the maintenance of female sexual polymorphisms. Female sexual polymorphisms could subsequently either be maintained as intrapopulational polymorphisms or provide the raw material for the formation of new species.     

Common MCL1 polymorphisms associated with risk of tuberculosis

MCL1 expression has been found to be up-regulated during infection with virulent Mycobacterium tuberculosis. We investigated the genetic polymorphisms in MCL1 as potential candidate gene for a host genetic study of clinical TB infection. We have sequenced exons and their boundaries of MCL1, including the 1.5 kb promoter region, to identify polymorphisms, and eight polymorphisms were identified. The genetic associations of polymorphisms in MCL1 with clinical TB patients (n=486) and normal controls (n=370) were analyzed. Using statistical analyses, one common promoter polymorphism (MCL1- 324C > A) which is absolutely linked with three other SNPs in the promoter and 3'UTR regions, were found to be significantly associated with increased risk of clinical TB disease. The frequency of the A-bearing genotype of -324C > A was higher in clinical TB patients than in normal controls (P=0.0008, OR= 1.68). Our findings suggest that polymorphisms in MCL1 might be one of genetic factors for the risk of clinical tuberculosis development.     

Correlations of SELE and SELP genetic polymorphisms with myocardial infarction risk: a meta-analysis and meta-regression

This meta-analysis was undertaken in an attempt to understand the relationships of functional polymorphisms in the SELE and SELP genes to myocardial infarction (MI) risk. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before March 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratios with 95 % confidence intervals were calculated. The effect of SELE and SELP genetic polymorphisms on the pathogenesis of MI was investigated in this meta-analysis with a total of ten case–control studies, including 2,696 MI patients and 4,724 healthy subjects. Eight single nucleotide polymorphisms were assessed, including polymorphisms 98G/T, 128S/R and 561A/C in the SELE gene, and polymorphisms 715T/P, 599V/L, 290S/N, 562N/D and 2123G/C in the SELP gene. The results of our meta-analysis suggested that SELE genetic polymorphisms might be correlated with an increased risk of MI, especially for 128S/R and 561A/C polymorphisms. A subgroup analysis by ethnicity was conducted to investigate its effects on susceptibility to MI. The results revealed positive significant correlations between SELE genetic polymorphisms and the risk of MI among Asians, but not among Caucasians (all P > 0.05). Nevertheless, no significantly correlations were found between SELP genetic polymorphisms and MI risk (all P > 0.05). In the subgroup analysis by ethnicity, we also did not observe significant associations between SELP genetic polymorphisms and MI risks among both Asians and Caucasians (all P > 0.05). The current meta-analysis suggests that SELE genetic polymorphisms may contribute to the development of MI, especially for the 128S/R and 561A/C polymorphisms among Asians. However, SELP genetic polymorphisms may not be important risk factors in MI.     

Genetic polymorphisms of the endocannabinoid system

Disturbances in the endocannabinoid system has been linked to diseases and conditions such as Parkinson's, schizophrenia, pain, energy metabolism, immune modulation, and bone density. Since the early 1990s, a number of genetic polymorphisms in the genes and proteins of the endocannabinoid system have been characterized. Currently identified genetic polymorphisms of the endocannabinoid system are reviewed here with particular consideration given to polymorphisms linked to drug and alcohol abuse, schizophrenia, other mental disorders, and energy metabolism.     

Global genetic analysis

The introduction of molecular markers in genetic analysis has revolutionized medicine. These molecular markers are genetic variations associated with a predisposition to common diseases and individual variations in drug responses. Identification and genotyping a vast number of genetic polymorphisms in large populations are increasingly important for disease gene identification, pharmacogenetics and population-based studies. Among variations being analyzed, single nucleotide polymorphisms seem to be most useful in large-scale genetic analysis. This review discusses approaches for genetic analysis, use of different markers, and emerging technologies for large-scale genetic analysis where millions of genotyping need to be performed.     

The Quantitative Genetics of Phenotypic Robustness

Phenotypic robustness, or canalization, has been extensively investigated both experimentally and theoretically. However, it remains unknown to what extent robustness varies between individuals, and whether factors buffering environmental variation also buffer genetic variation. Here we introduce a quantitative genetic approach to these issues, and apply this approach to data from three species. In mice, we find suggestive evidence that for hundreds of gene expression traits, robustness is polymorphic and can be genetically mapped to discrete genomic loci. Moreover, we find that the polymorphisms buffering genetic variation are distinct from those buffering environmental variation. In fact, these two classes have quite distinct mechanistic bases: environmental buffers of gene expression are predominantly sex-specific and trans-acting, whereas genetic buffers are not sex-specific and often cis-acting. Data from studies of morphological and life-history traits in plants and yeast support the distinction between polymorphisms buffering genetic and environmental variation, and further suggest that loci buffering different types of environmental variation do overlap with one another. These preliminary results suggest that naturally occurring polymorphisms affecting phenotypic robustness could be abundant, and that these polymorphisms may generally buffer either genetic or environmental variation, but not both.     

Origins and affinities of modern humans: a comparison of mitochondrial and nuclear genetic data.

To test hypotheses about the origin of modern humans, we analyzed mtDNA sequences, 30 nuclear restriction-site polymorphisms (RSPs), and 30 tetranucleotide short tandem repeat (STR) polymorphisms in 243 Africans, Asians, and Europeans. An evolutionary tree based on mtDNA displays deep African branches, indicating greater genetic diversity for African populations. This finding, which is consistent with previous mtDNA analyses, has been interpreted as evidence for an African origin of modern humans. Both sets of nuclear polymorphisms, as well as a third set of trinucleotide polymorphisms, are highly consistent with one another but fail to show deep branches for African populations. These results, which represent the first direct comparison of mtDNA and nuclear genetic data in major continental populations, undermine the genetic evidence for an African origin of modern humans.     

Outcome prediction in sepsis combined use of genetic polymorphisms - A study in Japanese population

Genetic polymorphisms have recently been found to be related to clinical outcome in septic patients. The present study investigated to evaluate the influence of genetic polymorphisms in Japanese septic patients on clinical outcome and whether use of genetic polymorphisms as predictors would enable more accurate prediction of outcome. Effects of 16 genetic polymorphisms related to pro-inflammatory mediators and conventional demographic/clinical parameters (age, sex, past medical history, and APACHE II score) on ICU mortality as well as disease severity during ICU stay were examined in the septic patients (n=123) admitted to the ICU between October 2001 and November 2007 by multivariable logistic regression analysis. ICU mortality was significantly associated with TNF -308GA, IL1β -31CT/TT, and APACHE II score. Receiver-operating characteristics (ROC) analysis demonstrated that, compared with APACHE II score alone (ROC-AUC=0.68), use of APACHE II score and two genetic parameters (TNF -308 and IL1β -31) enabled more accurate prediction of ICU mortality (ROC-AUC=0.80). Significant association of two genetic polymorphisms, TNF -308 and IL1β -31, with ICU mortality was observed in septic patients. In addition, combined use of these genetic parameters with APACHE II score may enable more accurate prediction of outcome in septic patients.     

Two more "private" polymorphisms of Amerindian tribes: LDHb GUA-1 and ACP1 B GUA-1 in the Guaymi in Panama.

A survey of Guaymi Indians of Panama for the occurrence of genetic variants of 25 proteins of the erythrocytes and sera have revealed, in addition to seven well-known genetic polymorphisms, four rare variants and two "private polymorphisms," the latter involving erythrocyte acid phosphatase and lactate dehydrogenase. The significance of such private polymorphisms in tribal populations to the interpretation of rare variants in civilized populations is emphasized.     

Contrasting patterns of gene diversity between microsatellites and mitochondrial SNPs in farm and wild Atlantic salmon

Levels of genetic variability at 12 microsatellite loci and 19 single nucleotide polymorphisms in mitochondrial DNA were studied in four farm strains and four wild populations of Atlantic salmon. Within populations, the farm strains showed significantly lower allelic richness and expected heterozygosity than wild populations at the 12 microsatellite loci, but a significantly higher genetic variability with respect to observed number of haplotypes and haplotype diversity in mtDNA. Significant differences in allele- and haplotype-frequencies were observed between farm strains and wild populations, as well as between different farm strains and between different wild populations. The large genetic differentiation at mitochondrial DNA between wild populations (F_ST = 0.24), suggests that the farm strains attained a high mitochondrial genetic variability when created from different wild populations seven generations ago. A large proportion of this variability remains despite an expected lower effective population size for mitochondrial than nuclear DNA. This is best explained by the particular mating schemes in the breeding programmes, with 2–4 females per male. Our observations suggest that for some genetic polymorphisms farm populations might currently hold equal or higher genetic variability than wild populations, but lower overall genetic variability. In the short-term, genetic interactions between escaped farm salmon and wild salmon might increase genetic variability in wild populations, for some, but not most, genetic polymorphisms. In the long term, further losses of genetic variability in farm populations are expected for all genetic polymorphisms, and genetic variability in wild populations will be reduced if escapes of farm salmon continue.     

Natural genetic variation caused by transposable elements in humans

Transposons and transposon-like repetitive elements collectively occupy 44% of the human genome sequence. In an effort to measure the levels of genetic variation that are caused by human transposons, we have developed a new method to broadly detect transposon insertion polymorphisms of all kinds in humans. We began by identifying 606,093 insertion and deletion (indel) polymorphisms in the genomes of diverse humans. We then screened these polymorphisms to detect indels that were caused by de novo transposon insertions. Our method was highly efficient and led to the identification of 605 nonredundant transposon insertion polymorphisms in 36 diverse humans. We estimate that this represents 25-35% of approximately 2075 common transposon polymorphisms in human populations. Because we identified all transposon insertion polymorphisms with a single method, we could evaluate the relative levels of variation that were caused by each transposon class. The average human in our study was estimated to harbor 1283 Alu insertion polymorphisms, 180 L1 polymorphisms, 56 SVA polymorphisms, and 17 polymorphisms related to other forms of mobilized DNA. Overall, our study provides significant steps toward (i) measuring the genetic variation that is caused by transposon insertions in humans and (ii) identifying the transposon copies that produce this variation.     

DNA polymorphisms amplified by arbitrary primers are useful as genetic markers.

Molecular genetic maps are commonly constructed by analyzing the segregation of restriction fragment length polymorphisms (RFLPs) among the progeny of a sexual cross. Here we describe a new DNA polymorphism assay based on the amplification of random DNA segments with single primers of arbitrary nucleotide sequence. These polymorphisms, simply detected as DNA segments which amplify from one parent but not the other, are inherited in a Mendelian fashion and can be used to construct genetic maps in a variety of species. We suggest that these polymorphisms be called RAPD markers, after Random Amplified Polymorphic DNA.     

The plant genome's methylation status and response to stress: implications for plant improvement

Plant improvement depends on generating phenotypic variation and selecting for characteristics that are heritable. Classical genetics and early molecular genetics studies on single genes showed that differences in chromatin structure, especially cytosine methylation, can contribute to heritable phenotypic variation. Recent molecular genetic and genomic studies have revealed a new importance of cytosine methylation for gene regulation and have identified RNA interference (RNAi)-related proteins that are necessary for methylation. Methylation differences among plants can be caused by cis- or trans-acting DNA polymorphisms or by epigenetic phenomena. Although regulatory proteins might be important in creating this variation, recent examples highlight the central role of transposable elements and DNA repeats in generating both genetic and epigenetic methylation polymorphisms. The plant genome's response to environmental and genetic stress generates both novel genetic and epigenetic methylation polymorphisms. Novel, stress-induced genotypes may contribute to phenotypic diversity and plant improvement.     

Evolution of modern humans: evidence from nuclear DNA polymorphisms.

Previously we have described studies of the evolution of modern humans based upon data for classical genetic markers and for nuclear DNA polymorphisms. Such polymorphisms provide a different point of view regarding human evolution than do mitochondrial DNA sequences. Here we compare revised dates for major migrations of anatomically modern humans, estimated from archaeological data, with separations suggested by a genetic tree constructed from classical marker allele frequencies. Analyses of DNA polymorphisms have now been extended and compared with those of classical markers; genetic trees continue to support the hypothesis of an initial African and non-African divergence for modern humans. We have also begun testing non-human primates for a set of human DNA polymorphisms. For most polymorphisms tested so far, humans share a single allele with other primates; such shared alleles are likely to be ancestral. Populations living in humid tropical environments have significantly higher frequencies of ancestral alleles than do other populations, supporting the hypothesis that natural selection acts to maintain high frequencies of particular alleles in some environments.