Polygenic Loci Research Articles

Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2V617F, are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2V617F clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2V617F positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2V617F carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study showcases how polygenic backgrounds underlying common hematological traits influence both clonal selection on somatic mutations and the subsequent phenotype of cancer.

Polygenic risk score (PRS) and its potential for breast cancer risk stratification.

Breast cancer is a complex, multifactorial disease influenced by many genetic factors. Besides the relatively rare pathogenic variants in high or moderate penetrant cancer predisposition genes, breast cancer risk is modified by numerous low risk alleles considered to be polygenic genetic factors. While the risks associated with individual polygenic loci are negligible, its cumulative effect can reach clinically significant values and it can be expressed as a polygenic risk score (PRS). PRS is recently considered to be a possible tool improving assessment of absolute and cumulative risks at the individual level. Several single nucleotide polymorphism sets for PRS assessment have recently been developed and prepared for their implementation into clinical practice. The following text aims to explain the fundamental principles of the PRS assessment and its interpretation as a candidate prediction tool. The use of the PRS should always depend on genetic analysis of pathogenic variants in cancer predisposition genes including its current limitations.

Genetic and epigenetic findings in anorexia nervosa

Abstract Polygenic factors are relevant for the genetic predispositions to the eating disorder anorexia nervosa (AN). The most recent genome-wide association study (GWAS) for AN comprised almost 17,000 patients with AN and controls. A total of eight genome-wide significant polygenic loci associated with AN have been identified. Each single polygenic locus makes only a small contribution to the development of AN. Analyses across different traits successfully identified regions/genes for AN that had not been detected by analyses of the single traits. Functional studies of the genes derived by GWAS studies aim to improve the understanding of the biological mechanisms involved in eating disorders. Epigenetic studies have not yet successfully contributed to the understanding of AN.

Polygenic and multi locus heritability of alcoholism: Novel therapeutic targets to overcome psychological deficits.

Polygenic and multi locus heritability of alcoholism: Novel therapeutic targets to overcome psychological deficits.

Inheritance Study for Popping Expansion in Popcorn vs. Flint Corn Genotypes

Popcorn is a popular snack food with higher economic value compared to field corn varieties of maize (Zea mays L.), but displays less favorable agronomic performance and greater susceptibility to diseases. The objective of the present work was to study the mode of inheritance of popping expansion (PE) from three different crosses of popcorn × flint corn with a classical model and a mixed model using inbred lines derived from tropical germplasm. The study will investigate if PE is encoded by one or two major genes, a few genes with large effect, or multiple genes of small effect. Four generations (P1 and P2, F1, F2, BC1‐Popcorn and BC1‐Flint) from each cross were evaluated in field experiments in the main growing season of 2013/2014, in two environments. A randomized complete block design was used, with a nested split‐plot arrangement of treatments with four replicates. Means of the four generations were determined for PE. A weighted least squares analysis of variance based on the generation means method was used to perform joint scaling tests on the data from each generation. Maximum likelihood estimators were used to test the effect of major genes and/or the presence of polygenic loci affecting the trait. Although inheritance studies with plot means can be used to estimate genetic effects, the effect numbers can be overestimated. In the current study, PE in popcorn vs. flint crosses was controlled by a major additive gene in conjunction with polygenic modifiers acting in both additive and dominant fashions.Core Ideas Popping expansion is a trait that exhibits quantitative inheritance. Knowledge about the genetic control will aid in breeding programs. We used contrasting crosses and a maximum likelihood approach for inheritance study. Popping expansion is controlled by additive gene with different modifiers.

Is there a dose-dependent effect of genetic susceptibility loci for gastric cancer on prognosis of the patients?

Literature suggests that genetic variants associated with increased susceptibility to gastric cancer (GCa) are mostly located in genes involved in carcinogenesis and possibly tumor progression. Therefore, we hypothesize that high genetic susceptibility is also associated with prognosis of the patients. To test this hypothesis, we selected a total of 42 common genetic variants that were reportedly associated with GCa risk with a high level of evidence obtained from either genome-wide association studies (GWASs) or meta-analyses and performed survival analysis of patients used in a case-control analysis. We first used 1115 GCa cases and 1172 cancer-free controls of ethnic Han Chinese to construct a weighted genetic risk score (GRS). Then, we included 633 GCa cases with available clinical information, fit GRS in a fractional polynomial Cox proportional hazards regression model to investigate whether there is a dose-dependent effect of GRS on risk of death in survival analysis. Dynamic predictive value of genetic risk for prognosis was also calculated. The results showed that the increase of GRS had no effect on risk of death in these GCa patients. Compared with GCa patients with the medium GRS, there was no significant difference in survival in patients with either a low (P = 0.349) or a high (P = 0.847) GRS. The results unchanged when data were stratified by tumor stage and Laurens classification. Time-dependent predictive value for prognosis in considering both clinical factors and GRS was comparable with that in considering clinical factors alone, for either all patients (P = 0.986) or stage- and Laruen type-based subgroups (P > 0.05 for all). In conclusion, higher polygenic susceptibility loci for GCa may not indicate worse prognosis of Chinese patients. Additional variants of relevant genes modulating GCa patients survival need to be further identified.

Genetic variations associated with six-white-point coat pigmentation in Diannan small-ear pigs.

A common phenotypic difference among domestic animals is variation in coat color. Six-white-point is a pigmentation pattern observed in varying pig breeds, which seems to have evolved through several different mechanistic pathways. Herein, we re-sequenced whole genomes of 31 Diannan small-ear pigs from China and found that the six-white-point coat color in Diannan small-ear pigs is likely regulated by polygenic loci, rather than by the MC1R locus. Strong associations were observed at three loci (EDNRB, CNTLN, and PINK1), which explain about 20 percent of the total coat color variance in the Diannan small-ear pigs. We found a mutation that is highly differentiated between six-white-point and black Diannan small-ear pigs, which is located in a conserved noncoding sequence upstream of the EDNRB gene and is a putative binding site of the CEBPB protein. This study advances our understanding of coat color evolution in Diannan small-ear pigs and expands our traditional knowledge of coat color being a monogenic trait.

How Can We Explain Very Low Odds Ratios in GWAS? I. Polygenic Models

Genome-wide association studies of common diseases often identify a number of disease-related SNPs that reach highly significant p values but at the same time show very low disease odds ratios (ORs), most <1.5 and many <1.2. Despite their statistical significance, associations involving very low ORs explain little about the genetic contribution to the disease and nothing about disease inheritance. A commonly accepted explanation for very low ORs involves a model of polygenic inheritance, i.e., where the disease being studied is caused by a large number of interacting genes, each gene contributing only a small increment to disease risk. Here we demonstrate the perhaps counterintuitive result that, within a reasonable range of disease population prevalences (≤10%), a pure polygenic model is incompatible with very low ORs, unless very large numbers (hundreds or even thousands) of polygenic loci are involved.

Submergence Tolerant Rice: SUB1’s Journey from Landrace to Modern Cultivar

Rice landraces tolerant of up to 2 weeks of complete submergence were collected from farmers’ fields in the 1950s. Success in fine mapping of SUBMERGENCE 1 (SUB1), a robust quantitative trait locus from the submergence tolerant FR13A landrace, has enabled marker-assisted breeding of high-yielding rice capable of enduring transient complete submergence. At the molecular level, SUB1 is a variable polygenic locus encoding two or three ethylene responsive factor (ERF) DNA binding proteins. All Oryza sativa accessions encode SUB1B and SUB1C at this locus. An additional ERF, SUB1A, is present at SUB1 in FR13A and other tolerant accessions. The induction of SUB1A expression by ethylene during submergence disrupts the elongation escape strategy typical of lowland and deepwater rice, by limiting ethylene-induced gibberellic acid-promoted elongation. Microarray and metabolite studies confirm that SUB1A orchestrates its effects on metabolism and growth in a submergence-dependent manner. Due to the conditional activity of SUB1A, new “Sub1” mega-varieties effectively provide submergence tolerance without apparent ill effect on development, productivity, or grain quality.

Polymorphism within the intron region of the bovine leptin gene in Iranian Sarabi cattle (Iranian Bos taurus)

The main goal of breeders is breeding superior animals. Most traits of the economic importance in farm animals are determined by polygenic loci with environmental factors. Progress in animal breeding may be improved by combining traditional performance data with molecular genetic information on quantitative loci in selection index. Candidate genes are chosen for study on the basis of known relationships between biochemical and physiological processes. Leptin is 16 KD protein that is synthesized by adipose tissue and it is involved in the regulation of feed intake, energy balance, fertility and immune functions. In cattle, the leptin gene is located on chromosome 4. It consists of 3 exons and 2 introns of which only two exons are translated into protein. Sixty six animals were genotyped for this project. A PCR was carried out between 2 exon (intron 2). A strategy employing polymerase chain reaction was used to amplify a 422 bp from blood, semen, hair root and milk DNA. Digestion of polymerase chain reaction products with Sau3AI revealed two alleles: Allele A was 390, 32 fragments and allele B was 303, 88, 32 (only 303 fragment visible on the gel). Three patterns were observed and frequencies were 0.31, 0.43, and 0.14 for AA, AB and BB respectively. This polymorphism could be further evaluated for marker assisted selection and developed PCR methodology would expedite screening for large numbers of animals required for such studies.

Estimation of epistasis among finite polygenic loci for complex traits with a mixed model using Gibbs sampling

Epistasis among loci is important factor behind the expression of many complex traits, but many analyses have ruled out its possibility. A method to estimate epistasis was introduced with a mixed model using Gibbs sampling (MMGS). The posterior mean estimate for every possible genotype combined from multiple loci was calculated as the mean of the conditional expected values of the parameters in post warming-up rounds from Gibbs sampling. A simulation study was performed to compare MMGS with restricted partition method (RPM). Mean square prediction error (MSPE) using MMGS was smaller than that using RPM ( P < 0.05), which might be due to information loss introduced by grouping of genotypes in RPM. This was also supported by the result that MSPE increased as the number of merged groups decreased. The simulation study implied that MMGS was more plausible in estimating epistatic effects than the RPM.

Identification and mapping of open chromatin regions within a 140 kb polygenic locus of human chromosome 19 using E. coli Dam methylase

Using transient expression of the E. coli Dam methylase gene and analysis of the distribution of methylated GATC sites, we studied the distribution of open chromatin regions within a 140 kb long human genome segment in HEK-293 cells. Dam methylated sites were found in gene introns, exons, and intergenic regions, and their distribution along DNA was uneven. There were regions of high and low density of Dam methylated GATC sites, presumably corresponding to "open" and "closed" chromatin regions, respectively, and to the functional profile of the genomic locus under study. The Dam methylation profile was also generally in agreement with transcriptional activity of genes in the locus. Moreover, DNA regions accessible to Dam methylase apparently coincided with those hypersensitive to DNase I.

Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury

Susceptibility to neuroinflammatory disease is influenced in part by genetics. Recent data indicate that survival of traumatized neurons is strain dependent and influenced by polygenic loci that control resistance/susceptibility to experimental autoimmune encephalomyelitis (EAE), a model of CNS autoimmune disease. Here, we describe patterns of neurodegeneration and intraparenchymal inflammation after traumatic spinal cord injury (SCI) in mice known to exhibit varying degrees of EAE susceptibility [EAE-resistant (r) or EAE-susceptible (s) mice]. Spinal cords from C57BL/6 (EAE-s), C57BL/10 (EAE-r), BALB/c (EAE-r), and B10.PL (EAE-s) mice were prepared for stereological and immunohistochemical analysis at 6 hours or 3, 7, 14, 28, or 42 days following midthoracic (T9) spinal contusion injury. In general, genetic predisposition to EAE predicted the magnitude of intraparenchymal inflammation but not lesion size/length or locomotor recovery. Specifically, microglia/macrophage activation, recruitment of neutrophils and lymphocytes, and de novo synthesis of MHC class II were greatest in C57BL/6 mice and least in BALB/c mice at all times examined. However, lesion volume and axial spread of neurodegeneration were similar in C57BL/6 and BALB/c mice and were significantly greater than in C57BL/10 or B10.PL mice. Strains with marked intraspinal inflammation also developed the most intense lesion fibrosis. Thus, strain-dependent neuroinflammation was observed after SCI, but without a consistent relationship to EAE susceptibility or lesion progression. Only in C57BL/6 mice was the magnitude of intraspinal inflammation predictive of secondary neurodegeneration, functional recovery, or fibrosis.

Inheritance of tolerance to leaf iron deficiency chlorosis in tomato

By using two tomato genotypes, “227/1” (Fe chlorosis susceptible) and “Roza” (Fe chlorosis tolerant), and their reciprocal F1, F2 and BC1 generations, the inheritance of tolerance to leaf Fe deficiency chlorosis of Roza was studied. Plants were grown in a nutrient solution and subjected to 2.0 × 10−6 M Fe EDDHA and 10 mM NaHCO3 to induce Fe deficiency stress by stabilization of pH to 7.8–8.2. A rating scale of 1–3 for chlorophyll was used and both monogenic and polygenic inheritance hypotheses were tested. Better responses to Fe deficiency, as measured by SPAD meter values, were obtained from the cross “Roza × 227/1” than from the reciprocal cross. Data from F2 and BC1 suggest Fe chlorosis tolerance of Roza is to be controlled by polygenic loci with a relatively high additive effect.

Linkage and association studies of QTL for nuclear families by mixed models.

The transmission disequilibrium test (TDT) has been utilized to test the linkage and association between a genetic trait locus and a marker. Spielman et al. (1993) introduced TDT to test linkage between a qualitative trait and a marker in the presence of association. In the presence of linkage, TDT can be applied to test for association for fine mapping (Martin et al., 1997; Spielman and Ewens, 1996). In recent years, extensive research has been carried out on the TDT between a quantitative trait and a marker locus (Allison, 1997; Fan et al., 2002; George et al., 1999; Rabinowitz, 1997; Xiong et al., 1998; Zhu and Elston, 2000, 2001). The original TDT for both qualitative and quantitative traits requires unrelated offspring of heterozygous parents for analysis, and much research has been carried out to extend it to fit for different settings. For nuclear families with multiple offspring, one approach is to treat each child independently for analysis. Obviously, this may not be a valid method since offspring of one family are related to each other. Another approach is to select one offspring randomly from each family for analysis. However, with this method much information may be lost. Martin et al. (1997, 2000) constructed useful statistical tests to analyse the data for qualitative traits. In this paper, we propose to use mixed models to analyse sample data of nuclear families with multiple offspring for quantitative traits according to the models in Amos (1994). The method uses data of all offspring by taking into account their trait mean and variance-covariance structures, which contain all the effects of major gene locus, polygenic loci and environment. A test statistic based on mixed models is shown to be more powerful than the test statistic proposed by George et al. (1999) under moderate disequilibrium for nuclear families. Moreover, it has higher power than the TDT statistic which is constructed by randomly choosing a single offspring from each nuclear family.

Mammalian recombination hot spot in a DNA loop anchorage region: a model for the study of common fragile sites.

We analyzed the replication pattern and the topological organization of a 200 kb long Chinese hamster polygenic locus, which spans the boundary of two isochores. One of them is G + C rich while the second one is highly A + T rich. Previous analysis of mutants amplified for this locus had identified, within the A + T rich isochore, a mitotic recombination hotspot and a replication origin separated by some 7 kb. The recombination hotspot exhibits structural features repeatedly observed at common fragile sites, including a typical enrichment in peaks of enhanced DNA helix flexibility. By studying the replication pattern of the same locus in the non-amplified CHO cells, we confirm here the localization of the replication origin and show that the mitotic recombination hotspot does not correspond to a replicon junction. This finding makes questionable current hypotheses correlating replication termination regions with recombination prone sequences. Using topoisomerase II-mediated DNA cleavage at matrix attachment sites, we identified a 40 kb-long DNA anchorage region extending all along a transcription unit nested within the A + T rich isochore. Both the recombination hotspot and the replication origin lie within this topoisomerase II sensitive region, which suggests that features essential for initiation of recombination and initiation of DNA replication cluster within DNA anchorage regions. Features common to this region and to common fragile sites are discussed. J. Cell. Biochem. Suppl. 36: 170-178, 2001.

Spatial differences in patterns of modification: selection on hairy in Drosophila melanogaster wings.

Artificial selection was carried out for over 45 generations to enhance and suppress expression of the mutation hairy on the Drosophila melanogaster wing. Whole chromosome mapping of X-linked and autosomal modifiers of sense organ number displayed regional differences in magnitude and direction of their effects. Regional specificity of modifier effects was also seen in some interchromosomal interactions. Scanning electron microscopy allowed precise measurement of sense organ size and position along the L3 longitudinal wing vein. Sense organ size varied in a predictable fashion along the proximal-distal axis, and the dorsal pattern differed from the ventral pattern. The high and low selection lines differed most in the proximal portion of the L3 vein. Extra sense organs in the High line were often associated with vein fragments at locations predicted from ancestral vein patterns. Thus, regional specificity of polygenic or quantitative trait locus modifier effects was identified in several different parts of the wing.

Complex Segregation Analyses: Uses and Limitations

Complex segregation analysis (CSA) is a general method for evaluating the transmission of a trait within pedigrees. It proceeds by testing models of varying degrees of generality, both to determine whether a Mendelian locus is likely to exert a large effect on the phenotype of interest and to estimate the magnitude of genetic sources of variation in the trait. This information is valuable both as a prelude to linkage analysis, which generally assumes Mendelian transmission, and in providing a model on which to base parametric linkage methods.

Matrix attachment regions and transcription units in a polygenic mammalian locus overlapping two isochores

Eukaryotic chromosomes are ponctuated by specialized DNA sequences (MARs) characterized by their ability to bind the network of nonhistone proteins that form the nuclear matrix or scaffold. We previously described an amplifiable cluster of genes with different tissue-specific expression patterns, located on Chinese hamster chromosome 1q. This model is especially appropriate to study the relationships between MARs and transcription units. We show here that four attachment regions, with sequences exhibiting motifs specific to MARs, are present within the 100 kb of screened DNA. Three of them are relatively short sequences localized in intergenic regions. The last one extends over one of the transcription units and contains a region previously identified as a recombination hot spot. Moreover, the analysis of a DNA sequence extending over some 50 Kb of this region and spanning at least four genes, disclosed a strikingly sharp change in G + C content. This strongly suggests that the studied region contains the boundary of two isochores. We propose that the frequency and the size of MARs are correlated to their localization in G + C rich or poor domains.

Linkage analyses in type I diabetes mellitus using CASPAR, a software and statistical program for conditional analysis of polygenic diseases.

We have developed software and statistical tools for linkage analysis of polygenic diseases. We use type I diabetes mellitus (insulin-dependent diabetes mellitus, IDDM) as our model system. Two susceptibility loci (IDDM1 on 6p21 and IDDM2 on 11p15) are well established, and recent genome searches suggest the existence of other susceptibility loci. We have implemented CASPAR, a software tool that makes it possible to test for linkage quickly and efficiently using multiple polymorphic DNA markers simultaneously in nuclear families consisting of two unaffected parents and a pair of affected siblings (ASP). We use a simulation-based method to determine whether lod scores from a collection of ASP tests are significant. We test our new software and statistical tools to assess linkage of IDDM5 and IDDM7 conditioned on analyses with 1 or 2 other unlinked type I diabetes susceptibility loci. The results from the CASPAR analysis suggest that conditioning of IDDM5 on IDDM1 and IDDM4, and of IDDM7 on IDDM1 and IDDM2 provides significant benefits for the genetic analysis of polygenic loci.