Incorporating functional annotation information in prioritizing disease associated SNPs from genome wide association studies

With recent advances in genotyping and sequencing technologies,many disease susceptibility loci have been identified.However,much of the genetic heritability remains unexplained and the replication rate between independent studies is still low.Meanwhile,there have been increasing efforts on functional annotations of the entire human genome,such as the Encyclopedia of DNA Elements(ENCODE)project and other similar projects.It has been shown that incorporating these functional annotations to prioritize genome wide association signals may help identify true association signals.However,to our knowledge,the extent of the improvement when functional annotation data are considered has not been studied in the literature.In this article,we propose a statistical framework to estimate the improvement in replication rate with annotation data,and apply it to Crohn’s disease and DNase I hypersensitive sites.The results show that with cell line specific functional annotations,the expected replication rate is improved,but only at modest level.

Identification of SSR markers linked to the abscission of cotton boll traits and mining germplasm in Cotton

Background Cotton is an economically important crop.It is crucial to find an effective method to improve cotton yield,and one approach is to decrease the abscission of cotton bolls and buds.However,the lack of knowledge of the genetic and molecular mechanisms underlying cotton boll abscission traits has hindered genetic improvements.Results Pearson’s correlation analysis revealed a significant positive correlation between boll abscission rates 1(AR1)and boll abscission rates 2(AR2).A genome-wide association study was conducted on 145 loci that exhibited high polymorphism and were uniformly distributed across 26 chromosomes(pair).The study revealed 18,46,and 62 markers that were significantly associated with boll abscission,fiber quality,and yield traits(P<0.05),explaining 1.75%–7.13%,1.16%–9.58%,and 1.40%–5.44%of the phenotypic variation,respectively.Notably,the marker MON_SHIN-1584b was associated with the cotton boll abscission trait,whereas MON_CGR5732a was associated with cotton boll abscission and fiber quality traits.Thirteen of the marker loci identified in this study had been previously reported.Based on phenotypic effects,six typical cultivars with elite alleles related to cotton boll abscission,fiber quality,and yield traits were identified.These cultivars hold great promise for widespread utilization in breeding programs.Conclusions These results lay the foundation for understanding the molecular regulatory mechanism of cotton boll abscission and provide data for the future improvement of cotton breeding.

Association mapping and domestication analysis to dissect genetic improvement process of upland cotton yield-related traits in China

Background: Cotton fiber yield is a complex trait,which can be influenced by multiple agronomic traits.Unravelling the genetic basis of cotton fiber yield-related traits contributes to genetic improvement of cotton.Results: In this study,503 upland cotton varieties covering the four breeding stages(BS1–BS4,1911–2011)in China were used for association mapping and domestication analysis.One hundred and forty SSR markers significantly associated with ten fiber yield-related traits were identified,among which,29 markers showed an increasing trend contribution to cotton yield-related traits from BS1 to BS4,and 26 markers showed decreased trend effect.Four favorable alleles of 9 major loci(R^(2)≥3)were strongly selected during the breeding stages,and the candidate genes of the four strongly selected alleles were predicated according to the gene function annotation and tissue expression data.Conclusions :The study not only uncovers the genetic basis of 10 cotton yield-related traits but also provides genetic evidence for cotton improvement during the cotton breeding process in China.

Familial aggregation in inflammatory bowel disease:Is it genes or environment?

Inflammatory bowel disease (IBD) develops in genetically susceptible individuals due to the influence of environmental factors, leading to an abnormal recognition of microbiota antigens by the innate immune system which triggers an exaggerated immune response and subsequent bowel tissue damage. IBD has been more frequently found in families, an observation that could be due to either genetic, environmental or both types of factors present in these families. In addition to expanding our knowledge on IBD pathogenesis, defining the specific contribution to familial IBD of each one of these factors might have also clinical usefulness. We review the available evidence on familial IBD pathogenesis.

Pooled genetic analysis in ultrasound measured non-alcoholic fatty liver disease in Indian subjects:A pilot study

AIM: To investigate genetic susceptibility in Indian subjects with non-alcoholic fatty liver disease(NAFLD) by performing a pooled genetic study.METHODS: Study subjects(n = 306) were recruited and categorized into NAFLD and control groups based on ultrasound findings of fatty infiltration. Of the 306 individuals, 156 individuals had fatty infiltration and thus comprised the NAFLD group. One hundred and fifty(n = 150) individuals were normal, without fatty infiltration of the liver, comprising the control group. Blood samples, demographic and anthropometric data from the individuals were collected after obtaining informed consent. Anthropometric data, blood glucose, lipids and liver function tests were estimated using standard methods. Genome wide association stud-ies done to date on NAFLD were identified, 19 single nucleotide polymorphisms(SNPs) were selected from these studies that were reported to be significantly associated with NAFLD and genotyping was performed on the Sequenom platform. Student's t test for continuous variables and χ2 test was applied to variant carriers from both groups. Required corrections were applied as multiple testing was done.RESULTS The mean age of the control group was 39.78 ± 10.83 and the NAFLD group was 36.63 ± 8.20 years. The waist circumference of males and females in the control and NAFLD groups were 80.13 ± 10.35; 81.77 ± 13.65 and 94.09 ± 10.53; 92.53 ± 8.27 respectively. The mean triglyceride and alanine transaminase(ALT) levels in the control and NAFLD groups were 135.18 ± 7.77; 25.39 ± 14.73 and 184.40 ± 84.31; 110.20 ± 67.05 respectively. When χ2 test was applied to the number of individuals carrying the variant risk alleles between the control and NAFLD group, a significant association was seen between rs738409 of the patatin-like phospholipase domain containing 3(PNPLA3) gene(P = 0.001), rs2073080 of the PARVB gene(P = 0.02), rs2143571 of SAMM50 gene(P = 0.05) and rs6487679 of the pregnancy zone protein(PZP) gene(P = 0.01) with the disease. Variant single nucleotide polymorphisms(SNPs) in NCAN and PNPLA3 gene were associated with higher levels of ALT, whereas variant SNPs in APOC3, PNPLA3, EFCAB4 B and COL13A1 were associated with high triglyceride levels. Apart from the above associations, rs2073080, rs343062 and rs6591182 were significantly associated with high BMI; rs2854117 and rs738409 with high triglyceride levels; and rs2073080, rs2143571, rs2228603, rs6487679 and rs738409 with high ALT levels.CONCLUSION: Pooled genetic analysis revealed an association of SNPs in PNPLA3, PARVB, SAMM50 and PZP genes with NAFLD. SNPs in NCAN and PNPLA3gene were associated with higher levels of ALT,whereas variant SNPs in APOC3, PNPLA3, EFCAB4 B and COL13A1 were associated with high triglyceride levels.

Inflammation,microbiome and colorectal cancer disparity in African-Americans:Are there bugs in the genetics?

Dysregulated interactions between host inflammation and gut microbiota over the course of life increase the risk of colorectal cancer(CRC).While environmental factors and socio-economic realities of race remain predominant contributors to CRC disparities in African-Americans(AAs),this review focuses on the biological mediators of CRC disparity,namely the under-appreciated influence of inherited ancestral genetic regulation on mucosal innate immunity and its interaction with the microbiome.There remains a poor understanding of mechanisms linking immune-related genetic polymorphisms and microbiome diversity that could influence chronic inflammation and exacerbate CRC disparities in AAs.A better understanding of the relationship between host genetics,bacteria,and CRC pathogenesis will improve the prediction of cancer risk across race/ethnicity groups overall.

Inherited susceptibility for aggressive prostate cancer

Whether or not there is inherited basis for prostate cancer aggressiveness is not clear, but advances in DNA analysis should provide an answer to this question in the very near future.

GhAP1-D3 positively regulates flowering time and early maturity with no yield and fiber quality penalties in upland cotton

Flowering time(FTi)is a major factor determining how quickly cotton plants reach maturity.Early maturity greatly affects lint yield and fiber quality and is crucial for mechanical harvesting of cotton in northwestern China.Yet,few quantitative trait loci(QTLs)or genes regulating early maturity have been reported in cotton,and the underlying regulatory mechanisms are largely unknown.In this study,we characterized 152,68,and 101 loci that were significantly associated with the three key early maturity traits—FTi,flower and boll period(FBP)and whole growth period(WGP),respectively,via four genome-wide association study methods in upland cotton(Gossypium hirsutum).We focused on one major early maturity-related genomic region containing three single nucleotide polymorphisms on chromosome D03,and determined that GhAP1-D3,a gene homologous to Arabidopsis thaliana APETALA1(AP1),is the causal locus in this region.Transgenic plants overexpressing GhAP1-D3 showed significantly early flowering and early maturity without penalties for yield and fiber quality compared to wild-type(WT)plants.By contrast,the mutant lines of GhAP1-D3 generated by genome editing displayed markedly later flowering than the WT.GhAP1-D3 interacted with GhSOC1(SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1),a pivotal regulator of FTi,both in vitro and in vivo.Changes in GhAP1-D3 transcript levels clearly affected the expression of multiple key flowering regulatory genes.Additionally,DNA hypomethylation and high levels of H3K9ac affected strong expression of GhAP1-D3 in early-maturing cotton cultivars.We propose that epigenetic modifications modulate GhAP1-D3 expression to positively regulate FTi in cotton through interaction of the encoded GhAP1 with GhSOC1 and affecting the transcription of multiple flowering-related genes.These findings may also lay a foundation for breeding early-maturing cotton varieties in the future.

Disease Resistance in Maize and the Role of Molecular Breeding in Defending Against Global Threat

Diseases are a potential threat to global food security but plants have evolved an extensive array of methodologies to cope with the invading pathogens. Non-host resistance and quantitative re- sistance are broad spectrum forms of resistance, and all kinds of resistances are controlled by extremely diverse genes called ＂R- genes＂. R-genes follow different mechanisms to defend plants and PAMP-induced defenses in susceptible host plants are referred to as basal resistance. Genetic and phenotypic diversity are vital in maize （Zea mays L.）; as such, genome wide association study （GWAS） along with certain other methodologies can explore the maximum means of genetic diversity. Exploring the complete genetic archi- tecture to manipulate maize genetically reduces the losses from hazardous diseases. Genomic studies can reveal the interaction be- tween different genes and their pathways. By confirming the specific role of these genes and protein-protein interaction （proteomics） via advanced molecular and bioinformatics tools, we can shed a light on the most complicated and abstruse phenomena of resistance.