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      Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth

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          Abstract

          Background

          Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans. Attempts to identify genetic loci associated with preterm birth using genome-wide association studies (GWAS) have only been successful with large numbers of cases and controls, and there has yet to be a convincing genetic association to explain racial/ethnic disparities. Indeed, the search for ancestry-specific variants associated with preterm birth has led to the conclusion that spontaneous preterm birth could be the consequence of multiple rare variants. The hypothesis that preterm birth is due to rare genetic variants that would go undetected in standard GWAS has been explored in the present study. The detection and validation of these rare variants present challenges because of the low allele frequency. However, some success in the identification of fetal loci/genes associated with preterm birth using whole genome sequencing and whole exome sequencing (WES) has recently been reported. While encouraging, this is currently an expensive technology, and methods to leverage the sequencing data to quickly identify and cost-effectively validate variants are needed.

          Methods

          We developed a WES data analysis strategy based on neonatal genomic DNA from PPROM cases and term controls that was unencumbered by preselection of candidate genes, and capable of identifying variants in African Americans worthy of focused evaluation to establish statistically significant associations.

          Results

          We describe this approach and the identification of damaging nonsense variants of African ancestry in the DEFB1 and MBL2 genes that encode anti-microbial proteins that presumably defend the fetal membranes from infectious agents. Our approach also enabled us to rule out a likely contribution of a predicted damaging nonsense variant in the METTL7B gene.

          Conclusions

          Our findings support the notion that multiple rare population-specific variants in the fetal genome contribute to preterm birth associated with PPROM.

          Electronic supplementary material

          The online version of this article (10.1186/s12881-018-0696-4) contains supplementary material, which is available to authorized users.

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          Most cited references15

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          Identification and characterization of associated with lipid droplet protein 1: A novel membrane-associated protein that resides on hepatic lipid droplets.

          Alcoholic and nonalcoholic liver steatosis and steatohepatitis are characterized by the massive accumulation of lipid droplets (LDs) in the cytosol of hepatocytes. Although LDs are ubiquitous and dynamic organelles found in the cells of a wide range of organisms, little is known about the mechanisms and sites of LD biogenesis. To examine the participation of these organelles in the pathophysiological disorders of steatotic livers, we used a combination of mass spectrometry (matrix-assisted laser desorption ionization-time of flight and LC-MS electrospray) and Western blot analysis to study the composition of LDs purified from rat liver after a partial hepatectomy. Fifty proteins were identified. Adipose differentiation-related protein was the most abundant, but other proteins such as calreticulin, TIP47, Sar1, Rab GTPases, Rho and actin were also found. In addition, we identified protein associated with lipid droplets I ALDI (tentatively named Associated with LD protein 1), a novel protein widely expressed in liver and kidney corresponding to the product of 0610006F02Rik (GI:27229118). Our results show that, upon lipid loading of the cells, ALDI translocates from the endoplasmic reticulum into nascent LDs and indicate that ALDI may be targeted to the initial lipid deposits that eventually form these droplets. Moreover, we used ALDI expression studies to view other processes related to these droplets, such as LD biogenesis, and to analyze LD dynamics. In conclusion, here we report the composition of hepatic LDs and describe a novel bona fide LD-associated protein that may provide new insights into the mechanisms and sites of LD biogenesis.
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            Spontaneous preterm birth: advances toward the discovery of genetic predisposition

            Evidence from family and twin-based studies provide strong support for a significant contribution of maternal and fetal genetics to the timing of parturition and spontaneous preterm birth. However, there has been only modest success in the discovery of genes predisposing to preterm birth, despite increasing sophistication of genetic and genomic technology. In contrast, DNA variants associated with other traits/diseases have been identified. For example, there is overwhelming evidence that suggests that the nature and intensity of an inflammatory response in adults and children are under genetic control. Because inflammation is often invoked as an etiologic factor in spontaneous preterm birth, the question of whether spontaneous preterm birth has a genetic predisposition in the case of pathologic inflammation has been of long-standing interest to investigators. Here, we review various genetic approaches used for the discovery of preterm birth genetic variants in the context of inflammation-associated spontaneous preterm birth. Candidate gene studies have sought genetic variants that regulate inflammation in the mother and fetus; however, the promising findings have often not been replicated. Genome-wide association studies, an approach to the identification of chromosomal loci responsible for complex traits, have also not yielded compelling evidence for DNA variants predisposing to preterm birth. A recent genome-wide association study that included a large number of White women (>40,000) revealed that maternal loci contribute to preterm birth. Although none of these loci harbored genes directly related to innate immunity, the results were replicated. Another approach to identify DNA variants predisposing to preterm birth is whole exome sequencing, which examines the DNA sequence of protein-coding regions of the genome. A recent whole exome sequencing study identified rare mutations in genes encoding for proteins involved in the negative regulation (dampening) of the innate immune response (eg, CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and antimicrobial peptide/proteins (eg, DEFB1, MBL2). These findings support the concept that preterm labor, at least in part, has an inflammatory etiology, which can be induced by pathogens (ie, intraamniotic infection) or "danger signals" (alarmins) released during cellular stress or necrosis (ie, sterile intraamniotic inflammation). These findings support the notion that preterm birth has a polygenic basis that involves rare mutations or damaging variants in multiple genes involved in innate immunity and host defense mechanisms against microbes and their noxious products. An overlap among the whole exome sequencing-identified genes and other inflammatory conditions associated with preterm birth, such as periodontal disease and inflammatory bowel disease, was observed, which suggests a shared genetic substrate for these conditions. We propose that whole exome sequencing, as well as whole genome sequencing, is the most promising approach for the identification of functionally significant genetic variants responsible for spontaneous preterm birth, at least in the context of pathologic inflammation. The identification of genes that contribute to preterm birth by whole exome sequencing, or whole genome sequencing, promises to yield valuable population-specific biomarkers to identify the risk for spontaneous preterm birth and potential strategies to mitigate such a risk.
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              Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature.

              We tested the opposing views concerning evolution of genes of the innate immune system that (i) being evolutionary ancient, the system may have been highly optimized by natural selection and therefore should be under purifying selection, and (ii) the system may be plastic and continuing to evolve under balancing selection. We have resequenced 12 important innate-immunity genes (CAMP, DEFA4, DEFA5, DEFA6, DEFB1, MBL2, and TLRs 1, 2, 4, 5, 6, and 9) in healthy volunteers (n = 171) recruited from a region of India with high microbial load. We have compared these data with those of European-Americans (EUR) and African-Americans (AFR). We have found that most of the human haplotypes are many mutational steps away from the ancestral (chimpanzee) haplotypes, indicating that humans may have had to adapt to new pathogens. The haplotype structures in India are significantly different from those of EUR and AFR populations, indicating local adaptation to pathogens. In these genes, there is (i) generally an excess of rare variants, (ii) high, but variable, degrees of extended haplotype homozygosity, (iii) low tolerance to nonsynonymous changes, (iv) essentially one or a few high-frequency haplotypes, with star-like phylogenies of other infrequent haplotypes radiating from the modal haplotypes. Purifying selection is the most parsimonious explanation operating on these innate immunity genes. This genetic surveillance system recognizes motifs in pathogens that are perhaps conserved across a broad range of pathogens. Hence, functional constraints are imposed on mutations that diminish the ablility of these proteins to detect pathogens.
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                Author and article information

                Contributors
                bhavimodi807@gmail.com
                hp7d@virginia.edu
                maria.teves@vcuhealth.org
                kulkarnirm2@mymail.vcu.edu
                Jiang.Liyu@vcuhealth.org
                prbchiefstaff@med.wayne.edu
                Timothy.York@vcuhealth.org
                (215) 519-0614 , Jerome.strauss@vcuhealth.org
                Journal
                BMC Med Genet
                BMC Med. Genet
                BMC Medical Genetics
                BioMed Central (London )
                1471-2350
                5 October 2018
                5 October 2018
                2018
                : 19
                : 181
                Affiliations
                [1 ]ISNI 0000 0004 0458 8737, GRID grid.224260.0, Department of Human and Molecular Genetics, , Virginia Commonwealth University, ; Richmond, VA USA
                [2 ]ISNI 0000 0004 0458 8737, GRID grid.224260.0, Department of Microbiology and Immunology, , Virginia Commonwealth University, ; Richmond, VA USA
                [3 ]ISNI 0000 0004 0458 8737, GRID grid.224260.0, Department of Obstetrics and Gynecology, , Virginia Commonwealth University School of Medicine, ; Sanger Hall 11-029, 1101 East Marshall Street, Richmond, VA 23298 USA
                [4 ]Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD USA
                [5 ]ISNI 0000 0000 9635 8082, GRID grid.420089.7, Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, ; Detroit, MI USA
                Article
                696
                10.1186/s12881-018-0696-4
                6173941
                30290772
                2a00b102-06c8-4e44-8601-e485ed62eb3c
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 5 June 2018
                : 25 September 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000861, Burroughs Wellcome Fund;
                Award ID: #1015040
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01 HD073555
                Funded by: FundRef http://dx.doi.org/10.13039/100009633, Eunice Kennedy Shriver National Institute of Child Health and Human Development;
                Award ID: HSN275201300006C
                Award Recipient :
                Categories
                Technical Advance
                Custom metadata
                © The Author(s) 2018

                Genetics
                preterm premature rupture of membranes,defensin β1,mannose binding lectin-2,methyltransferase like 7b,whole exome sequencing

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