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      An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing

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          Abstract

          Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.

          Author Summary

          The control of birth timing in humans is the greatest unresolved question in reproductive biology, and preterm birth is the most important medical issue in maternal and child health. To begin to address this critical problem, we test the hypothesis that genes accelerated in their rate of evolution in humans, as compared with other primates and mammals, are involved in birth timing. We first show that human gestational length has been altered relative to other non-human primates and mammals. Using allometric scaling, we demonstrate that human gestation is shorter than predicted based upon gestational length in other mammalian species. Next, we show that genes with rate acceleration in humans—in coding or regulatory regions—are plausible candidates to be involved in birth timing. Finally, we find that polymorphisms in the human accelerated gene ( FSHR), not before implicated in the timing for birth, may alter risk for human preterm birth. Our understanding of pathways for birth timing in humans is limited, yet its elucidation remains one of the most important issues in biology and medicine. The evolutionary genetic approach that we apply should be applicable to many human disorders and assist other investigators studying preterm birth.

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          Most cited references40

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          Recent segmental duplications in the human genome.

          Primate-specific segmental duplications are considered important in human disease and evolution. The inability to distinguish between allelic and duplication sequence overlap has hampered their characterization as well as assembly and annotation of our genome. We developed a method whereby each public sequence is analyzed at the clone level for overrepresentation within a whole-genome shotgun sequence. This test has the ability to detect duplications larger than 15 kilobases irrespective of copy number, location, or high sequence similarity. We mapped 169 large regions flanked by highly similar duplications. Twenty-four of these hot spots of genomic instability have been associated with genetic disease. Our analysis indicates a highly nonrandom chromosomal and genic distribution of recent segmental duplications, with a likely role in expanding protein diversity.
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            Risk alleles for multiple sclerosis identified by a genomewide study.

            Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis. We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis. A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)). Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis. Copyright 2007 Massachusetts Medical Society.
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              Ensembl 2007

              The Ensembl () project provides a comprehensive and integrated source of annotation of chordate genome sequences. Over the past year the number of genomes available from Ensembl has increased from 15 to 33, with the addition of sites for the mammalian genomes of elephant, rabbit, armadillo, tenrec, platypus, pig, cat, bush baby, common shrew, microbat and european hedgehog; the fish genomes of stickleback and medaka and the second example of the genomes of the sea squirt (Ciona savignyi) and the mosquito (Aedes aegypti). Some of the major features added during the year include the first complete gene sets for genomes with low-sequence coverage, the introduction of new strain variation data and the introduction of new orthology/paralog annotations based on gene trees.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                April 2011
                April 2011
                14 April 2011
                : 7
                : 4
                : e1001365
                Affiliations
                [1 ]Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America
                [2 ]Human and Statistic Genetics Program, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [3 ]Computational Biology Program, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [4 ]Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
                [5 ]Institute of Clinical Medicine, Department of Pediatrics, University of Oulu, Oulu, Finland
                [6 ]Departments of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland
                [7 ]The Perinatal Research Center, Nashville, Tennessee, United States of America
                [8 ]Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America
                [9 ]Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, United States of America
                [10 ]Finnish Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland
                [11 ]The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
                [12 ]Wellcome Trust Sanger Institute, Cambridge, United Kingdom
                [13 ]Department of Pediatrics, Lund University, Lund, Sweden
                [14 ]Department of Pediatrics, University of Helsinki, Helsinki, Finland
                [15 ]Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
                [16 ]Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [17 ]Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [18 ]Department of Genetics and Center for Genome Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [19 ]Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
                [20 ]Vanderbilt Kennedy Center for Human Development, Vanderbilt University, Nashville, Tennessee, United States of America
                Stanford University, United States of America
                Author notes

                Conceived and designed the experiments: JP SD TM JF LM. Performed the experiments: JP SD GO JJM MTO. Analyzed the data: JP SD TM RM TLM JJM MTO IB JF LM. Contributed reagents/materials/analysis tools: RH MH HP EK EN VS AP LP VF EAD BPC MTO KT LM. Wrote the paper: JP TM MH RM EN IB JF LM.

                ¶ These authors were joint senior authors on this work.

                Article
                10-PLGE-RA-NV-3649R3
                10.1371/journal.pgen.1001365
                3077368
                21533219
                049ae906-7288-415d-b0ef-c954f9444a70
                Plunkett et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 14 July 2010
                : 7 March 2011
                Page count
                Pages: 10
                Categories
                Research Article
                Genetics and Genomics/Comparative Genomics
                Genetics and Genomics/Complex Traits
                Genetics and Genomics/Genetics of Disease

                Genetics
                Genetics

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