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It appears not to be attributable to gonadal hormones, developmental delay in females, or preferential death of affected males. Recent studies of the <jats:italic>Trp53<\/jats:italic> mouse mutant showed that exencephaly susceptibility depends on the presence of two X chromosomes, not the absence of the Y. Over a decade ago, we hypothesized that the relevant difference between female and male mammalian embryos at the time of cranial neural tube closure is the fact that females methylate most of the DNA in the large inactive X chromosome after every cell division, reducing the methylation available for other needs in female cells. Recently, the Whitelaw laboratory identified several proteins in mice (<jats:italic>Momme D<\/jats:italic> genes) involved in epigenetic silencing and methylation and shared in the silencing of transgenes, retrotransposons, and the inactive\u2010X, and suggested that the inactive\u2010X acts as a \u201csink\u201d for epigenetic silencing proteins. The \u201cinactive\u2010X sink\u201d hypothesis can be used to suggest expected changes in sex ratio in cranial NTDs in response to various genetic or environmental alterations. We recommend that observation of sex ratio become a standard component of all NTD studies. We suggest that the female excess among cranial NTDs is an epigenetic phenomenon whose molecular investigation will produce insight into the mechanisms underlying NTDs. Birth Defects Research (Part A) 2012. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/bdra.23036","type":"journal-article","created":{"date-parts":[[2012,7,2]],"date-time":"2012-07-02T10:10:15Z","timestamp":1341223815000},"page":"849-855","source":"Crossref","is-referenced-by-count":51,"title":["Hypothesis: The female excess in cranial neural tube defects reflects an epigenetic drag of the inactivating x chromosome on the molecular mechanisms of neural fold elevation"],"prefix":"10.1002","volume":"94","author":[{"given":"Diana M.","family":"Juriloff","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muriel J.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,7,2]]},"reference":[{"key":"e_1_2_3_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(95)00183-7"},{"key":"e_1_2_3_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-12-r182"},{"key":"e_1_2_3_4_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a002592"},{"key":"e_1_2_3_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.12.031"},{"key":"e_1_2_3_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.142"},{"key":"e_1_2_3_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409375102"},{"key":"e_1_2_3_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20581"},{"key":"e_1_2_3_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1986"},{"key":"e_1_2_3_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420330209"},{"key":"e_1_2_3_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a010290"},{"key":"e_1_2_3_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.12.129"},{"key":"e_1_2_3_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.31.5.383"},{"key":"e_1_2_3_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3016.2008.00975.x"},{"key":"e_1_2_3_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03479"},{"key":"e_1_2_3_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.1974.tb03442.x"},{"key":"e_1_2_3_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.12.2199"},{"key":"e_1_2_3_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501963102"},{"key":"e_1_2_3_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20670"},{"key":"e_1_2_3_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.20581"},{"issue":"702","key":"e_1_2_3_21_1","first-page":"704","article-title":"Simplex PCR assay for sex determination in mice","volume":"38","author":"Clapcote SJ","year":"2005","journal-title":"Biotechniques"},{"key":"e_1_2_3_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420420412"},{"key":"e_1_2_3_23_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.26.3.160"},{"key":"e_1_2_3_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2640"},{"key":"e_1_2_3_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20511"},{"key":"e_1_2_3_26_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:BOLI.0000031096.81518.66"},{"key":"e_1_2_3_27_1","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1979.0092"},{"key":"e_1_2_3_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420420209"},{"key":"e_1_2_3_29_1","first-page":"164","article-title":"Defects of the central nervous system in Finland: I. 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