Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases

Can spontaneous premature ovarian failure (POF) patients derived from population-based biobanks reveal the association between copy number variations (CNVs) and POF? CNVs can hamper the functional capacity of ovaries by disrupting key genes and pathways essential for proper ovarian function. POF is defined as the cessation of ovarian function before the age of 40 years. POF is a major reason for female infertility, although its cause remains largely unknown. The current retrospective CNV study included 301 spontaneous POF patients and 3188 control individuals registered between 2003 and 2014 at Estonian Genome Center at the University of Tartu (EGCUT) biobank. DNA samples from 301 spontaneous POF patients were genotyped by Illumina HumanCoreExome (258 samples) and HumanOmniExpress (43 samples) BeadChip arrays. Genotype and phenotype information was drawn from the EGCUT for the 3188 control population samples, previously genotyped with HumanCNV370 and HumanOmniExpress BeadChip arrays. All identified CNVs were subjected to functional enrichment studies for highlighting the POF pathogenesis. Real-time quantitative PCR was used to validate a subset of CNVs. Whole-exome sequencing was performed on six patients carrying hemizygous deletions that encompass genes essential for meiosis or folliculogenesis. Eleven novel microdeletions and microduplications that encompass genes relevant to POF were identified. For example, FMN2 (1q43) and SGOL2 (2q33.1) are essential for meiotic progression, while TBP (6q27), SCARB1 (12q24.31), BNC1 (15q25) and ARFGAP3 (22q13.2) are involved in follicular growth and oocyte maturation. The importance of recently discovered hemizygous microdeletions of meiotic genes SYCE1 (10q26.3) and CPEB1 (15q25.2) in POF patients was also corroborated. This is a descriptive analysis and no functional studies were performed. Anamnestic data obtained from population-based biobank lacked clinical, biological (hormone levels) or ultrasonographical data, and spontaneous POF was predicted retrospectively by excluding known extraovarian causes for premature menopause. The present study, with high number of spontaneous POF cases, provides novel data on associations between the genomic aberrations and premature menopause of ovarian cause and demonstrates that population-based biobanks are powerful source of biological samples and clinical data to reveal novel genetic lesions associated with human reproductive health and disease, including POF. This study was supported by the Estonian Ministry of Education and Research (IUT20-43, IUT20-60, IUT34-16, SF0180027s10 and 9205), Enterprise Estonia (EU30020 and EU48695), Eureka's EUROSTARS programme (NOTED, EU41564), grants from European Union's FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, SARM, |EU324509) and Horizon 2020 innovation programme (WIDENLIFE, 692065), Academy of Finland and the Sigrid Juselius Foundation.Peer reviewe

In vitro fertilization does not increase the incidence of de novo copy number alterations in fetal and placental lineages

Although chromosomal instability (CIN) is a common phenomenon in cleavage-stage embryogenesis following in vitro fertilization (IVF)1,2,3, its rate in naturally conceived human embryos is unknown. CIN leads to mosaic embryos that contain a combination of genetically normal and abnormal cells, and is significantly higher in in vitro-produced preimplantation embryos as compared to in vivo-conceived preimplantation embryos4. Even though embryos with CIN-derived complex aneuploidies may arrest between the cleavage and blastocyst stages of embryogenesis5,6, a high number of embryos containing abnormal cells can pass this strong selection barrier7,8. However, neither the prevalence nor extent of CIN during prenatal development and at birth, following IVF treatment, is well understood. Here we profiled the genomic landscape of fetal and placental tissues postpartum from both IVF and naturally conceived children, to investigate the prevalence and persistence of large genetic aberrations that probably arose from IVF-related CIN. We demonstrate that CIN is not preserved at later stages of prenatal development, and that de novo numerical aberrations or large structural DNA imbalances occur at similar rates in IVF and naturally conceived live-born neonates. Our findings affirm that human IVF treatment has no detrimental effect on the chromosomal constitution of fetal and placental lineages

In vitro fertilization has no effect on prevalence of mosaic copy-number alterations in fetal and placental lineages

Chromosomal instability (CIN) is a common phenomenon in cleavage-stage embryogenesis that leads to a mixture of euploid and aneuploid cells within the same human embryo during in vitro fertilization (IVF). However, the rate of CIN in naturally conceived embryos is largely unknown, because it is impossible to study human embryos in vivo. Here, we developed and applied a novel haplarithmisis-based method to characterize allelic architecture of DNA samples derived from the placenta and cord blood of the same pregnancy. Specifically, we scrutinized genome-wide single nucleotide polymorphism profiles in DNA from the father, mother, placenta and neonate umbilical cord blood of 55 families (quartets), of which 26 and 29 quartets were from natural and IVF pregnancies, respectively. We demonstrate that CIN is not preserved at later stages of prenatal development, and that de novo genomic alterations occur at similar rates in IVF and naturally conceived neonates. The findings confirm that IVF treatment has no detrimental effect on the chromosomal constitution of fetal or placental lineages

Myosin XIX.” In Myosins: A Superfamily of Molecular Motors

The birth of widely available genomic databases at the turn of the millennium led to the identification of many previously unknown myosin genes and identification of novel classes of myosin, including MYO19. Further sequence analysis has revealed the unique evolutionary history of class XIX myosins. MYO19 is found in species ranging from vertebrates to some unicellular organisms, while it has been lost from some lineages containing traditional experimental model organisms. Unique sequences in the motor domain suggest class-specific mechanochemistry that may relate to its cellular function as a mitochondria-associated motor. Work over the past 10 years has demonstrated that MYO19 is an actin-activated ATPase capable of actin-based transport, and investigation of some of the conserved differences within the motor domain indicate their importance in MYO19 motor activity. The cargo-binding MyMOMA tail domain contains two distinct mechanisms of interaction with mitochondrial outer membrane components, and perturbation of MYO19 expression leads to alterations in mitochondrial movement and dynamics that impact cell function. This chapter summarizes the current state of the field and highlights potential new directions of inquiry