Inferring simple but precise quantitative models of human oocyte and early embryo development
Brian D Leahy, Catherine Racowsky, Daniel Needleman, Brian D Leahy, Catherine Racowsky, Daniel Needleman
Abstract
Macroscopic, phenomenological models are useful as concise framings of our understandings in fields from statistical physics to finance to biology. Constructing a phenomenological model for development would provide a framework for understanding the complicated, regulatory nature of oogenesis and embryogenesis. Here, we use a data-driven approach to infer quantitative, precise models of human oocyte maturation and pre-implantation embryo development, by analysing clinical in-vitro fertilization (IVF) data on 7399 IVF cycles resulting in 57 827 embryos. Surprisingly, we find that both oocyte maturation and early embryo development are quantitatively described by simple models with minimal interactions. This simplicity suggests that oogenesis and embryogenesis are composed of modular processes that are relatively siloed from one another. In particular, our analysis provides strong evidence that (i) pre-antral follicles produce anti-Müllerian hormone independently of effects from other follicles, (ii) oocytes mature to metaphase-II independently of the woman's age, her BMI and other factors, (iii) early embryo development is memoryless for the variables assessed here, in that the probability of an embryo transitioning from its current developmental stage to the next is independent of its previous stage. Our results both provide insight into the fundamentals of oogenesis and embryogenesis and have implications for the clinical IVF.
Keywords: human embryos; in-vitro fertilization; pre-implantation development; quantitative biology.
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References
- Zhu M, Zernicka-Goetz M. 2020Principles of self-organization of the mammalian embryo. Cell 183, 1467-1478. (10.1016/j.cell.2020.11.003)
- Wennekamp S, Mesecke S, Nédélec F, Hiiragi T. 2013A self-organization framework for symmetry breaking in the mammalian embryo. Nat. Rev. Mol. Cell Biol. 14, 452-459. (10.1038/nrm3602)
- Song Y, Shvartsman SY. 2020Chemical embryology redux: metabolic control of development. Trends Genet. 36, 577-586. (10.1016/j.tig.2020.05.007)
- Gross P, Kumar KV, Grill SW. 2017How active mechanics and regulatory biochemistry combine to form patterns in development. Annu. Rev. Biophys. 46, 337-356. (10.1146/annurev-biophys-070816-033602)
- Chan CJ, Heisenberg C-P, Hiiragi T. 2017Coordination of morphogenesis and cell-fate specification in development. Curr. Biol. 27, R1024-R1035. (10.1016/j.cub.2017.07.010)
- Fiorentino J, Torres-Padilla M-E, Scialdone A. 2020Measuring and modeling single-cell heterogeneity and fate decision in mouse embryos. Annu. Rev. Genet. 54, 167-187. (10.1146/annurev-genet-021920-110200)
- Clift D, Schuh M. 2013Restarting life: fertilization and the transition from meiosis to mitosis. Nat. Rev. Mol. Cell Biol. 14, 549-562. (10.1038/nrm3643)
- Shahbazi MN, Siggia ED, Zernicka-Goetz M. 2019Self-organization of stem cells into embryos: a window on early mammalian development. Science 364, 948-951. (10.1126/science.aax0164)
- Rossant J, Tam PP. 2009Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136, 701-713. (10.1242/dev.017178)
- White MD, Zenker J, Bissiere S, Plachta N. 2018Instructions for assembling the early mammalian embryo. Dev. Cell 45, 667-679. (10.1016/j.devcel.2018.05.013)
- Hassold T, Hunt P. 2001To err (meiotically) is human: the genesis of human aneuploidy. Nat. Rev. Genet. 2, 280-291. (10.1038/35066065)
- Niakan KK, Han J, Pedersen RA, Simon C, Pera RAR. 2012Human pre-implantation embryo development. Development 139, 829-841. (10.1242/dev.060426)
- Jaffe LA, Egbert JR. 2017Regulation of mammalian oocyte meiosis by intercellular communication within the ovarian follicle. Annu. Rev. Physiol. 79, 237-260. (10.1146/annurev-physiol-022516-034102)
- Sethna J. 2006Statistical mechanics: entropy, order parameters, and complexity, vol. 14. Oxford, UK: Oxford University Press.
- Bouchaud J-P, Potters M. 2003Theory of financial risk and derivative pricing: from statistical physics to risk management. Cambridge, UK: Cambridge University Press.
- Bialek W. 2012Biophysics: searching for principles. Princeton, NJ: Princeton University Press.
- Needleman D, Dogic Z. 2017Active matter at the interface between materials science and cell biology. Nat. Rev. Mater. 2, 1. (10.1038/natrevmats.2017.48)
- Eckmann J-P, Tlusty T. 2021Dimensional reduction in complex living systems: where, why, and how. BioEssays 43, e2100062. (10.1002/bies.202100062)
- Halabi N, Rivoire O, Leibler S, Ranganathan R. 2009Protein sectors: evolutionary units of three-dimensional structure. Cell 138, 774-786. (10.1016/j.cell.2009.07.038)
- Taheri-Araghi S, Bradde S, Sauls JT, Hill NS, Levin PA, Paulsson J, Vergassola M, Jun S. 2015Cell-size control and homeostasis in bacteria. Curr. Biol. 25, 385-391. (10.1016/j.cub.2014.12.009)
- Sauls JT, Li D, Jun S. 2016Adder and a coarse-grained approach to cell size homeostasis in bacteria. Curr. Opin. Cell Biol. 38, 38-44. (10.1016/j.ceb.2016.02.004)
- Kohram M, Vashistha H, Leibler S, Xue B, Salman H. 2020Bacterial growth control mechanisms inferred from multivariate statistical analysis of single-cell measurements. Curr. Biol. 31, 955-964. (10.1016/j.cub.2020.11.063)
- Weenen C, Laven JS, von Bergh AR, Cranfield M, Groome NP, Visser JA, Kramer P, Fauser BC, Themmen AP. 2004Anti-mullerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. MHR: Basic Sci. Reprod. Med. 10, 77-83. (10.1093/molehr/gah015)
- La Marca A, Broekmans F, Volpe A, Fauser B, Macklon N. 2009Anti-mullerian hormone (AMH): what do we still need to know? Human Reprod. 24, 2264-2275. (10.1093/humrep/dep210)
- Durlinger A, Visser J, Themmen A. 2002Regulation of ovarian function: the role of anti-Mullerian hormone. Reproduction 124, 601-609.
- La Marca A, Sighinolfi G, Radi D, Argento C, Baraldi E, Artenisio AC, Stabile G, Volpe A. 2010Anti-mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum. Reprod. Update 16, 113-130. (10.1093/humupd/dmp036)
- Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, Scott RT Jr. 2014The nature of aneuploidy with increasing age of the female partner: a review of 15 169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil. Steril. 101, 656-663.e1. (10.1016/j.fertnstert.2013.11.004)
- Talmor A, Dunphy B. 2015Female obesity and infertility. Best Pract. Res. Clin. Obstet. Gynaecol. 29, 498-506. (10.1016/j.bpobgyn.2014.10.014)
- Broughton DE, Moley KH. 2017Obesity and female infertility: potential mediators of obesity’s impact. Fertil. Steril. 107, 840-847. (10.1016/j.fertnstert.2017.01.017)
- Elder K, Dale B. 2020In-vitro fertilization. Cambridge, UK: Cambridge University Press.
- MacKay DJ, Mac Kay DJ. 2003Information theory, inference and learning algorithms. Cambridge, UK: Cambridge University Press.
- MacKay DJ. 1992Bayesian interpolation. Neural Comput. 4, 415-447. (10.1162/neco.1992.4.3.415)
- Friedman N, Linial M, Nachman I, Pe’er D. 2000Using Bayesian networks to analyze expression data. J. Comput. Biol. 7, 601-620. (10.1089/106652700750050961)
- Pearl J. 2009Causality. Cambridge, UK: Cambridge University Press.
- Bühlmann P, Kalisch M, Meier L. 2014High-dimensional statistics with a view toward applications in biology. Annu. Rev. Stat. Appl. 1, 255-278. (10.1146/annurev-statistics-022513-115545)
- Friedman N. 2004Inferring cellular networks using probabilistic graphical models. Science 303, 799-805. (10.1126/science.1094068)
- Bishop CM. 2006Pattern recognition and machine learning. Berlin, Germany: Springer.
- Pellatt L, Rice S, Mason HD. 2010Anti-Müllerian hormone and polycystic ovary syndrome: a mountain too high? Reproduction 139, 825-833. (10.1530/REP-09-0415)
- Erickson JD. (1978Down syndrome, paternal age, maternal age and birth order. Ann. Hum. Genet. 41, 289-298. (10.1111/j.1469-1809.1978.tb01896.x)
- Morris JK, Mutton DE, Alberman E. 2002Revised estimates of the maternal age specific live birth prevalence of Down’s syndrome. J. Med. Screen. 9, 2-6. (10.1136/jms.9.1.2)
- Gruhn JRet al.2019Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 365, 1466-1469. (10.1126/science.aav7321)
- Holubcová Z, Blayney M, Elder K, Schuh M. 2015Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes. Science 348, 1143-1147. (10.1126/science.aaa9529)
- Webster A, Schuh M. 2017Mechanisms of aneuploidy in human eggs. Trends Cell Biol. 27, 55-68. (10.1016/j.tcb.2016.09.002)
- Musacchio A. 2015The molecular biology of spindle assembly checkpoint signaling dynamics. Curr. Biol. 25, R1002-R1018. (10.1016/j.cub.2015.08.051)
- Mihajlović AI, FitzHarris G. 2018Segregating chromosomes in the mammalian oocyte. Curr. Biol. 28, R895-R907. (10.1016/j.cub.2018.06.057)
- Holt JE, Jones KT. 2009Control of homologous chromosome division in the mammalian oocyte. Mol. Hum. Reprod. 15, 139-147. (10.1093/molehr/gap007)
- Howe K, FitzHarris G. 2013Recent insights into spindle function in mammalian oocytes and early embryos. Biol. Reprod. 89, 71. (10.1095/biolreprod.113.112151)
- Hugues J, Soussis J, Calderon I, Balasch J, Anderson R, Romeu A. 2005Does the addition of recombinant LH in WHO group II anovulatory women over-responding to FSH treatment reduce the number of developing follicles? A dose-finding study. Hum. Reprod. 20, 629-635. (10.1093/humrep/deh682)
- Wikland M, Bergh C, Borg K, Hillensjö T, Howles C, Knutsson A, Nilsson L, Wood M. 2001A prospective, randomized comparison of two starting doses of recombinant FSH in combination with cetrorelix in women undergoing ovarian stimulation for IVF/ICSI. Hum. Reprod. 16, 1676-1681. (10.1093/humrep/16.8.1676)
- Cha J, Sun X, Dey SK. 2012Mechanisms of implantation: strategies for successful pregnancy. Nat. Med. 18, 1754-1767. (10.1038/nm.3012)
- Little RJ, Rubin DB. 2019Statistical analysis with missing data, vol. 793. New York, NY: John Wiley & Sons.
- Racowsky C, Stern JE, Gibbons WE, Behr B, Pomeroy KO, Biggers JD. 2011National collection of embryo morphology data into society for assisted reproductive technology clinic outcomes reporting system: associations among day 3 cell number, fragmentation and blastomere asymmetry, and live birth rate. Fertil. Steril. 95, 1985-1989. (10.1016/j.fertnstert.2011.02.009)
- Vernon M, Stern JE, Ball GD, Wininger D, Mayer J, Racowsky C. 2011Utility of the national embryo morphology data collection by the society for assisted reproductive technologies (SART): correlation between day-3 morphology grade and live-birth outcome. Fertil. Steril. 95, 2761-2763. (10.1016/j.fertnstert.2011.02.008)
- Gardner DK, Balaban B. 2016Assessment of human embryo development using morphological criteria in an era of time-lapse, algorithms and OMICS: is looking good still important? MHR: Basic Sci. Reprod. Med. 22, 704-718. (10.1093/molehr/gaw057)
- Braude P, Bolton V, Moore S. 1988Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature 332, 459-461. (10.1038/332459a0)
- Rienzi Let al.2015No evidence of association between blastocyst aneuploidy and morphokinetic assessment in a selected population of poor-prognosis patients: a longitudinal cohort study. Reprod. Biomed. Online 30, 57-66. (10.1016/j.rbmo.2014.09.012)
- Minasi MGet al.2016Correlation between aneuploidy, standard morphology evaluation and morphokinetic development in 1730 biopsied blastocysts: a consecutive case series study. Hum. Reprod. 31, 2245-2254. (10.1093/humrep/dew183)
- Campbell A, Fishel S, Bowman N, Duffy S, Sedler M, Hickman CFL. 2013Modelling a risk classification of aneuploidy in human embryos using non-invasive morphokinetics. Reprod. Biomed. Online 26, 477-485. (10.1016/j.rbmo.2013.02.006)
- Kaser DJ, Racowsky C. 2014Clinical outcomes following selection of human preimplantation embryos with time-lapse monitoring: a systematic review. Hum. Reprod. Update 20, 617-631. (10.1093/humupd/dmu023)
- Hill MJ, Richter KS, Heitmann RJ, Graham JR, Tucker MJ, DeCherney AH, Browne PE, Levens ED. 2013Trophectoderm grade predicts outcomes of single-blastocyst transfers. Fertil. Steril. 99, 1283-1289.e1. (10.1016/j.fertnstert.2012.12.003)
- Ahlström A, Westin C, Reismer E, Wikland M, Hardarson T. 2011Trophectoderm morphology: an important parameter for predicting live birth after single blastocyst transfer. Hum. Reprod. 26, 3289-3296. (10.1093/humrep/der325)
- Macklon NS, Stouffer RL, Giudice LC, Fauser BC. 2006The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr. Rev. 27, 170-207. (10.1210/er.2005-0015)
- Akin E, Lacker HM. 1984Ovulation control: the right number or nothing. J. Math. Biol. 20, 113-132. (10.1007/BF00285341)
- Lacker H. 1981Regulation of ovulation number in mammals. A follicle interaction law that controls maturation. Biophys. J. 35, 433-454. (10.1016/S0006-3495(81)84800-X)
- Lacker HM, Akin E. 1988How do the ovaries count? Math. Biosci. 90, 305-332. (10.1016/0025-5564(88)90072-7)
- Leary C, Leese HJ, Sturmey RG. 2015Human embryos from overweight and obese women display phenotypic and metabolic abnormalities. Hum. Reprod. 30, 122-132. (10.1093/humrep/deu276)
- Van de Velde H, Cauffman G, Tournaye H, Devroey P, Liebaers I. 2008The four blastomeres of a 4-cell stage human embryo are able to develop individually into blastocysts with inner cell mass and trophectoderm. Hum. Reprod. 23, 1742-1747. (10.1093/humrep/den190)
- Willadsen S. 1980The viability of early cleavage stages containing half the normal number of blastomeres in the sheep. Reproduction 59, 357-362. (10.1530/jrf.0.0590357)
- Allen W, Pashen R. 1984Production of monozygotic (identical) horse twins by embryo micromanipulation. Reproduction 71, 607-613. (10.1530/jrf.0.0710607)
- Hartwell LH, Hopfield JJ, Leibler S, Murray AW. 1999From molecular to modular cell biology. Nature 402, C47-C52. (10.1038/35011540)
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