World of Reproductive Biology

BOR–Papers in Press published 7 August 2013 DOI: 10.1095/biolreprod.113.113019 Two new studies tracing the origins of the Y chromosome challenge a long-standing notion in the field of human evolutionary genetics that the most recent common male ancestor of Homo sapiens is much younger than his female counterpart. Large regions of the Y chromosome do not recombine with the X chromosome and so can be used to generate phylogenetic trees based on the timing of appearance of single-nucleotide polymorphisms (SNPs). Researchers can calibrate the SNP “clock” by comparing the genetic findings with archeological records of key human migration events that established new Y-chromosome lineages. The result is a rough estimate of when various Y-chromosome types emerged. Previous analyses of the Y chromosome have been limited to examining a relatively small number of individuals from a few populations, but advances in sequencing technology are now allowing larger-scale analyses. G. David Poznik et al. [1] sequenced the complete Y chromosomes of 69 males from a globally diverse population and calibrated their clock using major migration events into the Americas. They then applied the same analytical techniques to previously sequenced mitochondrial DNA to estimate when mitochondrial “Eve” was on the planet. Their analysis suggests that the most recent common male ancestor emerged between 120,000 to 156,000 years ago, and the female ancestor between 99,000 and 148,000 years ago—approximately the same time frame. In a separate study, Paolo Francalacci et al. [2] sequenced a large non-recombining region of the Y chromosome (about 9 megabases) in a diverse population of 1,204 males from Sardinia, calibrating their clock using known migration events to that island. They concluded that our most recent common male ancestor was alive between 180,000 and 200,000 years ago. The findings suggest that our common male and female ancestor both lived in roughly the same time period, which is in sync with other emerging studies that overturn the notion of a very large age gap. The new results will aid in analyzing the timing of human migration events, such as the emergence out of Africa, which Francalacci et al. place at 110,000 years ago. That date is in accordance with the analysis of fossil remains, but is at odds with mitochondrial DNA studies that place this event closer to the present. Poznik GD, Henn BM, Yee MC, Sliwerska E, Euskirchen GM, Lin AA, Snyder M, Quintana-Murci L, Kidd JM, Underhill PA, Bustamante CD. Sequencing Y chromosomes resolves discrepancy in time to common ancestor of males versus females. Science 2013; 341(6145):562–565. Francalacci P, Morelli L, Angius A, Berutti R, Reinier F, Atzeni R, Pilu R, Busonero F, Maschio A, Zara I, Sanna D, Useli A, et al. Low-pass DNA sequencing of 1200 Sardinians reconstructs European Y-chromosome phylogeny. Science 2013; 341(6145):565–569. BOR–Papers in Press published 14 August 2013 DOI: 10.1095/biolreprod.113.113167 Induction of a single transcription factor can prompt undifferentiated cells in a dish to take on the fate of primordial germ cells (PGCs), according to findings presented this July at the Annual Meeting of the Society for the Study of Reproduction and published in Nature. PGCs arise shortly after implantation through signals originating from the cells that give rise to the extraembryonic tissue: the placenta and yolk sac. These extraembryonic tissues send signals to cells in the epiblast, the region that gives rise to all the cells of the fetus, initiating the PGC fate. In previous work, Mitinori Saitou and his colleagues identified many of the molecules that go into making a PGC. For instance, they successfully generated PGCs in culture from embryonic stem cells and induced pluripotent stem cells. Using various signaling molecules, they first nudged the cells into becoming epiblast-like cells and then used additional signaling molecules to turn the epiblast-like cells into PGCs, which the researchers have shown to be capable of becoming either sperm or oocytes, depending on the in vitro and in vivo extracellular environment. Saitou and other researchers have also discovered a trove of transcription factors that are involved in PGC specification. Saitou et al. have now taken a look at how some of the key transcription factors interact to determine whether they are sufficient to induce PGC cell fate. The researchers were able to generate PGCs by turning on three transcription factors in epiblast-like cells, but not embryonic stem cells or induced pluripotent stem cells. The three transcription factors were Blimp1 (also known as Prdm1), Prdm14, and Tfap2c (also known as AP2c). The researchers then found that only one factor, Prdm14, could also prompt PGC development, although it did so less efficiently than all three factors combined. The researchers then examined the cellular and molecular response of the cells to these various factors, and outlined how the factors interact and co-regulate each other (see Figure 1). For instance, they found that Prdm14 could turn on pluripotency factors, such as Nanog, as well as core PGC genes, including the other two transcription factors, Blimp1 and Tfap2c. Prdm14 also negatively regulates DNA methylation, which is part of the process unique to PGCs of resetting epigenetic marks. The PGCs induced by Prdm14 gave rise to functional sperm when transplanted into mice, yielding offspring that appeared healthy and had, on the gross level, normal placentas and imprinting. A model for the induction of primordial germ cells. Image reproduced with permission from Nature (DOI 10.1038/nature12417). In addition to outlining the steps that make a PGC, the new system of generating PGCs may prove a boon to researchers who study the development of germ cells. Such research has long been limited by lack of access to the rare and difficult-to-study cells. Nonetheless, there remains one important impediment: the PGCs must undergo differentiation in the in vivo environment, i.e., the testis or the ovary. Unraveling the complexity of this environment is a major challenge to reproductive biologists. Nakaki F, Hayashi K, Ohta H, Kurimoto K, Yabuta Y, Saitou M. Induction of mouse germ-cell fate by transcription factors in vitro. Nature 2013; 501(7466):222–226. BOR–Papers in Press published 21 August 2013 DOI: 10.1095/biolreprod.113.113324 A new analysis of single cells in the embryo provides a unique glimpse into the earliest events of human development. The findings also provide insight into the long-standing question of how early embryonic cells differ from cultured human embryonic stem cells (hESCs). RNA analyses of embryos have traditionally been hampered by scarcity of material. For instance, when embryos are pooled for analysis, it isn't possible to distinguish distinct profiles of individual blastomeres. To overcome such hurdles, several research groups have been honing the technology to generate RNA profiles from single cells. Liying Yan and Mingyu Yang et al. have now used a previously developed protocol to analyze 90 single cells from 20 morphologically normal oocytes and embryos, and from 34 single hESCs. The researchers found that early embryos expressed a broad swath of the genome: approximately half of the known human genes and transcripts were expressed in oocytes and blastomeres at various stages. These included 22,687 maternally expressed genes, up from 9,735 maternal genes previously detected by cDNA microarray methods. The researchers observed several global patterns of RNA expression, including a major shift in the RNA expression profile between 4- and 8-cell blastomeres, presumably corresponding to the maternal-zygotic transition (in which transcription begins to be initiated from zygotic genes). They also observed that 983 genes were up-regulated between the 2- and 4-cell stage, which is probably a sign of an earlier, minor zygotic gene-activation event. At the 8-cell stage, but not earlier, cells within an embryo showed signs of being different. The researchers also found that many genes showed expression of more than one spliced isoform. The findings point to a central role for long noncoding RNAs (lncRNAs) in early development. The researchers detected a total of 18,383 known lncRNAs (64 percent of those currently known) and identified 2,733 novel lncRNAs. These lncRNAs were expressed in distinct, developmental stage-specific patterns, suggesting that they have a regulatory role in early development. The data also provide a comprehensive look at how hESCs differ from epiblast cells, the pluripotent embryonic cells from which they are derived. At the earliest stages of cell culture, the hESCs assume different transcription patterns from epiblast cells, with 1,498 genes showing differential expression. These findings are a rich resource for other scientists and will serve as a springboard for research into questions such as the role of alternative splicing and long noncoding RNAs in early development. Yan L, Yang M, Guo H, Yang L, Wu J, Li R, Liu P, Lian Y, Zheng X, Yan J, Huang J, Li M, et al. Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells. Nat Struct Mol Biol 2013; 20(9):1131–1139. BOR–Papers in Press published 28 August 2013 DOI: 10.1095/biolreprod.113.113530 Feeding male mice a high-fat diet induces molecular changes in their sperm and affects the health of their children and subsequent generations, according to a new study. Those children are then prone to obesity and metabolic dysregulation, a finding that showcases emerging data suggesting that environmental effects on fathers can affect subsequent generations. This was also a theme of research presented at the Annual Meeting of the Society for the Study of Reproduction (SSR 2013) in July. In the new study [1], Tod Fullston et al. fed mice a diet that caused them to increase their adiposity by 21 percent, short of overt diabetes. Both the male and female F1 offspring had impaired glucose tolerance and insulin resistance, and the female F1 offspring were obese, with a 71-percent increase in adiposity, even though the offspring were fed normal diets. The F2 offspring were also affected, although this depended on the gender of the parent and offspring. The finding that female offspring of fat males are particularly susceptible to metabolic disturbance is consistent with the effects seen in a previous study of rats fed a high-fat diet. In that study, obese diabetic males produced daughters with impaired metabolic health, though the offspring were not obese and the sons were apparently unaffected. Uncovering the mechanisms behind such paternal effects remains a major research goal. These results hint at a role for microRNAs, which are known to be delivered to the oocyte and are implicated in embryonic development. The researchers observed altered expression of several microRNAs in the sperm of mice fed a high-fat diet. They also saw altered expression in some of the predicted target genes of those microRNAs, many of which are known to affect processes such as spermatogenesis, embryonic development, and metabolic function. One affected microRNA, for instance, is known to regulate the expression of insulin-like growth factor 1 receptor (Igf-1R). Igf-1R participates in the formation of the trophectoderm, the tissue that gives rise to the placenta and is involved in implantation, a process that is impaired by paternal obesity. The researchers also showed a global 25-percent reduction in methylation of germ-cell DNA in male mice fed a high-fat diet. The events that might link changes in diet, microRNA expression, and shifts in epigenetic marks comprise a giant puzzle to be resolved in the future. Separate studies presented at SSR 2013 also look at the father's environment and its effect on sperm and offspring. Adam Watkins and colleagues [2] at the University of Nottingham in Loughborough, Leicestershire, U.K., fed male mice a low-protein diet and observed that offspring were heavier than normal and that they developed low blood pressure, vascular dysfunction, and impaired glucose tolerance. The researchers observed hypomethylation at calcium-signaling and apoptotic-pathway loci in sperm, and they also observed effects in uteri after fertilization, hinting at an effect of seminal plasma. The uteri showed a decrease in the expression of prostaglandin and lipoxygenese genes, and reductions in cytokine and glucose levels. These findings are in sync with earlier studies that have shown that a low-protein paternal diet affects cytosine methylation of DNA in the liver of offspring, as well as the expression of genes involved in lipid and cholesterol metabolism. Also at SSR 2013, Mylène Landry et al. [3] at McGill University in Montreal found that folate deficiency in fathers affects the quality of the embryos they fertilize. Embryos from such fathers had an elevated rate of pre-implantation loss. Together, these and other studies showing that paternal diet can affect subsequent generations fit with earlier data on mothers. For instance, maternal diet has transgenerational effects in animal models, which is supported by human epidemiological studies. A mechanistic understanding of how these effects arise in animal models could lead to a clearer assessment of the molecular effects of diet—and other types of environmental exposures—on human gametes. If a similar phenomenon occurs in people, then the public health implications are vast. Fullston T, Ohlsson Teague EM, Palmer NO, Deblasio MJ, Mitchell M, Corbett M, Print CG, Owens JA, Lane M. Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J 2013; 27(10):4226–4243. Watkins AJ. Periconceptual environment and offspring health. In: Supplement to Biology of Reproduction for the 46th Annual Meeting of the Society for the Study of Reproduction, July 22–26, 2013, Montréal, Québec. Biol Reprod 2013; Suppl: Abstract 10. Landry M, Chan D, Trasler JM. Effects of paternal folate deficiency and supplementation on progeny outcome. In: Supplement to Biology of Reproduction for the 46th Annual Meeting of the Society for the Study of Reproduction, July 22–26, 2013, Montréal, Québec. Biol Reprod 2013; Suppl: Abstract 536.

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