Meiosis comprises fundamental processes that permit sexual reproduction and species evolution. In addition to producing haploid gametes, it provides for a stochastic distribution of maternally and paternally inherited chromosomes, which undergo allelic recombination thereby increasing genetic variability in the next generation. Thus it provides for diversity within a population, and is essential for the formation of euploid germ cells that will contribute to a euploid healthy embryo after fertilization. Meiosis is therefore the basis for maintaining genomic integrity, high developmental potential, and health of the embryo and offspring, and normal fertility in males and females [1,2]. Furthermore, it is the basis of changes in the genome that are important for adaptation and evolution of species.

There are two types of genomic information accurately inherited or maintained following DNA replication: the entire genomic DNA sequence and epigenetic information in the form of patterns of CpG methylation on a subset of the genome. These DNA methylation patterns are crucially important for mammalian development, primarily because they regulate gene transcription. There are cyclical declines and increases in DNA methylation during gametogenesis and embryogenesis, and the oscillations in methylation occurring across generations must depend on de novo methylation and demethylation processes to rearrange the existing methylation patterns. Within any single reproductive cycle, changes in genomic methylation are the outcome of a linked sequence of active and passive processes that rearrange genomic methylation to generate epigenetic milestones, each with a defined future role. For example, genomic imprints are established during gametogenesis by de novo methylation to generate mature gametes with complete complements of paternal methylation imprints in sperm and maternal methylation imprints in oocytes. The establishment of a collective set of imprints within a sperm and an oocyte is an epigenetic milestone, whose purpose after sperm–oocyte fusion is to ensure monoallelic expression of imprinted genes during fetal development. We postulate that another essential epigenetic milestone is found in the blastocyst-stage embryo; this milestone is achieved at the generation, through the poorly understood process of epigenetic reprogramming, of pluripotent embryo stem cells, whose role is to contribute to the development of the conceptus. Primordial germ cells (PGCs), largely devoid of genomic methylation and poised to differentiate into gametes with sex-specific imprints, and adult stem cells, poised to differentiate into organs, would be other possible epigenetic milestones. The developmental locations of three fundamental milestones (gametes, blastocyst, and PGCs), and the epigenetic processes by which they are crafted, are depicted in Figure 5.1.

The release of the human genome sequence has revealed that our genes represent only a minor fraction, with exons making up less than 2% of our DNA. In contrast, transposable elements represent some 45% of the genomic mass. Contrary to other species such as Drosophila or plants, these elements are not clustered in specific chromosomal regions in mammals, but are rather scattered throughout the genome, residing between but also inside genes. The transposon landscape of our genome reflects an evolutionary tug-of-war between integration and propagation events orchestrated by these elements, and counteracting defense mechanisms exerted by the host.

The genetic causes of male infertility are highly heterogeneous, and a large portion of these causes remains unexplained. More than 2300 testes-specific genes may contribute to male infertility [1]. Primary testicular disorders affecting spermatogenesis are commonly associated with abnormal semen parameters, including sperm concentration (oligozoospermia or azoospermia), morphology, motility, and vitality. Studies in infertile men have demonstrated that up to 20% carry constitutional chromosome aberrations [2–5]. Genomic aberrations found in these patients include numerical abnormalities, such as Klinefelter syndrome and its variants; XYY karyotype; testicular disorders of sex development, such as XX males; structural chromosome rearrangements, including Robertsonian translocations, balanced reciprocal translocations and inversions; as well as submicroscopic DNA copy number alterations (microdeletions and microduplications) encompassing genes associated with spermatogenesis or gonadal development.

This chapter on the ethics of human reproductive genetics focuses on current debates in three corners of the field of medically assisted reproduction (MAR). First, we discuss preimplantation genetic testing (PGT). Until recently, ethical debates concentrated on PGT “on indication,” formerly termed preimplantation genetic diagnosis (PGD), namely testing of embryos on behalf of couples mostly at high risk of transmitting a specific genetic disorder. As important, however, is the ethics of (the offer of) routine testing of in vitro fertilization (IVF) embryos, formerly termed preimplantation genetic screening (PGS). Although it is still unclear what the precise value of such screening may turn out be, the scenario of next generation sequencing (NGS)-based “comprehensive PGS” raises a number of challenging ethical issues. Secondly, we discuss carrier screening. In MAR, until recently this type of screening targeted gamete donors. Presently, however, a growing number of clinics have started offering carrier screening to applicants of MAR as well. As discussed in Chapter 10, new NGS technologies are expected to make broad-scope testing for many genetic conditions feasible and affordable. Accordingly, what should we test gamete donors and applicants of MAR for and why? Finally, we add a brief ethical reflection on what may become a (or the) real revolution in human reproduction: germline genome editing.

Reproduction in humans is considered to be a relatively inefficient process, as the chance of achieving a spontaneous pregnancy after timed intercourse is only approximately 30%. This is much lower than the 70–90% estimated for other species, such as the rhesus monkey, the captive baboon, or rodents and rabbits. The inefficiency of human reproduction is mainly explained by the high incidence of preclinical losses, an estimated 40–60% of all conceptions. Early pregnancy loss is mainly explained due to the occurrence of chromosome abnormalities, which have been identified in most spontaneous abortion samples investigated.

Preimplantation genetic testing (PGT), until recently known as preimplantation genetic diagnosis (PGD), is an early form of prenatal testing for couples at high risk of transmitting a genetic condition to their offspring, either for monogenic disorders (PGT-M) or chromosomal structural rearrangements (PGT-SR). The goal is to test for the specific genetic status in cells biopsied from oocytes/zygotes or embryos obtained in vitro through assisted reproductive technology (ART) and, following analysis, to transfer to the uterus only those embryos identified as genetically suitable relative to the condition under consideration. The selective transfer of unaffected embryos to the uterus for implantation means that PGT minimizes the need to consider the termination of affected pregnancies. This advantage of PGT means that it has become a widely acceptable alternative to conventional prenatal diagnosis. Of course, PGT is not applied without some ethical concerns. In patients with high risk for transmitting specific genetic conditions to their offspring, including serious single gene disorders and chromosomal rearrangements, there is usually little ethical debate. However, the increased availability and emergence of new uses, such as PGT for autosomal dominant late-onset disorders, cancer predisposition syndromes, PGT for histocompatibility (HLA) typing, and mitochondrial DNA (mtDNA) mutations, are associated with greater ethical controversy and important ethical questions (see Chapter 15).

Mitochondria are typically described as the powerhouse of the cell, because they are the cytoplasmic organelles responsible for the production of ATP through oxidative phosphorylation. Over the years, it has become clear that their function within the cell is more complex as they are also involved in numerous other processes, including lipid and carbohydrate metabolism, heme biosynthesis, apoptosis, and calcium homeostasis [1]. Human cells contain multiple mitochondria, with the exception of red blood cells that have none. The numbers, mass, morphology, and distribution vary greatly across different cell types, generally depending on the energy demands of the tissues. For instance, sperm contain 20–75 mitochondria in their midpiece, while hepatocytes and muscle cells contain thousands.

In the past decade the development of new technologies and innovations have revolutionized genetic testing. The ability to diagnose and prevent genetic disorders before an existing pregnancy and to detect embryonic and fetal genetic errors has dramatically increased, and has substantially changed the care for couples wanting a child.

This brief reminder chapter aims to freshen up what professionals in reproduction may have learned a while ago at university, and will also serve the reader as a source of information to comprehend the following, more complex chapters. At the end of this chapter, basic study books or broad reviews are recommended for further reading rather than regular scientific references, to help the reader in the further understanding of this textbook.

Infertility is a genetically heterogeneous condition affecting about 10% of women of reproductive age. Genetic studies on animal models have identified thousands of candidate genes that are essential for gonadal development, germline cell differentiation, complex oocyte–granulosa intercellular signaling, gametogenesis, fertilization, and fetal development. A subset of these candidate genes derived from animal models has been found to cause ovarian dysfunction and infertility in humans.

The World Health Organization (WHO) defines infertility as the inability to conceive within 12 months despite regular unprotected intercourse, a condition that concerns about 10–15% of couples globally. Infertility is considered as primary or secondary depending on whether a couple has experienced a prior pregnancy or not.

Preimplantation genetic testing (PGT) allows the detection of genetic abnormalities in biopsies that comprise 1–10 cells from preimplantation embryos and is performed to avoid the transmission of inherited and de novo genetic abnormalities to the offspring (Figure 2.1) (see Chapter 13). The minute amount of genomic DNA in a single cell represented a challenge for whole-genome profiling of embryo biopsies on development of PGT in the 1990s because whole-genome analysis technologies required micrograms of input DNA. Before the adaptation of these technologies to single-cell input by whole-genome amplification (WGA) methods, PGT was performed using targeted approaches according to the couple’s indication [1] (Table 2.1). For instance, fluorescence in situ hybridization (FISH) was used to detect unbalanced karyotypes in the embryos from balanced translocation carriers or from couples with recurrent miscarriage or implantation failure. In case of Mendelian disorders, embryo biopsies were subjected to multiplex polymerase chain reaction (PCR) of the risk allele(s) together with several cosegregating polymorphic markers. These targeted approaches were developed for each family specifically, rendering them labor-intensive, costly, and time-consuming. Moreover, some mutations (e.g. a priori unknown small deletions and duplications or complex chromosomal rearrangements) were practically impossible to diagnose using these strategies. The development of WGA technologies in the early 2000s, their application in genomic array technologies thereafter, and the decrease in cost of next generation sequencing (NGS) helped to overcome these limitations and enabled whole-genome profiling of single cells. Furthermore, the improvements in embryo culture made trophectoderm (TE) biopsy possible at the blastocyst stage, enabling 5–10 cells to be biopsied and tested. Besides increasing the diagnostic accuracy, this allowed for the detection of the mosaic status of genetic variants genome-wide [1]. In parallel, the advancement of embryo cryopreservation techniques expanded the time frame required for embryo diagnosis and therefore also contributed to the development and application of new PGT technologies and data analysis.

Since the birth of the first baby via in vitro fertilization (IVF) in 1978, there has been concern about the safety of IVF and other assisted reproduction technology (ART) procedures for the health of ART-conceived children. Data show that ART singletons are at increased risk for adverse perinatal outcomes such as low birthweight and being small for gestational age, and congenital malformations [1]. The biological mechanism behind these risks is mainly unresolved. Since the publication of a few case reports on the incidence of rare imprinting disorders such as Angelman and Beckwith–Wiedemann syndromes in ART-conceived children, epigenetic deregulation has gained increasing attention as a possible common cause for the adverse outcomes. This led to an expansion of ART literature on epigenetic effects. In this chapter, I focus on the current knowledge of epigenetic disturbances in humans, reported after ART in general and in relation to specific ART components, and the difficulties encountered in these kinds of studies. When needed, animal studies will also be mentioned. The subfertility of the population as a possible cause for the epigenetic deregulation is also taken into consideration. Finally, I discuss whether epigenetic effects can be related to the reported health outcome in ART children and if these possible derangements can affect their health at adult age.

The Human Genome Project officially began in the USA in October 1990 under the auspices of the Department of Energy and the National Institutes of Health (NIH) under the direction of Francis Collins. The objective was to build genetic and physical maps of the entire human genome, and at the same time to develop the technology needed to perform DNA sequencing on a large scale. Extensive international collaboration and advances in the field of genomics and bioinformatics enabled the first essentially complete version of the human genome (92.3% of the total) to be officially announced 13 years later, two years ahead of schedule, on April 14, 2003, with 99.9% reliability.