Genetics, epigenetics and germ cells

Every animal that reproduces sexually depends on a small population of cells, the germ line, that will eventually become sperm or eggs. These cells carry the genome into the next generation, but they also carry, and in some cases deliberately reset, a layer of chemical information that sits on top of the DNA sequence. Research in this field asks how germ cells are specified, how they protect and repair their DNA, how they handle that epigenetic layer, and what goes wrong when any of these steps fails.

Setting aside the germ line

In mammals, the precursors of sperm and eggs, called primordial germ cells, are established in the embryo at around the time of gastrulation, when the basic body plan is being laid down. Signals from the tissues surrounding the embryo switch on a distinctive network of genes in a small group of competent cells and commit them to the germ-cell fate. The same programme also launches a sweeping reset of the cells’ epigenome, including a global loss of DNA methylation and a reorganisation of chromatin, the packaging of DNA and proteins inside the nucleus.

Much of what is known comes from the mouse, which has been studied in great detail. Studies of human germ cells, reviewed in 2016, suggest that the overall sequence of events is similar in the two species, but that the molecular switches used to specify germ cells differ in important ways. That difference matters, because it limits how directly results from mice can be applied to human fertility.

Epigenetics: information on top of the sequence

“Epigenetic” describes heritable changes in how genes are used that do not involve a change in the DNA sequence itself. The best-studied mark is DNA methylation, the addition of a small methyl group, mostly at sites where the base cytosine is followed by guanine. In the differentiated cells of the body, methylation patterns are generally stable and are copied each time a cell divides.

Mammals, however, have at least two windows in which methylation is reprogrammed across almost the whole genome: in the developing germ cells and in the early embryo before it implants. These waves of erasure and re-establishment are thought to restore the broad developmental potential of the cells concerned and to wipe away much of the epigenetic information acquired during the parent’s life. They are also central to imprinting, discussed below, and are relevant to cloning, in which the nucleus of a specialised cell must be reprogrammed to support development.

Genomic imprinting: why both parents are needed

For most genes, a person carries two working copies, one inherited from each parent. A small percentage of human genes are different: only the copy inherited from one particular parent is active, while the other is silenced. This is called genomic imprinting, and the parental origin of each copy is marked largely through methylation laid down during egg or sperm formation. In humans, many imprinted genes cluster in two regions, on chromosomes 11 and 15.

The idea emerged from embryo experiments in mice published in 1984. When fertilised eggs were rebuilt so that both sets of chromosomes came from the mother, the embryos developed poorly after implantation, whereas eggs given one maternal and one paternal set could develop to term. The authors proposed that the genome is “imprinted” during gametogenesis, and noted that the paternal contribution seemed especially important for the membranes and trophoblast that later form the placenta.

Imprinting has clinical relevance. When a child inherits both copies of a chromosome region from the same parent (uniparental disomy), or when imprinting marks are set incorrectly, the result can be a missing or doubled dose of active genes. Prader–Willi syndrome and Angelman syndrome, linked to chromosome 15, and Beckwith–Wiedemann syndrome, linked to chromosome 11, are the best-known examples.

In 2004 a Japanese team reported a mouse, nicknamed Kaguya, that developed to adulthood with two maternal genomes and no father. To achieve this, the researchers combined chromosomes from an immature and a fully grown egg and used a genetically modified donor carrying a deletion in the imprinted H19 region, so that key imprinted genes were expressed in a more “paternal” pattern. The animal was able to reproduce. Rather than showing that parthenogenesis is natural in mammals, the result supported the view that paternal imprinting is precisely what normally prevents it.

Chromosomes, the Y and male fertility

Before molecular tools were available, reproductive genetics relied heavily on cytogenetics: counting and comparing chromosomes under the microscope in domestic animals, wild species and humans. That tradition, well represented in the older parts of the archive, revealed rearrangements such as fused chromosomes and their consequences for fertility, and it prepared the ground for the molecular study of individual genes.

The Y chromosome offers a clear example of genetics affecting fertility directly. Regions of the chromosome known as AZF (azoospermia factor) regions contain genes involved in sperm production. Deletions there are estimated to affect roughly one in 2,000 to one in 3,000 males and account for about 13 percent of cases in which no sperm are found in the semen and about 5 percent of cases with very low sperm counts. Most such deletions arise anew in the father’s sperm-forming cells, so there is usually no family history. If an affected man becomes a father, naturally or through assisted reproduction, all of his sons inherit the deletion; daughters do not. Related research themes in the archive include how germ cells repair DNA damage and how oxidative stress may affect the integrity of the paternal genome, topics that connect to the testis and spermatogenesis page.

What is established and what is still debated

Several points are now well supported:

• germ cells are specified early in development and undergo extensive epigenetic resetting;
• in mammals, maternal and paternal genomes are not equivalent, and imprinting explains why both are required for normal development;
• specific deletions on the Y chromosome are a recognised genetic cause of severely reduced sperm production.

Other questions remain open. Researchers are still working out how closely human germ-cell development follows the mouse model, and how imprints are protected from the waves of reprogramming that erase most other marks. The extent to which experiences of a parent, such as diet or environmental exposures, can leave epigenetic traces that escape reprogramming and influence offspring is an active area of research; because reprogramming normally removes acquired marks, claims of such inheritance in humans require careful evidence. Assisted reproduction and cloning, which manipulate eggs and embryos during these sensitive windows, have made such questions practical as well as theoretical.

Taken together, the articles collected under this topic trace the field’s move from chromosome counts in the 1960s and 1970s, through the discovery of imprinting in the 1980s, to the molecular epigenetics of the 2000s and 2010s.