A handful of autosomal genes in the mammalian genome are inherited in a silent state from one of the two parents, and in a fully active form from the other, thereby rendering the organism functionally hemizygous for imprinted genes. To date 19 imprinted genes have been identified; 5 are expressed from the maternal chromosome while the rest are expressed from the paternal chromosome. Allele-specific methylation of CpG residues, established in one of the germlines and maintained throughout embryogenesis, has been clearly implicated in the maintenance of imprinting in somatic cells. Although the function of imprinting remains a subject of some debate, the process is thought to have an important role in regulating the rate of fetal growth.

Genomic imprinting in mammals.

RANDOM X inactivation makes the female mammal a natural mosaic for clones of cells having either the maternally derived X (Xm) or paternally derived one (Xp) which is genetically inactive1. There are, however, instances in which inactivation is obviously not random2–7. Non-randomness was inferred from studies made on differentiated cells remote from early embryonic cells in which inactivation occurred. Thus it is not clear whether the randomness of the X inactivation process was influenced or whether cell selection occurring after random inactivation was responsible for the ultimate non-random appearance4–9. In an effort to determine the embryonic stage at which the X chromosome initiates differentiation in famale mouse embryos heterozygous for Cattanach's translocaton10, we found that the mosaic composition was consistently biased in extraembryonic membranes, whereas it was not necessarily so in the embryonic body.

Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse

The emerging awareness of the contribution of epigenetic processes to genome function in health and disease is underpinned by decades of research in model systems. In particular, many principles of the epigenetic control of genome function have been uncovered by studies of genomic imprinting. The phenomenon of genomic imprinting, which results in some genes being expressed in a parental--origin-specific manner, is essential for normal mammalian growth and development and exemplifies the regulatory influences of DNA methylation, chromatin structure and non-coding RNA. Setting seminal discoveries in this field alongside recent progress and remaining questions shows how the study of imprinting continues to enhance our understanding of the epigenetic control of genome function in other contexts.

Genomic imprinting: The emergence of an epigenetic paradigm

https://www.cell.com/cell/pdf/S0092-8674(13)00205-5.pdf

X-Inactivation, Imprinting, and Long Noncoding RNAs in Health and Disease

Summary

1. The review considers information from mammalian embryology relevant to X-chromosome inactivation, and from X-inactivation relevant to mammalian embryology.



2. Properties of the inactive-X, by which it may be recognized are: sex chromatin, heteropycnosis, late replication and the absence of gene product. Each of these has advantages and disadvantages in particular circumstances. In some species the X carries constitutive heterochromatin, which must be distinguished from the facultative region.



3. The time of X-chromosome inactivation can be estimated from the time of appearance of sex chromatin or late replication, or inferred from the appearance of heterozygotes for X-linked genes or of experimental chimaeras. The estimated time varies with species, and in the mouse and rabbit is near the time of increase in RNA synthesis.



4. Whereas in eutherian mammals either the maternally or the paternally derived X may be inactivated in different cell lines, in marsupials the paternal X is always the inactive one.



5. During development various factors act to distort the patterns produced by random X-inactivation. These factors include cell selection, transfer of gene product, and migration and mingling of cells.



6. There is no clear evidence that X-chromosome inactivation is not complete.



7. In female germ cells both X-chromosomes appear to be active. In male ones both X and Y appear inactive during most of spermatogenesis, although probably in early stages all X chromosomes present are active.



8. The active and inactive X-chromosomes may be differentiated by presence or absence of some non-histone protein or other polyanionic substance.



9. If the genes concerned in synthesis or attachment of this substance are on the X-chromosome then the differentiation will be self-maintaining.



10. The initiation of the differentiation requires either the attachment of different X-chromosomes to different sites, or some interaction of X-linked and autosomal genes, concerned in inducing or repressing activity. Some possible models are discussed.

X-chromosome inactivation and developmental patterns in mammals

REDUCED activity of the glycolytic enzyme phosphoglycerate kinase (EC 2723 : ATP : 3 phospho-D-glycerate 1 phosphotransferase, PGK) is associated with hereditary haemolytic anaemia1–3. A family study suggests that the gene involved is sex linked. Beutler has described a starch gel technique for electrophoresing and detecting the human erythrocytic enzyme4. He examined Caucasian, Negro and Oriental blood donors and found no variants. We have surveyed several hundred erythrocyte samples from a number of species of kangaroos (Macropodidae) using his technique.

Phosphoglycerate kinase polymorphism in kangaroos provides further evidence for paternal X inactivation.

Random inactivation of one or other of the X chromosomes in female eutherians could have evolved from an ancestral paternal X inactivation, which has been retained in marsupials.

Directed genetic change model for X chromosome inactivation in eutherian mammals.

Mammalian testis phosphoglycerate kinase.

Lactate dehydrogenase (LDH) isozymes have been examined from tissues of mammalian species representative of the five families of marsupials and of the monotremes. Immunochemical, molecular hybridization, and tissue distribution studies showed that three genes (A, B and C) are responsible for LDH synthesis giving rise to five major isozymes in most tissues (LDH's A4, A3B1, A2B2, A1B3, and B4) and an additional isozyme (LDH-C4) which is present only in mature testes. The LDH phenotypes of 93 erythrocyte samples from 31 marsupial and 2 monotreme species were analysed. Although the isozymic composition varied markedly within the marsupial families Macropodidae and Phalangeridae, the Dasyuridae showed remarkable uniformity, containing only LDH-A4. The two monotreme species analysed also exhibited this latter pheno-type in their erythrocytes. Ontogenic studies of the LDH isozymes of pouch young from Macropus parryi (pretty-face wallaby) showed changes similar to those reported for the developing mammalian fetus in utero. The immature pouch young exhibited similar tissue patterns of LDH isozymes which diverged during growth in the pouch thus reflecting differential genetic activity. A comparison of the relative maturity of the eutherian fetus with marsupial pouch young may be made. From these observations, it is concluded that a high degree of correlation exists among the properties of eutherian, marsupial, and monotreme LDH isozymes.

D. W. Cooper

Papers

Phosphoglycerate kinase polymorphism in kangaroos provides further evidence for paternal X inactivation.

Directed genetic change model for X chromosome inactivation in eutherian mammals.

Mammalian testis phosphoglycerate kinase.

Marsupial and monotreme lactate dehydrogenase isozymes: phylogeny, ontogeny, and homology with eutherian mammals.

Phosphoglycerate kinase A polymorphism in the wallaby Macropus parryi: activity of both X chromosomes in muscle.